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Title:
METHODS AND INTERMEDIATES FOR PREPARING A THERAPEUTIC COMPOUND USEFUL IN THE TREATMENT OF RETROVIRIDAE VIRAL INFECTION
Document Type and Number:
WIPO Patent Application WO/2019/161280
Kind Code:
A1
Abstract:
The present disclosure relates to methods and intermediates useful for preparing a compound of formula (I): (I) or a co-crystal, solvate, salt or combination thereof.

Inventors:
ALLAN, Kevin McCormack (Inc.333 Lakeside Driv, Foster City California, 94404, US)
BATTEN, Amanda Lynn (Inc.333 Lakeside Driv, Foster City California, 94404, US)
BRIZGYS, Gediminas (Inc.333 Lakeside Driv, Foster City California, 94404, US)
DHAR, Sachin (Inc.333 Lakeside Driv, Foster City California, 94404, US)
DOXSEE, Ian James (Inc.333 Lakeside Driv, Foster City California, 94404, US)
GOLDBERG, Alex (Inc.333 Lakeside Driv, Foster City California, 94404, US)
HEUMANN, Lars V. (Inc.333 Lakeside Driv, Foster City California, 94404, US)
HUANG, Zilin (Inc.333 Lakeside Driv, Foster City California, 94404, US)
KADUNCE, Nathaniel Thomas (Inc.333 Lakeside Driv, Foster City California, 94404, US)
KAZERANI, Shahrokh (Inc.333 Lakeside Driv, Foster City California, 94404, US)
LEW, Willard (Inc.333 Lakeside Driv, Foster City California, 94404, US)
NGO, Vinh Xuan (17179 Oak Street, Fountain Valley, California, 92708, US)
O'KEEFE, Brian Michael (Inc.333 Lakeside Driv, Foster City California, 94404, US)
RAINEY, Trevor James (Inc.333 Lakeside Driv, Foster City California, 94404, US)
ROBERTS, Benjamin James (Inc.333 Lakeside Driv, Foster City California, 94404, US)
SHI, Bing (Inc.333 Lakeside Driv, Foster City California, 94404, US)
STEINHUEBEL, Dietrich P. (Inc.333 Lakeside Driv, Foster City California, 94404, US)
TSE, Winston C. (801 Windblown Lane, Redwood City, California, 94065, US)
WAGNER, Anna Michelle (Inc.333 Lakeside Driv, Foster City California, 94404, US)
WANG, Xianghong (Inc.333 Lakeside Driv, Foster City California, 94404, US)
WOLCKENHAUER, Scott Alan (Inc.333 Lakeside Driv, Foster City California, 94404, US)
WONG, Chloe Yuyi (Inc.333 Lakeside Driv, Foster City California, 94404, US)
ZHANG, Jennifer R. (Inc.333 Lakeside Driv, Foster City California, 94404, US)
Application Number:
US2019/018323
Publication Date:
August 22, 2019
Filing Date:
February 15, 2019
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
GILEAD SCIENCES, INC. (333 Lakeside Drive, Foster City, California, 94404, US)
International Classes:
C07D401/14; C07C45/61; C07D213/61; C07D231/54; C07D231/56; C07D339/06; C07D401/12; C07D495/10
Domestic Patent References:
WO2016033243A12016-03-03
WO2014134566A22014-09-04
WO2013006738A12013-01-10
WO2018035359A12018-02-22
WO2018203235A12018-11-08
WO2019035973A12019-02-21
WO2019035904A12019-02-21
Foreign References:
US201715680041A2017-08-17
Other References:
MICHAEL HANACK ET AL: "cis- und trans bicyclo[3.1.0]hexano-(2)", CHEMISCHE BERICHTE, vol. 97, no. 6, 1 January 1964 (1964-01-01), pages 1669 - 1672, XP055573746, Retrieved from the Internet [retrieved on 20190325]
HAMMER, S.M. ET AL., JAMA, vol. 300, 2008, pages 555 - 570
TAIWO, B., INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, vol. 13, 2009, pages 552 - 559
SMITH, R. J., SCIENCE, vol. 327, 2010, pages 697 - 701
FOSTER: "Deuterium Isotope Effects in Studies of Drug Metabolism", TRENDS PHARMACOL. SCI., vol. 5, no. 12, 1984, pages 524 - 527, XP025943358, DOI: doi:10.1016/0165-6147(84)90534-0
P. G. M. WUTS; T. W. GREENE: "Greene's Protective Groups in Organic Synthesis", 2006, WILEY
T. ISHIYAMA, J. ORG. CHEM., vol. 60, 1995, pages 7508 - 7510
N. MIYAURA; A. SUZUKI, CHEM. REV., vol. 95, 1995, pages 2457 - 2483
LOUDON: "Organic Chemistry", 2009, OXFORD UNIVERSITY PRESS
SMITH: "Afarch's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2013, WILEY-INTERSCIENCE
"Introduction to Modern Liquid Chromatography", 1979, JOHN WILEY AND SONS
"Thin Layer Chromatography", 1969, SPRINGER-VERLAG
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 2006, WILEY
Attorney, Agent or Firm:
CHOI, Lydia B. et al. (Gilead Sciences, Inc.333 Lakeside Driv, Foster City California, 94404, US)
Download PDF:
Claims:
CLAIMS

What was claimed is:

1. A process for preparing a compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof;

comprising combining a compound of formula VIII:

or a co-crystal, solvate, salt, or combination thereof, with

a compound of formula IX:

IX

or a co-crystal, solvate, or combination thereof,

a base a

a solvent, and to provide the compound of formula VI or a co-crystal, solvate, salt, or combination thereof.

2. The process of claim 1, wherein the compound of formula VIII is a compound of formula VIII-02:

VIII 02

or a co-crystal, solvate, or combination thereof, wherein HX is a chiral or achiral acid.

3 The process of claim 2, wherein HX is a chiral acid.

4. The process of claim 2 or 3, wherein HX is selected from the group consisting of L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D-glucuronic acid,

(1 R, 35)-(+)-camphoric acid, ( lX)-(+)-camphor- 10-sulfonic acid, (R)-(+)-Ar-(i- phenyl ethy 1 ) succi nam i c acid, carb ob enzyl oxy-L-proli ne, di b enzoyl -L-tartari c acid, (R)-(+)~ 3- methyladipic acid, (+)-m enthyl oxy aceti c acid, (-)-pyroglutamic acid, (-)-n-acetyl-L-leucine, (-)- N-acetyl-D-leucine, /V-Boc-D-leucine, 7V-(+)-BOC-phenylalanine, (-)-quinic acid, (+)-«-acetyl- L-phenylalanine, (+)-V-BOC-isoleucine, L-(-)-acetyl glutamic acid, (-)-acetyl mandelic acid, (i?)-(-)-citramalic acid, ( )-camphanic acid, and (A)-mandelic acid.

5. The process of claim 2 or 3, wherein HX is (A)-mandelic acid.

6. The process of claim 2 or 3, wherein HX is V-Boc-D-leucine or (-)-N-acetyl-D-leucine-.

7. The process of claim 2, wherein HX is an achiral acid.

8. The process of claim 2 or 7, wherein HX is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, / oluenesulfonic acid, and phosphoric acid.

9. The process of any one of claims 1-8, wherein the catalyst is a palladium catalyst.

10. The process of any one of claims 1-8, wherein the catalyst is a copper catalyst.

1 1 The process of claim 9, wherein the palladium catalyst is selected from the group consisting of [( -allyl)PdCl]2, Pd(acac)2, (SIPr)PdCl2, PdCl2(PPh3)2, PdCh., Pd(OAc)2: PdCl2(CH3CN)2, and Pd2(dba)3, optionally, in combination with a tertiary phosphine, selected from the group consisting of triphenylphosphine, tri-cyclohexylphosphine, Cή-tert- butylphosphine, 1 ,2-bis(diphenylphosphino)ethane, 1 , 3 -bi s(di phenyl phosp hi no)propane, and 1 , G -bi s(diphenylphosphino)ferrocene .

12. The process of claim 11, wherein the palladium catalyst is PdCl2(PPh3)2.

13. The process of claim 10, wherein the copper catalyst is selected from the group consisting of copper(I) iodide, copper(I) bromide, and copper(I) chloride.

14. The process of any one of claims 1 -13, wherein the base is selected from the group consisting of triethylamine, diisopropylamine, ethyl dii sopropyl amine, pyrrolidine, 1,4- diazabicylo[2.2.2]-octane, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo-4.3.0]non-5- ene, pyridine, cesium carbonate, potassium carbonate, sodium carbonate, piperidine, potassium phosphate, and tetrabutyl ammonium fluoride.

15. The process of any one of claims 1-13, wherein the base is triethylamine.

16. The process of any one of claims 1-15, wherein the solvent is selected from the group consisting of di ethyl ether, methyl fe/7-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, benzene, toluene, xylenes, AvV-dimethylformamide, AyV-dimethylacetamide, N- methylpyrrolidinone, acetonitrile, water, and combinations thereof.

17. The process of any one of claims 1-15, wherein the solvent is 2-methyltetrahydrofuran.

18. The process of any one of claims 1-17, wherein the process is carried out in the temperature range of from about 0 °C to about 120 °C.

19. The process of any one of claims 1 -17, wherein the process is carried out in the temperature range of from about 50 °C to about 80 °C.

20. A process for preparing a compound of formula IV :

or a co-crystal, solvate, salt, or combination thereof;

comprising combining a compound of formula VI

or a co-crystal, solvate, salt, or combination thereof, with

a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof,

a base,

a solvent,

optionally a coupling reagent,

and optionally an activating agent,

to provide the compound of formula IV or a co-crystal, solvate, salt, or combination thereof

21. The process of claim 20, wherein the coupling reagent is selected from the group consisting of w-propylphosphonic anhydride, 2-chloro-4,6-dimethoxy-l ,3,5-triazine, 4-(4,6- dimethoxy- 1 ,3 , 5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro- 1 -methylpyridinium iodide, boric acid, tetram ethyl orthosilicate, trimethoxy silane, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1 -ethyl -3-(3-dimethylaminopropyl)carbodiimide, carbonyl diimidazole, isobutyl chloroform ate, diphenylphosphinic chloride, 2-(7-aza-lH-benzotri azole- 1- yl)-l, 1 ,3,3 -tetram ethyluronium hexafluorophosphate, O-b enzotri azol e-Y, NN N - tetramethyluronium-hexafluoro-phosphate, 0-(7-azabenzotri azole- l-yl)-AYYAr'Y - tetramethyluronium tetrafluorob orate, 0-(benzotriazol - 1 -yl)-Ar,/V,/V’,A^’-tetram ethyluronium tetrafluoroborate, 0-(6-chl orob enzotri azol - 1 -y\)-NNN’,iV’-tetramethyluronium

hexafluorophosphate, (benzotriazol-l -yloxy)tris(dimethy amino)phosphonium

hexafluorophosphate, chloro-Y,Y,Y^,V ;etramethylforrnamidimum hexafluorophosphate, (benzotriazol- 1 -yloxy)tri pyrrolidi nophosphonium hexafluorophosphate, , 4-(4,6-dimethoxy- 1 ,3 , 5-triazin-2-yl)-4-methylmorphonium chloride and ( 1 -cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate.

22. The process of claim 20, wherein the coupling reagent is «-propylphosphonic cyclic anhydride.

23. The process of claim 20, wherein the activating agent is selected from the group consisting of oxalyl chloride, thionyl chloride, pivaloyl chloride, cyanuric chloride,

methanesulfonyl chloride and diphenylphosphinic chloride.

24. The process of any one of claims 20-23, wherein the base is selected from the group consisting of triethylamine, tributylamine, ethyl di i sopropyl amine, Y-methylmorpholine, pyridine, 2,6-lutidine, and iV-methylimidazole.

25. The process of any one of claims 20-23, wherein the base is triethylamine.

26. The process of any one of claims 20-25, wherein the solvent is selected from the group consisting of acetonitrile, ethyl acetate, n -butyl acetate, isopropyl acetate, diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, A^-dimethylformamide, N, /V-d I rn ethyl aceta m i de , /V-m eth yl pyrrol i di n on e,

dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, propionitrile, butyronitrile, and combinations thereof.

27. The process of any one of claims 20-25, wherein the solvent is acetonitrile.

28. The process of any one of claims 20-27, wherein the process is carried out in the temperature range of from about -20 °C to about 120 °C.

29. The process of any one of claims 20-27, wherein the process is carried out in the temperature range of from about 0 °C to about 40 °C.

30. The process of any one of claims 20-29, further comprising a coupling additive.

31. The process of claim 30, wherein the coupling additive is selected from the group consisting of 4-(dimethylamino)pyridine, /V-hydroxysuccinimide, ethyl

cyanohydroxyiminoacetate, 1 -hydroxybenzotri azole, N-methylimidazole and l-hydroxy-7- azabenzotri azole.

32. A process for preparing a compound of formula III:

III

or a co-crystal, solvate, salt, or combination thereof, comprising:

combining a compound of formula IV

IV

or a co-crystal, solvate, salt, or combination thereof, with

a compound of formula V:

V

or a co-crystal, solvate, salt, or combination thereof, wherein R1 is B(OH)2,

B(0CH(Me)CH2C(Me)20), B((l,2-di-0)C6H4), B(0CH2C(Me)2CH20), BF3K,

B(02CCH2N(Me)CH2C02), or B(0C(Me)2C(Me)20),

a palladium catalyst,

a base, and

a solvent,

to provide the compound of formula III or a co-crystal, solvate, salt, or combinati on thereof.

33. The process of claim 32, wherein R1 is B(0C(Me)2C(Me)20).

34. The process of claim 32 or 33, wherein the palladium catalyst is selected from the group consisting of dichlorobis(tricyclohexylphosphine)palladium(II), bis(di-fer/-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine]palladium(II) chloride,

dichlorobis(triphenylphosphine)palladium(II), [ 1 , - bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2- bis(diphenylphosphino)ethane]dichloropalladium(II), dichloro[9, 9-dimethyl -4,5- bis(diphenylphosphino)xanthene]palladium(II), chloro[(tricyclohexylphosphine)-2-(2'- aminobiphenyl)]palladium(II), [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate, PCy3 Pd G4, palladium chloride, palladium acetate, and palladium trifluoroacetate.

35. The process of claim 28, further comprising a phosphine ligand and wherein the palladium catalyst is selected from the group consisting of palladium chloride, palladium acetate, palladium trifluoroacetate, dichloro(l,5-cyclooctadiene)palladium(II), allylpalladium(II) chloride dimer, palladium(II) acetylacetonate, (tetrakis(triphenylphosphine)palladium(O) and bis(dibenzylideneacetone)palladium(0).

36. The process of claim 35, wherein the phosphine ligand is selected from the group consisting of di-/er/-butyl(4-dimethylaminophenyl)phosphine, di cyclohexyl (4- dimethylaminophenyl)phosphine, 1 ,2-bi s(diphenylphosphino)ethane, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2,2'- bis(diphenylphosphino)-l, l '-binaphthalene, l,3-bis(diphenylphosphino)propane,

ethyl enebis(diphenylphosphine), 1, 1 '-ferrocenedi yl -bi s(diphenylphosphi ne, 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene, tricyclohexylphosphine, triphenylphosphine, cyclohexyl diphenylphosphine,dicyclohexylphenylphosphine, tritertbutylphosphine,

cycl ohexyl di tertbutyl phosphi ne, and di cy cl ohexyl tertbutyl phosphine.

37 The process of claim 32 or 33, wherein the palladium catalyst is

38. The process of any one of claims 32-37, wherein the base is selected from the group consisting of potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, di cy cl ohexyl amine, N- methylmorpholine, and triethylamine.

39. The process of any one of claims 32-37, wherein the base is potassium bicarbonate.

40. The process of any one of claims 32-39, wherein the solvent is selected from the group consisting of n-butyl acetate, water, di-n-butyl ether, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, LnU-dimethylformamide, /V,Y-dimethylacetamide, /V-methyl-2- pyrrolidine, and combinations thereof.

41. The process of any one of claims 32-39, wherein the solvent is a mixture of n-butyl acetate and water.

42. The process of any one of cl aims 32-41, wherein the process is carried out in the temperature range of from about 20 °C to about 120 °C.

43. The process of any one of claims 32-41, wherein the process is carried out in the temperature range of from about 75 °C to about 95 °C.

44. The process of any one of claims 32-43, further comprising: (a) combining the compound of formula III, or a co-crystal, solvate, salt, or combination thereof, with a second solvent and an acid to provide a compound of formula HI-

02:

III-02

or a co-crystal, solvate, or combination thereof, wherein HY is selected from the group consisting of acetic acid, oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid, chloroacetic acid, citric acid, nitric acid, formic acid, lactic acid, ascorbic acid, benzoic acid, propionic acid, ethanesulfonic acid, -toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; and

(b) free-basing the compound of formula III -02 or a co-crystal, solvate, or combination thereof, by combining it with a second base and a third solvent to provide the compound of formula III or a co-crystal, or solvate, or combination thereof.

45. The process of claim 44, wherein HY is methanesulfonic acid.

46. The process of claim 44 or 45, wherein the second solvent is selected from the group consisting of 1 -propanol, isopropanol, ethanol, methanol, te/t-amyl alcohol, acetonitrile, methyl isobutyl ketone, dichloromethane, 2-methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl fer/-butyl ether, toluene, and cyclopentyl methyl ether.

47. The process of any one of claims 44-46, wherein the compound of formula HI-02 is produced as a solvate.

48. The process of any one of claims 44-46, wherein the compound of formula III-02 is produced as an ethanol solvate.

49. The process of any one of claims 44-46, wherein the compound of formula III-02 is produced as a 1 -propanol solvate.

50. The process of any one of claims 44-49, wherein the compound of formula III-02 is produced in the temperature range of from about -20 °C to about 20 °C.

51. The process of any one of claims 44-50, wherein the second base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate,

b enzyltri m ethyl am m onium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide, triethylamine, l,4-diazabicyclo[2.2.2]octane, 1,8- diazabicyclo[5.4.0]undec-7-ene, ammonium hydroxide, and diethylamine.

52. The process of any one of claims 44-50, wherein the second base is sodium hydroxide.

53. The process of any one of claims 44-52, wherein the third solvent is selected from the group consisting of water, diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran,

dimethoxyethane, methyl tert-butyl ether, toluene, xylenes, ethyl acetate, isopropyl acetate, and combinations thereof.

54. The process of any one of claims 44-52, wherein the third solvent is 2- methyltetrahydrofuran and water.

55. The process of any one of claims 44-54, wherein the free-basing step is carried out in the temperature range of from about -20 °C to about 80 °C.

56. The process of any one of claims 44-54, wherein free-basing step is carried out in the temperature range of from about 0 °C to about 50 °C.

57. A process for preparing a compound of formula I:

I or a co-crystal, solvate, salt, or combination thereof, comprising combining a compound of formula III:

III

or a co-crystal, solvate, salt, or combination thereof, with

a mesylating reagent, and

a solvent,

to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.

58. The process of claim 57, wherein the mesylating reagent is selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride.

59. The process of claim 57, wherein the mesylating reagent is methanesulfonic anhydride.

60. The process of any one of claims 57-59, wherein the solvent for the mesylating step is selected from the group consisting of ethyl acetate, isopropyl acetate, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, N /V-dimethylform amide, A^iV-dimethylacetamide, /V-methylpyrrolidinone, toluene, xylenes, chloroform, dichloroethane, and combinations thereof.

61. The process of any one of claims 57-59, wherein the solvent for the mesylating step is cyclopentyl methyl ether.

62. The process of any one of claims 57-61, wherein the process is carried out in the temperature range of from about 20 °C to about 120 °C.

63. The process of any one of claims 57-61, wherein the process is carried out in the temperature range of from about 70 °C to about 90 °C.

64. A process for preparing a compound of formula I:

or a co-crystal, solvate, salt, or combination thereof, comprising:

(a) combining a compound of formula III:

or a co-crystal, solvate, salt, or combination thereof with a mesylating reagent, a base, and a solvent to provide a compound of formula II:

or a co-crystal, solvate, salt, or combination thereof; and

(b) hydrolyzing the compound of formula II or a co-crystal, solvate, salt, or combination thereof, with a nucleophilic reagent and optionally, a phase transfer catalyst, in a solvent to provide the compound of formul a I or a co-crystal, solvate, salt, or combination thereof

65. The process of claim 64, wherein the mesylating reagent is selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride.

66. The process of claim 64, wherein the mesylating reagent is methanesulfonyl chloride.

67. The process of any one of claims 64-66, wherein the phase transfer catalyst is selected from the group consisting of tetra-n-butylammonium chloride, b enzyl tri -n-butyl amm oni um bromide, 1 -methylimidazolium hydrogen sulfate, tetra-n-butylammonium hydrogen sulfate, and tetra-n-butylphosphonium chloride.

68. The process of any one of claims 64-66, wherein the phase transfer catalyst is tetra-n- butylammonium hydrogen sulfate.

69. The process of any one of claims 64-68, wherein the base is selected from the group consisting of /V-methylmorpholine, tri-n-propylamine, ethyl diisopropylamine, tri-n-butylamine, triethylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, sodium tert-amylate, and sodium tert-butoxide.

70. The process of any one of claims 64-68, wherein the base is triethylamine.

71. The process of any one of claims 64-70, wherein the solvent for the mesylating step is selected from the group consisting of diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxy ethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, di chi orom ethane, acetonitrile, and combinations thereof.

72. The process of any one of claims 64-70, wherein the solvent for the mesylating step is 2- methyltetrahydrofuran .

73. The process of any one of claims 64-72, wherein the mesylating step is carried out in the temperature range of from about -20 °C to about 100 °C.

74. The process of any one of claims 64-72, wherein the mesylating step is carried out in the temperature range of from about -10 °C to about 20 °C.

75. The process of any one of cl aims 64-74, wherein the nucleophilic reagent selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, A’-acetylcysteine, sodium thiophenolate, choline, sodium methoxide, sodium eth oxide, potassium ethoxide, sodium n-propoxide, sodium isoropoxide, sodium t-butoxide, methylamine, ethylamine, n-propyl amine, dimethylamine, diethylamine, and hydroxylamine.

76. The process of any one of claims 64-74, wherein the nucleophilic reagent is sodium hydroxide.

77. The process of any one of claims 64-76, wherein the solvent for the hydrolyzing step is selected from the group consisting of water, methanol, ethanol, isopropanol, 1 -propanol, n- butanol, s-butanol, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, N,N- dimethylformamide, N-m ethyl -2-pyrroli done, /V^V-dimethylacetamide, and combinations thereof.

78. The process of any one of claims 64-76, wherein the solvent for the hydrolyzing step is water and 2 -m ethyl tetrahydrofuran .

79. The process of any one of claims 64-78, wherein the hydrolyzing step is carried out in the temperature range of from about -20 °C to about 100 °C.

80. The process of any one of claims 64-78, wherein the hydrolyzing step is carried out in the temperature range of from about 10 °C to about 60 °C

81. A process for preparing a compound of formula I:

I or a co-crystal, solvate, salt, or combination thereof, comprising:

(a) combining a compound of formula VIII:

Vffl

or a co-crystal, solvate, salt, or combination thereof, with a compound of formula IX:

IX

or a co-crystal, solvate, or combination thereof, under alkynylation conditions to provide the compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof;

(b) combining the compound of formula VI or a co-crystal, solvate, salt, or combinati on thereof, with a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof, under amide coupling conditions to provide a compound of formula IV:

IV

or a co-crystal, solvate, salt, or combination thereof;

(c) combining the compound of formula IV or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V:

V

or a co-crystal, solvate, salt, or combination thereof, wherein R1 is B(OH)2,

B(0CH(Me)CH2C(Me)20), B((l,2-di-0)C6H4), B(0CH2C(Me)2CH20), BF3K,

B(02CCH2N(Me)CH2C02), or B(0C(Me)2C(Me)20), under palladium-catalyzed cross-coupling conditions to provide a compound of formula III:

III

or a co-crystal, solvate, salt, or combination thereof; and

(d) combining the compound of formula III or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent under mesylating conditions to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof

82. The process of claim 81, further comprising:

(a) forming the sodium salt of the compound of formula I to provide a compound of formula 1-02:

1-02

by combining the compound of formula I with a sodium source and a solvent; and

(b) neutralizing the compound of formula 1-02 with an acid and a solvent to provide the compound of formula I.

83. The process of claim 82, wherein the sodium source is selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium phosphate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium t-but oxide, sodium

hexam ethyl di sil azi de, and sodium metal and an alcohol selected from the group consisting of methanol, ethanol, isopropanol, 1 -propanol, «-butanol, and sec-butanol .

84. The process of claim 82, wherein the sodium source is sodium hydroxide.

85. The process of any one of claims 82-84, wherein the solvent for the salt forming step is selected from the group consisting of diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethan e, n-heptane, toluene, xylenes, ethyl acetate, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, acetone, methyl ethyl ketone, methyl isobutylketone, methanol, ethanol, isopropanol, 1 -propanol, «-butanol, sec-butanol, and combinations thereof.

86. The process of any one of claims 82-84, wherein the solvent for the salt forming step is ethanol and n-heptane.

87. The process of any one of claims 82-86, wherein the salt forming step is carried out in the temperature range of from about -20 °C to about 100 °C.

88. The process of any one of claims 82-86, wherein the salt forming step is carried out in the temperature range of from about 0 °C to about 50 °C.

89. The process of any one of claims 82-88, wherein the acid for the neutralizing step is selected from the group consisting of acetic acid, oxali c acid, sulfuric acid, hydrochloric acid, phosphoric acid, chloroacetic acid, citric acid, nitric acid, formic acid, lactic acid, ascorbic acid, benzoic acid, and propionic acid.

90. The process of any one of claims 82-88, wherein the acid for the neutralizing step is acetic acid.

91 . The process of any one of claim s 82-90, wherein the neutralizing step is carried out in the temperature range of from about -20 °C to about 100 °C.

92. The process of any one of claims 82-90, wherein the neutralizing step is carried out in the temperature range of from about 0 °C to about 50 °C.

93. The process of any one of claims 82-92, wherein the solvent in step (b) is water and ethanol .

94. A process for preparing a compound of formula I:

i

or a co-crystal, solvate, salt, or combination thereof, comprising:

(a) combining a compound of formula IV:

IV or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V-04-A:

V-04-A

or a co-crystal, solvate, salt, or combination thereof, wherein R is B(GH)2,

B(0CH(Me)CH2C(Me)20), B((l,2-di-0)C6H4), B(0CH2C(Me)2CH20), BF3K,

B(02CCH2N(Me)CH2C02), or B(0C(Me)2C(Me)20),

a base,

a solvent, and

a catalyst,

to provide a compound of II:

or a co-crystal, solvate, salt, or combination thereof; and

(b) hydrolyzing the compound of formula II or a co-crystal, solvate, salt, or combination thereof, with a base, a solvent, and optionally a phase transfer catalyst, to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.

95. The process of claim 94, wherein R is B(0C(Me)2C(Me)20).

96. The process of claim 94 or 95, wherein the catalyst used in step (a) is selected from the group consisting of bis(di-fer/-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride,

dichlQrobis(triphenyiphosphine)palladium(n), [ 1 , - bi s(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2- bis(diphenylphosphino)ethane]dichloropalladium(II), and di chi oro[9, 9-dimethyl -4, 5- bis(diphenylphosphino)xanthene]palladium(II).

97. The process of any one of claim s 94-96, wherein the catalyst used in step (a) is selected from the group consisting of palladium (II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0), and

bis(dibenzylideneacetone)palladium(0).

98. The process of any one of claims 94-97, wherein the catalyst further comprises a phosphine ligand selcted from the group consisting of tricyclohexylphosphine,

tri phenyl phosphine, cyclohexyl diphenyl phosphine, and di cy cl ohexy 1 phenyl phosphin e .

99. The process of any one of claims 94-98, wherein the palladium catalyst used in step (a) is palladium (II) chloride and cyclohexyldiphenylphosphine.

100. The process of any one of claims 94-99, wherein the base used in step (a) is selected from the group consisting of sodium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, di cy cl ohexyl amine, N- methylmorpholine, triethylamine, and diisopropyl ethylamine.

101. The process of any one of claims 94-100, wherein the base used in step (a) is sodium hydroxide or potassium bicarbonate.

102. The process of any one of claims 94-101, wherein the solvent used in step (a) is selected from the group consisting of water, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine, and a combination thereof.

103. The process of any one of claims 94-102, wherein the solvent used in step (a) is 2- methy 1 tetrahydrofuran and water.

104. The process of any one of claims 94-103, wherein step (a) is carried out in the temperature range of from about 20 °C to about 120 °C.

105. The process of any one of claims 94-104, wherein the base used in step (b) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, bicarbonate bases, sodium bicarbonate, potassium bicarbonate, benzy!tri methyl ammonium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide, triethylamine, DABCO, DBU, and diethylamine.

106. The process of any one of claims 94-105, wherein the base used in step (b) is sodium hydroxide.

107. The process of any one of claims 94-106, wherein the solvent used in step (b) is selected from the group consisting of diethyl ether, 1 ,4-dioxane, 2-methyltetrahydrofuran,

dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, A,/V-dimethylformamide, 7V-methyl -2-pyrrolidone, A Y-dimethyl acetamide, and a combination thereof.

108. The process of any one of claims 94-107, wherein the solvent used in step (b) is 2- methyltetrahydrofuran .

109. The process of any one of claims 94-108, wherein the phase transfer catalyst used in step (b) is selected from the group consisting of tetrabutyl ammonium chloride,

benzyltributylammonium bromide, 1 -methylimidazolium hydrogen sulfate, and

tetrabutylphosphonium chloride.

1 10. The process of any one of claims 94-109, wherein step (b) is carried out in the temperature range of from about 10 °C to about 60 °C.

111. A process for preparing a compound of formula I:

I

or a co-crystal, solvate, salt, or combination thereof, comprising combining a compound of formula IV:

or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V-03-A:

V-03-A

or a co-crystal, solvate, salt, or combination thereof, wherein R is

B(0CH(Me)CH2C(Me)20), B((l,2-di-0)C6H4), B(0CH2C(Me)2CH20), BF3K,

B(02CCH2N(Me)CH2C02), or B(0C(Me)2C(Me)20),

a base,

a solvent, and to provide the compound of formula I, or a co-crystal, solvate, salt, or combination thereof.

112. The process of claim 111, wherein R is B(0C(Me)2C(Me)20).

113. The process of any one of claims 111-112, wherein the catalyst is selected from the group consisting of bis(di-/<?rt-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride,

dichlQrobis(triphenyiphosphine)palladium(n), [ 1 , G - bi s(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2- bis(diphenylphosphino)ethane]dichloropalladium(II), and di chi oro[9, 9-dimethyl -4, 5- bis(diphenylphosphino)xanthene]palladium(II); or

wherein the catalyst is selected from the group consisting of palladium(II) chloride,

palladium(II) acetate, palladium (II) trifluoroacetate,

tetrakis(triphenylphosphine)palladium(0),and bis(dibenzylideneacetone)palladium(0)) and the catalyst further comprises a phosphine ligand selected from the group consisting of

tricyclohexylphosphine, triphenylphosphine, cyclohexyldiphenylphosphine, and

dicyclohexylphenylphosphine.

114. The process of any one of claims 111-113, wherein the catalyst is palladium (II) chloride and cyclohexyldiphenylphosphine.

1 15. The process of any one of claims 11 1 -1 14, wherein the base is selected from the group consisting of potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, di cy cl ohexyl ami ne, /V-methylmorpholine, triethylamine, and

diisopropylethylamine.

116. The process of any one of claims 111-115, wherein the base is potassium bicarbonate.

117. The process of any one of claims 111-116, wherein the solvent is selected from the group consisting of water, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl -2-pyrrolidine, and a combination

118. The process of any one of claims 111-117, wherein the solvent is 2- methyltetrahydrofuran and water.

119. The process of any one of cl aims 1 11-118, wherein the process is carried out in the temperature range of from about 20 °C to about 120 °C.

120. A process for preparing a compound of formula V-03-A:

V-03-A

or a co-crystal, solvate, salt, or combination thereof, comprising:

(a) combining a compound of formula V:

or a co-crystal, solvate, salt, or combination thereof, wherein R is

B(0CH(Me)CH2C(Me)20), B((l,2-di-0)C6H4), B(QCH2C(Me)2CH2Q), BF3K,

B(02CCH2N(Me)CH2C02), or B(0C(Me)2C(Me)20), with a mesylating reagent, a base and a solvent to provide a compound of V-04-A:

V-04-A

or a co-crystal, solvate, salt, or combination thereof; and

(b) hydrolyzing the compound of formula V-04-A or a co-crystal, solvate, salt, or combination thereof, with a nucleophilic reagent, a solvent, and optionally, a phase transfer catalyst to provide the compound of formula V-03-A or a co-crystal, solvate, salt, or combination thereof.

121. The process of claim 120, wherein R is B(0C(Me)2C(Me)20).

122. The process of claim 120 or 121, wherein the mesylating reagent used in step (a) is methanesulfonic anhydride or methanesulfonyl chloride.

123. The process of any one of claims 120-122, wherein the base used in step (a) is selected from the group consisting of triethylamine, iV-methylmorpholine, tri -n-propyl amine, ethyl diisopropylamine, tri-n-butylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, sodium tert-amylate, and sodium tert-butoxide.

124. The process of any one of claims 120-123, wherein the base used in step (a) is triethylamine.

125. The process of any one of claims 120-124, wherein the solvent used in step (a) is selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and a combination thereof.

126. The process of any one of cl aims 120-125, wherein the sol vent used in step (a) is 2- methyltetrahydrofuran.

127. The process of any one of claims 120-126, wherein step (a) is carried out in the temperature range of from about -20 °C to about 100 °C.

128. The process of any one of claims 120-127, wherein the nucleophilic reagent used in step (b) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, A^-acetyl cy steine, sodium thiophenolate, choline, sodium methoxide, sodium eth oxide, potassium ethoxide, sodium w-propoxide, sodium 7-propoxide, sodium /-butoxide, methyl amine, ethyl amine, «-propylamine, dimethylamine, diethylamine, and hydroxylamine.

129. The process of any one of claims 120-128, wherein the nucleophilic reagent used in step (b) is sodium hydroxide.

130. The process of any one of claims 120-129, wherein the solvent used in step (b) is selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyl tetrahydrofuran, dimethoxy ethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, di chi orom ethane, acetonitrile, A?,A?-dimethylformamide, A?-methyl-2-pyrrolidone, NN-d\ m ethyl acetami de, and a combination thereof

131. The process of any one of claims 120-130, wherein solvent used in step (b) is 2- methyltetrahydrofuran and water.

132. The process of any one of claims 120-131, wherein the phase transfer catalyst used in step (b) is selected from the group consisting of tetrabutyl ammonium hydrogen sulfate, tetrabutylammonium chloride, benzyltributylammonium bromide, 1 -methylimidazolium hydrogen sulfate, and tetrabutylphosphonium chloride.

133. The process of any one of claims 120-132, wherein the phase transfer catalyst used in step (b) is tetrabutyl ammonium hydrogen sulfate.

134. The process of any one of claims 120-133, wherein step (b) is carried out in the temperature range of from about -20 °C to about 100 °C.

135. A process for preparing a compound of formula V-5 :

V-5

or a co-crystal, solvate, salt, or combination thereof, comprising:

(a) combining a compound of formula V-A:

V-A or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent, a base and a solvent to provide a compound of V-6:

V-6

or a co-crystal, solvate, salt, or combination thereof; and

(b) hydrolyzing the compound of formula V-6 or a co-crystal, solvate, salt, or combination thereof, with a nucleophilic reagent, a solvent, and optionally, a phase transfer catalyst to provide the compound of formula V-5 or a co-crystal, solvate, salt, or combination thereof.

136. The process of claim 135, wherein the mesylating reagent used in step (a) is methanesulfonyl anhydride or methansulfonyi chloride.

137. The process of any one of claims 135-136, wherein the base used in step (a) is selected from the group consisting of triethylamine, V-methylmorpholine, tri -n-propyl ami ne, ethyl diisopropylamine, tri-n-butylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, sodium tert-amylate, and sodium tert-butoxide.

138. The process of any one of claims 135-137, wherein the base used in step (a) is triethylamine.

139. The process of any one of claims 135-138, wherein the solvent used in step (a) is selected from the group of consisting of diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and a combination thereof.

140. The process of any one of claims 135-139, wherein the solvent used in step (a) is 2- methyltetrahydrofuran.

141. The process of any one of claims 135-140, wherein step (a) is carried out in the temperature range of from about -20 °C to about 100 °C.

142. A process for preparing a compound of formula V-04-A:

V-04-A

or a co-crystal, solvate, salt, or combination thereof, wherein R is B(OH)2,

B(0CH(Me)CH2C(Me)20), B((l,2-di-0)C6H4), B(0CH2C(Me)2CH20), BF3K,

B(02CCH2N(Me)CH2C02), or B(0C(Me)2C(Me)20), comprising combining a compound of formula V-6:

V-6

or a co-crystal, solvate, salt, or combination thereof, with a boron coupling agent, a base, a solvent, and a catalyst, to provide the compound of V-04-A, or a co-crystal, solvate, salt, or combination thereof.

143. The process of claim 142, wherein R is B(0C(Me)2C(Me)20).

144. The process of any one of claims 142-143, wherein the boron coupling agent is selected from the group consisting of b i s(pi nacol ato)di b or on , bis(neopentyl glycol ato)diboron, bisboronic acid, and bis(ethylene glycolato diboron).

145. The process of any one of claims 142-144, wherein the base is selected from the group consisting of cesium acetate, potassium propionate, sodium propionate, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, dicyclohexylamine, A’-methylmorpholine, triethylamine, and diisopropyl ethylamine.

146. The process of any one of claim s 142-145, wherein the base is potassium acetate.

147. The process of any one of claims 142-146, wherein the solvent is selected from the group of consisting of 1,4-dioxane, 2-m ethyltetrahydrofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl -2-pyrrolidine, and a combination

148. The process of any one of claims 142-147, wherein the solvent is toluene and N,N- dimethylformamide.

149. The process of any one of claims 142-148, wherein the catalyst is selected from the group of consisting of bi s(di-/er/-butyl (4- dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine]palladium(II) chloride, bis(triphenylphosphine)palladium(II) di chloride, [1, -bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2- bis(diphenylphosphino)ethane]dichloropalladium(II), and dichloro[9, 9-dimethyl -4, 5- bis(diphenylphosphino)xanthene]palladium(II).

150. The process of any one of claims 142-149, wherein the catalyst is palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0), or bis(dibenzylideneacetone)palladium(0); and the catalyst optionally further comprises a phosphine ligand selected from the group consisting of tricyclohexylphosphine,

triphenylphosphine, cycl ohexyl diphenylphosphine, and dicyclohexylphenylphosphine.

151. The process of any one of claims 142-150, wherein the catalyst is

bis(triphenylphosphine)palladium(II) di chloride.

152. The process of any one of claims 142-151, wherein the process is carried out in the temperature range of from about 20 °C to about 120 °C.

153. A process for preparing a compound of formula V-5:

V-5

or a co-crystal, solvate, salt, or combination thereof, comprising hydrolyzing a compound of formula V-6:

V-6

or a co-crystal, solvate, salt, or combination thereof, with a base, a solvent, and optionally, a phase transfer catalyst, to provide the compound of formul a V5 or a co-crystal, solvate, salt, or combination thereof.

154. The process of claim 153, wherein the base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, N- acetylcysteine, sodium thiophenolate, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium w-propoxide, sodium /-propoxide, sodium /-butoxide, methylamine, ethyl amine, «-propylamine, dimethyl amine, diethylamine, and hydroxyl amine.

155. The process of any one of claims 1 53-154, wherein the base is sodium hydroxide.

156. The process of any one of claims 153-155, wherein the solvent is selected from the group consisting of diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, di chi orom ethane, acetonitrile, N,N- dimethylform amide, V-m ethyl -2-pyrrolidone, AVY-dimethylacetamide, water, and a combination thereof.

157. The process of any one of claims 153-156, wherein the solvent is 2- methyltetrahydrofuran and water.

158. The process of any one of claims 153-157, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, benzyl tri butyl am m oni um bromide, 1 -methylimidazolium hydrogen sulfate, phosphonium salts, and tetrabutylphosphonium chloride.

159. The process of any one of claims 153-158, wherein the phase transfer catalyst is tetrabutyl ammoni um hydrogen sulfate.

160. The process of any one of claims 153-159, wherein the process is carried out in the temperature range of from about 10 °C to about 60 °C.

161. A process for preparing a compound of formula V-03-A:

V-03-A

or a co-crystal, solvate, salt, or combination thereof, wherein R is B(OH)2,

B(0CH(Me)CH2C(Me)20), B((l,2-di-0)C6H4), B(0CH2C(Me)2CH20), BF3K,

B(02CCH2N(Me)CH2C02), or B(0C(Me)2C(Me)20), comprising combining a compound of formula V-5:

or a co-crystal, solvate, salt, or combination thereof, with a boron coupling agent, a base, a solvent, and a catalyst, to provide the compound of V-03-A, or a co-crystal, solvate, salt, or combination thereof.

162. The process of claim 161, wherein R is B(0C(Me)2C(Me)20).

163. The process of any one of claims 161-162, wherein the boron coupling agent is selected from the group consisting of bi s(pinacol ato)diboron, bis(neopentyl glycolato)diboron, bisboronic acid, and bis(ethylene glycolato diboron).

164. The process of any one of claims 161 -163, wherein the boron coupling agent is bi s(pinacol ato)dib oron .

165. The process of any one of claims 161-164, wherein the base is selected from the group consisting of cesium acetate, potassium propionate, sodium propionate, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide,

di cy cl oh exyl ami ne, /V-methylmorpholine, tri ethyl amine, and diisopropyl ethylamine.

166. The process of any one of claims 161-165, wherein the base is potassium acetate.

167. The process of any one of claims 161 -166, wherein the solvent is selected from the group of consisting of l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl -2-pyrrolidine, and a combination thereof.

168. The process of any one of claims 161-167, wherein the solvent is toluene and N,N- dimethylform amide.

169. The process of any one of claims 161 -168, wherein the catalyst is selected from the group of consisting of bis(di-/er/-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine]palladium(II) chloride,

dichlQrobis(triphenyiphosphine)palladium(n), [ 1 , - bis(diphenyiphosphino)ferrocene]dichloropalladium(II), [ 1 ,2- bis(diphenylphosphino)ethane]dichloropalladium(II), dichloro[9, 9-dimethyl -4,5- bis(diphenyiphosphino)xanthene]palladium(II), or wherein the catalyst comprises palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0), or bis(dibenzylideneacetone)palladium(0), and the catalyst optionally further comprises a phosphine ligand selected from the group consisting of tricyclohexylphosphine, triphenylphosphine, cy cl ohexyl di p heny 1 p hosphi ne, and

dicyclohexylphenylphosphine.

170. The process of any one of claims 161-169, wherein the palladium catalyst is bis(triphenylphosphine)palladium (II) dichloride.

171. The process of any one of claims 161-170, wherein the process is carried out in the temperature range of from about about 20 °C to about 120 °C.

172. A process for preparing a compound of formula VIII:

VIII

or a co-crystal, solvate, salt, or combination thereof, comprising resolving a compound of formula X:

X

or a co-crystal, solvate, salt, or combination thereof, with a chiral or achiral acid in a solvent, optionally in the presence of an aldehyde catalyst and/or optionally a metal catalyst to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

173. The process of claim 172, wherein the compound of formul a VIII is a compound of formula VIII-02:

or a co-crystal, solvate, or combination thereof, wherein HX is a chiral acid

174. The process of claim 172 or 173, wherein HX is selected from the group consi sting of lactic acid, L-lactic acid L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1 R, 35)-(+)-camphoric acid, (lX)-(+)-camphor-lO-sulfonic acid, (R)-(+)-JV- (l -pheny!ethy )succinamic acid, carb ob enzyl oxy- L-proli ne, dibenzoyl-L-tartaric acid, (/?)-(+)- 3- methyladipic acid, (+)-m enthyl oxy aceti c acid, (-)-pyroglutamic aci d, (-)-n-acetyl -L-l eu cine, (-)- TV'-acetyl-D-leucine, /V-Boc-D-leucine, 7Vr-(+)-BOC-phenylalanine, (-)-quinic acid, (+)-«-acetyl- L-phenylalanine, (+)-Y-BOC-isoleucine, L-(-)-acetyl glutamic acid, (-)-acetyl mandelic acid, (7?)-(-)-citramalic acid, (-)-camphanic acid, and (i?)-mandelic acid.

175. The process of any one of claims 172-174, wherein HX is AYBoc-D-leucine or acetyl-D-leucine.

176. The process of any one of claims 172-175, wherein HX is (A’)-mandelic acid.

177. The process of any one of claims 172-176, wherein the solvent is selected from the group consisting of n-heptane, ethyl acetate, butyl acetate, isobutyl acetate, diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2 -meth yltetrah y drofuran, l,4-dioxane, benzene, xylenes, toluene, dichloromethane, d ochl oroethanne, chloroform, methanol, ethanol, 2-propanol, acetone, methyl ethyl ketone, methylisobutylketone, N,N-dimethylform amide, N,N-dimethyl acetamide, N- methylpyrrolidone, dimethylsulfoxide, acetonitrille, propionitrille, butyronitrille, water, and combinations thereof.

178. The process of any one of claims 172-177, wherein the solvent is methyl fe/7-butyl ether and toluene, or toluene.

179. The process of any one of claims 172-178, wherein the process is carried out in the temperature range of from about -20 °C to about 120 °C.

180. The process of any one of claims 172-179, wherein the process is carried out in the temperature range of from about -20 °C to about 50 °C.

181. The process of any one of claim s 172-180, wherein the compound of formula X is treated with a base in a first solvent prior to the resolving.

182. The process of claim 181, wherein the base is selected from the group consisting of potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, ammonium hydroxide, potassium phosphate dibasic, potassium phosphate tribasic, sodium phosphate dibasic, and sodium phosphate tribasic.

183. The process of claim 181 or 182, wherein the base is sodium hydroxide.

184. The process of any one of claims 181 -183, wherein the first solvent is selected from the group consisting of diethyl ether, methyl fert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, aromatic solvents, di chi orom ethane, and a combination thereof.

185. The process of any one of claims 181 -184, wherein the first solvent is 2- methyltetrahydrofuran.

186. The process of any one of claims 181-185, wherein the compound of formula X is treated with a base in a first solvent in the temperature range of from about 0 °C to about 100

°C.

187. The process of any one of claims 172-180, further comprising:

(a) condensing a compound of formula la:

l

or a co-crystal, solvate, salt, or combination thereof, with aminodiphenylmethane in a solvent, optionally in the presence of an additive, to provide a compound of formula l b-02:

lb-02

or a co-crystal, solvate, salt, or combination thereof;

(b) alkylating the compound of formula lb-02, or a co-crystal, solvate, salt, or combination thereof, with a compound of formula lc:

lc

wherein Y is Br, Cl, I, OMs, OTs, or 0S02CF3, in the presence of a base and optionally, a phase transfer catalyst, in a solvent to provide a compound of formula ld-02:

ld-02

or a co-crystal, solvate, salt, or combination thereof; and

(c) deprotecting the compound of formula ld-02 with an acid in a solvent to provide a compound of formula X:

or a co-crystal, solvate, salt, or combination thereof.

188. The process of claim 187, wherein the solvent for the condensing step is selected from the group consisting of diethyl ether, methyl fe/ -butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, A^-dimethylformamide, AyA'-dimethylacetamide, Ar-methylpyrrolidinone, acetonitrile, benzene, xylenes, toluene, and di chi oromethane .

189. The process of claim 187 or 188, wherein the solvent for the condensing step is toluene.

190. The process of any one of claims 187-189, wherein the additive for the condensing step is a dehydrating agent.

191. The process of any one of claims 187-189, wherein the additive for the condensing step is magnesium sulfate.

192. The process of any one of claim s 187-191, wherein the condensing step is carried out in the temperature range of from about -20 °C to about 120 °C.

193. The process of any one of claims 187-192, wherein the condensing step is carried out in the temperature range of from about 20 °C to about 90 °C.

194. The process of any one of claims 187-193, wherein Y is Br, Cl, or I.

195. The process of any one of claims 187-194, wherein Y is Br.

196. The process of any one of claims 187-195, wherein the base for the alkylating step is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium ethoxide, sodium te/7-butoxide, sodium fe/ -pentoxide, potassium tert- butoxide, tri ethyl amine, diisopropyl ethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, isopropylmagnesium chloride lithium chloride complex, seobutylmagnesium chloride, lithium chloride complex, n- butyllithium, lithium AvV-dimethylaminoethanol complex, mesityllithium, lithium di isopropyl amide, and phenyllithium.

197. The process of any one of claims 187-196, wherein the base for the alkylating step is potassium hydroxide.

198. The process of any one of claims 187-197, wherein the phase transfer catalyst for the alkylating step is selected from the group consisting of tetramethylammonium chloride, tetramethylammonium bromide, tetram ethyl ammonium iodide, tetramethylammonium hydrogen sulfate, tetraethyl ammonium chloride, tetraethyl am m onium bromide, tetra-n-butyl -amm oni um bromide, tetraethylammonium iodide, tetraethyl ammonium hydrogen sulfate, and benzyltrimethyl ammonium.

199. The process of any one of claims 187-198, wherein the phase transfer catalyst for the alkylating step is tetra-n-butyl -am m onium bromide.

200. The process of any one of claims 187-199, wherein the solvent for the alkylating step is selected from the group consisting of diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2- m ethyl tetrahydrofuran, l,4-dioxane, A’,A?-dimethylfomiamide, Ά', -dimethyl acetamide, N- methylpyrrolidinone, benzene, xylenes, toluene, dichloromethane, water, and combinations thereof.

201. The process of any one of claims 187-200, wherein the solvent for the alkylating step is toluene and water.

202. The process of any one of claims 187-201, wherein the compound of formula lc is selected from the group consisting of 3,5-difluorobenzyl bromide, 3,5-difluorobenzyl chloride, 3 , 5 -di fluorob enzyl mesylate, 3 , 5 -difluorobenzyl iodide, 3 , 5 -difluorobenzyl triflate, and 3,5-

203. The process of any one of claims 187-202, wherein the compound of formula lc is 3,5- difluorobenzyl bromide.

204. The process of any one of claims 187-203, wherein the alkylating step is carried out in the temperature range of from about -20 °C to about 120 °C.

205. The process of any one of claims 187-204, wherein the alkylating step is carried out in the temperature range of from about 10 °C to about 80 °C.

206. The process of any one of claims 187-205, wherein the acid for the deprotecting step is selected from the group consisting of hydrochloric acid, hydrobromic acid, methanesulfonic acid, -toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid, and oxalic acid.

207. The process of any one of claims 187-206, wherein the acid for the deprotecting step is methanesulfonic acid.

208. The process of any one of claims 187-207, wherein the solvent for the deprotecting step is selected from the group consisting of diethyl ether, methyl /e/7-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane, benzene, xylenes, toluene, di chi orom ethane, and combinations thereof.

209. The process of any one of claim s 187-208, wherein the sol vent for the deprotecting step is 2-methyltetrahydrofuran.

210. The process of any one of claims 187-209, wherein the deprotecting step is carried out in the temperature range of from about -40 °C to about 120 °C.

211. The process of any one of claims 187-210, wherein the deprotecting step is carried out in the temperature range of from about 10 °C to about 40 °C

212. The process of any one of claims 187-211, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, methanesulfonic acid, -toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid, and oxalic acid.

213. The process of any one of claims 187-212, wherein the acid is methanesulfonic acid.

214. The process of any one of claims 172-180, further comprising:

(a) combining a compound of formula XIII:

or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent, a base, a solvent, and optionally, an additive, to provide a compound of formula XIII- A:

XIII-A

or a co-crystal, solvate, salt, or combination thereof; and

(b) combining the compound of formula XI II -A or a co-crystal, solvate, salt, or combination thereof with an amination reagent and optionally a solvent, to provide the compound of formula X:

or a co-crystal, solvate, salt, or combination thereof.

215. The process of claim 214, wherein the mesylating reagent is selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride.

216. The process of claim 214 or 215, wherein the mesylating reagent is methanesulfonyl chloride.

217. The process of any one of claims 214-216, wherein the base for the mesylating step is selected from the group consisting of tri ethyl amine, dii sopropylethylamine, pyridine, 2,3,5- collidine, 2,4,6-collidine, A./V-dicyclohexylmethylamine, and A-methylimidazole.

218. The process of any one of claims 214-217, wherein the base for the mesylating step is triethylamine.

219. The process of any one of claims 214-218, wherein the additive for the mesylating step is 4-(dimethylamino)pyridine.

220. The process of any one of claims 214-219, wherein the solvent for the mesylating step is selected from the group consisting of diethyl ether, methyl tert-buXy\ ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, 7v,/V-di m ethyl form ami de, NN- di m ethyl acetami de, iV-methylpyrrolidinone, di chi ororn ethane, and combinations thereof.

221. The process of any one of claims 214-220, wherein the solvent for the mesylating step is tetrahydrofuran.

222. The process of any one of claim s 214-221, wherein the mesylating step is carried out in the temperature range of from about -80 °C to about 60 °C.

223. The process of any one of claims 214-222, wherein the mesylating step is carried out in the temperature range of from about 0 °C to about 40 °C.

224. The process of any one of claims 214-223, wherein the amination reagent is ammonia.

225. The process of any one of claims 214-224, wherein the solvent for the aminating step is selected from the group consisting of ethanol, 1 -propanol, 2 -propanol, diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, water, and combinations thereof.

226. The process of any one of claim s 214-225, wherein the sol vent for the aminating step is methanol and water.

227. The process of any one of claims 214-226, wherein step (b) is carried out in the temperature range of from about 0 °C to about 100 °C.

228. The process of any one of claims 214-227, wherein step (b) is carried out in the temperature range of from about 40 °C to about 80 °C.

229. A process for preparing a compound of formula V:

v

or a co-crystal, solvate, salt, or combination thereof, wherein R1 is B(OH)2,

B(0CH(Me)CH2C(Me)20), B((l,2-di-0)C6H4), B(0CH2C(Me)2CH20), BF3K,

B(02CCH2N(Me)CH2C02), or B(0C(Me)2C(Me)20, comprising:

(a) combining a compound of formula V-A:

V-A

or a co-crystal, solvate, salt, or combination thereof with

a silylating agent,

a base, and

a solvent to provide a compound of formula 7a:

7a

or a co-crystal, solvate, salt, or combination thereof,

wherein each R2 is independently Ci-6 alkyl that is unsubstituted or substituted with one to five Ci-6 alkyl groups; and

(b) combining the compound of formula 7a with

an organometallic reagent, and

a borylation reagent,

to provide the compound of formula V or a co-crystal, solvate, salt, or combination thereof

230. The process of claim 229, wherein the base for step (a) is selected from the group consisting of sodium hydride, potassium hydride, methylmagnesium bromi de, phenyl m agnesium bromide, sodium h ex am ethyl di si 1 azi de, potassium hexamethyl disilazide, and lithium hexamethyldisilazide.

231. The process of claim 229 or 230, wherein the base for step (a) is lithium

hexamethyidisilazide

232. The process of any one of claim s 229-231, wherein the silylating agent for step (a) is selected from the group consisting of trim ethyl silyl bromide, A^O-bisltrimethylsilyljacetamide, and trimethyl silyl chloride.

233. The process of any one of claims 229-232, wherein the silylating agent for step (a) is trimethyl silyl chloride.

234. The process of any one of claims 229-233, wherein the solvent is selected from the group consisting of diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran,

dimethoxyethane, n-hexane, toluene, xylenes, and combinations thereof.

235. The process of any one of claims 229-234, wherein the solvent is tetrahydrofuran.

236. The process of any one of claims 229-235, wherein the organometallic reagent for step (b) is selected from the group consisting of n-butyl lithium, s-butylmagnesium chloride lithium chloride complex, tert-butylmagnesium chloride, and i sopropylmagnesium chloride lithium chloride complex.

237. The process of any one of claims 229-236, wherein the organometallic reagent for step (b) is i sopropylmagnesium chloride· lithium chloride complex.

238. The process of any one of claims 229-237, wherein the borylation reagent for step (b) is selected from the group consisting of trimethyl borate, tri ethyl borate, pinacolborane, 2- m ethoxy-4, 4, 5 , 5 -tetram ethyl - 1 , 3 ,2-dioxaboral ane, 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane, B-catecholborane, and 2-bromo- 1 ,3 ,2-benzodioxaborole.

239. The process of any one of claims 229-238, wherein the borylation reagent for step (b) is 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane.

240. The process of any one of claims 229-239, wherein the process is carried out in the temperature range of from about -80 °C to about 40 °C.

241. The process of any one of claims 229-240, wherein the process is carried out in the temperature range of from about -40 °C to about 20 °C.

242. The process of any one of claim s 229-241, wherein R1 is B(0C(Me)2C(Me)20).

243. A process for preparing a compound of formula VIII:

or a co-crystal, solvate, salt, or combination thereof; comprising

(a) hydrogenating a compound of formula XI:

XI

or a co-crystal, solvate, salt, or combination thereof, in the presence of an asymmetric catalyst and a solvent to provide a compound of formula XII:

or a co-crystal, solvate, salt, or combination thereof;

(b) forming the azide of the compound of formula XII or a co-crystal, solvate, salt, or combination thereof with an azidification reagent in the presence of a base and a solvent to produce a compound of formula XVI:

or a co-crystal, solvate, salt, or combination thereof; and

(c) reducing the compound of formula XVI using a reducing agent, to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof

244. The process of claim 243, wherein the asymmetric catalyst is selected from the group consisting of [Rh(cod)((>S -segphos]BF4, IrCl(cod)((X)-segphos), [RuCl(p-cymene)(segphos)]Cl, Ru(OAc)2(segphos), (Me2MI2)[RuCl((V)-segphos)]2(p-Cl)3, and (A)-RuC Y -XylBINAP .

245. The process of claim 243 or 244, wherein the asymmetric catalyst is (R)- RuCY- XylBINAP.

246. The process of any one of claims 243-245, wherein the solvent for the hydrogenating step is selected from the group consisting of n-propyl acetate, isopropyl acetate, ethanol, 1- propanol, 2-propanol, diethyl ether, methyl erZ-butyl ether, tetrahydrofuran, 2- m ethyl tetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, di chi orom ethane, chloroform,

1 ,2-dichloroethane, and combinations thereof.

247. The process of any one of claims 243-246, wherein the solvent for the hydrogenating step is ethanol and 2 -propanol.

248. The process of any one of claims 243-247, wherein the hydrogenating step is carried out in the temperature range of from about -20 °C to about 150 °C.

249. The process of any one of claims 243-248, wherein the hydrogenating step is carried out in the temperature range of from about 0 °C to about 60 °C.

250. The process of any one of claims 243-249, wherein the azidification reagent is methanesulfonyl chloride and sodium azide or diphenylphosphoryl azide.

251. The process of any one of claims 243-250, wherein the azidification reagent is diphenylphosphoryl azide.

252. The process of any one of claims 243-251, wherein the base is selected from the group consisting of tri ethyl amine, dii sopropylethylamine, YA'-dimethylaminopyridine, and 1,8- diazabicyclo[5.4.0]undec-7-ene.

253. The process of any one of claims 243-252, wherein the base is 1,8- diazabicyclo[5.4.0]undec-7-ene.

254. The process of any one of claims 243-253, wherein the solvent for steps (b) and (c) is selected from the group consisting of diethyl ether, methyl fe/ -butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, AyV-dimethylform amide, NN- di m ethyl acetami de, AZ-methylpyrrolidinone, dichlorom ethane, and combinations thereof.

255. The process of any one of claims 243-254, wherein the solvent for steps (b) and (c) is tetrahydrofuran.

256. The process of any one of claims 243-255, wherein steps (b) and (c) are carried out in the temperature range of from about -10 °C to about 60 °C.

257. The process of any one of claims 243-256, wherein steps (b) and (c) are carried out in the temperature range of from about 0 °C to about 40 °C.

258. The process of any one of claims 243-257, wherein the reducing agent is selected from the group consisting of trimethylphosphine, triethylphosphine, trimethylphosphite,

triethylphosphite, tributyl phosphine, trifurylphosphine, tri s(hydroxym ethyl )phosphine, and triphenylphosphine.

259. The process of any one of claims 243-258, wherein the reducing agent is

triphenylphosphine.

260. The process of any one of claims 243-259, wherein the reducing step is carried out in the temperature range of from about -10 °C to about 60 °C.

261. The process of any one of claims 243-260, wherein the reducing step is carried out in the temperature range of from about 0 °C to about 40 °C.

262. A process for preparing a compound of formula VIII:

or a co-crystal, solvate, salt, or combination thereof, comprising:

(a) combining a compound of formul a XI:

XI

or a co-crystal, solvate, salt, or combination thereof, with a hydroxylamine source, a base and a solvent to provide a compound of formula le:

le

or a co-crystal, solvate, salt, or combination thereof;

(b) combining the compound of formula le with a reducing agent, an acylating reagent, and a solvent to provide a compound of formula lf-1:

or a co-crystal, solvate, salt, or combination thereof, wherein R6 is selected from the group consisting of acetyl, benzyl, trichloroacetyl, trifluoroacetyl, and propionyl; and

(c) hydrogenating the compound of formula lf-1 with an asymmetric catalyst in a solvent to provide a compound of formula lg-1 :

or a co-crystal, solvate, salt, or combination thereof; and

(d) deprotecting the compound of lg-1 with an acid and a solvent to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

263. The process of claim 262, wherein R

264. The process of claim 262 or 263, wherein the hydroxylamine source for step (a) is hydroxyl amine hydroxide.

265. The process of any one of claims 262-264, wherein the solvent for step (a) is selected from the group consisting of n-propyl acetate, isopropyl acetate, methanol, 1- or 2-propanol, diethyl ether, methyl tert-bx yl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, di chi orom ethane, chloroform, 1 ,2-dichloroethane, and a combination thereof.

266. The process of any one of claims 262-265, wherein the solvent for step (a) is ethanol.

267. The process of any one of claims 262-266, wherein the base for step (a) is selected from the group consi sting of pyridine, triethylamine, tri -«-propyl amine, tri -«-butyl amine, N- methy morpholine, /V-methylpyrrolidine, A'-methylpiperidine, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, lithium pivalate, sodium eth oxide, potassium eth oxide, sodium /<?r/-butoxide, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide.

268. The process of any one of claims 262-267, wherein the base for step (a) is pyridine.

269. The process of any one of claims 262-268, wherein step (a) is carried out in the temperature range of from about 10 °C to about 60 °C.

270. The process of any one of claims 262-269, wherein the reducing agent for step (b) is selected from the group consisting of palladium on carbon, hydrogen, iron(II)acetate, samarium diiodide, titanium(IV) tetrachloride/tin(II) chloride, and metallic zinc.

271. The process of any one of claims 262-270, wherein the reducing agent for step (b) is iron(II)acetate.

272. The process of any one of cl aims 262-271, wherein the acylating reagent for step (b) is selected from the group consisting of acetyl chloride, trichloroacetyl chloride, acetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, benzyl chloride, and benzyl bromide.

273. The process of any one of claims 262-272, wherein the acylating reagent for step (b) is acetic anhydride.

274. The process of any one of claims 262-273, wherein the solvent for step (b) is selected from the group consisting of acetic acid, n-propyl acetate, isopropyl acetate, acetate, methanol, 1- or 2-propanol, diethyl ether, methyl er -butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, dichloromethane, chloroform,

1 ,2-dichloroethane and a combination thereof.

275. The process of any one of claims 262-274, wherein the solvent for step (b) is isopropyl acetate and acetic acid.

276. The process of any one of claims 262-275, wherein step (b) is carried out in the temperature range of from about 30 °C to about 70 °C.

277. The process of any one of claims 262-276, wherein the asymmetric catalyst for step (c) is selected from the group consisting of IrCl(cod)((5')-segphos), Rh(cod)((5)-segphos]BF4, and (Me2NH2)[RuCl((A)-segphos)]2(p-Cl)3.

278. The process of any one of claims 262-277, wherein the asymmetric catalyst for step (c) is (IrCl(cod)((>S -segphos).

279. The process of any one of cl aims 262-278, wherein the solvent for step (c) and step (d) is selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, ethanol,

1- or 2-propanol, diethyl ether, methyl fe/7-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, dichlorom ethane, chloroform,

1 ,2-dichloroethane and a combination thereof.

280. The process of any one of claims 262-279, wherein the solvent for step (c) and step (d) is ethyl acetate.

281. The process of any one of claims 262-280, wherein step (c) is carried out in the temperature range of from about 80 °C to about 150 °C.

282. The process of any one of claims 262-281, wherein the acid for step (d) is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, methanesulfonic acid, and -toluenesulfonic acid.

283. The process of any one of claims 262-282, wherein the acid for step (d) is hydrochloric

284. The process of any one of claims 262-283, wherein step (d) is carried out in the temperature range of from about 20 °C to about 80 °C.

285. A process for preparing a compound of formula VIII:

VIII

or a co-crystal, solvate, salt, or combination thereof;

comprising reductively aminating a compound of formula XI:

XI

or a co-crystal, solvate, salt, or combination thereof, with:

a hydrogen source,

a ctatalyst,

an amine,

an acid, and

a solvent,

to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof

286. The process of claim 285, wherein the hydrogen source is selected from the group consisting of hydrogen gas, ammonium formate, and formic acid triethylamine complex.

287. The process of claim 285 or 286, wherein the hydrogen source is hydrogen gas.

288. The process of any one of claims 285-287, wherein the solvent is selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, xylenes, AyV-dimethylform amide, AyV-dimethyl acetamide, N- methy 1 pyrroli dinone, methanol, isopropanol, tert- amyl alcohol, water, dimethyl sulfoxide, and combinations thereof.

289. The process of any one of claims 285-288, wherein the solvent is methanol.

290. The process of any one of claims 285-289, wherein the catalyst is an asymmetric catalyst or an enzymatic catalyst.

291. The process of any one of claims 285-290, wherein the asymmetric catalyst is a ruthenium or iridium catalyst with a chiral ligand selected from the group consisting of SegPhos, DM-SegPhos, tert-butyl-Josiphos, DuPhos, MonoPhos, and BINAP.

292. The process of any one of claims 285-290, wherein the catalyst is a ruthenium or iridium catalyst selected from the group consisting of RuCE, ruthenium(III) acetyl acetonate,

chlorocyclopentadienylbis(triphenylphosphine)ruthemium(II),

chlorohydridotris(triphenylphosphine) ruthenium(II) toluene adduct,

chlorotris(triphenylphosphine)ruthenium(II) acetate, [Ru(Cl)H(CO)(PPh3)3], [Ir(COD)Cl]2, (acetylacetonato)(l,5-cyclooctadiene)iridium(I), and (acetylacetonato)dicarbonyliridium(I).

293. The process of any one of claims 285-290, wherein the catalyst is Ru(OAc)2((R)- SegPhos).

294. The process of any one of claims 285-290, wherein the enzymatic catalyst is an amine transaminase and a cofactor in a buffer.

295. The process of claim 294, wherein the amine transaminase is a w -transaminase selected from the group consisting of AT A- 1, ATA-2, ATA-007, ATA-013, ATA-025, ATA-113, ATA- 117, ATA-200, ATA-217, ATA-234, ATA-237, ATA-238, ATA-251, ATA-254, ATA-256, ATA-260, ATA-301, ATA-303, ATA-412, ATA-415, ATA-P1-B04, ATA-P1-F03, ATA-P1- G05, ATA-P2-A01, ATA-P2-A07, and ATA-P2-B01.

296. The process of claim 294 or 295, wherein the buffer is selected from the group consisting of triethanolamine, tris, tricine, BBS, MOPS, HEPES, sodium phosphate, and potassium phosphate.

297. The process of any one of claims 294-296, wherein the cofactor is pyridoxal phosphate.

298. The process of any one of claims 285-297, wherein the amine is selected from the group consisting of ammonia, ammonium acetate, ammonium salicylate, ammonium formate, a- methylbenzyl amine, isopropylamine, benzhydrylamine, DL-alanine, and aspartame.

299. The process of any one of claims 285-298, wherein the amine is ammonia.

300. The process of any one of claims 285-299, wherein the acid is selected from the group consisting of -toluenesulfonic acid, hydrochloric acid, and phosphoric acid.

301. The process of any one of claims 285-300, wherein the acid is p-toluenesulfonic acid.

302. The process of any one of claims 285-290 and 298-301, wherein the catalyst is an asymmetric catalyst and the process is carried out at a pressure of from about 100 to about 1000 psi.

303. The process of any one of claims 285-290 and 298-302, wherein the catalyst is an asymmetric catalyst and the process is carried out at a pressure of from about 200 to about 600 psi.

304. The process of any one of claims 285-290 and 298-303, wherein the catalyst is an asymmetric catalyst and the process is carried out in the temperature range of from about 0 °C to about 120 °C.

305. The process of any one of claims 285-290 and 298-304, wherein the catalyst is an asymmetric catalyst and the process is carried out in the temperature range of from about 55 °C to about 65 °C.

306. The process of any one of claims 285-290 and 298-301, wherein the catalyst is an enzymatic catalyst and the process is carried out in the temperature range of from about 5 °C to about 100 °C.

307. A process for preparing a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof;

comprising hydrolyzing a compound of formula VII- A:

VII-A

or a co-crystal, solvate, salt, or combination thereof in the presence of a base and a solvent to provide a compound of formula VII.

308. The process of claim 307, wherein the base is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, and potassium trimethylsilanoate.

309. The process of claim 307 or 308, wherein the base is potassium hydroxide.

310. The process of any one of claims 307-309, wherein the solvent is selected from the group consisting of dichloromethane, ethanol, tetrahydrofuran, 2-m ethyl tetrahydrofuran, toluene, water, and combinations thereof.

31 1. The process of any one of claims 307-3 10, wherein the solvent is dichloromethane and ethanol .

312. The process of any one of claims 307-31 1, wherein the process is carried out in the temperature range of from about 10 °C to about 100 °C.

313. The process of any one of claims 307-312, wherein the process is carried out in the temperature range of from about 10 °C to about 60 °C.

314. A process for preparing a compound of formula VII-A:

VII-A

or a co-crystal, solvate, salt, or combination thereof, comprising fluorinating a compound of formula 5h-l:

or a co-crystal, solvate, salt, or combination thereof, wherein n is 1 or 2, with a fluorinating reagent, in a solvent, and in the presence of an activator, to provide the compound of formula VII-A or a co-crystal, solvate, salt, or combination thereof

315. The process of claim 314, wherein n is 1.

316. The process of claim 314 or 315, wherein the fluorinating reagent is selected from the group consisting of hydrogen fluoride pyridine, calcium fluoride, potassium hydrogenfluoride, triethylamine trihydrofluoride, elemental fluorine, bromine tri fluoride, iodine pentafluoride, tetra-A butyl ammonium di hydrogen tri fluoride, 4-iodotoluene di fluoride, and hydrogen fluoride melamine.

317. The process of any one of claims 314-316, wherein the fluorinating reagent is hydrogen fluoride pyridine.

318. The process of any one of claims 314-317, wherein the solvent is selected from the group consisting of diethyl ether, methyl /e/7-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, acetone, iV, Y-dimethylformamide, AyV-dimethyl acetamide, /V-methylpyrrolidinone, benzene, toluene, xylenes, dichlorom ethane, and a combination thereof

319. The process of any one of claims 314-318, wherein the solvent is di chi orom ethane .

320. The process of any one of claims 314-319, wherein the activator is selected from the group consisting of 1 ,3 -dibromo-5 , 5 -dimethylhydantoin, Ar-bromosuccinimide, N- iodosuccinimide, nitrosonium tetrafl uor ob orate, sulfuryl chloride fluoride, triflic acid, and mercuric fluoride.

321. The process of any one of claims 314-320, wherein the activator is l,3-dibromo-5,5- dimethylhydantoin.

322. The process of any one of claims 314-321, wherein the process is carried out in the temperature range of from about -30 °C to about 20 °C.

323. A process for preparing a compound of formula 5h-l:

5h-l

or a co-crystal, solvate, salt, or combination thereof, wherein n is 1 or 2, comprising combining a compound of formula XIV:

or a co-crystal, solvate, salt, or combination thereof, with a dithiol reagent and a promoter, in a solvent, to provide the compound of formula 5h-l or a co-crystal, solvate, salt, or combination thereof.

324. The process of claim 323, wherein the dithiol reagent is 1 ,2-enthanedithiol or 1,2- propanedithiol.

325. The process of claim 323 or 324, wherein the solvent is selected from the group consisting of diethyl ether, methyl ferf-butyi ether, tetrahydrofuran, 2-methyltetrahydrofuran,

1 ,4-di oxaneacetone, AyA-dimethylformamide, A^V-dimethyl acetamide, AAnethyipyrrolidinone, benzene, toluene, xylenes, di chi orom ethane, and a combination thereof.

326. The process of any one of claims 323-325, wherein the promoter is selected from the group consisting of boron trifluoride acetic acid complex, -toluenesulfonic acid, i odine, 1,3- dibromo-5,5-dimethylhydantoin, copper(II) dodecyl sulfate, ytterbium(III) triflate, yttrium (III) triflate, bismuth(III) triflate, bismuth(III) chloride, tungstophosphoric acid, perchloric acid, praseodymium triflate, hafnium(IV) triflate, iron(III) chloride, hydrogen chloride, / dodecyl benzenesulfonic acid, BF3OEt2, BF3 OMe2, BF3 THF, BF3 OBu2, BF3 MeOH, BF3 Me2S, and BF3 PhOHBF3 2H20.

327. The process of any one of claims 323-326, wherein the promoter is boron tri fluoride acetic acid complex.

328. The process of any one of claims 323-327, wherein the process is carried out in the temperature range of from about -20 °C to about 100 °C.

329. A process for preparing a compound of formula XIV:

or a co-crystal, solvate, salt, or combination thereof;

comprising alkylating a compound of formula XIV-A:

XIV-A

or a co-crystal, solvate, salt, or combination thereof, with an alkylating agent in the presence of a base, a solvent, and opti onally a phase transfer catalyst, to provide the compound of formula XIV or a co-crystal, solvate, salt, or combination thereof.

330. The process of claim 329, wherein the alkylating agent is selected from the group consisting of ethyl chloroacetate, ethyl iodoacetate, ethyl (methanesulfonyloxy)acetate, ethyl (p- tosyloxy)acetate, ethyl (((trifluoromethyl)sulfonyl)oxy)acetate, and ethyl bromoacetate.

331. The process of claim 329 or 330, wherein the alkylating agent is ethyl bromoacetate.

332. The process of any one of claims 329-331, wherein the base is selected from the group consisting of ethyl diisopropylamine, triethylamine, tri -n-propyl amine, tri-n-butylamine, N- methylmorpholine, A-methylpyrrolidine, A’-methylpiperidine, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, potassium ethoxide, sodium fer/-butoxide, sodium hydride, lithium hexamethyldisilazide, sodium hexamethylsilazide, and potassium hexam ethyl disilazide.

333. The process of any one of claims 329-332, wherein the base is ethyl diisopropylamine.

334. The process of any one of claims 329-333, wherein the phase transfer catalyst is selected from the group consisting of tetra-A'-buty 1 ammonium hydrogensulfate and tetra-AA

butyl ammonium iodide.

335. The process of any one of claims 329-334, wherein the solvent is selected from the group consisting of diethyl ether, methyl toT-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,

1 ,4-dioxane, A',A-dimethylformamide, AyV-dimethylacetami de, A'-methylpyrrolidinone, benzene, toluene, xylenes, dichloromethane, ethyl acetate, isopropyl acetate, «-butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, water, and combinations thereof.

336. The process of any one of claims 329-335, wherein the solvent is acetonitrile.

337. The process of any one of claims 329-336, wherein the process is carried out in the temperature range of from about -20 °C to about 100 °C.

338. The process of any one of claims 329-337, wherein the process is carried out in the temperature range of from about -20 °C to about 30 °C.

339. A process for preparing a compound of formula XIV- A:

XIV-A

or a co-crystal, solvate, salt, or combination thereof, comprising oxidizing a compound of formula 3c:

3c or a co-crystal, solvate, salt, or combination thereof, with an oxidant, a promoter, a solvent, and a catalyst, to provide the compound of formula XIV- A or a co-crystal, sol vate, salt, or combination thereof.

340. The process of claim 339, wherein the oxidant is selected from the group consisting of fe/7-butyl hydroperoxide, peracetic acid, hydrogen peroxide, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium peroxymonosulfate, 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone, 1 ,4-benzoquinone, periodic acid, potassium bromate, m-CPBA, and magnesium monoperoxypthalate.

341. The process of claim 339 or 340, wherein the oxidant is /er/-butyl hydroperoxide.

342. The process of any one of claims 339-341, wherein the promoter is selected from the group consisting of pyridine, bipyridine, neocuproine, 1 , 10-phenanthroline, 2,6-lutidine, 4- picoline, 2-picoline, 3-methylpyridine, Isonicotinamide, nicotinamide, picolinic acid, (2, 2,6,6- tetramethylpiperidin-l-yf)oxyl, and di decy 1 di m ethyl am m onium bromide.

343. The process of any one of claims 339-342, wherein the promoter is pyridine.

344. The process of any one of claims 339-343, wherein the solvent is selected from the group consisting of acetic acid, acetonitrile, n-butyl acetate, isopropyl acetate, ethyl acetate, acetaone, di chi orom ethane, dimethyl carbonate, tetrahydrofuran, methanol, tert-butanol, di chi orom ethane, sulfolane, water, and a combination thereof.

345. The process of any one of claims 339-344, wherein the solvent is water.

346. The process of any one of claims 339-345, wherein the catalyst is selected from the group consisting of manganese(II) trif ate, copper(II) chloride, (26',2A-(-)-[iVr,A7'-Bis(2- pyridy!methyl)]-2,2f-bipyrro!idinebis(acetonitrile)iron(II) hexafluoroantimonate, bismuth, cobalt(II) acetate, manganese(III) acetate, ruthenium(III) chloride, V-hydroxyphthalimide, bis(cyclopentadienyl)vanadium(TV) dichloride, and manganese dioxide.

347. The process of any one of claims 339-346, wherein the catalyst is copper(II) chloride

348. The process of any one of claims 339-347, wherein the process is carried out in the temperature range of from about 10 °C to about 50 °C.

349. A process for preparing a compound of formula 3c:

3c

or a co-crystal, solvate, salt, or combination thereof, comprising:

a) cyclizing a compound of formula 3a:

3a

or a co-crystal, solvate, or combination thereof, with a hydrazine derivative and a promoter, in a solvent, to provide a compound of formula 3b:

or a co-crystal, solvate, salt or combination thereof; and

(b) chromatographically separating the compound of formula 3b, or a co-crystal, solvate, salt or combination thereof, with a chiral stationary phase and a solvent to provide the compound of formula 3c, or a co-crystal, solvate, salt, or combination thereof.

350. The process of claim 349, wherein the hydrazine derivative of step (a) is selected from the group consisting of anhydrous hydrazine, hydrazine monohydrate, aqueous hydrazine, hydrazine acetate, hydrazine dihydrochloride, hydrazine monohy drochl ori de, hydrazine sulfate, hydrazine hemi sulfate, and hydrazine monohydrobromide.

351. The process of claim 349 or 350, wherein the hydrazine derivative of step (a) is hydrazine hydrate.

352. The process of any one of claims 349-351, wherein the solvent in step (a) is selected from the group consisting of water, m ethanol, ethanol, 1- or 2-propanol diethyl ether, methyl /e/7-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, NN- dimethylformamide, iV, A-dimethyl acetamide, TV-methylpyrrolidinone, benzene, toluene, xylenes, carboxylic acids, acetic acid, formic acid, propionic acid, butanoic acid, and a combination thereof.

353. The process of any one of claims 349-352, wherein the solvent in step (a) is acetic acid.

354. The process of any one of claims 349-353, wherein the promoter in step (a) is selected from the group consisting of hydrogen chloride, hydrogen bromi de, sulfuric acid,

methanesulfonic acid, toluenesulfonic acid, zinc chloride, magnesium chloride, and titanium tetrachloride.

355. The process of any one of claims 349-354, wherein step (a) is carried out at a

temperature range of from about -40 to about 120 °C.

356. The process of any one of claims 349-355, wherein the chiral stationary phase used in step (b) is selected from the group consisting of Chiralpaks AD, AS, AY, AZ, T101, OD, IA, IB, IC, ID, IE, IF, IG; Lux Celluloses 2, 3, 4; and (R,R) Whelk-O, (R,R) ULMO, and (S,S) Dach DNB.

357. The process of any one of claims 349-356, wherein the chiral stationary phase used in step (b) is Chiralpak IG.

358. The process of any one of claims 349-357, wherein the solvent used in step (b) is selected from the group consisting of hexanes, heptanes, octanes, esters, ethyl acetate, n-propyl acetate, isopropyl acetate, methanol, ethanol, 1- or 2-propanol, diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, benzene, toluene, xylenes, di chi orom ethane, chloroform, 1 ,2-dichloroethane, acetonitrile, and a combination thereof.

359. The process of any one of claims 349-358, wherein the solvent used in step (b) is acetontrile.

360. The process of any one of claims 349-359, wherein step (b) is carried out at a temperature range of from about 10 °C to about 50 °C.

361. A process for preparing a compound of formula XIV:

or a co-crystal, solvate, salt, or combination thereof; comprising kinetically resolving a compound of formula XVII:

XVII

or a co-crystal, solvate, or combination thereof, with:

a catalyst,

a reducing agent, and

a solvent,

to provide a compound of formula XIV or a co-crystal, solvate, salt, or combination thereof

362. The process of claim 361, wherein the catalyst is selected from the group consisting of (i?)-(+)-o-tolyl-CBS-oxazaborolidine, (7?)-(+)-2-butyl-CBS-oxazaborolidine, (i?)-(-)-2-m ethyl - CBS-oxazoborolidine, /ra«s-RuCl2[(f?)-xylbinap]-[(i?)-diapen], RuBr2[( R)-BINAP],

[RuCl(PhH)(f?)-BINAP)]Cl, RuCl(p-cymene)[(S,S)-Ts-DPEN], RuCl(mesitylene)[(S,S)-Ts- DPEN], RuBF4(p-cymene)[(S,S)-Ts-DPEN], RuCl(p-cymene)[(S,S)-Fs-DPEN], RuCl(p- cymene)[(R,R)-Teth-Ts-DPEN], and Baker’s yeast.

363. The process of claim 361 or 362, wherein the catalyst is (f?)-(-)-2 -methyl -CBS- oxazoborolidine.

364. The process of any one of claims 361-363, wherein the reducing agent is selected from the group consisting of borane dimethylsulfide complex, borane tetrahydrofuran complex, borane trimethylamine complex, borane triethylamine complex, borane V.iV-diethylaniline complex, catecholborane, hydrogen gas, formic aci d/tri ethyl ami ne, and 2 -propanol .

365. The process of any one of claims 361-364, wherein the reducing agent is boranedimethyl sulfi de compl ex .

366. The process of any one of claims 361 -365, wherein the solvent is selected from the group consisting of diethyl ether, methyl tert-butyl ether, l,4-dioxane, 2-m ethyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, n-hexane, heptane, toluene, xylenes, ethyl acetate, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and combinations thereof.

367. The process of any one of claims 361 -366, wherein the solvent is tetrahydrofuran.

368. The process of any one of claims 361-367, wherein the process is carried out at a temperature range of from about -20 °C to about 100 °C.

369. The process of any one of claims 361 -368, wherein the process is carried out at a temperature range of from about 0 °C to about 10 °C.

370. A process for preparing a compound of formula XIV:

XIV

or a co-crystal, solvate, or combination thereof; comprising:

(a) oxidizing a compound of formula 5a:

or a co-crystal, solvate, or combination thereof, with an oxidant, a base, and a solvent to provide a compound of formul a 5b:

5b

or a co-crystal, solvate, or combination thereof, wherein each R3 is independently Cl-6 alkyl that is unsubstituted or substituted with one to five Cl-6 alkyl groups; (b) further oxidizing the compound of formula 5b or a co-crystal, solvate, or combination thereof, with an oxidant, a base, and a solvent, to provide a compound of formula 5c:

R30 OR3

5c

or a co-crystal, solvate, or combination thereof;

(c) combining the compound of formula 5c or a co-crystal, solvate, or combination thereof with a trifluoroacetylating agent and a lithium base in a solvent, to provide a compound of formula 5d:

5d

or a co-crystal, solvate, or combination thereof; and

(d) combining the compound of formula 5d or a co-crystal, solvate, or combination thereof with ethyl hydrazinoacetate hydrochloride, an acid and optionally, an additive, to provide the compound of formula XIV or a co-crystal, solvate, salt, or combination thereof

371. The process of claim 370, wherein the oxidant used in step (a) is selected from the group consisting of iodine, thianthrenium tetrafluorob orate, di acetoxyi odob enzen e, and potassium iodide/platinum electrode.

372. The process of claim 370 or 371, wherein the oxidant used in step (a) is

diacetoxyi odob enzene .

373. The process of any one of claims 370-372, wherein the base used in step (a) is selected from the group consisting of sodium hydroxide, lithium hydroxide, and potassium hydroxide.

374. The process of any one of claims 370-373, wherein the base used in step (a) is potassium hydroxide.

375. The process of any one of claims 370-374, wherein the solvent used in step (a) is selected from the group consisting of methanol, ethanol, 1 -propanol, and ethylene glycol.

376. The process of any one of claims 370-375, wherein the solvent used in step (a) is methanol .

377. The process of any one of claims 370-376, wherein step (a) is carried out in the temperature range of from about -20 °C to about 100 °C.

378. The process of any one of claims 370-377, wherein step (a) is carried out in the temperature range of from about -15 °C to about 30 °C.

379. The process of any one of claims 370-378, wherein the oxidant used in step (b) is selected from the group consisting of dimethyl sulfoxi de and an activating agent selected from the group consisting of cyanuric chloride, oxalyl chloride, dicyclohexylcarbodiimide, NN- diisopropylcarbodiimide, Tf-chlorosuccinimide, benzoic anhydride, methanesulfonic anhydride, tosic anhydride, triflic anhydride, methyl chi oroglyoxy late, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, tosyl chloride, benzenesulfonyl chloride,

tri chi oroacetonitri 1 e, 2-chloro- 1 ,2-dimethylimi dazolinium chloride, polyphosphoric acid, PCI3, triphenylphosphine dichloride, triphenylphosphine dibromide, POCI3, phosphorous pentoxide, acetyl chloride, benzoyl chloride, acetyl bromide, phenyl dichlorophosphate, diphenyl chlorophosphate, diethyl chlorophosphate, and ethoxyacetylene, TEMPO and bleach, chromium tri oxide, Dess-Martin periodinane, 2-iodoxybenzoic acid, and sulfur trioxide pyridine complex.

380. The process of any one of claims 370-379, wherein the oxidant used in step (b) is dimethyl sulfoxide and oxalyl chloride.

381. The process of any one of claims 370-380, wherein the base used in step (b) is selected from the group consisting of dii sopropyl ethyl ami ne, tri -«-propyl amine, triethylamine, pyridine, and 2,6-lutidine.

382. The process of any one of claims 370-381, wherein the base used in step (b) is triethylamine.

383. The process of any one of claims 370-382, wherein the solvent used in step (b) is selected from the group consisting of dichloroethane, di chi or om ethane, toluene, and combinations thereof.

384. The process of any one of claims 370-383, wherein the solvent used in step (b) is dichloromethane.

385. The process of any one of claims 370-384, wherein step (b) is carried out in the temperature range of from about -80 °C to about 50 °C.

386. The process of any one of claims 370-385, wherein step (b) is carried out in the temperature range of from about -60 °C to about -10 °C.

387. The process of any one of claims 370-386, wherein R3 is methyl.

388. The process of any one of claims 370-387, wherein the trifluoroacetylating agent is selected from the group consisting of trifluoroacetic anhydride, phenyltrifluoroacetate, methyl trifluoroacetate, ethyl trifluoroacetate, and trifluoroethyl trif!uoroacetate.

389. The process of any one of claims 370-388, wherein the trifluoroacetyl ating agent is ethyl trifluoroacetate.

390. The process of any one of claims 370-389, wherein the lithium base is selected from the group consisting of lithium hexam ethyl di sil azide, lithium diisopropylamine, lithium

tetramethylpiperidide, lithium methoxide, lithium ethoxide, and lithium fe/7-butoxide.

391. The process of any one of claims 370-390, wherein the lithium base is lithium

hexamethyl disilazide.

392. The process of any one of claims 370-391, wherein the solvent used in step (c) is selected from the group consisting of diethyl ether, l,4-dioxane, 2-m ethyltetrahydrofuran, tetrahydrofuran, dimethoxyethane, methyl tert-butyl ether, «-hexane, «-heptane, toluene, xylenes, dichloromethane, AyV-dimethylformamide, A', /V- d i m eth y I a c eta m i de , N- methylpyrrolidinone, and acetonitrile.

393. The process of any one of claims 370-392, wherein the solvent used in step (c) is tetrahydrofuran.

394. The process of any one of claims 370-393, wherein step (c) is carried out in the temperature range of from about -30 °C to about 30 °C.

395. The process of any one of claims 370-394, wherein step (c) is carried out in the temperature range of from about -80 °C to about 60 °C.

396. The process of any one of claims 370-395, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, hydrogen bromide, methanesulfonic acid, -toluenesulfonic acid, magnesium chloride, zinc chloride, scandium triflate, and bismuth chloride.

397. The process of any one of claims 370-396, wherein the acid is sulfuric acid.

398. The process of any one of claims 370-397, wherein the additive is selected from the group consisting of ethyl orthoacetate, ethyl orthoformate, molecular sieves, and Dean- Stark distillation.

399. The process of any one of claims 370-398, wherein the additive is ethyl orthoformate.

400. The process of any one of claims 370-399, wherein the solvent used in step (d) is selected from the group consisting of diethyl ether, methyl fe/ -butyl ether, tetrahydrofuran, 2- m ethyl tetrahydrofuran, l,4-dioxane, acetone, A^-dimethylform amide, L Ά'-di m ethyl acetami de, YV-methylpyrrolidinone, benzene, toluene, xylenes, ethyl acetate, isopropyl acetate, ethylene glycol, propylene glycol, methanol, ethanol, isopropanol, di chi or om ethane, and combinations thereof.

401. The process of any one of claims 370-400, wherein the solvent used in step (d) is ethanol.

402. The process of any one of claims 370-401, wherein step (d) is carried out in the temperature range of from about -20 °C to about 60 °C.

403. The process of any one of claims 370-402, wherein step (d) is carried out in the temperature range of from about -20 °C to about 20 °C.

404. A compound of formula VI:

or a co-crystal, solvate, or combination thereof.

405. A compound of formula VIII:

VIII

or a co-crystal, solvate, salt or combination thereof.

406. The compound of claim 405, wherein the compound of formula VIII is:

VIII-02

or a co-crystal, solvate, or combination thereof, wherein HX is selected from the group consisting of hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p- toluenesulfonic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D- glucuronic acid, (If?, 3X)-(+)-camphoric acid, (LS)-(+)-camphor-lO-sulfonic acid, (R)-(+)-7V-(l- phenyl ethyl) su ccinami c acid, carbobenzyloxy-L-proline, dibenzoyl-L-tartaric acid, (/?)-(+)- 3- methyladipic acid, (+)-menthyloxyacetic acid, (-)-pyroglutamic aci d,(-)4V-acetyl-L4 eucine, (-)- A-acetyi-Ddeucine, A-Boc-D-leucine, fV-(+)-BOC-phenylalanine, (-)-quinic acid,(+)-«-acetyl- L-phenyl alanine, (-f)-A-BOC-i sol eucine, L-( )-acetyl glutamic acid, (-)-acetyl mandelic acid, (f?)-(---)-citramalic acid, (-)-camphanic acid, and (f?)-mandelic acid.

407. The compound of claim 406, wherein HX is A-Boc-D-leucine or (-)-V-acetyl-D-leucine.

408. The compound of claim 406, wherein HX is (7?)-mandelic acid.

409. A compound of formula IV:

or a co-crystal, solvate, salt, or combination thereof.

410. A compound of formula III:

or a co-crystal, solvate, salt, or combination thereof.

411. The compound of claim 410, wherein the compound of formula III is:

111-03

or a co-crystal or solvate or combination thereof.

412. The compound of claim 410, wherein the compound of formula III is:

or a co-crystal or combination thereof.

413. The compound of claim 410, wherein the compound of formula III is:

III-05

or a co-crystal or combination thereof.

414. A compound of formula II:

or a co-crystal, solvate, salt, or combination thereof.

415. A process for preparing a compound of formula 5e

5e or a co-crystal, solvate, or combination thereof, comprising:

(a) oxi dizing a compound of formula 5a:

or a co-crystal, solvate, or combination thereof, with an oxidant, a base, and a solvent to provide a compound of formula 4a

4a

or a co-crystal, solvate, or combination thereof;

(b) combining the compound of formula 4a or a co-crystal, solvate, or combination thereof, with l,2-ethanedithiol, a solvent, and a catalyst, to provide a compound of formula 5i:

5i

or a co-crystal, solvate, or combination thereof; and

(c) hydrolyzing the compound of formula 5i or a co-crystal, solvate, or combination thereof, with an acid, a solvent, and a promoter, to provide the compound of formula 5e or a co- crystal, solvate, salt, or combination thereof.

416. The process of claim 415, wherein the oxidant used in step (a) is selected from the group consisting of isopentyl nitrite, «-butyl nitrite, tert-butyl nitrite, ethyl nitrite, sodium nitrite, potassium nitrite, nitrosyl chloride, nitrosyl sulfate, tetrafluorob orate, and hydrogen sulfate.

417. The process of claim 415 or 416, wherein the oxidant used in step (a) is tert-butyl nitrite.

418. The process of any one of claims 415-417, wherein the base used in step (a) is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, lithium tert- but oxide, sodium isopropoxide, sodium ethoxide, sodium methoxide, sodium hydride, lithium tetramethylpiperadide, lithium hexam ethyl di sil azi de, and phosphazenes.

419. The process of any one of claim s 415-418, wherein the base used in step (a) is potassium tert-butoxide.

420. The process of any one of claims 415-419, wherein the solvent used in step (a) is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl fert-butyl ether, cyclopentyl methyl ether, 2-methyltetrahydrofuran, l,4-dioxane, A Y-dimethylformamide, N,N- dimethylacetamide, /V-methylpyrrolidinone, dichloromethane, methanol, ethanol, isopropanol, sulfolane, and a combination thereof.

421. The process of any one of claims 415-420, wherein the solvent used in step (a) is tetrahydrofuran.

422. The process of any one of claims 415-421, wherein step (a) is carried out in the temperature range of from about -78 °C to about 70 °C.

423. The process of any one of claims 415-422, wherein step (a) is carried out in the temperature range of from about -10 °C to about 10 °C.

424. The process of any one of claims 415-423, wherein the catalyst used in step (b) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, para- toluenesulfonic acid monohydrate, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, iodine, l,3-dibromo-5,5-dimethylhydantoin, copper(II) dodecyl sulfate, ytterbium(III) triflate, yttrium(III) triflate, bismuth(III) triflate, bismuth(III) chloride, tungstophosphoric acid, perchloric acid, praseodymium triflate, hafnium(IV) triflate, iron(III) chloride, hydrogen chloride, p-dodecyl benzenesulfonic acid, BF3 OEt2, BF3 OMe2, BF3 THF, BF3 OBU2, BF3 MeOH, BF3 Me2S, BF3 PhOFI, and BF3 2FI20.

425. The process of any one of claims 415-424, wherein the catalyst used in step (b) is para- toluenesulfonic acid monohydrate.

426. The process of any one of claims 415-425, wherein the solvent used in step (b) is selected from the group consisting of diethyl ether, methyl fert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, benzene, xylenes, NN- dimethylform amide, AyV-dimethylacetamide, A'-methylpyrrolidinone, acetonitrile,

dichloromethane, dichloroethane, acetic acid, propionic acid, sulfolane, and a combination thereof

427. The process of any one of claims 415-426, wherein the solvent used in step (b) is acetic acid.

428. The process of any one of claims 415-427, wherein step (b) is carried out in the temperature range of from about 80 °C or less.

429. The process of any one of claims 415-428, wherein step (b) is carried out in the temperature range of from about 0 °C to about 80 °C.

430. The process of any one of claims 415-429, wherein the acid used in step (c) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid,

methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid monohydrate, trifluoroacetic acid, phosphoric acid, levulinic acid, glyoxylic acid, sodium bisulfite, sodium metabi sulfite, potassium bisulfite, and sodium dithionite.

431. The process of any one of claims 415-430, wherein the acid used in step (c) is para- toluenesulfonic acid monohydrate.

432. The process of any one of claims 415-431, wherein the solvent used in step (c) is selected from the group consisting of diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane, benzene, xylenesA^Y-dimethylformamide, N,N- di m ethyl acetami de, TZ-methylpyrrolidinone, acetonitrile, dichloromethane, dichloroethane, methyl ethyl ketone, acetone, methyl isobutyl ketone, formaldehyde/formalin, acetaldehyde, i sobuty ral dehy de, water, and a combination thereof.

433. The process of any one of claims 415-432, wherein the solvent used in step (c) is methyl ethyl ketone and water.

434. The process of any one of claims 415-433, wherein step (c) is carried out in the temperature range of from about 100 °C or less.

435. The process of any one of claims 415-434, wherein step (c) is carried out in the temperature range of from about 20 °C to about 100 °C.

436. A process for preparing a compound of formula 5a:

5a

or a co-crystal, solvate, or combination thereof, comprising combining a compound of formula 4e:

4e

or a co-crystal, solvate, salt, or combination thereof, with a catalyst, an acid, a base, a solvent, and optionally an additive to provide the compound of formul a 5a, or a co-crystal, solvate, or combination thereof,

wherein X1 is selected from the group consisting of tosyloxy, chloro, bromo, iodo, mesyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2,4,6-triisopropylbenzenesufonyloxy, acetoxy, trichloroacetoxy, and trifluoroacetoxy.

437. The process of claim 436, wherein X1 is tosyloxy.

438. The process of claim 436 or 437, wherein the catalyst is selected from the group consisting of (8a,95)-6'-methoxycinchonan-9-amine trihydrochloride, cinchona alkaloid derivatives, D- or L-phenylglycine, D- or L-cyclopentylglycine, D- or L-proline, 1- pheny 1 ethyl ami ne, 2-methylpyrrolidine, 2,5-dimethylpyrrolidine, and aldolase.

439. The process of any one of claims 436-438, wherein the catalyst is (8a,95)-6'- m ethoxy ci nchonan-9-ami ne trihydrochloride.

440. The process of any one of claims 436-439, wherein the acid is selected from the group consisting of acetic acid, trifluoroacetic acid, trichloroacetic acid, tartaric acid, camphorsulfonic acid, sulfuric acid, phosphonic acids, phosphoric acid, and triflic acid.

441. The process of any one of claims 436-440, wherein the acid is trifluoroacetic acid.

442. The process of any one of claims 436-441, wherein the base is selected from the group consisting of lithium acetate, sodium acetate, potassium acetate, lithium benzoate, sodium benzoate, lithium bicarbonate, lithium carbonate, sodium bicarbonate, sodium carbonate, lithium sulfate, sodium sulfate, sodium phosphates, potassium phosphate, imidazole, triethylamine, and DABCO.

443. The process of any one of claims 436-442, wherein the base is lithium acetate.

444. The process of any one of claims 436-443, wherein the solvent is selected from the group consisting of methanol, ethanol, 2-propanol, ethyl acetate, butyl acetate, isobutyl acetate, diethyl ether, methyl tert- butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, NN-d m ethyl form am i de, LnU-dimethylacetamide, A’-methylpyrrolidinone, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, acetonitrile, propionitrile, butyronitrile, water, and a combination thereof.

445. The process of any one of claims 436-444, wherein the solvent is 2- methyltetrahydrofuran and water.

446. The process of any one of claims 436-445, wherein the process is carried out in the temperature range of from about 120 °C or less.

447. The process of any one of claims 436-446, wherein the process is carried out at about 20 °C.

Description:
METHODS AND INTERMEDIATES FOR PREPARING A THERAPEUTIC COMPOUND USEFUL IN THE TREATMENT OF RETROVIRIDAE VIRAL INFECTION

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Provisional Application 62/710,575, filed on February 16, 2018, the entire content of which is hereby incorporated by reference in its entirety.

FIELD

[0002] The present disclosure relates to methods and intermediates for the synthesis of novel compounds for use in the treatment of a Retroviridae viral infection, including an infection caused by the HIV virus.

BACKGROUND

[0003] The present disclosure relates generally to the field of organic synthetic methodology for the preparation of antiviral compounds and their synthetic intermediates.

[0004] Positive-single stranded RNA viruses comprising the Retroviridae family include those of the subfamil y Orthoretrovirinae and genera A Ipharetrovirns, Betaretrovirus,

Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus , Lentivirus, and Spumavirus which cause many human and animal di seases. Among the Lentivirus , HIV-1 infection in humans leads to depletion of T helper cells and immune dysfunction, producing immunodefi ci ency and vulnerability to opportunistic infections. Treating HIV-1 infections with highly active antiretroviral therapies (HAART) has proven to be effective at reducing viral load and significantly delaying disease progression (Hammer, S.M., et al.; JAMA 2008, 300: 555-570). However, these treatments could lead to the emergence of HIV strains that are resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, R. J., et al., Science 2010, 327:697-701). Therefore, there is a pressing need to discover and synthesize new antiretroviral agents that are active against emerging drug-resistant HIV variants.

[0005] U.S. Patent Application No. 15/680,041 discloses novel compounds useful for treating a Retroviridae viral infection, including an infection caused by the HIV vims. One specific compound identified therein is a compound of formula I:

I

[0006] There is currently a need for improved synthetic methods and intermediates that can be used to prepare the compound of formula I and co-crystals, solvates, salts, and combinations thereof. There is also a need for improved methods for preparing intermediate compounds that can be used to prepare the compound of formula I and its co-crystals, solvates, salts, and combinations thereof. The improved methods and intermediates may reduce the cost, time, and/or the amount of waste associated with the existing methods for preparing the compound of formula I and co-crystals, solvates, salts, and combinations thereof.

SUMMARY

[0007] In some embodiments, the present disclosure provides a process for making a compound of formula I:

I

or a co-crystal, solvate, salt or combination thereof. The compound of formula I may also be named or identified as: N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluo roethyl)- 1 H-indazol-7-yl)-6-(3-methyl-3 -(methyl sulfonyl)but- 1 -yn- 1 -yl)pyridin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoro methyl)-3b,4,4a,5-tetrahydro-lH- cyclopropa[3,4]cyclopenta[l ,2-c]pyrazol-l-yl)acetamide.

[0008] In some embodiments, disclosed herein is a process for preparing a compound of formula I:

I or a co-crystal, solvate, salt, or combination thereof, comprising:

(a) combining a compound of formula VIII:

VIII or a co-crystal, solvate, salt, or combination thereof, with a compound of formula IX:

IX or a co-crystal, solvate, or combination thereof, under alkynylation conditions to provide the compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof;

(b) combining the compound of formula VI or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof, under amide coupling conditions to provide a compound of formula IV:

IV

or a co-crystal, solvate, salt, or combination thereof;

(c) combining the compound of formula IV or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V:

or a co-crystal, solvate, salt, or combination thereof, wherein R 1 is B(OH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-G)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 4 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0), under palladium-catalyzed cross-coupling conditions to provide a compound of formula III:

III or a co-crystal, solvate, salt, or combination thereof; and

(d) combining the compound of formula III or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent under mesylating conditions to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.

[0009] In some embodiments, provided herein are novel intermediates (e.g., intermediates of formulae II, III, IV, VI, and VIII, identified below) for the formati on of the compound of formula I or a co-crystal, solvate, salt, or combination thereof.

[0010] Accordingly, in one embodiment, a compound of formula II:

II or a co-crystal, solvate, salt, or combination thereof is provided.

[0011] In another embodiment, a compound of formula III:

or a co-crystal, solvate, salt, or combination thereof is provided.

[0012] In another embodiment, a compound of formula IV:

or a co-crystal, solvate, salt, or combination thereof is provided.

[0013] In another embodiment, a compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof is provided.

[0014] In another embodiment, a compound of formula VIII:

or a co-crystal, solvate, salt, or combination thereof is provided.

[0015] The synthetic routes and intermediates disclosed herein reduce the cost, time, and amount of waste associated with the preparation of the compound of formula I and its co- crystals, solvates, and salts, and combinations thereof. Additionally, the synthetic methods disclosed herein provide the compound of formula I in fewer steps (for example, carbamate protection and deprotection of amino groups is avoided) than in previous synthetic methods, and atropi somers are introduced later in the sequence than in previous synthetic methods.

[0016] Additional embodiments of the disclosure, including additional novel synthetic intermediates and methods for preparing such intermediates, are provided herein.

DETAILED DESCRIPTION

[0017] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0018] When trade names are used herein, it is intended to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.

[0019] As used herein and in the appended claims, the singular forms "a" and "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays, and so forth.

[0020] Isomers” are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers and diastereomers. [0021] “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.

[0022] “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a“racemic” mixture. A mixture of enantiomers at a ratio other than 1 : 1 is a“scalemic” mixture.

[0023] “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0024] The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (— ) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and/or hindered rotation about a bond axis and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present disclosure is meant to include all such possible isomers, including racemic mixtures, scalemic mixtures, diastereomeric mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0025] Except as expressly defined otherwise, the present disclosure includes all tautomers of compounds detailed herein, even if only one tautomer is expressly represented ( e.g ., both tautomeric form s are intended and described by the presentation of one tautomeric form where a pair of two tautomers may exist). For example, if reference is made to a compound containing an amide (e.g., by structure or chemical name), it is understood that the corresponding imidic acid tautomer is included by this disclosure and described the same as if the amide were expressly recited either alone or together with the imidic acid. Where more than two tautomers may exist, the present disclosure includes all such tautomers even if only a single tautomeric form is depicted by chemical name and/or structure.

[0026] Compounds described herein may have chiral centers and/or geometric isomeric centers (E- and Z- isomers), and it is to be understood that all such optical, enantiomeric, diastereoisomeric and geometric isomers are encompassed. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific di astereom eri cal 1 y or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein,“scalemic mixture” is a mixture of stereoisomers at a ratio other than 1 : 1.

[0027] The terms“amine transaminase” and“AT A” as used herein refer to a polypeptide having an enzymatic capability of exchanging an amino group of a donor amine with a carbonyl group of an acceptor molecule. The transamination reaction is carried out in presence of pyridoxal-phosphate (PLP), which acts as a cofactor. In transamination reactions using transaminase enzymes, the amine group of the amino donor is transferred to the coenzyme to produce a ketone as a by-product, while pyridoxal-5 '-phosphate is converted to pyridoxamine phosphate. The transfer of the amine group from pyridoxamine phosphate to the ketone substrate produces a chiral amine and regenerates the coenzyme. S-selective transaminases include, but are not limited to ATA-l, ATA-2, ATA-007, ATA-013, ATA-025, ATA-l 13, ATA- 1 17, ATA-200, ATA-217, ATA-234, ATA-237, ATA-238, ATA-251, ATA-254, ATA-256, ATA-260, ATA-301, ATA-303, ATA-412, ATA-415, ATA-P1-B04, ATA-P1-F03, ATA-P1- G05, ATA-P2-A01, ATA-P2-A07, ATA-P2-B01 , and mixtures thereof.

[0028] The term“asymmetric catalyst” as used herein refers to a catalyst that promotes the enantioselective and/or diastereoselective transformation of an achiral center or molecule into a chiral center or molecule, respectively. For example, an asymmetric catalyst may generate an enantiomeric excess of a product. Exemplary asymmetric catalysts comprise a transition metal and a chiral ligand. Non-limiting examples of chiral ligands include B IN AP/ SEGPHO S ® , salens, bisoxazolines, tartrate ligands, cinchona alkaloids, DuPhos phospholanes, BPE phospholanes, DSM phosphoramidites, Solvias® Josiphos families, phosphine-oxazolines, the Reetz and Trost ligands, and Chiral Quest phosphines.

[0029] Also provided are pharmaceutically acceptable hydrates, solvates, co-crystals, tautom eric form s, polymorphs, and prodrugs of the compounds described herein.

[0030] The term“hydrate” refers to the complex formed by the combining of a compound of Formula I, or any Formula disclosed herein, and water.

[0031] The term“solvate” refers to a complex formed by the combining of a compound of Formula I, or any other Formula as disclosed herein, and a solvent or a crystalline solid containing amounts of a solvent incorporated within the crystal structure. As used herein, the term“solvate” includes hydrates. [0032] The term“co-crystal” refers to a crystalline material formed by combining a compound of Formula I, or any Formul a discl osed herein and one or more co-crystal formers (i.e., a molecule, ion or atom). In certain instances, co-crystals may have improved properties as compared to the parent form (i.e., the free molecule, zwitterion, etc.) or a salt of the parent compound. Improved properties can be increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, a crystalline form of a normally amorphous compound, a crystalline form of a difficult to salt or unsal table compound, decreased form diversity, more desired morphology, and the like. Methods for making and characterizing co-crystals are known to those of skill in the art.

[0033] Any formula or structure given herein, including Formula I, or any Formula disclosed herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to Ή (deuterium, D), FI (tritium), C, C, C, N, F, 31 P, 3 P, 35 S, 36 C1 and 125 I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as Ή, l C and 14 C are incorporated. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0034] The disclosure also includes compounds of Formula I, or any Formula disclosed herein, in which from 1 to“n” hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal. See, for example, Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0035] Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent in the compound of the Formula I, or any Formul a disclosed herein.

[0036] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as Ή" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium .

[0037] The modifier“about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context ( e.g ., includes the degree of error associated with measurement of the particular quantity).

[0038] The term“chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, and the term“achiral” refers to molecules which are superimposable on their mirror image partner.

[0039] “Alkyl” is a straight or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 8 carbon atoms (i.e., (Ci-C 8 )alkyl) or 1 to 6 carbon atoms (i.e., (Ci-C fi alkyl) or 1 to 4 carbon atoms (i.e., (Ci-C 4 )alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, - CH 2 CH 2 CH 3 ), 2-propyl (i.-Pr, i-propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ),

2 -m ethyl- 1 -propyl (i-Bu, i -butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2- methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1 -pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3 -pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ),

3 -methyl -2 -butyl (-CH(CH 3 )CH(CFI 3 ) 2 ), 3 -methyl -1 -butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-l- butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1 -hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl

(-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3 -hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3 -methyl -2-pentyl (-CH(CH 3 )CH(CH3)CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3 -methyl-3 -pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (- CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3 -dimethyl -2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3, 3 -dimethyl -2-butyl (- CH(CH 3 )C(CH 3 ) 3 , and octyl (-(CH 2 ) 7 CH 3 )

[0040] “Alkenyl” is a straight or branched hydrocarbon with at least one carbon -carbon, sp 2 double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2 -C 8 alkenyl), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ) and 5-hexenyl

(-CH 2 CH 2 CH 2 CH 2 CH=CH 2 ).

[0041] Alkynyl” is a straight or branched hydrocarbon with at least one carbon-carbon, sp triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C 2 -C 8 alkyne,) or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-CººCH), propargyl (-CH 2 CººCH), and the like.

[0042] The term“halo” or“halogen” as used herein refers to fluoro, chloro, bromo and iodo.

[0043] The term“haloalkyl” as used herein refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are each independently replaced by a halo substituent. For example, (Ci-C 6 )haloalkyl is a (Ci-C 6 )alkyl wherein one or more of the hydrogen atoms of the (Ci-C 6 )alkyl have been replaced by a halo substituent. Examples of haloalkyls include but are not limited to fluoromethyl, fluorochlorom ethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1, 1, 1, trifluoroethyl and pentafluoroethyl.

[0044] The term“aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. It is also to be understood that when reference is made to a certain atom -range membered aryl (e.g., 6-12 membered aryl), the atom range is for the total ring atoms of the aryl. For example, a 6- membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1, 2,

3, 4-tetrahydronaphthyl . Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

[0045] The term“heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur;“heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus,“heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example 1,8- naphthyridinyl), heterocycles, (to form for example l,2,3,4-tetrahydro-l,8-naphthyridinyl), carbocycles (to form for example 5,6,7, 8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1 , 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system. It is also to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). It also to be understood that when a reference is made to a certain atom-range membered heteroaryl (e.g., a 5-14 membered heteroaryl), the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5- membered heteroaryl would include a thiazolyl and a 10-membered heteroaryl would include a quinolinyl. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrol o [2, 3 -b ] pyri di nyl , quinazolinyl-4(3H)-one, triazolyl, 4,5,6, 7-tetrahydro- lH-indazole and 3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyra zole.

[0046] The term“heterocyclyl” or“heterocycle” as used herein refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially un saturated ring, which multiple condensed ring systems are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term“heterocycle” also includes multiple condensed ring systems (e.g., ring systems compri sing 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from heterocycles (to form for example a 1 ,8- decahydronapthyridinyl ), carbocycles (to form for example a decahydroquinolyl) and aryls to form the multiple condensed ring system. Thus, a heterocycle (a single saturated or single partially unsaturated ring or multiple condensed ring system) has about 2-20 carbon atoms and 1-6 heteroatoms within the heterocycle ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the multipl e condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a

heterocycle, aryl and carbocycle portion of the ring. It is also to be understood that the point of attachment for a heterocycle or heterocycle multiple condensed ring system can be at any suitable atom of the heterocycle or heterocycle multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). It is also to be understood that when reference is made to a certain atom-range membered heterocycle (e.g., a 3-14 membered heterocycle), the atom range is for the total ring atoms of the heterocycle and includes carbon atom s and heteroatoms. For example, a 3 -membered heterocycle would include an aziridinyl and a 10- membered heterocycle would include a 1,2, 3, 4- tetrahydroquinolyl . Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahy drofuranyl , dihydrooxazolyl,

tetrahydropyranyl, tetrahydrothi opyrany 1 , 1 ,2,3,4- tetrahydroquinolyl, benzoxazinyl,

dihydrooxazolyl, chromanyl, l,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, l,3-benzodioxolyl, 1 ,4-benzodioxanyl, spiro[cyclopropane- 1 , 1 '-isoindolinyl]-3'-one, isoindolinyl-l-one, 2-oxa-6- azaspiro[3.3]heptanyl, imidazolidin-2-one and pyrrolidin-2-one.

[0047] The term“cycloalkyl” refers to a cyclic alkyl and alkenyl groups. A cycloalkyl group can have one or more cyclic rings and includes fused and bridged groups that are fully saturated or partially unsaturated. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcycloproyl (cy clopropy 1 m ethyl), ethyl cy cl opropyl , cyclohexenyl and the like.

[0048] The term“fused” refers to a ring which is bound to an adjacent ring.

[0049] “Bridged” refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as an alkylenyl or heteroalkyl enyl group or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

[0050] “Spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1 , 1 -diethyl cyclopentane, dimethyl -dioxolane, and 4- benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.

[0051] The term“azido” refers to a group

[0052] The term“keto” or“oxo” refers to a group =0.

[0053] The term“carboxyl” refers to a group -C(0)-OH.

[0054] The term“hydroxy” or“hydroxyl” refers to a group -OH.

[0055] The term“amine protecting group” is well understood by the person skilled in synthetic organic chemistry as a moiety that can be selectively installed onto and removed from, and masks or alters the properties of, a suitable amine functional group. The field of protecting group methodology is advanced, and many amine protecting groups, and methods for using them, are well known in the art, such as those described in the authoritative treatise on the subject, P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis , 4 th Edition (Wiley, 2006).

[0056] The term“borylation agent” also is well understood in the field of organic synthesis as a reagent that is useful for installing any one of a wide range of boronate moieties onto a suitable substrate to provide an organoboron reagent. Non-limiting examples of boryl ation agents and related synthetic methodology are set forth in T. Ishiyama et al, J Org. Ghent. 1995, 60, 7508-7510 and N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483.

[0057] As used herein, the term“alkynylation conditions” refers to the reaction conditions under which a terminal alkyne is coupled to another compound (e.g., a suitable aryl or heteroaryl halide substrate) in the presence of a catalyst, solvent, and optionally a base, to form an alkyne (e.g., an internal alkyne). Non-limiting examples of catalysts for“alkynylation conditions” include palladium catalysts such as [(7t-allyl)PdCl] 2 , Pd(acac) 2 , (SIPr)PdCl 2 , PdCl 2 (PPh 3 ) 2 ,

PdCl 2 , Pd(OAc) 2 , PdCl 2 (CH 3 CN) 2 , Pd 2 (dba) 3 , and the like, in combination with a tertiary phosphine, e.g., triphenylphosphine, tri-cyclohexylphosphine, tri-fcrt-butylphosphine, 1,2- bi s(diphenylphosphino)ethane, 1 , 3 -bi s(di phenyl phosphino)propane, and 1,1’- bis(diphenylphosphino)ferrocene), such as dichlorobis(triphenylphosphine)palladium(II); copper catalysts such as copper(I) iodide, copper(I) bromide, copper(I) chloride, and the like; and combinations thereof. In some embodiments, the catalyst is PdCl 2 (PPh 3 ) 2.

[0058] The“alkynylation conditions” as disclosed herein typically comprise a base. Non limiting examples of the base include amines (e.g., tri ethyl amine, diisopropylamine,

ethyl diisopropylamine, pyrrolidine, l,4-diazabicylo[2.2.2]-octane, l,8-diazabicyclo[5.4.0]undec- 7-ene, l,5-diazabicyclo-4.3.0]non-5-ene, pyridine, piperidine, etc.), carbonates (e.g., cesium carbonate, potassium carbonate, etc ), phosphates (e.g., potassium phosphate, etc ), and tetra alkyl ammonium salts (e.g., tetrabutyl ammonium fluoride), and the like. In some embodiments, the base is triethylamine.

[0059] The alkynylation conditions further comprise a solvent. Non-limiting examples of the solvent include ethers (e.g., diethyl ether, methyl tert-buiy\ ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane, etc.), aromatic solvents (e.g., benzene, xylenes, etc.), polar protic solvents (e.g., A(A ? -dimethylformamide, NN-d\ m ethyl acetami de, iV-methylpyrrolidinone, etc.), water, and combinations thereof. In some embodiments, the solvent is 2- methyltetrahydrofuran .

[0060] In some embodiments, the alkynylation conditions comprise a temperature range of about 120 °C or less. In some embodiments, the alkynylation conditions comprise a temperature range of from about 0 °C to about 120 °C. In certain embodiments, the alkynylation conditions comprise a temperature range of from about 50 °C to about 80 °C.

[0061] The term“amide coupling conditions” refers to the reaction conditions under which an amine and a carboxylic acid couple to form an amide, using a coupling reagent and, optionally, a coupling additive, in the presence of a base. Non-limiting examples of coupling reagents include n-propyl phosphonic anhydride, oxalyl chloride, thionyl chloride,

dicyclohexylcarbodiimide, di i sopropyl carb odi i mi de, 1 -ethyl-3 -(3- dimethylaminopropyl)carbodiimide (EDC), carbonyl diimidazole, isobutyl chloroformate, 2-(7- aza-lH-benzotri azole- 1 -yl)- 1 , 1,3,3 -tetram ethyl uronium hexafluorophosphate, O-benzotriazole- N,N,N’,N’-tetramethyluronium-hexafluoro-phosphate, 0-(7-azabenzotri azole-1 -yl)-N,N,N',N'- tetramethyluronium tetrafl uorob orate, 0-(benzotriazol- 1 -yl)-N,N,N’ ,N’ -tetramethyluronium tetrafluorob orate, 0-(6-chlorobenzotri azol- 1 -yl)-N,N,N’ ,N’ -tetram ethyl uronium

hexafluorophosphate, (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium

hexafluorophosphate, (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate, (l-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morph olino-carbenium

hexafluorophosphate, and the like. In some embodiments, the coupling reagent is n-propyl phosphonic anhydride. Non-limiting examples of coupling additives include 4- (di m ethyl am ino)py ri di ne, 1 -hydroxybenzotri azole, l-hydroxy-7-azabenzotri azole, and the like.

[0062] Non-limiting examples of the base used for the“amide coupling condi tion s” include aliphatic amines (e.g., triethylamine, tributylamine, ethyldiisopropylamine, N- methylmorpholine, etc.), aromatic amines (e.g., pyridine, 2,6-lutidine, /V-rn ethyl i iri i dazoi e, etc.), and the like. In some embodiments, the base is triethylamine.

[0063] The amide coupling conditions further comprise a solvent. Non-limiting examples of the solvent include nitriles (e.g., propionitrile, butyronitrile, acetonitrile, etc.), esters (e.g., ethyl acetate, butyl acetate, isobutyl acetate, etc.), ethers (e.g., diethyl ether, methyl te/7-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), aromatic hydrocarbon solevents (e.g., toluene, benzene, xylenes, etc.), polar aprotic solvents (e.g., AyV-dimethylformamide,

A, A ; -di m ethyl acetami de, iV-methylpyrrolidinone, dimethyl sul foxi de, etc.), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform, etc.), and combinations thereof. In some embodiments, the solvent is acetonitrile.

[0064] In some embodiments, the amide coupling conditions comprise a temperature range of from about 120 °C or less. In some embodiments, the amide coupling conditions comprise a temperature range of from about -20 °C to about 120 °C. In certain embodiments, the amide coupling conditions comprise a temperature range of from about 0 °C to about 40 °C.

[0065] As used herein, the term“palladium-catalyzed cross-coupling conditions” refers to the reaction conditions under which an aryl halide or an aryl sulfonate (e.g., a triflate, mesylate, tosylate) couples with an organoboron reagent to form a compound, such as a biaryl compound, in the presence of a palladium catalyst and a base. In some embodiments, the organoboron reagent is aryl-R’, wherein R’ is B(OH) 2 , B(OR) 2 wherein R is unsubstituted or substituted alkyl, BF 4 K, and the like. Non-limiting examples of organoboron reagents include aryl boronic acids (aryl-B(OH) 2 ), arylboronic esters (e.g., aryl-B(OR) , e.g., aryl-B(0C(Me) 2 C(Me) 2 0), aryl-B(0CH(Me)CH 2 C(Me) 2 0), aryl-B((l,2-di-0)C 6 H 4 ), and aryl-B(0CH 2 C(Me) 2 CH 2 0)), and aryl trifluoroborate salts (e.g. , aryl-BF 3 K). In some embodiments, the organoboron reagent is aryl-B (OC (Me) 2 C (M e) 2 O) .

[0066] In some embodiments, non-limiting examples of palladium catalysts for the “palladium-catalyzed cross-coupling conditions” include

dichlorobis(tricyclohexylphosphine)palladium(II), bis(di-/er/-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine]palladium(II) chloride,

dichlorobis(triphenylphosphine)palladium(II), [ 1 , G - bi s(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2- bis(diphenylphosphino)ethane]dichloropalladium(II), dichloro[9, 9-dimethyl -4,5- bis(diphenyiphosphino)xanthene]palladium(II), palladium(II) precatalyst (palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or palladium(O) precatalyst (tetrakis(triphenylphosphine)palladium(O), bis(dibenzylideneacetone)palladium(0), in combination with a phosphine ligand such as tricyclohexylphosphine, triphenylphosphine, cyclohexyl diphenylphosphine, dicyclohexylphenylphosphine, and the like. In some

embodiments, the palladium catalyst is dichl orobi s(tricyclohexylphosphine)pal 1 adium(II) .

[0067] In some embodiments, non-limiting examples of the base for the“palladium- catalyzed cross-coupling conditions” include carbonates (e.g., potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), inorganic bases (e.g., potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, etc.), aliphatic amines (e.g., dicyclohexylamine, N- methylmorpholine, triethylamine, etc.), and the like. In some embodiments, the base is potassium bicarbonate. [0068] In some embodiments, the“palladium-catalyzed cross-coupling conditions” further comprise a sol vent. In some embodiments, non-limiting examples of the sol vent include ethers (e.g., diethyl ether, 1 ,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, etc.), aromatic hydrocarbon solvents (e.g., toluene, xylenes, etc.), esters (ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, etc), alcohols (ethanol, isopropanol, etc), polar aprotic solvents (NN- dimethylformamide, AvV-dimethylacetamide, Y-methyl-2-pyrrolidine, etc), water, and combinations thereof. In some embodiments, the solvent is a mixture of n-butyl acetate and water.

[0069] In some embodiments, the palladium-catalyzed cross-coupling conditions comprise a temperature range of from 120 °C or less. In some embodiments, the palladium-catalyzed cross coupling conditions comprise a temperature range of from about 20 °C to about 120 °C. In some embodiments, the pal 1 adium-catalyzed cross-coupling conditions comprise a temperature range of from about 75 °C to about 95 °C.

[0070] As used herein, the term“mesylating reagent” refers to a reagent used to install a mesyl, or methanesulfonyl (/.<?., CH3SO2 ), group onto a suitable hydroxy group or a suitable amino group. In some embodiments, non-limiting examples of mesylating reagents include methanesulfonyl chloride, methanesulfonic anhydride, and methanesulfonic acid in combination with an activating agent such as oxalyl chloride, thionyl chloride, or cyanuric chloride. In some embodiments, the mesylating reagent is methanesulfonic anhydride. In some embodiments, the mesylating reagent is methanesulfonyl chloride.

[0071] As used, herein the term“mesylation conditions” refers to the reaction conditions under which a mesyl, or methanesulfonyl (i.e., CH 3 S0 2 ), group is installed onto a suitable hydroxy group or a suitable amino group. When installing a methanesulfonyl group onto a suitable hydroxy group, the mesylation conditions as disclosed herein typically comprise a base, a catalyst and a solvent.

[0072] In some embodiments, when installing a methanesulfonyl group onto a suitable hydroxy group, non-limiting examples of the base for the mesylation conditions include aliphatic amines (e.g., triethylamine, diisopropyl ethylamine, /V.A-dicyclohexylmethylamine, etc.) and aromatic amines (e.g., pyridine, 2,3,5-collidine, 2,4,6-collidine, iV-methylimidazole, etc.). In some embodiments, the base is triethylamine.

[0073] In some embodiments, when installing a methanesulfonyl group onto a suitable hydroxy group, non-limiting examples of suitable catalysts for the“mesylation conditions” include 4-dimethylaminopyridine (DMAP), and the like. [0074] In some embodiments, when installing a methanesulfonyl group onto a suitable hydroxy group, non-limiting examples of solvents for the mesylation conditions include ethers ( e.g ., diethyl ether, 1 ,4-dioxane, cyclopentyl methyl ether, tetrahydrofuran, 2- m ethyl tetrahydrofuran, dimethoxyethane, etc), aromatic hydrocarbon solvents (e.g., toluene, xylenes, etc), esters (e.g., ethyl acetate, isopropyl acetate, isobutyl acetate, etc), chlorinated solvents (e.g., di chi orom ethane, chloroform, dichloroethane, etc), nitriles (e.g., acetonitrile, etc), polar aprotic solvents (e.g, N /V-dimethylformamide, /VW-dimethylacetamide, and N- methylpyrrolidinone, etc), and combinations thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is tetrahydrofuran and the catalyst is DMAP.

[0075] In some embodiments, when installing a methanesulfonyl group onto a suitable hydroxy group, the mesylating conditions comprise a temperature range of from about 60 °C or less. In some embodiments, the mesylating conditions comprise a temperature range of from about 80 °C to about 60 °C. In some embodiments, the mesylating conditions comprise a temperature range of from about 0 °C to about 40 °C.

[0076] When installing a methanesulfonyl group onto a suitable amino group, the mesylation conditions as disclosed herein typically comprise a solvent, and optionally, a base.

[0077] In some embodiments, when installing a methanesulfonyl group onto a suitable amino group, non-limiting examples of the base for the mesylation conditions include alkyl amines (e.g., triethylamine, /V-methylmorpholine, tri -n-propyl ami ne, ethyl di i sopropyl ami ne, tri- n-butylamine, etc), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, etc), carbonates (e.g, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, inorganic bases (e.g., sodium phosphate monobasic, sodium phosphate dibasic, potassium phosphate monobasic, potassium phosphate dibasic, etc), and alkoxide bases (e.g., sodium tert-amylate, sodium tert-butoxide, etc). In some embodiments, the base is triethylamine.

[0078] In some embodiments, when installing a methanesulfonyl group onto a suitable amino group, non-limiting examples of solvents for the mesylation conditions include ethers (e.g., diethyl ether, 1,4-dioxane, cyclopentyl methyl ether, tetrahydrofuran, 2- m ethyl tetrahydrofuran, dimethoxyethane, etc), aromatic hydrocarbon solvents (e.g., toluene, xylenes, etc), esters (e.g., ethyl acetate, isopropyl acetate, isobutyl acetate, etc), chlorinated solvents (e.g., di chi orom ethane, chloroform, dichloroethane, etc), nitriles (e.g., acetonitrile, etc.), polar aprotic solvents (e.g., A^/V-dimethylformamide, /VW-dimethylacetamide, N- methylpyrrolidinone, etc), and combinations thereof. In some embodiments, the solvent is 2- m ethyl tetrahydrofuran . In some embodiments, the solvent is cyclopentyl methyl ether.

[0079] In some embodiments, when installing a methanesulfonyl group onto a suitable amino group, the mesylating conditions comprise a temperature range of from about 100 °C or less. In some embodiments, the mesylating conditions comprise a temperature range of from about -20 °C to about 100 °C. In some embodiments, the mesylating conditions comprise a temperature range of from about 10 °C to about 20 °C. In some embodiments, the mesylating conditions comprise a temperature range of from about 20 °C to about 120 °C. In some embodiments, the mesylating conditions comprise a temperature range of from about 70 °C to about 90 °C.

[0080] The term“borylation conditions” refers to the reaction conditions under which a compound such as an aryl halide is converted into an organoboron reagent ( e.g ., an arylboron derivative such as compound of formula V). The borylation conditions as disclosed herein typically compri se a borylation agent and either an organometallic reagent or a catalyst. When the borylation conditions comprise a borylation agent and an organometallic reagent, non limiting examples of borylation agents include trimethyl borate, tri ethyl borate, pinacolborane, 2-methoxy-4,4,5,5-tetramethyl-l,3,2-dioxaboralane, B-catecholborane, 2-bromo-l,3,2- b enzodi oxab orol e, and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. In some embodiments, the borylation agent is 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane or i sopropoxyb oroni c acid pinacol ester. Non-limiting examples of organometallic reagents include lithium metal, magnesium metal, n-butyllithium, s-butyl m agnesium chloride lithium chloride complex, tert-butylmagnesium chloride, i sopropylmagnesium chloride lithium chloride complex, and i sopropylmagnesium chloride. In some embodiments, the organometallic reagent is i sopropylmagnesium chloride. In some embodiments, the organometallic reagent is i sopropylmagnesium chloride lithium chloride complex.

[0081] In some embodiments, the borylation conditions further comprise a solvent. Non limiting examples of solvents include ethers (e.g, diethyl ether, l,4-dioxane, 2- m ethyl tetrahydrofuran, dimethoxyethane, etc), hydrocarbons (e.g., n-hexane, n-heptane, etc.), aromatic hydrocarbons (e.g., toluene, xylenes, etc.), and combinations thereof. In some embodiments, the solvent is tetrahydrofuran.

[0082] In some embodiments, the borylation conditions comprise a temperature range of from about 40 °C or less. In some embodiments, the borylation conditions comprise a temperature range of from about -80 °C to about 40 °C. In some embodiments, the borylation conditions comprise a temperature range of from about -40 °C to about 20 °C. In some embodiments, the borylation conditions compri se a temperature range of from about -20 °C to about 20 °C.

[0083] In some embodiments, when the borylation conditions comprise a borylation agent and a catalyst, non-limiting examples of borylation agents include bis(neopentyl

glycolato)diboron, tetrahy droxy dib or on, bis(hexylene glycolato)diboron, and

bi s(pi nacol ato)dib oron . In some embodiments, the borylation reagent is bis(pinacolato)diboron. Non-limiting examples of catalysts include bis(di-/er/-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine]palladium(II) chloride,

dichlorobis(triphenylphosphine)palladium(II), and [ 1 , G - bi s(di phenylphosphino)ferrocene] dichl oropal 1 adium(II). In one embodiment, the catalyst is

[0084] In some embodiments, non limiting examples of solvents for the borylation conditions include ethers (e.g., diethyl ether, methyl /<?r/-butyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.), polar aprotic solvents (A,A-dimethylacetamide, A,A- dimethylform amide, A-methylpyrrolidinone, etc.), aromatic hydrocarbon solvents (e.g., benzene, toluene, xylenes, etc.), chlorinated solvents (dichloromethane, etc.), alcohols (e.g., methanol, ethanol, isopropanol, etc ), esters (e.g., ethyl acetate, isopropyl acetate, etc.), and combinations thereof. In some embodiments, the solvent is a mixute of dioxane and A,A-dimethylformamide.

[0085] In some embodiments, the borylation conditions comprise a temperature range of from about 130 °C or less. In some embodiments, the borylation conditions comprise a temperature range of from about 10 °C to about 130 °C. In some embodiments, the alkynylation conditions comprise a temperature range of from about 80 °C to about 1 10 °C.

[0086] In addition, abbreviations as used herein have respective meanings as follows:

ACN or MeCN acetonitrile

acac acetyl acetonate

AcOH or HO Ac acetic acid

Ac O acetic anhydride

aq. aqueous

ATA amine transaminase

BEMP 2-fer/-butylimino-2-diethylamino- 1,3- Ό-

BINAP (1, 1 '-binaphthalene-2, 2'-diyl)bis(diphenylphosphine) Bn

Boc or BOC tert-b utoxy carb ony 1

BOP (b enzotri azol - 1 -yl oxy)tris(di m ethyl am in o)phosphoni uni hexaf!uorophosphate

BPD bis(pinacolato)diboron

Bu butyl

n-BuOAc «-butyl acetate

CBS Corey-Bakshi-Shibata (oxazaborolidine)

CDI carbonyl diimidazole

cod 1.5 -cy cl ooctadi ene

COMU or COMU ® (l-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate

cyclopentyl methyl ether

Cy cyclohexyl

DAB CO 1.4-diazabicyclo[2.2.2]octane

dba dib enzyli deneacetone

DBDMH 1 ,3 -dibromo-5 , 5 -dimethylhydantoin

DBMP 3,6-dibromo-2-methylpyridine

DBN 1.5-diazabicyclo[4.3.0]non-5-ene

2,5-DBP 2.5 -dibromopyridine

DBU l,8-diazabicyclo[5.4.0]undec-7-ene

DCC NN-d\ cy cl ohexyl carb odiimide

DCE dichloroethane

DCM di chi orom ethane

dd doublet of doublets

ddd doublet of doublet of doublets

dddd doublet of doublet of doublets of doublets

DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone

DFBZ (3,5-difluorobenzyl)zinc(II)bromide

DIC Ay/V-dii sopropyl carbodiimi de

iV,iV-diisopropyl ethyl amine

DMAC AC'V-dimethyl acetamide

DMAP 4-(dimethylamino)pyridine

DMF dimethylformamide

DMS dimethyl sulfide

DMSO dimethylsulfoxide

DPEN 1 ,2-di phenyl ethyl enedi amine I, -bi s(diphenylphosphino)ferrocene

DuPhos l-[2-(2,5-dialkylphospholan-l-yl)phenyl]-2,5- dq doublet of quartets

dt doublet of triplets

EDC 1 -ethyl -3 -(3 -dimethyl aminopropyl) carbodiimide

EDO 1 -ethyl -3 -(3 -dimethyl aminopropyl) carbodiimide

EDTA ethyl enedi aminetetraac eti c aci d

EHA

Et ethyl

Et 3 N triethylamine

EtOAc ethyl acetate

EtOH ethanol

h hour(s)

HATH 2-(7-aza- 1 H-benzotri azole- 1 -yl)- 1 , 1 ,3,3 -tetram ethyl uronium hexafluorophosphate

HBTU 0-benzotriazole-N,N,N’,N’-tetramethyluronium-hexafluoro- phosphate

HCTU 0-(6-chlorobenzotriazol- 1 -yl)-N,N,N’ , N’ - tetram ethyluronium hexafl uorophosphate

HOAt 1 -hydroxy-7-azabenzotriazol e

1 -hydroxybenzotri azole

HOSA hydroxylamine-O-sulfonic acid

HPLC high pressure liquid chromatography

Hz hertz

1PA isopropyl alcohol

iPAc isopropyl acetate

J coupling constant

Josiphos a [2-(diphenylphosphino)ferrocenyl]ethyl dialkyl or

diarylphosphine

KHMDS potassium hexamethyldisilazane

lithium diisopropylamide

lithium hexamethyldisilazane

LiHMDS lithium hexamethyldisilazane

m multiple†

M Molar

MTBE methvl tert- butvl ether mCPBA 3-chloroperbenzoic acid

Me methyl

MeOH methanol

MeCN acetonitrile

MeTHF 2-m ethyltetrahydrofuran

MHz megahertz

min. minute(s)

mmol millimole

niL milliliter

mol mole

MP Melting point

MS mass spectroscopy

MM SB 3 -methyl -3 -(methyl sulfonyl )but- 1 -yne

Monophos a (2,6-dimethyl-3,5-dioxa-4-phospha-cyclohepta[2, l-a;3,4- a']dinaphthalen-4-yl)dialkylamine

Ms mesyl or methanesulfonyl

MsO or OMs mesylate or methanesulfonate

MsOH methanesulfonic acid

MTBE ethyl -/tr /-butyl ether

m/z Mass to charge

NaHMDS sodium hexamethyldisilazane

NCS N-chlorosuccinimide

N1S N-iodosuccinimide

NLT no later than

NMM N-methylmorpholine

NMP N-methylpyrrolidine

NMR nuclear magnetic resonance

NMT not more than

OAc acetate

Ph phenyl

PhMe toluene

PhOH phenol

PMB methoxyb enzyl

PPA polyphosphoric acid

PPh 3 triphenylphosphine

ppm parts per million Pr propyl

py pyridine

PyBOP (benzotri azoi- 1 -yloxy)tripyrrolidinophosphonium

hexafluorophosphate

pyr pyridine

q quartet

qNMR quantitative nuclear magnetic resonance

RT room temperature

(A)-RuCY-XylBINAP RuCl[(/?)-daipena][(i?)-xylbinap] or [l-[2-bis(3,5- or (i?)-RuCY ® - dimethylphenyl)phosphanylnaphthalen- 1 -yl ] naphthal en-2- Xy!BINAP yl]-bis(3 , 5 -dimethylphenyl)phosphan e; (2R)-l, l -bis(4- methoxyphenyl)-3 -methylbutane- 1 ,2-diamine;

ruthenium(l+) chloride

s singlet

segphos (+)-5,5'-bis(diphenylphosphino)-4,4'-bi-l,3-henzodioxole

SIPr l,3-bis(2,6-diisopropylphenyl)-2-imidazolidinylidene

SMB simulated moving bed

SMPS (5)-(-)-2-methyl-2-propanesulfmamide

t triplet

T3P propylphosphonic anhydride or propanephosphoni c acid anhydride

TATU 0-(7-azabenzotri azole- l -yl)-N,N,N',N'-tetramethyluronium tetrafluorob orate

TBTU 0-(benzotri azol- 1 -yl)-N,N,N’ ,N’ -tetramethyluronium tetrafluorob orate

td Triplet of doublets

TEA triethylamine

TEMPO 2,2,6,6-tetramethyl-l -piperidinyloxy, free radical

TFA trifluoroacetic acid

Tf triflyl or trifluoromethanesulfonyl

TfO or OTf triflate or trifluoromethanesulfonate

TfOH triflic acid or trifluoromethanesulfonic acid

2,2,6,6-tetramethylpiperidinyl

triphenylphosphine

Ts tosyl or -toluenesulfonyl

TsO or OTs tosylate or -toluenesulfonate TsOH or ?-TsOH -toluenesulfonic acid

tt

UPLC ultra performance liquid chromatography

[0087] Except as otherwise noted, the methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, 5 th edition, New York: Oxford University Press, 2009; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th edition, Wi 1 ey-Interscience, 2013.

[0088] In certain instances, the processes disclosed herein involve a step of forming a salt of a compound of the present disclosure.

[0089] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, supercritical fluid chromatography (SFC), and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2 nd ed., ed. L. R Snyder and J. J Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed ), Springer- Verlag, New York, 1969.

[0090] During any of the processes for preparation of the subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4 ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0091] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. One of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. In some embodiments, each of the reactions depicted in the general schemes is run at a temperature from about -80 °C to the reflux temperature of the organic solvent used. [0092] The compounds disclosed herein may display atropisomerism resulting from steric hindrance affecting the axial rotation rate around a single bond. The resultant conformational isomers may each be observed as distinct entities by characterization techniques such as NMR and HPLC. The compounds disclosed herein may exist as a mixture of atropi somers. However, the detection of atropi somers is dependent on factors such as temperature, solvent, conditions of purification, and timescale of spectroscopic technique. The interconversion rate at room temperature has a half-life of minutes to hours, hours to days, or days to years. The ratio of atropi somers at equilibrium may not be unity. Characterization data presented herein may not represent the equilibrium state depending on the conditions of i solation and characterization which may include but not limited to handling, solvents used, and temperature.

[0093] The present disclosure provides in some embodiments processes and intermediates for preparing the compound of formula I and co-crystals, solvates, salts and combinations thereof. In other embodiments, the disclosure provides processes for preparing intermediates that can be used to prepare the compound of formula I and co-crystals, solvates, salts and combinations thereof.

[0094] In some embodiments, a process for preparing a compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula VIII:

or a co-crystal, solvate, salt, or combination thereof, with a compound of formula IX:

IX or a co-crystal, solvate, or combination thereof, a base, a solvent, and a catalyst, to provide the compound of formula VI or a co-crystal, solvate, salt, or combination thereof.

[0095] In certain embodiments, the compound of formula VIII is a compound of formula VHI-02:

VIII-02 or a co-crystal, solvate, or combination thereof, wherein HX is a chiral or achiral acid.

[0096] In particular embodiments, HX is selected from the group consisting of L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1 R, 35)-(+)-camphoric acid, (l5)-(+)-camphor-l0-sulfonic acid, (R)-(+)-V-(l- phenyl ethy 1 ) succi nam i c acid, carb ob enzyl oxy-L-proli ne, di b enzoyl -L-tartari c acid, (R)-(+)~ 3- methyladipic acid, (+)-m enthyl oxy aceti c acid, (-)-pyroglutamic acid, (-)-A acetyl-L-leucine, (- )-A 7 -acetyl-D-leucine, A Boc-D-leucine, V-(+)-BOC-phenylalanine, (-)-quinic acid, (+)-«-acetyl- L-phenylalanine, (+)-A-BOC-isoleucine, L-(-)-acetyl glutamic acid, (-)-acetyl mandelic acid, (i?)-(-)-citramalic acid, (-)-camphanic acid, and (A)-mandelic acid.

[0097] In certain embodiments, HX is a chiral acid. In particular embodiments, HX is selected from the group consisting of L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L- glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1 R, 35)-(+)-camphoric acid, (LS -(+)- camphor- 10-sulfonic acid, (R)-(+)-A r -(l -phenyl ethyi)succinamic acid, carb ob enzyl oxy-L- proline, dibenzoyl -L-tartari c acid, (R)-(+)-3 -methyladipic acid, (+)-m enthyl oxy acetic acid, (-)- pyroglutamic acid, (^-A'-acetyl-L-leucine, V-Boc-D-leucine, V-(+)-BOC-phenylalanine, (-)- quinic acid, (+)-«-acetyl-L-phenylalanine, (+)-iV-BOC-isoieucine, L-( -)-acetyl glutamic acid, (- )-acetyl mandelic acid, (i?)-(-)-citramalic acid, (-)-camphanic acid, and (i?)-mandelic acid. In some embodiments, HX is ( ?)-mandelic acid in some embodiments, HX is A-Boc-D-leucine.

[0098] In some embodiments, HX is (-^A-acetyl-D-leucine.

[0099] In certain embodiments, HX is an achiral acid. In particular embodiments, HX is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, p- toluenesulfonic acid, and phosphoric acid. In some embodiments, HX is methanesulfonic acid.

[00100] In certain embodiments, the catalyst comprises a palladium catalyst and a copper catalyst. In particular embodiments, the palladium catalyst is selected from the group consisting of [(7i-aIlyI)PdCl] 2 , Pd(acac) 2 , (SIPr)PdCl 2 , PdCl 2 (PPh 3 ) 2 , PdCl 2 , Pd(OAc) 2 , PdCl 2 (CH 3 CN) 2 , and Pd 2 (dba) 3 , optionally, in combination with a tertiary phosphine. In some embodiments, the tertiary phosphine is selected from the group consisting of triphenylphosphine, tri

cyclohexyl phosphine, tri-fe/7-butylphosphine, l,2-bis(diphenylphosphino)ethane, 1,3- bis(diphenylphosphino)propane, and 1, r-bis(diphenylphosphino)ferrocene. In particular embodiments, the copper catalyst is selected from the group consisting of copper(I) iodide, copper(I) bromide, copper(I) chloride, and combinations thereof. In particular embodiments, the catalyst comprises PdCl 2 (PPh 3 ) 2 and copper(I) iodide.

[00101] In certain embodiments, the catalyst is a palladium catalyst. In particular

embodiments, the palladium catalyst is selected from the group consisting of [(7c-ailyl)PdCl] 2 , Pd(acac) 2 , (SIPr)PdCl 2 , PdCI 2 (PPh 3 ) 2 , PdCI 2 , Pd(OAc) 2 , PdCl 2 (CH 3 CN) 2 , and Pd 2 (dba) 3 , optionally, in combination with a tertiary phosphine. In some embodiments, the tertiary phosphine is selected from the group consisting of triphenylphosphine, tri-cyclohexylphosphine, tri-tert-butyiphosphine, 1 ,2-bis(diphenylphosphino)ethane, 1 ,3 -bi s(diphenylphosphino)propane, and 1, r-bis(diphenylphosphino)ferrocene. In some embodiments, the palladium catalyst is PdCl 2 (PPh 3 ) 2 .

[00102] In particular embodiments, the copper catalyst is selected from the group consisting of copper(I) iodide, copper(I) bromide, copper(I) chloride, and combinations thereof.

[00103] In certain embodiments, the catalyst is a copper catalyst. In particular embodiments, the copper catalyst is selected from the group consisting of copper(I) iodide, copper(I) bromide, and copper(I) chloride.

[00104] In certain embodiments, the base is selected from the group consisting of

triethylamine, diisopropylamine, ethyldiisopropylamine, pyrrolidine, l,4-diazabicylo[2.2.2]- octane, l,8-diazabicyclo[5 4.0]undec-7-ene, l,5-diazabicyclo-4.3.0]non-5-ene, pyridine, cesium carbonate, potassium carbonate, sodium carbonate, piperidine, potassium phosphate, and tetrabutyl ammonium fluoride. In certain embodiments, the base is tri ethyl amine.

[00105] In certain embodiments, the solvent is selected from the group consisting of an ether (e.g., diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane), aromatic solvents (e.g., benzene, toluene, xylenes), a polar aprotic solvent (e.g., N,N- dimethylformamide, V,iV-dimethylacetamide, ¥-methylpyrrolidinone), water, acetonitrile, and a combination thereof.

[00106] In certain embodiments, the solvent is selected from the group consisting of an ether (e.g., diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane), aromatic solvents (e.g., benzene, toluene, xylenes), a polar aprotic solvent (e.g., N,N- dimethylformamide, A^V-dimethylacetamide, V-methylpyrrolidinone), water, and a combination thereof. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[00107] In some embodiments, the process is carried out in the temperature range of about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about 0 °C to about 120 °C. In particular embodiments, the process is carried out in the temperature range of from about 50 °C to about 80 °C.

[00108] In some embodiments, a process for preparing a compound of formula IV:

or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof,

a base,

a solvent,

optionally a coupling agent; and

optionally an activating agent.

[00109] In some embodiments, a process for preparing a compound of formula IV:

or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof,

a coupling reagent or an activating agent, a base, and

a solvent,

to provide the compound of formula IV or a co-crystal, solvate, salt, or combination thereof.

[00110] In certain embodiments, the coupling reagent is an aryl boronic acid. Non-limiting examples of aryl boronic acids include phenylboronic acid, 3,5- bis(trifluoromethyl)phenylboronic acid, 3 -nitrophenylb oroni c acid, and 2-iodophenylboronic

[00111] In certain embodiments, the coupling reagent is selected from the group consisting of n-propyl phosphonic cyclic anhydride, n-propyl phosphonic anhydride, 2-chloro-4,6-dimethoxy- l,3,5-triazine, 4-(4, 6-dim ethoxy- 1, 3, 5-triazin-2-yl)-4-methy!morpho!inium chloride, 2-chloro-l- methylpyridinium iodide, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1 -ethyl -3 -(3- dimethylaminopropyl)carbodiimide, carbonyl diimidazole, isobutyl chloroformate, 2-(7-aza-lH- benzotri azole- 1 -yl)- 1,1,3 ,3 -tetramethyluronium hexafluorophosphate, ( -benzotriazole- AyA'iA^A' -tetramethyluroniurn-hexafluQro-phosphate, 0-(7 -azabenzotriazole- 1 -yl)-NNN',N'- tetramethyluronium tetrafluorob orate, ( -(benzotriazol-l-yl)-V,V,V’,A’-tetramethyluronium tetrafluorob orate, (9-(6-chlorobenzotriazol- 1 -y\)-A T ,N,N’,A r ’-tetramethyluronium

hexafluorophosphate, (b enzotri azol - 1 -yl oxy)tri s(di m ethyl ami no)p hosphonium hexafluorophosphate, (benzotriazol-l -yloxy)tripyrrolidinophosphonium hexafluorophosphate, (l-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morph olino-carbenium

hexafluorophosphate, 4-(4,6-dimethoxy- 1 ,3 , 5-triazin-2-yl)-4-m ethylmorphonium chi ori de, bori c acid, tetramethyl orthosilicate, trimethyoxy silane, diphenylphosphinic chloride, chloro-A ? , N, N’, V’-tetramethylformamidinium hexafluorophosphate, tri isopropyl borate, phenylboronic acid,

3 , 5 -bi s(trifluoromethyl)phenylboronic acid, 3 -nitrophenylb oroni c acid, and 2 -i odophenylb oroni c acid.

[00112] In certain embodiments, the coupling reagent is selected from the group consisting of n-propyl phosphonic anhydride, 2-chloro-4,6-dimethoxy-l,3,5-triazine, 4-(4, 6-dimethoxy- 1,3,5- triazin-2-yl)-4-methy morpholinium chloride, 2-chloro-l -methylpyridinium iodide,

dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1 -ethyl-3 -(3- dimethylaminopropyl)carbodiimide, carbonyl diimidazole, isobutyl chloroformate, 2-(7-aza-lH- benzotri azole- 1 -yl)- 1,1,3 ,3 -tetramethyluronium hexafluorophosphate, 0-benzotriazole-VA^V’.iV -tetramethyluronium-hexafluoro-phosphate, O-(7 -azabenzotriazol e- 1 -y\)-N,N, N',N'- tetramethyluronium tetrafluorob orate, 0-(benzotriazol- 1 -yl)-NA T ,N N’-tetramethyluronium tetrafluorob orate, ( ' /-(6-chi orobenzotri azol- l -yl )-:V,.'V,/V’./V’-tetramethyluronium

hexafluorophosphate, (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium

hexafluorophosphate, (benzotriazol-l -yloxy)tripyrrolidinophosphonium hexafluorophosphate, and (l-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morph olino-carbenium hexafluorophosphate. In particular embodiments, the coupling reagent is n-propyl phosphonic anhydride. In particular embodiments, the coupling reagent is n-propyl phosphonic cyclic anhydride.

[00113] In certain embodiments, the activating agent is selected from the group consisting of oxalyl chloride, thionyl chloride, diphenylphosphinic chloride, pivaloyl chloride, cyanuric chloride, and methanesulfonyl chloride, wherein a compound of formula VII-B:

VII-B

or a or a co-crystal, solvate, salt, or combination thereof, is produced from the compound of formula VII, or a co-crystal, solvate, salt, or combination thereof [00114] In certain embodiments, the activating agent is selected from the group consisting of oxalyl chloride, thionyl chloride, and diphenylphosphinic chloride, wherein a compound of formula VII-B:

or a co-crystal, solvate, salt, or combination thereof, is produced from the compound of formula VII, or a co-crystal, solvate, salt, or combination thereof.

[00115] In certain embodiments, the base is selected from the group consisting of

tri ethyl amine, tributyl amine, ethyl di isopropylamine, /V-m eth y I m orph o! i n e, pyridine, 2,6- lutidine, and V-methylimidazole. In particular embodiments, the base is triethylamine.

[00116] In certain embodiments, the solvent is selected from the group consisting of an ester (e.g., ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate), an ether ( e.g ., diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), a polar aprotic solvent (e.g., NN- dimethylformamide, AyV-dimethylacetamide, A-methylpyrrolidinone, dimethylsulfoxide), a chlorinated solvent (e.g., dichloromethane, dichloroethane, chloroform), a nitrile (e.g., propionitrile, butyronitrile, acetonitrile), and a combination thereof. In particular embodiments, the solvent is acetonitrile.

[00117] In some embodiments, the process is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -20 °C to about 120 °C. In particular embodiments, the process is carried out in the temperature range of from about 0 °C to about 40 °C.

[00118] In some embodiments, the process further comprises a coupling additive. In certain embodiments, the coupling additive is selected from the group consisting of 4- (dimethylamino)pyridine, A^-hydroxysuccinimide, ethyl cyanohydroxyiminoacetate, 1- hydroxybenzotri azole, l-hydroxy-7-azabenzotri azole, and A-methylimidazole. In certain embodiments, the coupling additive is selected from the group consisting of 4- (dimethylamino)pyridine, Ariiydroxysuccinimide, ethyl cyanohydroxyiminoacetate, 1- hydroxybenzotri azole, and 1 -hy droxy-7-azab enzotri azol e .

[00119] In some embodiments, a process for preparing a compound of formula III:

or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula IV :

or a co-crystal, solvate, salt, or combination thereof, with

a compound of formula V:

V

or a co-crystal, solvate, salt, or combination thereof, wherein R 1 is B(OH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 3 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0),

a palladium catalyst,

a base, and

a solvent,

to provide the compound of formula III or a co-crystal, solvate, salt, or combination thereof. [00120] In some embodiments, a process for preparing a compound of formula III:

or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula IV :

or a co-crystal, solvate, salt, or combination thereof, with

a compound of formula V:

V

or a co-crystal, solvate, salt, or combination thereof, wherein R 1 is B(OH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 4 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0),

a palladium catalyst,

a base, and

a solvent, to provide the compound of formula III or a co-crystal, solvate, salt, or combination thereof. [00121] In certain embodiments, R 1 is B(0C(Me) 2 C(Me) 2 0).

[00122] In certain embodiments, the palladium catalyst is selected from the group consisting of dichlorobis(tricyclohexylphosphine)palladium(II), bis(di-fer/-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II), bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine]palladium(II) chloride,

dichlorobis(triphenylphosphine)palladium(II), [ I , - bi s(di phenylphosphino)ferrocene] dichl oropal 1 adium(II), [1,2- bis(diphenylphosphino)ethane]dichloropalladium(II), dichloro[9, 9-dimethyl -4,5- bis(diphenylphosphino)xanthene]palladium(II), chloro[(tricyclohexylphosphine)-2-(2'- aminobiphenyl)]palladium(II), [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate, PCy 3 Pd G4, palladium chloride, palladium acetate, and palladium trifluoroacetate. In certain embodiments, the palladium catalyst further comprises a phosphine ligand, wherein the pall adium catalyst is selected from the group consisting of palladium chloride, palladium acetate, palladium trifluoroacetate, dichloro(l,5- cyclooctadiene)palladium(II), allylpalladium(II) chloride dimer, palladium(II) acetyl acetonate, (tetrakis(triphenylphosphine)palladium(O) and bis(dibenzylideneacetone)pal ladium(0). In particular embodiments, the phosphine ligand is selected from the group consisting of di -tert- butyl (4-di m ethylam inopheny 1 )phosphine, di cycl ohexyl (4-dimethylaminophenyl)phosphine, 1,2- bis(diphenylphosphino)ethane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2,2 '-bi s(diphenylphosphino)- 1,1 '- binaphthalene, 1 ,3 -bi s(diphenylphosphino)propane, ethyl enebi s(diphenylphosphine), 1,1 '- ferrocenediyl-bis(diphenylphosphine, 4,5 -bi s(diphenylphosphino)-9,9-dimethylxanthene, tricyclohexylphosphine, triphenylphosphine,

cyclohexyl diphenylphosphine,dicyclohexylphenylphosphine, tritertbutylphosphine,

cycl ohexyl di tertbutyl phosphi ne, and di cy cl ohexyltertbutyl phosphine. In some embodiments, the palladium catalyst is dichlorobis(tricyclohexylphosphine)palladium(II).

[00123] In certain embodiments, the base is selected from the group consisting of potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, di cycl ohexyl amine, /V-methylmorpholine, and triethylamine.

In particular embodiments, the base is potassium bicarbonate. [00124] In certain embodiments, the solvent is selected from the group consisting of an ether {e.g., diethyl ether, 2 -m ethy 1 tetr ahy dr of ur an , l,4-dioxane, dimethoxyethane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), an ester (e.g., ethyl acetate, n-butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate), an alcohol (e.g., ethanol, isopropanol), a polar aprotic solvent (e.g., AvV-dimethylformamide, /V,/V-di m ethyl ac etam i de, N- methylpyrrolidinone), water, and a combination thereof. In particular embodiments, the solvent is a mixture of n-butyl acetate and water.

[00125] In some embodiments, the process is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about 20 °C to about 120 °C. In particular embodiments, the process is carried out in the temperature range of from about 75 °C to about 95 °C.

[00126] In some embodiments, the process of making the compound of formula III:

Ill

or a co-crystal, solvate, salt, or combination thereof,

further comprises:

(a) combining the compound of formula III, or a co-crystal, solvate, salt, or combination thereof, with a second solvent and an acid to provide a compound of formula III-

III-02 or a co-crystal, solvate, or combination thereof, wherein HY is selected from the group consisting of acetic acid, oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid, chloroacetic acid, citric acid, nitric acid, formic acid, lactic acid, ascorbic acid, benzoic acid, propionic acid, ethanesulfonic acid, -toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; and

(b) free-basing the compound of formula III-02, or a co-crystal, solvate, or combination thereof, by combining it with a second base and a third solvent to provide the compound of formula III or a co-crystal, solvate, salt, or combination thereof

[00127] In certain embodiments, HY is methanesulfonic acid.

[00128] In certain embodiments, the second solvent is selected from the group consisting of an alcohol (e.g., methanol, ethanol, 1 -propanol, isopropanol, tert- amyl alcohol), a nitrile ( e.g ., acetonitrile), a ketone (e.g., methyl isobutyl ketone), a chlorinated solvent (e.g · .,

dichloromethane), an ester (e.g., ethyl acetate, isopropyl acetate), an aromatic hydrocarbon solvent (e.g., toluene), an ether (e.g., methyl /er/-butyl ether, cyclopentyl methyl ether, 2- m ethyl tetrahydrofuran), and a combination thereof.

[00129] In certain embodimnets, the compound of formula 111-02 is produced as a bis- methanesulfonic acid.

[00130] In certain embodiments, the compound of formula 01-02 is produced as a solvate. In particular embodiments, the compound of formula III-02 is produced as a 1 -propanol, isopropanol, ethanol, methanol, fe/7-amyl alcohol, acetonitrile, methyl isobutyl ketone, dichloromethane, 2-methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl tert-buty ether, toluene, or cyclopentyl methyl ether solvate. In some embodiments, the compound of formula III-02 is produced as an ethanol solvate. In other embodiments, the compound of formula III-02 is produced as a 1 -propanol solvate. In other embodiments, the compound of formula III-02 is produced as an isopropanol solvate. In other embodiments, the compound of formula III-02 is produced as a methanol solvate. In other embodiments, the compound of formula III-02 is produced as a fert-amyl alcohol solvate. In other embodiments, the compound of formula III-02 is produced as an acetonitrile solvate. In other embodiments, the compound of formula III-02 is produced as a methyl isobutyl ketone solvate. In other embodiments, the compound of formula III-02 is produced as a dichloromethane solvate. In other embodiments, the compound of formula III-02 is produced as a 2-methyl tetrahydrofuran solvate. In other embodiments, the compound of formula HI-02 is produced as an ethyl acetate solvate. In other embodiments, the compound of formula III-02 is produced as an isopropyl acetate solvate. In other embodiments, the compound of formula III-02 is produced as a methyl fert-butyi ether solvate. In other embodiments, the compound of formula III-02 is produced as a toluene solvate. In other embodiments, the compound of formula HI-02 is produced as a cyclopentyl methyl ether solvate.

[00131] In some embodiments, the compound of formula III-02 is produced in the temperature range of from about 20 °C or less. In certain embodiments, the compound of formula III-02 is produced in the temperature range of from about -20 °C to about 20 °C.

[00132] In certain embodiments, the second base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, b enzyltri m ethyl am m oni urn hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide,

tri ethyl amine, l,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, ammonium hydroxide, and diethyl amine. In particular embodiments, the second base is sodium hydroxide.

[00133] In certain embodiments, the third solvent is selected from the group consisting of an ether (e.g., diethyl ether, methyl fert-butyl ether, 2-methyltetrahydrofuran, l,4-dioxane, dimethoxyethane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), an ester (e.g., ethyl acetate, isopropyl acetate), water, and a combination thereof. In particular embodiments, the third solvent is a mixture of 2-methyltetrahydrofuran and water.

[00134] In some embodiments, the free-basing step is carried out in the temperature range of from about 80 °C or less. In certain embodiments, the free-basing step is carried out in the temperature range of from about -20 °C to about 80 °C. In particular embodiments, free-basing step is carried out in the temperature range of from about 0 °C to about 50 °C.

[00135] In some embodiments, the process of making the compound of formula III:

III or a co-crystal, solvate, salt, or combination thereof, further comprises: (a) combining the compound of formula III, or a co-crystal, solvate, salt, or combination thereof, with a second solvent and an acid to provide a compound of formula HI-

02:

III-02

or a co-crystal, solvate, or combination thereof, wherein HY is selected from the group consisting of acetic acid, oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid, chloroacetic acid, citric acid, nitric acid, formic acid, lactic acid, ascorbic acid, benzoic acid, propionic acid, ethanesulfonic acid, >-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; and

(b) free-basing the compound of formula HI-02, or a co-crystal, solvate, or combination thereof, by combining it with a second base and a third solvent to provide the compound of formula III or a co-crystal, solvate, salt, or combination thereof.

[00136] In certain embodiments, HY is methanesulfonic acid.

[00137] In certain embodiments, the second solvent is selected from the group consisting of an alcohol (e.g., methanol, ethanol, 1 -propanol, isopropanol, tert-amyl alcohol), a nitrile (e.g., acetonitrile), a ketone (e.g., methyl isobutyl ketone), a chlorinated solvent (e.g.,

dichloromethane), an ester (e.g., ethyl acetate, isopropyl acetate), an aromatic hydrocarbon solvent (e.g., toluene), an ether (e.g., methyl te/7-butyl ether, cyclopentyl methyl ether, 2- methyltetrahydrofuran), and a combination thereof.

[00138] In certain embodiments, the compound of formula 01-02 is produced as a solvate. In particular embodiments, the compound of formula III-02 is produced as a 1 -propanol, isopropanol, ethanol, methanol, tert-amyl alcohol, acetonitrile, methyl isobutyl ketone, dichloromethane, 2-methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, toluene, or cyclopentyl methyl ether solvate. In some embodiments, the compound of formula HI-02 is produced as an ethanol solvate. In other embodiments, the compound of formula III-02 is produced as a 1 -propanol solvate. In other embodiments, the compound of formula HI-02 is produced as an isopropanol solvate. In other embodiments, the compound of formula III-02 is produced as a methanol solvate. In other embodiments, the compound of formula III-02 is produced as a fert-amyl alcohol solvate. In other embodiments, the compound of formula 111-02 is produced as an acetonitrile solvate. In other embodiments, the compound of formula HI-02 is produced as a methyl isobutyl ketone solvate. In other embodiments, the compound of formula 111-02 is produced as a dichlorom ethane solvate. In other embodiments, the compound of formula III-02 is produced as a 2-methyl tetrahydrofuran solvate. In other embodiments, the compound of formula 111-02 is produced as an ethyl acetate solvate. In other embodiments, the compound of formula III-02 is produced as an isopropyl acetate solvate. In other embodiments, the compound of formul a 111-02 is produced as a methyl /cr/-butyl ether solvate. In other embodiments, the compound of formula III-02 is produced as a toluene solvate. In other embodiments, the compound of formula III-02 is produced as a cyclopentyl methyl ether solvate.

[00139] In some embodiments, the compound of formula III-02 is produced in the temperature range of from about 20 °C or less. In certain embodi m ents, the compound of formula III-02 is produced in the temperature range of from about -20 °C to about 20 °C.

[00140] In certain embodiments, the second base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, benzyltrimethylammonium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide,

triethylamine, l,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.Q]undec-7-ene, ammonium hydroxide, and diethyl amine. In particular embodiments, the second base is sodium hydroxide.

[00141] In certain embodiments, the third solvent is selected from the group consisting of an ether (e.g., diethyl ether, methyl ferf-butyl ether, 2-methyltetrahydrofuran, l,4-dioxane, di ethoxyethane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), an ester (e.g., ethyl acetate, isopropyl acetate), water, and a combination thereof. In particular embodiments, the third solvent is a mixture of 2-methyltetrahydrofuran and water.

[00142] In some embodiments, the free-basing step is carried out in the temperature range of from about 80 °C or less. In certain embodiments, the free-basing step is carried out in the temperature range of from about -20 °C to about 80 °C. In particular embodiments, free-basing step is carried out in the temperature range of from about 0 °C to about 50 °C.

[00143] In some embodiments, a process for preparing a compound of formula I:

I

or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula III:

III

or a co-crystal, solvate, salt, or combination thereof, with

a mesylating reagent, and

a solvent,

to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.

[00144] In certain embodiments, the mesylating reagent is selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride. In particular embodiments, the mesylating reagent is methanesulfonic anhydride.

[00145] In certain embodiments, the solvent is selected from the group consisting of an ester (e.g., ethyl acetate, isopropyl acetate), an ether (e.g., cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane), a nitrile (e.g., acetonitrile), a polar aprotic solvent (e.g., tV,A r -dimethy{formamide, /V, r -dimethyl acetamide, 7V-methyl pyrroli di none), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), a chlorinated solvent (e.g., dichloromethane, dichloroethane, chloroform), and a combination thereof. In particular embodiments, the solvent for the mesylating step is cyclopentyl methyl ether. [00146] In some embodiments, the process is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about 20 °C to about 120 °C. In particular embodiments, the process is carried out in the temperature range of from about 70 °C to about 90 °C.

[00147] In some embodiments, a process for preparing a compound of formula I:

I

or a co-crystal, solvate, salt, or combination thereof is provided, comprising:

(a) combining a compound of formula III:

or a co-crystal, solvate, salt, or combination thereof with a mesylating reagent, a base, and a solvent to provide a compound of formula II:

II or a co-crystal, solvate, salt, or combination thereof; and

(b) hydrolyzing the compound of formula II or a co-crystal, solvate, salt, or combination thereof, with a nucleophilic reagent, and optionally, a phase transfer catalyst, in a solvent, to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof

[00148] In certain embodiments, the mesylating reagent is selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride. In particular embodiments, the mesylating reagent is methanesulfonyl chloride.

[00149] In certain embodiments, a phase transfer catalyst i s used in step (b). In certain embodiments, the phase transfer catalyst used in step (b) is an ammonium or phosphonium salt. In certain embodiments, the phase transfer catalyst is selected from the group consisting of tetra- n-butylammonium chloride, b enzy ltri -n-b utyl amm onium bromide, 1 -methylimidazolium hydrogen sulfate, tetra-n -butyl ammonium hydrogen sulfate, and tetra-n-butylphosphonium chloride. In particular embodiments, the phase transfer catalyst is tetra-n-butylammonium hydrogen sulfate.

[00150] In certain embodiments, the base is selected from the group consisting of N- methylmorpholine, tri-n-propylamine, ethyl diisopropylamine, tri-n-butylamine, triethylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, sodium tert-amylate, and sodium tert- butoxide. In particular embodiments, the base is triethylamine.

[00151] In certain embodiments, the solvent for the mesylating step is selected from the group consisting of an ether ( e.g ., diethyl ether, 2-methyltetrahydrofuran, l,4-dioxane, dimethoxyethane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), an ester (e.g., isobutyl acetate, isopropyl acetate), a chlorinated solvent (e.g., dichloromethane), a nitrile (e.g · ., acetonitrile), and a combination thereof. In particular embodiments, the solvent for the mesylating step is 2-methyltetrahydrofuran.

[00152] In certain embodiments, the mesylating step is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the mesylating step is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, the mesylating step is carried out in the temperature range of from about -10 °C to about 20 °C.

[00153] In certain embodiments, the nucleophilic reagent for the hydrolyzing step is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, A r -acetylcysteine, sodium thiophenolate, choline, sodium methoxide, sodium ethoxide, potassium eth oxide, sodium n-propoxide, sodium isopropoxide, sodium t- butoxide, methyl amine, ethyl amine, n-propylamine, dimethylamine, diethyl amine, and hydroxylamine. In particular embodiments, the nucleophilic reagent for the hydrolyzing step is sodium hydroxide.

[00154] In certain embodiments, the solvent for the hydrolyzing step is selected from the group consisting of an alcohol (e.g., methanol, ethanol, 1 -propanol, i sopropanol, n-butanol, sec- butanol), an ether (e.g., diethyl ether, 2-methyltetrahydrofuran, l,4-dioxane, dimethoxyethane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), an ester (e.g., isobutyl acetate, isopropyl acetate), a chlorinated solvent (e.g., dichloromethane), a nitrile (e.g., acetonitrile), a polar aprotic solvent (e.g., A^-dimethylform amide, AyV-dimethylacetamide, N- methylpyrrolidinone), water, and a combination thereof. In particular embodiments, the solvent for the hydrolyzing step is water and 2 -methyltetrahy drofuran .

[00155] In some embodiments, the hydrolyzing step is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the hydrolyzing step is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, the hydrolyzing step is carried out in the temperature range of from about 10 °C to about 60 °C

[00156] In some embodiments, a process for preparing a compound of formula I:

I

or a co-crystal, solvate, salt, or combination thereof is provided, comprising:

(a) combining a compound of formula VIII:

VIII

or a co-crystal, solvate, salt, or combination thereof, with a compound of formula IX:

IX

or a co-crystal, solvate, or combination thereof, under alkynylation conditions to provide the compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof;

(b) combining the compound of formula VI or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof, under amide coupling conditions to provide a compound of formula IV:

or a co-crystal, solvate, salt, or combination thereof;

(c) combining the compound of formula IV or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V:

V

or a co-crystal, solvate, salt, or combination thereof, wherein R 1 is B(OH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 3 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0), under palladium-catalyzed cross-coupling conditions to provide a compound of formula III:

or a co-crystal, solvate, salt, or combination thereof; and

(d) combining the compound of formula III or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent under mesylating conditions to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof

[00157] In some embodiments, a process for preparing a compound of formula I:

I or a co-crystal, solvate, salt, or combination thereof is provided, comprising: (a) combining a compound of formula VIII:

VIII or a co-crystal, solvate, salt, or combination thereof, with a compound of formula IX:

IX or a co-crystal, solvate, or combination thereof, under alkynylation conditions to provide the compound of formula VI:

or a co-crystal, solvate, salt, or combination thereof;

(b) combining the compound of formula VI or a co-crystal, solvate, salt, or combination thereof, with a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof, under amide coupling conditions to provide a compound of formula IV:

IV

or a co-crystal, solvate, salt, or combination thereof;

(c) combining the compound of formula IV or a co-crystal, solvate, salt, or combination thereof, with a compound of formula V:

or a co-crystal, solvate, salt, or combination thereof, wherein R 1 is B(OH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-G)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 4 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0), under palladium-catalyzed cross-coupling conditions to provide a compound of formula III:

or a co-crystal, solvate, salt, or combination thereof; and

(d) combining the compound of formula III or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent under mesylating conditions to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.

[00158] In some embodiments, the process for preparing a compound of formula I:

I

or a co-crystal, solvate, salt, or combination thereof, further comprises:

(a) forming the sodium salt of the compound of formula I to provide a compound of formula 1-02:

by combining the compound of formula I with a sodium source and a solvent; and (b) neutralizing the compound of formula 1-02 with an acid, in a solvent, to provide the compound of formula I.

[00159] In some embodiments, the process for preparing a compound of formula I:

I

or a co-crystal, solvate, salt, or combination thereof, further comprises:

(a) forming the sodium salt of the compound of formula I to provide a compound of formula 1-02:

1-02

by combining the compound of formula I with a sodium source and a solvent; and

(b) neutrali zing the compound of formula 1-02 with an acid to provide the compound of formula I.

[00160] In certain embodiments, the sodium source for the sodium salt forming step (a) is selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium phosphate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium t- butoxide, sodium hexamethyldisilazide, and sodium metal and an alcohol selected from the group consisting of methanol, ethanol, isopropanol, 1 -propanol, «-butanol, and see-butanol . In particular embodiments, the sodium source is sodium ethoxide. In particular embodiments, the sodium source is sodium hydroxide. [00161] In certain embodiments, the solvent for the sodium salt forming step (a) is selected from the group consisting of of an ether ( e.g ., diethyl ether, 2-methyltetrahydrofuran, 1,4- dioxane, dimethoxyethane), a hydrocarbon solvent (e.g., n-heptane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), an ester (e.g., ethyl acetate, isobutyl acetate, isopropyl acetate), a chlorinated solvent (e.g., di chi oromethan e), a nitrile (e.g., acetonitrile), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutylketone), an alcohol (e.g., methanol, ethanol, 1 -propanol, isopropanol, n-butanol, sec-butanol), and a combination thereof In particular embodiments, the solvent for the sodium salt forming step is ethanol and n-heptane.

[00162] In certain embodiments, the sodium salt forming step (a) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the sodium salt forming step is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, the sodium salt forming step is carried out in the temperature range of from about 0 °C to about 50 °C.

[00163] In certain embodiments, the acid for the neutralizing step (b) is selected from the group consisting of acetic acid, oxalic acid, sulfuric acid, hydrochloric acid, phosphoric acid, chloroacetic acid, citric acid, nitric acid, formic acid, lactic acid, ascorbic acid, benzoic acid, and propionic acid. In particular embodiments, the acid for the neutralizing step is acetic acid.

[00164] In certain embodiments, the solvent for the neutralizing step (b) is selected from water, ethers (e.g., diethyl ether, l,4-dioxane, 2 -m ethyltetrahy drofuran, dimethoxyethane, methyl tert-butyl ether), hydrocarbon solvents (e.g.,n-hexane, n-heptane, toluene, xylenes), esters (e.g., ethyl acetate, isopropyl acetate, isobutyl acetate), dichloromethane, acetonitrile, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutylketone), alcohols (e.g., methanol, ethanol, isopropyl alcohol, tert-butyl alcohol), and a combination thereof. In particular embodiments, the solvent for the neutralizing step (b) is water and alcohol (e.g., methanol, ethanol, isopropyl alcohol, tert-butyl alcohol). In particular embodiments, the solvent for the neutralizing step (b) is water and ethanol. In particular embodiments, the solvent for the neutralizing step (b) is water. In particular embodiments, the ratio of the acid to water is from 2:5 to 2:30. In particular embodiments, the ratio of the acetic acid to water is from 2:5 to 2:30.

[00165] In certain embodiments, the neutralizing step (b) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the neutralizing step is carried out in the temperature range of from about -20 °C to about 100 °C. In particul ar embodiments, the neutralizing step is carried out in the temperature range of from about 0 °C to about 50 °C.

[00166] In some embodiments, a process for preparing a compound of formula I:

I or a co-crystal, solvate, salt, or combination thereof is provided, comprising: (a) combining a compound of formula IV :

or a co-crystal, solvate, salt, or combination thereof, with a base, a solvent, a catalyst, and a compound of formula V-04-A:

V-04-A or a co-crystal, solvate, salt, or combination thereof, wherein R is B(OH) 2 , B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ),

B(0CH 2 C(Me) 2 CH 2 0), BF 3 K, B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0), to provide a compound of II:

II

or a co-crystal, solvate, salt, or combination thereof; and

(b) hydrolyzing the compound of formula II or a co-crystal, solvate, salt, or combination thereof, with a base, a solvent, and optionally a phase transfer catalyst, to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof

[00167] In certain embodiments, R is B(0C(Me) 2 C(Me) 2 0).

[00168] In certain embodiments, the catalyst used in step (a) is selected from the group consisting of bis(di-fer/-butyl(4-dimethylaminophenyl)phosphine)dichloropa lladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium (II) chloride,

dichlorobis(triphenylphosphine)palladium(II), [I, - bis(diphenylphosphino)ferrocene]dichloropalladium(II), [ 1 ,2- bis(diphenylphosphino)ethane]dichloropalladium(II), and di chi oro[9, 9-dimethyl -4,5- bis(diphenylphosphino)xanthene]palladium(II). In certain embodiments, the catalyst used in step (a) is palladium(II) precatalyst (e.g , palladium(II) chloride, palladium(II) acetate, palladium (II) trifluoroacetate) or palladium(O) precatalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bis(dibenz.ylideneacetone)palladium(0)) and the catalyst used in step (a) further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine,

cycl ohexyl diphenylphosphine, dicyclohexylphenylphosphine). In certain embodiments, the catalyst used in step (a) is selected from the group consisting of palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0), and bis(dibenzylideneacetone)palladium(0). In some embodiments, the palladium catalyst used in step (a) is palladium (II) chloride and cyclohexyldiphenylphosphine.

[00169] In certain embodiments, the base used in step (a) is selected from the group consisting of sodium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, di cyclohexyl amine, /V-methylmorpholine,

tri ethyl amine, and di i sopropyl ethyl amine . In parti cular embodiments, the base used in step (a) is potassium bicarbonate.

[00170] In certain embodiments, the solvent used in step (a) is selected from the group consisting of water, ethers (e.g., 1,4-dioxane, 2-methyltetrahydrofuran, dim ethoxy ethane), aromatic hydrocarbon solvents (e.g., toluene, xylenes), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol,), and polar aprotic solvents (e.g., N,N-di m ethylformami de, N,N-dimethylacetamide, N -methyl -2-pyrrolidine), and a combination thereof. In certain embodiments, the solvent used in step (a) is selected from the group consisting of water, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N -di m ethyl acetami de, N-methyl-2-pyrrolidine, and a combination thereof. In particular embodiments, the solvent used in step (a) is 2-methyltetrahydrofuran and water.

[00171] In some embodiments, step (a) is carried out in the temperature range of from about 120 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about 20 °C to about 120 °C. In particular embodiments, step (a) is carried out in the temperature range of from about 65 °C to about 75 °C.

[00172] In some embodiments, the base used in step (b) is selected from the group consisting of hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide), carbonate bases (sodium carbonate, potassium carbonate), bicarbonate bases (e.g., sodium bicarbonate potassium bicarbonate), tetraal ky 1 ammonium hydroxides (e.g., benzyltrimethylammonium hydroxide, choline hydroxide), alkoxide bases (e.g., sodium or potassium methoxide, sodium or potassium ethoxide), and amine bases (e.g., triethylamine, l,4-diazabicyclo[2.2.2]octane (DABCO), l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine). In some embodiments, the base used in step (b) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, bicarbonate bases, sodium bicarbonate, potassium bicarbonate, benzyltrimethylammonium hydroxide, choline hydroxide, sodium or potassium methoxide, sodium or potassium ethoxide, triethylamine, DABCO, DBU, and diethylamine. In particular embodiments, the base used in step (b) is sodium hydroxide. [00173] In some embodiments, the solvent used in step (b) is selected from the group consisting of ethers (e.g., diethyl ether, l,4-dioxane, 2 -methyl tetrahydrofuran,

dimethoxy ethane), hydrocarbon solvents (e.g., toluene, xylenes), esters (e.g., isopropyl acetate, isobutyl acetate), di chi orom ethane, acetonitrile, polar aprotic solvents (e.g., N,N- dimethylformamide, iV-methyl-2-pyrrolidone, /V, V-di m ethyl acetam i de), and a combination thereof. In some embodiements, the solvent used in step (b) is selected from the group consisting of diethyl ether, l,4-dioxane, 2-m ethyl tetrahydrofuran, di m ethoxy ethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, N,N~

dimethylformamide, N-m ethyl -2-pyrrol i done, N,N-di m ethyl acetam i de, and a combination thereof. In particular embodiments, the solvent used in step (b) is 2-methyltetrahydrofuran.

[00174] In some embodiments, a phase transfer catalyst is used in step (b). In some embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of ammonium salts (e.g., tetrabutylammonium chloride, b enzyl tributyl ammonium bromide, 1- methylimidazolium hydrogen sulfate), and phosphonium salts (e.g., tetrabutylphosphonium chloride). In particular embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of tetrabutylammonium chloride, b enzyl tributyl am m oni um bromide, 1- methylimidazolium hydrogen sulfate, and tetrabutylphosphonium chloride

[00175] In some embodiments, step (b) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (b) is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, step (b) is carried out in the temperature range of from about 10 °C to about 60 °C.

[00176] In some embodiments, a process for preparing a compound of formula I:

I

or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula IV:

IV

or a co-crystal, solvate, salt, or combination thereof, with

a base,

a solvent,

a catalyst, and

a compound of formula V-03-A:

V-03-A

or a co-crystal, solvate, salt, or combination thereof,

wherein R is B(OH) 2 , B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ),

B(OCH 2 C(Me) 2 CH 2Q ), BF 3 K, B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or

B(0C(Me) 2 C(Me) 2 0),

to provide the compound of formula I, or a co-crystal, solvate, salt, or combination thereof [00177] In certain embodiments, R is B(0C(Me) 2 C(Me) 2 0).

[00178] In certain embodiments, the catalyst is selected from the group consisting of bis(di- ter/-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II), bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine]palladium(II) chloride,

dichlorobis(triphenylphosphine)palladium(II), [ 1 , G - bi s(diphenylphosphino)fenOcene]dichloropalladium(II), [1,2- bis(diphenylphosphino)ethane]dichloropalladium(II), and dichloro[9,9-dimethyl-4,5- bis(dipheny{phosphino)xanthene]palladium(II) In certain embodiments, the catalyst is palladium(II) precatalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or palladium(O) precatalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0)) and the catalyst further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyl diphenylphosphine,

dicyclohexylphenylphosphine). In some embodiments, the catalyst is selected from the group consisting of palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0),and bis(dibenzylideneacetone)palladium(0)) and the catalyst further comprises a phosphine ligand selected from the group consisting of

tricyclohexylphosphine, triphenylphosphine, cyclohexyl diphenylphosphine, and

dicyclohexylphenylphosphine. In some embodiments, the palladium catalyst is palladium (II) chloride and cyclohexyl diphenylphosphine.

[00179] In certain embodiments, the base is selected from the group consisting of potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, dicyclohexylamine, iV-methylmorpholine, triethylamine, and diisopropyl ethylamine. In particular embodiments, the base is potassium bicarbonate.

[00180] In certain embodiments, the solvent is selected from the group consisting of water, ethers (e.g., l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylenes), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol,), and polar aprotic solvents (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine), and a combination thereof. In certain embodiments, the solvent is selected from the group consisting of water, 1,4- dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylform amide, N,N- dimethylacetamide, N-methyl-2-pyrrolidine, and a combination thereof. In particular embodiments, the solvent is 2 -methyl tetrahydrofuran and water.

[00181] In some embodiments, the process is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about 20 °C to about 120 °C. In particular embodiments, the process is carried out in the temperature range of from about 65 °C to about 75 °C.

[00182] In some embodiments, a process for preparing a compound of formula V-03-A:

V-03-A

or a co-crystal, solvate, salt, or combination thereof is provided, comprising:

(a) combining a compound of formul a V:

or a co-crystal, solvate, salt, or combination thereof, wherein R is B(OH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 3 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0), with a mesylating reagent, a base and a solvent to provide a compound of V-04-A:

V-04-A

or a co-crystal, solvate, salt, or combination thereof; and

(b) hydrolyzing the compound of formula V-04-A or a co-crystal, solvate, salt, or combination thereof, with a nucleophilic reagent, a solvent, and optionally, a phase transfer catalyst to provide the compound of formul a V-03-A or a co-crystal, solvate, salt, or combination thereof.

[00183] In certain embodiments, R is B(0C(Me) 2 C(Me) 2 0). [00184] In certain embodiments, the mesylating reagent used in step (a) is methanesulfonic anhydride. In some embodiments, the mesylating reagent used in step (a) is methanesulfonyl chloride.

[00185] In certain embodiments, the base used in step (a) is selected from the group consisting of tertiary amines (e.g., triethylamine, Ά'-methylmorpholine, tri -n-propyl ami ne, ethyl diisopropylamine, tri-n-butylamine), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine), inorganic bases (e.g., sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic), and alkoxide bases (e.g., sodium tert-amylate, sodium tert-butoxide). In certain embodiments, the base used in step (a) is selected from the group consisting of triethylamine, yV-methylmorpholine, tri -n-propyl amine, ethyl

diisopropylamine, tri-n-butylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, sodium tert-amylate, and sodium tert-butoxide. In particular embodiments, the base used in step (a) is triethylamine.

[00186] In certain embodiments, the solvent used in step (a) is selected from the group consisting of ethers (e.g., diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran,

dimethoxyethane,), hydrocarbon solvents (e.g., toluene, xylenes), esters (e.g., isopropyl acetate, isobutyl acetate), dichloromethane, acetonitrile, and a combination thereof In certain embodiments, the solvent used in step (a) is selected from the group consisting of diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, di chi oromethane, acetonitrile, and a combination thereof. In particular embodiments, the solvent used in step (a) is 2-methyltetrahydrofuran.

[00187] In certain embodiments, step (a) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, step (a) is carried out in the temperature range of from about -10 °C to about 20 °C.

[00188] In certain embodiments, the nucleophilic reagent used in step (b) is selected from the group consisting of hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide), sulfur nucleophiles (e.g., sodium ethanethiolate, /V-acetylcysteine, sodium thiophenolate), choline, alkoxide bases (e.g., sodium methoxide, sodium ethoxide, potassium ethoxide, sodium w-propoxide, sodium /-propoxide, sodium /-butoxide), and amines (e.g., methylamine, ethylamine, «-propylamine, dimethylamine, diethylamine, hydroxylamine). In certain embodiments, the nucleophilic reagent used in step (b) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethanethiolate, A-acetyl cysteine, sodium thiophenolate, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium «-propoxide, sodium z-propoxide, sodium /-butoxide, methylamine, ethylamine, «-propylamine, dimethylamine, diethylamine, and hydroxylamine. In particular embodiments, the base used in step (b) is sodium hydroxide.

[00189] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ethers (e.g., diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran,

dimethoxyethane), hydrocarbon solvents (e.g., toluene, xylenes), esters (e.g., isopropyl acetate, isobutyl acetate), dichloromethane, acetonitrile, polar aprotic solvents (e.g., A,A- dimethylform amide, A-m ethyl -2-pyrrolidone, A,A-dimethylacetamide), and a combination thereof. In certain embodiments, the solvent used in step (b) is selected from the group consisting of diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, N,N- dimethylformamide, A-m ethyl -2-pyrrolidone, A,A-dimethylacetamide, and a combination thereof. In particular embodiments, the solvent used in step (b) is 2-methyltetrahydrofuran and water.

[00190] In certain embodiments, a phase transfer catalyst is used in step (b). In certain embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of ammonium salts (e.g., tetrabuty 1 ammonium hydrogen sulfate, tetrabutyl ammonium chloride, b enzyl tributyl ammonium bromide, 1 -methylimidazolium hydrogen sulfate), and phosphonium salts (e.g., tetrabutylphosphonium chloride). In certain embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of tetrabutyl ammonium hydrogen sulfate, tetrab utyl ammonium chloride, benzyltributylammonium bromide, 1 -methylimidazolium hydrogen sulfate, and tetrabutyl p hosphoni um chloride. In particular embodiments, the phase transfer catalyst used in step (b) is tetrabutylammonium hydrogen sulfate.

[00191] In certain embodiments, step (b) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (b) is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, step (b) is carried out in the temperature range of from about 10 °C to about 60 °C.

[00192] In some embodiments, a process for preparing a compound of formula V-5:

V-5

or a co-crystal, solvate, salt, or combination thereof is provided, comprising:

(a) combining a compound of formul a V-A:

V-A

or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent, a base and a solvent to provide a compound of V-6:

V-6

or a co-crystal, solvate, salt, or combination thereof; and

(b) hydrolyzing the compound of formula V-6 or a co-crystal, solvate, salt, or combination thereof, with a nucleophilic reagent, a solvent, and optionally, a phase transfer catalyst to provide the compound of formula V-5 or a co-crystal, solvate, salt, or combination

[00193] In certain embodiments, the mesylating reagent used in step (a) is methanesulfonic anhydride or methanesulfonyl chloride. In certain embodiments, the mesylating reagent used in step (a) is methanesulfonic anhydride. In certain embodiments, the mesylating reagent used in step (a) is methanesulfonyl chloride. [00194] In certain embodiments, the base used in step (a) is selected from the group consisting of tertiary amines (triethylamine, L'-rnethyl iri orphol i ne, tri -n -propyl am in e, ethyl diisopropylamine, tri-n-butylamine, etc.), aromatic amines (pyridine, 2,6-lutidine, collidine, etc.), inorganic bases (sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, etc.), and alkoxide bases (sodium tert-amylate, sodium tert-butoxide, etc). In certain embodiments, the base used in step (a) is selected from the group consisting of triethylamine, A-methylmorpholine, tri-n-propylamine, ethyl

di i sopropyl ami ne, tri-n-butylamine, pyridine, 2,6-lutidine, collidine, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, sodium tert-amylate, and sodium tert-butoxide. In particular embodiments, the base used in step (a) is triethylamine.

[00195] In certain embodiments, the solvent used in step (a) is selected from the group consisting of ethers (diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, etc.), hydrocarbon solvents (toluene, xylenes, etc.), esters (isopropyl acetate, isobutyl acetate, etc.), dichloromethane, acetonitrile, and a combination thereof. In certain embodiments, the solvent used in step (a) is selected from the group of consisting of diethyl ether, l,4-dioxane, 2- methyltetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, and a combination thereof. In particular embodiments, the solvent used in step (a) is 2-m ethyl tetrahy drofuran .

[00196] In certain embodiments, step (a) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, step (a) is carried out in the temperature range of from about -10 °C to about 20 °C.

[00197] In certain embodiments, the nucleophilic reagent used in step (b) is selected from the group consisting of hydroxide bases (sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.), sulfur nucleophiles (sodium ethanethiolate, A-acetylcysteine, sodium thiophenolate, etc.), choline, alkoxide bases (sodium methoxide, sodium ethoxide, potassium ethoxide, sodium «-propoxide, sodium /-propoxide, sodium /-butoxide, etc.), and amines (methyl amine, ethyl amine, «-propylamine, dim ethyl amine, diethylamine, hydroxyl amine, etc.). In particular embodiments, the base used in step (b) is sodium hydroxide. [00198] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ethers (diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane, etc.), hydrocarbon solvents (toluene, xylenes, etc.), esters (isopropyl acetate, isobutyl acetate, etc.), dichloromethane, acetonitrile, polar aprotic sol vents (A(A " -dimethylformamide, A-methyl- 2-pyrrolidone, A/A'-dimethylacetamide, etc), and a combination thereof. In particular

embodiments, the solvent used in step (b) is 2-methyltetrahydrofuran and water.

[00199] In certain embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of ammonium salts (tetrabutylammonium hydrogen sulfate,

tetrabutylammonium chloride, benzyltributylammonium bromide, 1 -methylimidazolium hydrogen sulfate, etc), and phosphonium salts (tetrabutylphosphonium chloride, etc). In particular embodiments, the phase transfer catalyst used in step (b) is tetrabutylammonium hydrogen sulfate.

[00200] In certain embodiments, step (b) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (b) is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, step (b) is carried out in the temperature range of from about 10 °C to about 60 °C.

[00201] In some embodiments, a process for preparing a compound of formul a V-04-A:

V-04-A or a co-crystal, solvate, salt, or combination thereof, wherein R is B(OH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 3 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0), is provided, comprising combining a compound of formula V-6:

V-6 or a co-crystal, solvate, salt, or combination thereof, with a boron coupling agent, a base and a solvent, and a catalyst, to provide the compound of V-04-A, or a co-crystal, solvate, salt, or combination thereof.

[00202] In certain embodiments, R is B(0C(Me) 2 C(Me) 2 0).

[00203] In certain embodiments, the boron coupling agent is selected from the group consisting of bis(pinacolato)diboron, bis(neopentyl glycol ato)diboron, bisboronic acid, and bis(ethylene glycolato diboron). In particular embodiments, the boron coupling agent is bi s( pi nacol ato)di b oron .

[00204] In certain embodiments, the base is selected from the group consisting of cesium acetate, potassium propionate, sodium propionate, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, di cy cl ohexyl amine, N- methylmorpholine, triethylamine, and diisopropyl ethylamine. In particular embodiments, the base is potassium acetate.

[00205] In certain embodiments, the solvent is selected from the group of consisting of ethers (e.g., l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylenes), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol), and polar aprotic solvents (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine,), and a combination thereof. In certain embodiments, the solvent is selected from the group of consisting of 1,4- dioxane, 2-m ethyl tetrahy drofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N- di m ethyl acetami de, N-methyl-2-pyrrolidine, and a combination thereof. In particular embodiments, the solvent is toluene and N,N-dimethylformamide.

[00206] In certain embodiments, the catalyst is selected from the group consisting of bis(di- te/7-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II), bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine]palladium(II) chloride, bis(triphenylphosphine)palladium (II) di chloride, [ 1 , G -bi s(di phenylphosphino)ferrocen e] dichloropal 1 adium(II), [1,2- bis(diphenylphosphino)ethane]dichloropalladium(II), dichloro[9, 9-dimethyl -4,5- bis(diphenylphosphino)xanthene]palladium(II). In certain embodiments, the palladium catalyst is palladium(II) precatalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or palladium(O) precatalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0)) and optionally further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenyl phosphi ne, cyclohexyldiphenylphosphine,

dicyclohexylphenylphosphine). In certain embodiments, the catalyst is palladium(II) chloride, palladium(II) acetate, palladium (II) trifluoroacetate, tetrakis(triphenylphosphine)palladium(0), or bis(dibenzylideneacetone)palladium(0); and the catalyst optionally further comprises a phosphine ligand selected from the group consisting of tricyclohexylphosphine,

triphenylphosphine, cyclohexyldiphenylphosphine, and dicyclohexylphenylphosphine. In particular embodiments, the palladium catalyst is bis(triphenylphosphine)palladium (II) di chloride.

[00207] In certain embodiments, the process is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about 20 °C to about 120 °C. In particular embodiments, the process is carried out in the temperature range of from about 95°C to about 105 °C.

[00208] In some embodiments, a process for preparing a compound of formula V-5:

V-5

or a co-crystal, solvate, salt, or combination thereof is provided, comprising hydrolyzing a compound of formula V-6:

V-6

or a co-crystal, solvate, salt, or combination thereof, with a base, a solvent, and optionally, a phase transfer catalyst, to provide the compound of formula V5 or a co-crystal, solvate, salt, or combination thereof. [00209] In certain embodiments, the base is selected from the group consisting of hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide), sulfur nucleophiles (e.g., sodium ethanethiolate, Y-acetyl cysteine, sodium thiophenolate), choline, alkoxide bases (e.g., sodium methoxide, sodium ethoxide, potassium ethoxide, sodium «-propoxide, sodium /- propoxide, sodium /-butoxide), and amines (e.g., methyl amine, ethylamine, «-propylamine, dimethylamine, diethylamine, hydroxylamine). In certain embodiments, the base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hy droxi de, sodi um ethanethiolate, Y-acetyl cysteine, sodium thiophenolate, choline, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium «-propoxide, sodium z-propoxide, sodium /-butoxide, methylamine, ethylamine, «-propylamine, dimethylamine, diethylamine, and hydroxylamine. In particular embodiments, the base is sodium hydroxide.

[00210] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, l,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane,), hydrocarbon solvents (e.g., toluene, xylenes,), esters (e.g., isopropyl acetate, isobutyl acetate),

dichloromethane, acetonitrile, polar aprotic solvents (e.g., YY-dimethylformarnide, Y-methyl-2- pyrrolidone, Y,zV-dimethyl acetamide), water, and a combination thereof. In certain

embodiments, the solvent is selected from the group consisting of diethyl ether, l,4-dioxane, 2- m ethyl tetrahydrofuran, dimethoxyethane, toluene, xylenes, isopropyl acetate, isobutyl acetate, di chi orom ethane, acetonitrile, /V,zY-dimethylformamide, zV-m ethyl -2-pyrroli done, N,N- dimethylacetamide, water, and a combination thereof In particular embodiments, the solvent is 2-methyltetrahydrofuran and water.

[00211] In some embodiments, the process comprises a phase transfer catalyst. In some embodiments, the phase transfer catalyst is selected from the group consisting of ammonium salts (e.g., tetrabutyl ammonium hydrogen sulfate, tetrabutyl ammonium chloride,

benzyltributylammonium bromide, 1 -methylimidazolium hydrogen sulfate), and phosphonium salts (e.g., tetrabutylphosphonium chloride). In some embodiments, the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydrogen sulfate,

tetrabutyl ammonium chloride, benzyltributylammonium bromide, 1 -methylimidazolium hydrogen sulfate, phosphonium salts, and tetrabutylphosphonium chloride. In particular embodiments, the phase transfer catalyst is tetrabu ty 1 am m oni um hydrogen sulfate.

[00212] In some embodiments, the process is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -20 °C to about 100 °C. In particul ar embodiments, the process is carried out in the temperature range of from about 10 °C to about 60 °C. [00213] In some embodiments, a process for preparing a compound of formula V-03-A:

V-03-A or a co-crystal, solvate, salt, or combination thereof, wherein R is B(GH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 3 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0), is provided, comprising combining a compound of formula V-5:

or a co-crystal, solvate, salt, or combination thereof, with a boron coupling agent, a base, a solvent, and a catalyst, to provide the compound of V-03-A, or a co-crystal, solvate, salt, or combination thereof.

[00214] In certain embodiments, R is B(0C(Me) 2 C(Me) 2 0).

[00215] In certain embodiments, the boron coupling agent is selected from the group consisting of bis(pinacolato)diboron, bis(neopentyl glycolato)diboron, bisboronic acid, and bis(ethylene glycolato diboron). In particular embodiments, the boron coupling agent is bis(pinacolato)diboron.

[00216] In certain embodiments, the base is selected from the group consisting of cesium acetate, potassium propionate, sodium propionate, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide, dicyclohexylamine, N- methylmorpholine, triethylamine, and dii sopropyl ethyl amine . In particular embodiments, the base is potassium acetate. [00217] In certain embodiments, the solvent is selected from the group of consisting of ethers (e.g., l,4-dioxane, 2 -methyl tetrahydrofuran, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylenes), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol), and polar aprotic solvents (e.g., N,N- dimethylformamide, N,N -dimethyl acetamide, N-methyl-2-pyrrolidine, etc.), and a combination thereof. In certain embodiments, the solvent is selected from the group of consisting of 1,4- dioxane, 2-m ethyl tetrahydrofuran, dimethoxyethane, toluene, xylenes, ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate, ethanol, isopropanol, N,N-dimethylformamide, N,N- di m ethyl acetami de, N-methyl-2-pyrrolidine, and a combination thereof. In particular embodiments, the solvent is toluene and N,N-dimethylformamide.

[00218] In certain embodiments, the catalyst is selected from the group consisting of bis(di- /e/7-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II), bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine]palladium(II) chloride, bis(triphenylphosphine)palladium (II) di chloride, [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2- bis(diphenylphosphino)ethane]dichloropalladium(II), and dichloro[9,9-dimethyl-4,5- bis(dipheny{phosphino)xanthene]palladium(II). In certain embodiments, the catalyst is palladium(II) precatalyst (e.g., palladium(II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or palladium(O) precatalyst (e.g., tetrakis(triphenylphosphine)palladium(0), bi s(dib enzy 1 i den eaceton e)pal 1 adium (0)) and further comprises a phosphine ligand (e.g., tricyclohexylphosphine, triphenylphosphine, cyclohexyl diphenylphosphine,

dicyclohexylphenylphosphine). In certain embodiments, the catalyst comprises pall adium (II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate,

tetrakis(tri phenyl phosphine)palladium(O), or bi s(dibenzylideneacetone)pall adium(0), and the catalyst optionally further comprises a phosphine ligand selected from the group consisting of tricyclohexylphosphine, triphenylphosphine, cyclohexyl diphenyl phosphine, and

dicyclohexylphenylphosphine. In particular embodiments, the palladium catalyst is

bis(triphenylphosphine)pall adium (II) di chloride.

[00219] In certain embodiments, the process is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about 20 °C to about 120 °C. In particular embodiments, the process is carried out in the temperature range of from about 95°C to about 105 °C.

[00220] In some embodiments, a process for preparing a compound of formula VIII:

VIII

or a co-crystal, solvate, salt, or combination thereof is provided, comprising resolving a compound of formula X:

X

or a co-crystal, solvate, salt, or combination thereof, with a chiral acid in a solvent and optionally in the presence of an aldehyde catalyst and/or optionally a metal catalyst, to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

[00221] In some embodiments, a process for preparing a compound of formula VIII:

VIII

or a co-crystal, solvate, salt, or combination thereof is provided, comprising resolving a compound of formula X:

X or a co-crystal, solvate, salt, or combination thereof, with a chiral acid in a solvent, to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

[00222] In some embodiments, the compound of formula VIII is a compound of formula

VIII-02:

or a co-crystal, solvate, or combination thereof, wherein HX is a chiral acid selected from the group consisting of lactic acid, L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L-glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1 R, 3V)-(+)-camphoric acid, (l£)-(+)-camphor-lO- su!fonic acid, (R)-(+)-7V-(l- phenyl ethyl ) succi nam i c acid, carbobenzyloxy-L-proline, di benzoyl - L-tartaric acid, (7?)-(+)-3 -methyladipic acid, (+)-menthyl oxy aceti c acid, (-)-pyroglutamic acid,(- [-/V- acetyl -L-l euci ne, (-)-V-acetyl-D-leucine, V-Boc-D-leucine, V-(+)-BOC-phenylalanine, (-)- quinic acid, (+)-«-acetyl-L-phenylalanine, (+)-V-BOC-isoleucine, L-(-)-acetyl glutamic acid, (- )-acetyl mandelic acid, (A)-(-)-citramalic acid, (-)-camphanic acid, and (A)-mandelic acid.

[00223] In some embodiments, the compound of formula VIII is a compound of formula

VIII-02:

[00224] or a co-crystal, solvate, or combination thereof, wherein HX is a chiral acid selected from the group consisting of lactic acid, L-(+ [-tartaric acid, L-aspartic acid, L-glutamic acid, L- (-)-malic acid, D-glucuronic acid, (1 R, 3V)-(+)-camphoric acid, ( l£)-(+)-camphor- 10-sulfonic acid, (R)-(+)-A' r -(l- ph enyl ethyl ) succi nami c acid, carb ob enzyl oxy- L-proli ne, dibenzoyl-L- tartaric acid, (i?)-(+)-3 -methyladipic acid, (+)-menthyloxy acetic acid, (-)-pyroglutamic acid,(-)- V-acetyl-L-leucine, V-Boc-D-leucine, V-^-BOC-phenylalanine, (-)-quinic acid, (+)-«-acetyl- L-phenylalanine, (+)-V-BOC-isoleucine, L-( )-acetyl glutamic acid, (-)-acetyl mandelic acid, (i?)-(-)-citramalic acid, (-)-camphanic acid, and (f?)-mandelic acid. In some embodiments, HX is V-Boc-D-leucine or (-)-iV-acetyl-D-leucine. In some embodiments, HX is (i?)-mandelic acid in some embodiments, HX is A'-Boc-D-leucine.

[00225] In some embodiments, HX is (-^N-acetyl-D-leucine.

[00226] In certain embodimetns, the solvent is selected from the group consisting of a hydrocarbon solvent (e.g., n-heptane), an ether (e.g., diethyl ether, methyl /ert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), a chlorinated solvent (e.g., dichloromethane), an alcohol (e.g., methanol, ethanol, 1 -propanol, isopropanol), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), water, an ester (e.g..ethyl acetate, butyl acetate, isobutyl acetate,),

dichloroethane, chloroform, polar aprotic solvents (e.g., A^/V-dimethylformamide, NN- dimethylacetamide, JV-methylpyrrolidinone, dimethyl sulfoxide), nitriles (e.g., acetonitril e, propionitrile, butyronitrile), and a combination thereof.

[00227] In certain embodiments, the solvent is selected from the group consisting of a hydrocarbon solvent (e.g., n-heptane), an ether (e.g., diethyl ether, methyl ieri- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), a chlorinated solvent (e.g., di chi orom ethane), an alcohol (e.g., methanol, ethanol, 1 -propanol, isopropanol), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutylketone), water, and a combination thereof. In particular embodiments, the solvent is methyl fert-butyl ether and toluene.

[00228] In particular embodiments, the solvent is toluene.

[00229] In certain embodiments, the process is carried out in the presence of an aldehyde catalyst and/or a metal catalyst. In certain embodiments, the aldehyde catalyst is selected from the group consisting of aromatic aldehydes (e.g., benzaldehyde, 2,4-dichlorobenzaldehyde, 2- methoxybenzaldehyde, 4-(dimethylamino)benzaldehyde, 2-(dimethylamino)benzaldehyde, 2- hy droxy- 5 -methoxyb enzal dehy de, 2-hydroxy-5-nitrobenzaldehyde, 5-chloro-2- hy dr oxyb enzal deh y de, 4-hy droxyb enzal dehy de, 2-hydroxybenzaldehyde, 3,5-dichloro-2- hy droxyb enzal dehy de, 3 -hy droxyb enzal dehy de, 2-hydroxy-3-nitrobenzaldehyde,),

heteroaromatic aldehydes (e.g., 2-formylpyridine, 3-(trifluoromethyl)picolinaldehyde, 4- chl oropi colinal dehyde, nicotinaldehyde, quinolone-4-carbaldehyde, quinolone-2-carb aldehyde, etc.), and aliphatic aldehydes (e.g., formaldehyde, ethylglyoxylate, glyoxylic acid). In certain embodiments, the metal catalyst is selected from the group consisting of zinc salts (e.g., zinc(II) oxide, zinc(II) acetate, zinc(II) trifluoromethanesulfonate, zinc(II) trifluoroacetate, zinc(II) chloride, zinc (II) stearate, zinc (II) neodecanoate, zinc (II) tetrafluoroborate); nickel salts (e.g., nickel(II) acetate, nickel(II) chloride, nickel (II) triflate); indium salts (e.g., indium (III) acetate); copper salts (e.g., copper(II) acetate); cobalt salts (e.g., cobalt(II) acetate); and manganese salts (e.g., manganese(II) acetate). In certain embodiments, the process is carried out in the presence of an aldehyde catalyst and/or a metal catalyst. In particular embodiments, the process is carried out in the presence of an aldehyde catalyst and a metal catalyst. In particular embodiments, the aldehyde catalyst is 2-formylpyridine and the metal catalyst is zinc(II) oxide.

[00230] In some embodiments, the process is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -20 °C to about 120 °C. In particular embodiments, the process is carried out in the temperature range of from about -20 °C to about 50 °C. In some embodiments, the process is carried out at a temperature of about 35°C.

[00231] In some embodiments, the process is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, the process is carried out in the temperature range of from about -20 °C to about 20 °C. In particular embodiments, the process is carried out at a temperature of about 35°C.

[00232] In certain embodiments, the compound of formula X may be treated with a base in a first solvent before the resolving. In certain embodiments, the base is selected from the group consisting of potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, ammonium hydroxide, potassium phosphate dibasic, potassium phosphate tribasic, sodium phosphate dibasic, and sodium phosphate tribasic. In particular embodiments, the base is sodium hydroxide. In certain embodiments, the first solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl te /-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, l,4-dioxane), aromatic solvents (e.g., benzene, xylenes), chlorinated solvents (e.g., dichloromethane), and a combination thereof. In certain embodiments, the first solvent is selected from the group consisting of diethyl ether, methyl tert- butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, l,4-dioxane, aromatic solvents, dichloromethane, and a combination thereof. In particular embodiments, the solvent is 2- methyltetrahydrofuran. In certain embodiments, the compound of formula X is treated with a base in a first solvent at the temperature range of from about 0 °C to about 100 °C. In certain embodiments, the compound of formula X is treated with a base in a first solvent at the temperature range of from about 10 °C to about 50 °C. [00233] In some embodiments, a process for preparing a compound of formula la: la or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining 2,5- dibromopyridine: with an electrophile, a base and a solvent to provide a compound of formula la or a co-crystal, solvate, salt, or combination thereof.

[00234] In some embodiments, the electrophile is selected from the group consisting of formyl ated amines (e.g., iV,iV-diethylformamide, 1 -formylpyrrolidine, 4-formylmorpholine, N- methylform anilide); formate esters (e.g., cyanomethyl formate, phenyl formate, ethyl formate, trifluoroethyl formate); ortho esters (e.g., tri ethyl orthoformate, diethyl phenyl orthoformate); formamide acetals (e.g., /V.A^-dimethylformamide dipropyl acetal, A^V-dimethylformamide dimethyl acetal); and (chloromethylene)dimethyliminium chloride. In particular embodiments, the electrophile is A^-dimethylform amide.

[00235] In some embodiments, the base is selected from the group consisting of 2, 2,6,6- tetramethylpiperidinylmagnesium chloride lithium chloride complex, n-butyllithium, i sopropylmagnesium chloride lithium chloride complex, seobutylmagnesium chloride lithium chloride complex, phenyllithium, phenylmagnesium chloride, n-butyllithium lithium N,N- dimethylaminoethanol complex, mesityllithium, lithium di -i sopropyl ami d e, phenyllithium, lithium 2,2,6,6-tetramethylpiperidide, lithium dichloro(2,2,6,6-tetramethylpiperidinato)zincate, and lithium di-tert-butyl-(2,2,6,6-tetramethylpiperidino)zincate. In particular embodiments, the base is 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex.

[00236] In some embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl fe/7-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane, dimethoxyethane), aromatic solvents (e.g., benzene, toluene, xylenes) amines (e.g., triethylamine, ethyldiisopropylamine), cyclic amides (e.g., iV-ethyl-2-pyrrolidone, iV-methyl-2- pyrrolidone, A'-butyl-2-pyrrolidone), urea derivatives (e.g., /V, ;V-di methyl propyl ene urea) and a combination thereof. In particular embodiments, the solvent is tetrahydrofuran. In some embodiments, the process is carried out in the temperature range of from about 50 °C or less. In certain embodiments, the process is carried out in the temperature range of from about - 80 °C to about 50 °C. In particular embodiments, the process is carried out in the temperature range of from about -40 °C to about 0 °C.

[00237] In some embodiments, a process for preparing a compound of formula X:

X

or a co-crystal, solvate, salt, or combination thereof is provided, comprising:

(a) condensing a compound of formula la: la or a co-crystal, solvate, salt, or combination thereof, with a suitable amine (e.g.,

aminodiphenylmethane) in a solvent, and optionally in the presence of an additive, to provide a compound of formula lb:

lb

or a co-crystal, solvate, salt, or combination thereof, wherein R 4 and R 5 are each independently hydrogen, methyl, phenyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzylamine, or 4- methoxybenzyl;

(b) alkylating the compound of formula lb, or a co-crystal, solvate, salt, or combinati on thereof, with a compound of formula lc: lc

wherein Y is Br, Cl, I, OMs, OTs, or 0S0 2 CF 3 , in the presence of a base and optionally a phase transfer catalyst, in a solvent to provide a compound of formula Id:

Id

or a co-crystal, solvate, salt, or combination thereof; and

(c) deprotecting the compound of formula Id with an acid in a solvent to provide a compound of formula X:

or a co-crystal, solvate, salt, or combination thereof.

[00238] In some embodiments, a process for preparing a compound of formula X:

X

or a co-crystal, solvate, salt, or combination thereof is provided, comprising:

(a) condensing a compound of formula la: or a co-crystal, solvate, salt, or combination thereof, with a suitable amine (e.g.,

aminodiphenylmethane) in a solvent to provide a compound of formula lb:

lb

or a co-crystal, solvate, salt, or combination thereof, wherein R 4 and R 3 are each independently hydrogen, methyl, phenyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzylamine, or 4- methoxybenzyl;

(b) alkylating the compound of formula lb, or a co-crystal, solvate, salt, or combination thereof, with a compound of formula lc: lc wherein Y is Br, Cl, I, OMs, OTs, or OSO 2 CF 3 , in the presence of a base and optionally, a phase transfer catalyst, in a solvent to provide a compound of formula Id:

Id or a co-crystal, solvate, salt, or combination thereof; and

(c) deprotecting the compound of formula Id with an acid in a solvent to provide a compound of formula X:

X

or a co-crystal, solvate, salt, or combination thereof.

[00239] In some embodiments, the suitable amine for forming the compound of formula lb, or a co-crystal, solvate, salt, or combination thereof, is aminodiphenylamine, benzylamine, 4- nitrob enzyl amine, 4-chlorobenzylamine, 4-bromobenzylamine, 4-methoxybenzylamine, or a- methylbenzylamine. In some embodiments, the suitable amine for forming the compound of formula lb, or a co-crystal, solvate, salt, or combination thereof, is aminodiphenylamine.

[00240] In some embodiments, the compound of formula lb, or a co-crystal, solvate, salt, or combination thereof, is a compound of formula lb-02:

lb-02

or a co-crystal, solvate, salt, or combination thereof.

[00241] In some embodiments, the compound of formula Id, or a co-crystal, solvate, salt, or combination thereof, is a compound of formula ld-02:

ld-02

or a co-crystal, solvate, salt, or combination thereof.

[00242] In certain embodiments, the solvent for the condensing step (a) is selected from the group consisting of an ether ( e.g ., diethyl ether, methyl tert-bu yX ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane), an ester (e.g., ethyl acetate, isopropyl acetate), a polar aprotic solvent (e.g., AAV-dimethylformamide, iV,A r -dimethylacetamide, A-methylpyrrolidinone), a nitrile (e.g., acetonitrile), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), a chlorinated solvent (e.g., di chi orom ethane), and a combination thereof. In particular

embodiments, the solvent for the condensing step (a) is toluene.

[00243] In some embodiments, the condensing step (a) is performed in the presence of an additive,. In certain embodiments, the additive used in the condensation step (a) is a

dehydrating reagent (e.g., magnesium sulfate).

[00244] In certain embodiments, the condensing step (a) is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the condensing step (a) is carried out in the temperature range of from about -20 °C to about 120 °C. In particul ar embodi m ents, the condensing step (a) is carried out in the temperature range of from about 20 °C to about 90 °C. In particular embodiments, the condensing step (a) is carried out in the temperature range of from about 20 °C to about 80 °C.

[00245] In certain embodiments, Y is Br, Cl, or I. In particular embodiments, Y is Br.

[00246] In certain embodiments, the base for the alkylating step (b) is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium ethoxide, sodium fe/7-butoxide, sodium fer/-pentoxide, potassium fert-butoxide, triethylamine, dii sopropyl ethyl ami ne, l,8-diazabicyclo[5.4.Q]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, i sopropylmagnesium chloride lithium chloride complex, sec- butylmagnesium chloride, lithium chloride complex, n-butyl lithium, lithium N,N- dimethylaminoethanol complex, mesityllithium, lithium di -i sopropyl ami de, and phenyllithium.

In particular embodiments, the base for the alkylating step (b) is potassium hydroxide.

[00247] In certain embodiments, a phase transfer catalyst is used in the alkylating step (b).

[00248] In certain embodiments, the phase transfer catalyst for the alkylating step (b) is selected from the group consisting of tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetramethylammonium hydrogen sulfate,

tetraethylammonium chloride, tetraethyl ammoni um bromide, tetra-n-butyl-ammonium bromide, tetraethyl am m onium iodide, tetraethylammonium hydrogen sulfate, and

benzyltrimethylammonium. In particular embodiments, the phase transfer catalyst for the alkylating step (b) is tetra-n-butyl-ammonium bromide.

[00249] In certain embodiments, the solvent for the alkylating step (b) is selected from the group consisting of diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2- m ethyl tetr ahy dr of ur an , l,4-dioxane, iYA-dimethylform amide, AfA-dimethylacetami de, N- methylpyrrolidinone, benzene, xylenes, toluene, dichloromethane, water, and combinations thereof. In parti cular embodiments, the solvent for the alkylating step (b) is a mixture of toluene and water.

[00250] In certain embodiments, the compound of formula lc is selected from the group consisting of 3,5-difluorobenzyl bromide, 3,5-difluorobenzyl chloride, 3 , 5 -difluorobenzyl mesylate, 3 , 5 -difluorobenzyl iodide, 3 , 5 -di fluorob enzyl triflate, and 3 , 5 -difluorobenzyl tosylate. In particular embodiments, the compound of formula lc is 3 , 5 -difl uorobenzyl bromide.

[00251] In certain embodiments, the alkylating step (b) is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the alkylating step (b) is carried out in the temperature range of from about -20 °C to about 120 °C. In particular embodiments, the alkylating step (b) is carried out in the temperature range of from about 10 °C to about 80 °C.

[00252] In certain embodiments, the acid for the deprotecting step (c) is selected from the group consisting of hydrochloric acid, hydrobromic acid, methanesulfonic acid,/

toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, formic acid, and oxalic acid. In particular embodiments, the acid for the deprotecting step (c) is

methanesulfonic acid.

[00253] In particular embodiments, the acid equivalent is 1 to 10. In particular embodiments, the acid equivalent is 1 to 3.

[00254] In certain embodiments, the solvent for the deprotecting step (c) is selected from the group consisting of an ether ( e.g ., diethyl ether, methyl ferf-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), a chlorinated solvent (e.g., dichloromethane), and a combination thereof. In particular embodiments, the solvent for the deprotecting step (c) is 2-methyltetrahydrofuran.

[00255] In certain embodiments, the deprotecting step (c) is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the deprotecting step (c) is carried out in the temperature range of from about -40 °C to about 120 °C. In particular embodiments, the deprotecting step (c) is carried out in the temperature range of from about 10 °C to about 40 °C.

[00256] In some embodiments, a process for forming the compound of formula X:

X

or a co-crystal, solvate, salt, or combination thereof is provided, comprising:

(a) combining a compound of formula CΪΪΪ:

or a co-crystal, solvate, salt, or combination thereof, with a mesylating reagent, a base, a solvent, and optionally an additive, to provide a compound of formula XIII- A:

XIII-A

or a co-crystal, solvate, salt, or combination thereof: and

(b) combining the compound of formula XIII-A or a co-crystal, solvate, salt, or combination thereof, with an amination reagent and optionally a solvent, to provide the compound of formula X: or a co-crystal, solvate, salt, or combination thereof.

[00257] In certain embodiments, the mesylating reagent for mesylating step (a) is selected from the group consisting of methanesulfonyl chloride and methanesulfonic anhydride. In particular embodiments, the mesylating reagent is methanesulfonyl chloride.

[00258] In certain embodiments, the base for mesylating step (a) is selected from the group consisting of tri ethyl amine, dii sopropyl eth yl ami ne, pyridine, 2, 3, 5-collidine, 2,4,6-collidine, AAV-dicyclohexylmethylamine, and iV-methylimidazole. In particular embodiments, the base for the mesylating step is tri ethyl amine.

[00259] In certain embodiments, mesylating step (a) uses an additive. In particular embodiments, the additive for step (a) is selected from the group consisting of 4- (dimethylamino)pyridine (DMAP), A’-methylimidazole, pyridine A-oxide,

diphenyl cyclopropenone, and antimony pentachloride. In some embodiments, the additive for step (a) is 4-(dimethylamino)pyridine (DMAP).

[00260] In certain embodiments, the solvent for mesylating step (a) is selected from the group consisting of an ether (e.g., diethyl ether, methyl te 7-butyl ether, tetrahydrofuran, 2- m ethyl tetr ahy dr of ur an , 1,4-dioxane), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), a polar aprotic solvent (e.g., AyV-dimethylformamide, AyV-dimethylacetamide, N- methylpyrrolidinone), a chlorinated solvent (e.g., dichlorom ethane), and a combination thereof. In particular embodiments, the solvent for mesylating step (a) is tetrahydrofuran.

[00261] In certain embodiments, the mesylating step (a) is carried out in the temperature range of from about 60 °C or less. In certain embodiments, the mesylating step (a) is carried out in the temperature range of from about -80 °C to about 60 °C. In particular embodiments, the mesylating step (a) is carried out in the temperature range of from about 0 °C to about 40 °C.

[00262] In certain embodiments, the ami nation reagent for the aminating step (b) is ammonia.

[00263] In certain embodiments, the aminating step (b) comprises a solvent. [00264] In certain embodiments, the solvent for the aminating step (b) is selected from the group consisting of an alcohol (e.g · ., methanol, ethanol, 1 -propanol, i sopropanol), an ether (e.g., diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2-m ethyltetrahydrofuran, 1 ,4-dioxane), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), water, and a combination thereof. In particular embodiments, the solvent for the aminating step (b) is methanol and water.

[00265] In certain embodiments, the aminating step (b) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the aminating step (b) is carried out in the temperature range of from about 0 °C to about 100 °C. In particualr embodiments, the aminating step (b) is carried out in the temperature range of from about 40 °C to about 80 °C.

[00266] In alternative embodiments, the compound of formula XIII-A:

XIII-A

or a co-crystal, solvate, salt, or combination thereof may be combined with an amine equivalent (e.g., di-fer/-buty!-iminodicarboxylate, phthalimide, benzylamine, dibenzylamine,

hexamethyldisilazane) followed by deprotection (using, e.g., hydrochloric acid, hydrazine, hydrogen, Pd/C) to provide the compound of formula X:

or a co-crystal, solvate, salt, or combination thereof.

[00267] In some embodiments, a process for preparing a compound of formula VIII:

or a co-crystal, solvate, salt, or combination thereof is provided, comprising:

(a) hydrogenating a compound of formula XI:

XI

or a co-crystal, solvate, salt, or combination thereof, in the presence of an asymmetric catalyst and a solvent to provide a compound of formula XII:

or a co-crystal, solvate, salt, or combination thereof;

(b) forming the azide of the compound of formula XII or a co-crystal, solvate, salt, or combination thereof with an azidification reagent in the presence of a base and a solvent to produce a compound of formula XVI:

or a co-crystal, solvate, salt, or combination thereof; and

(c) reducing the compound of formula XVI using a reducing agent, to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

[00268] In certain embodiments, the asymmetric catalyst for hydrogenating step (a) is selected from the group consisting of [Rh(cod)((.S)-segphos]BF 4 , IrCl(cod)((5)-segphos),

[RuCl(p-cymene)(segphos)]Cl, Ru(OAc)2(segphos), Me 2 NH 2 )[RuCl((5)-segphos)] 2 ^-Cl) 3 , and (f?)-RuCY-XylBINAP. In particular embodiments, the asymmetric catalyst is (f?)-RuCY- XylBINAP.

[00269] In certain embodiments, wherein the solvent for the hydrogenating step (a) is selected from the group consisting of an ester (e.g., isopropyl acetate, n-propyl acetate), an alcohol (e.g., ethanol, 1 -propanol, isopropanol), an ether (e.g., diethyl ether, methyl fe/7-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), a chlorinated solvent (e.g., dichloromethane, 1 ,2-dichloroethane, chloroform), and a combination thereof. In particular embodiments, the solvent for the hydrogenating step is ethanol and isopropanol.

[00270] In certain embodiments, the hydrogenating step (a) is carried out in the temperature range of from about 150 °C or less. In certain embodiments, the hydrogenating step (a) is carried out in the temperature range of from about -20 °C to about 150 °C. In particul ar embodiments, the hydrogenating step (a) is carried out in the temperature range of from about 0 °C to about 60 °C.

[00271] In certain embodiments, the azidifi cation reagent for step (b) is methanesulfonyl chloride and sodium azide or diphenylphosphoryl azide. In particular embodiments, the azidification reagent is diphenylphosphoryl azide.

[00272] In certain embodiments, the base for step (b) is selected from the group consisting of triethylamine, diisopropylethylamine, AvV-dimethylaminopyridine, and 1,8- diazabicyclo[5.4.0]undec-7-ene. In particular embodiments, the base is 1,8- di azabicycl o [ 5.4.0] undec-7-ene .

[00273] In certain embodiments, the solvent for steps (b) and (c) is selected from the group consisting of an ether (e.g., diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2- m ethyl tetrahydrofuran, 1,4-dioxane), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), a polar aprotic solvent (e.g., AVV-dimethylformamide, iV,A r -dimethylacetamide, N- methylpyrrolidinone), a chlorinated solvent (e.g., dichloromethane), and a combination thereof. In particular embodiments, the solvent for steps (b) and (c) is tetrahydrofuran.

[00274] In certain embodiments, steps (b) and (c) are carried out in the temperature range of from about 60 °C or less. In certain embodiments, steps (b) and (c) are carried out in the temperature range of from about -10 °C to about 60 °C. In particular embodiments, steps (b) and (c) are carried out in the temperature range of from about 0 °C to about 40 °C. In certain embodiments, the reducing agent for reducing step (c) is selected from the group consisting of trimethyl phosphine, triethylphosphine, trimethylphosphite, triethylphosphite, tributylphosphine, trifurylphosphine, tris(hydroxymethyl)phosphine, and triphenylphosphine. In particular embodiments, the reducing agent is triphenylphosphine.

[00275] In certain embodiments, the reducing step (c) is carried out in the temperature range of from about 60 °C or less. In certain embodiments, the reducing step (c) is carried out in the temperature range of from about -10 °C to about 60 °C. In particular embodiments, the reducing step (c) is carried out in the temperature range of from about 0 °C to about 40 °C.

[00276] In some embodiments, a process for preparing a compound of formula VIII:

or a co-crystal, solvate, salt, or combination thereof is provided, comprising:

(a) combining a compound of formula XI:

XI or a co-crystal, solvate, salt, or combination thereof, with a hydroxyl amine source, a base and a solvent to provide a compound of formula le:

or a co-crystal, solvate, salt, or combination thereof;

(b) combining the compound of formula le with a reducing agent, an acylating reagent, and a solvent to provide a compound of formula lf-1 :

or a co-crystal, solvate, salt, or combination thereof, wherein R 6 is selected from the group consisting of acetyl, benzyl, trichloroacetyl, trifluoroacetyl, and propionyl; and

(c) hydrogenating the compound of formula lf-1 with a catalyst and a solvent to provide a compound of formula lg-1:

or a co-crystal, solvate, salt, or combination thereof; and

(d) deprotecting the compound of lg-1 with an acid and a solvent to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

[00277] In certain embodiments, R 6 is selected from the group consisting of acetyl, _benzyl, trichloroacetyl, trifluoroacetyl, and propionyl. In particular embodiments, R 6 is acetyl.

[00278] In certain embodiments, the hydroxylamine source for step (a) is selected from hydroxylamine hydroxide.

[00279] In certain embodiments, the solvent for step (a) is selected from the group consisting of esters (e g., n-propyl acetate, i sopropyl acetate), alcohols (e.g., methanol, 1- or 2-propanol, ethanol), ethers (e.g., diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2- m ethyl tetr ahy dr of ur an , 1,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylenes), chlorinated solvents (e.g., dichloromethane, chloroform, 1 ,2-dichloroethane) and a combination thereof. In certain embodiments, the solvent for step (a) is selected from the group consisting of n-propyl acetate, isopropyl acetate, methanol, 1- or 2-propanol, diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylenes, di chi oromethan e, chloroform, 1 ,2-dichloroethane, and a combination thereof. In particular embodiments, the solvent for step (a) is ethanol.

[00280] In certain embodiments, the base for step (a) is selected from the group consisting of tertiary amines (e.g., pyridine, triethylamine, tri -«-propyl amine, tri-«-butylamine, N- methylmorpholine, L-methylpyrrolidine, /V-methylpiperidine), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), carboxyl ate bases (e.g., sodium acetate, lithium pivalate), alkoxide bases (e.g., sodium ethoxide, potassium ethoxide, sodium tert- butoxide), sodium hydride, and di si 1 azide bases (e.g., lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide). In certain embodiments, the base for step (a) is selected from the group consisting of pyridine, triethylamine, tri -«-propyl amine, tri-«- butylamine, /V-methylmorpholine, V-methylpyrrolidine, /V-methylpiperidine, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, lithium pivalate, sodium ethoxide, potassium ethoxide, sodium /er/-butoxide, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. In particular embodiments, the base for step (a) is pyridine.

[00281] In certain embodiments, step (a) is carried out in the temperature range of from about 150 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about 0 °C to about 150 °C. In particular embodiments, step (a) is carried out in the temperature range of from about 10 °C to about 60 °C. In particular embodiments, step (a) is carried out in the temperature range of about 20 °C.

[00282] In certain embodiments, the reducing agent for step (b) is selected from the group consisting of hydrogenation agents (e.g., palladium on carbon, hydrogen), iron(II)acetate, samarium diiodide, titanium(IV) tetrachl ori de/tin(II) chloride, and metallic zinc. In certain embodiments, the reducing agent for step (b) is selected from the group consisting of palladium on carbon, hydrogen, iron(II)acetate, samarium diiodide, titanium(IV) tetrachl ori de/tin(II) chloride, and metallic zinc. In particular embodiments, the reducing agent is iron(II)acetate. In some embodiments, the reducing agent is iron(II)acetate prepared in situ.

[00283] In certain embodiments, the acylating reagent for step (b) is selected from the group consisting of acid chlorides (e.g., acetyl chloride, trichloroacety! chloride), anhydrides (e.g., acetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride), and alkyl halides (e.g., benzyl chloride, benzyl bromide). In certain embodiments, the acylating reagent for step (b) is selected from the group consisting of acetyl chloride, trichloroacetyl chloride, acetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, benzyl chloride, and benzyl bromide. In particular embodiments, th acylating reagent is acetic anhydride.

[00284] In certain embodiments, the solvent for step (b) is selected from the group consisting of acetic acid, esters (e.g., n -propyl acetate, isopropyl acetate, acetate), alcohols (e.g., methanol,

1 -propanol, 2-propanol), ethers (e.g., diethyl ether, methyl fcrt-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylenes), chlorinated solvents (e.g., di chi or om ethane, chloroform, 1 ,2-dichloroethane) and a combination thereof. In certain embodiments, the solvent for step (b) is selected from the group consisting of acetic acid, n-propyl acetate, isopropyl acetate, acetate, methanol, 1- or 2-propanol, diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, toluene, benzene, xylenes, di chi or om ethane, chloroform, 1 ,2-dichloroethane and a combination thereof. In particular embodiments, the solvent for the step (b) is isopropyl acetate and acetic acid. [00285] In certain embodiments, step (b) is carried out in the temperature range of from about 150 °C or less. In certain embodiments, step (b) is carried out in the temperature range of from about 0 °C to about 150 °C. In particular embodiments, step (b) is carried out in the temperature range of from about 30 °C to about 70 °C. In particular embodiments, step (b) is carried out in the temperature range of about 50 °C.

[00286] In certain embodiments, the catalyst for step (c) is selected from the group consisting of IrCl(cod)((ri)-segphos), Rh(cod)((ri’)-segphos]BF 4 , and (Me2Mi 2 )[RuCl(CS’)-segphos)]2(p-Cl)3. In particular embodiments, the catalyst is (IrCl(cod)((ri)-segphos).

[00287] In certain embodiments, the solvent for step (c) and step (d) is selected from the group consisting of esters (e.g., ethyl acetate, n-propyl acetate, isopropyl acetate), alcohols (e.g., ethanol, 1 -propanol, 2-propanol), ethers (e.g., diethyl ether, methyl fer/-butyl ether,

tetrahydrofuran, 2-methyl tetrahydrofuran, l,4-dioxane,), aromatic solvents (e.g., toluene, benzene, xylenes), chlorinated solvents (e.g., di chi orom ethane, chloroform, 1 ,2-dichloroethane) and a combination thererof. In certain embodiments, the solvent for step (c) and step (d) is selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, ethanol, 1- or 2-propanol, diethyl ether, methyl ferf-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane, toluene, benzene, xylenes, dichloromethane, chloroform,

1 ,2-dichloroethane and a combination thereof. In particular embodiments, the solvent for step (c) and step (d) is ethyl acetate.

[00288] In certain embodiments, step (c) is carried out in the temperature range of from about 150 °C or less. In certain embodiments, step (c) is carried out in the temperature range of from about 0 °C to about 150 °C. In particular embodiments, step (c) is carried out in the temperature range of from about 80 °C to about 150 °C.

[00289] In certain embodiments, the acid for step (d) is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, methanesulfonic acid, and -toluenesulfonic acid. In particular embodiments, the acid for step (d) is hydrochloric acid.

[00290] In certain embodiments, step (d) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (d) is carried out in the temperature range of from about 20 °C to about 100 °C. In particular embodiments, step (d) is carried out in the

temperature range of from about 20 °C to about 80 °C.

[00291] In some embodiments, a process for preparing a compound of formula VIII:

VIII

or a co-crystal, solvate, salt, or combination thereof is provided, comprising reductively aminating a compound of formula XI:

XI

or a co-crystal, solvate, salt, or combination thereof, with:

a hydrogen source,

a catalyst,

an amine,

an acid, and

a solvent,

to provide the compound of formula VIII or a co-crystal, solvate, salt, or combination thereof.

[00292] In certain embodiments, the hydrogen source is selected from the group consisting of hydrogen gas, ammonium formate, and formic acid triethylamine complex. In particular embodiments, the hydrogen source is hydrogen gas.

[00293] In certain embodiments, the solvent is selected from the group consisting of an ether ( e.g ., diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane), an aromatic hydrocarbon solvent (e.g., benzene, xylenes), a polar aprotic solvent (e.g., AyV-dimethylformamide, VJV-dimethylacetamide, iV-methylpyrrolidinone, dimethylsulfoxide), an alcohol (e.g., methanol, isopropanol, tert-a y\ alcohol), water, and a combination thereof. In particular embodiments, the solvent is methanol. [00294] In certain embodiments, the water is at pH 6-10.

[00295] In certain embodiments, the catalyst is an asymmetric catalyst or an enzymatic catalyst.

[00296] In certain embodiments, the catalyst is an asymmetric catalyst. In some

embodiments, the asymmetric catalyst is a ruthenium or iridium catalyst with a chiral ligand (e.g., SegPhos, DM-SegPhos, tert-buty 1 - Josiphos, DuPhos, MonoPhos, or BINAP). In particular embodiments, the catalyst is a ruthenium or iridium catalyst selected from the group consisting of RuCl 3 , ruthenium(III) acetyl aceton ate,

chlorocyclopentadienylbis(triphenylphosphine)ruthemium(II ),

chlorohydridotris(tri phenyl phosphine) ruthenium(II) toluene adduct,

chlorotris(triphenylphosphine)ruthenium(II) acetate, [Ru(Cl)H(CO)(PPh 3 )3], [Ir(COD)Cl] 2 , (acetyl acetonato)( 1 , 5 -cy cl ooctadi ene)i ri dium(I), and (acetyl aceton ato)di carb onyl i ri dium(I) . In some embodiments, the catalyst is Ru(OAc) 2 ((A)-SegPhos).

[00297] In certain embodiments, the catalyst is an enzymatic catalyst. In some embodiments, the enzymatic catalyst is an amine transaminase and a cofactor in a buffer. In particular embodiments, the amine transaminase is a w -transaminase selected from the group consisting of ATA-l, ATA-2, ATA-007, ATA-013, ATA-025, ATA-113, ATA-117, ATA-200, ATA-217, ATA-234, ATA-237, ATA-238, ATA-251, ATA-254, ATA-256, ATA-260, ATA-301, ATA- 303, ATA-412, ATA-415, ATA-P1-B04, ATA-P1-F03, ATA-P1-G05, ATA-P2-A01, ATA-P2- A07, and ATA-P2-B01.

[00298] In certain embodiments, the buffer is selected from the group consisting of triethanolamine, tris, tricine, BES, MOPS, HEPES, sodium phosphate, and potassium phosphate.

[00299] In certain embodiments, the cofactor is pyridoxal phosphate.

[00300] In certain embodiments, the amine is selected from the group consisting of ammonia, ammonium acetate, ammonium salicylate, ammonium formate, a-methylbenzylamine, isopropylamine, b enzhy dryl ami ne, DL-alanine, and aspartame. In particular embodiments, the amine is ammonia.

[00301] In certain embodiments, the acid is selected from the group consisting of p- toluenesulfonic acid, hydrochloric acid, and phosphoric acid. In particular embodiments, the acid is -toluenesulfonic acid.

[00302] In certain embodiments, the catalyst is an asymmetric catalyst and the process is carried out at a pressure of from about 100 to about 1000 psi. In certain embodiments, the catalyst is an asymmetric catalyst and the process is carried out at a pressure of from about 200 to about 600 psi.

[00303] In some embodiments, the is an asymmetric catalyst and the process is carried out in the temperature range of from 120 °C or less. In certain embodiments, the catalyst is an asymmetric catalyst and the process is carried out in the temperature range of from about 0 °C to about 120 °C. In certain embodiments, the catalyst is an asymmetric catalyst and the process is carried out in the temperature range of from about 55 °C to about 65 °C.

[00304] In certain embodiments, the catalyst is an enzymatic catalyst and the process is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the catalyst is an enzymatic catalyst and the process is carried out in the temperature range of from about 5 °C to about 100 °C.

[00305] In some embodiments, disclosed herein is a process for preparing a compound of formula V:

or a co-crystal, solvate, salt, or combination thereof, wherein R 1 is B(OH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 3 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0), comprising:

(a) combining a compound of formula V-A:

V-A

or a co-crystal, solvate, salt, or combination thereof, with

a silylating agent,

a base, and

a solvent to provide a compound of formula 7a:

7a or a co-crystal, solvate, salt, or combination thereof, wherein each R 2 is independently Ci- 6 alkyl or C 6 aryl, wherein the Ci- 6 alkyl and C 6 aryl are independently unsubstituted or substituted with one to five Ci -6 alkyl groups; and (b) combining the compound of formula 7a with an organometallic reagent, and a borylation reagent, to provide the compound of formula V, or a co-crystal, solvate, salt, or combination thereof.

[00306] In some embodiments, disclosed herein is a process for preparing a compound of formula V:

V or a co-crystal, solvate, salt, or combination thereof, wherein R 1 is B(OH) 2 ,

B(0CH(Me)CH 2 C(Me) 2 0), B((l,2-di-0)C 6 H 4 ), B(0CH 2 C(Me) 2 CH 2 0), BF 3 K,

B(0 2 CCH 2 N(Me)CH 2 C0 2 ), or B(0C(Me) 2 C(Me) 2 0), comprising:

(a) combining a compound of formula V-A:

V-A

or a co-crystal, solvate, salt, or combination thereof, with a silylating agent, a base, and a solvent to provide a compound of formula 7a:

7a

or a co-crystal, solvate, salt, or combination thereof,

wherein each R 2 is independently C l-6 alkyl that is unsubstituted or substituted with one to five Ci- 6 alkyl groups; and

(b) combining the compound of formula 7a with

an organometallic reagent, and

a borylation reagent,

to provide the compound of formula V, or a co-crystal, solvate, salt, or combination thereof.

[00307] In certain embodiments, the base for step (a) is selected from the group consisting of sodium hydride, potassium hydride, methylmagnesium bromide, phenylmagnesium bromide, sodium hexamethyldisilazide, potassium hexamethyl disilazide, and lithium

hexam ethyl di sil azi de . In particular embodiments, the base for step (a) is lithium

hexamethyl disilazide.

[00308] In certain embodiments, the silylating agent for step (a) is selected from the group consisting of trimethyl silyl bromide, 7V,0-bis(trimethylsilyl)acetamide, trimethylsilyl chlori de, chloro(dimethyl)phenylsilane, chloro(methyl)diphenylsilane, and 1,2- bis(chlorodimethylsilyl)ethane.

[00309] In certain embodiments, the silylating agent for step (a) is selected from the group consisting of trimethylsilyl bromide, /V,( -bis(trimethylsilyl)acetamide, and trimethylsilyl chloride. In particular embodiments, the silylating agent for step (a) is trimethylsilyl chloride.

[00310] In certain embodiments, the solvent is selected from the group consisting of an ether ( e.g ., diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, dimethoxyethane), a hydrocarbon solvent (e.g., n-hexane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), and a combination thereof. In particualr embodiments, the solvent is tetrahydrofuran.

[00311] In certain embodiments, the organometallic reagent for step (b) is selected from the group consisting of n-butyllithium, s-butylmagnesium chloride lithium chloride complex, tert- butylmagnesium chloride, i sopropylmagnesium chloride, and isopropylmagnesium chloride lithium chloride complex.

[00312] In certain embodiments, the organometallic reagent for step (b) is selected from the group consisting of n-butyllithium, s-butylmagnesium chloride lithium chloride complex, tert- butylmagnesium chloride, and i sopropy 1 m agnesium chloride lithium chloride complex. In particular embodiments, the organometallic reagent is isopropylmagnesium chloride lithium chloride complex.

[00313] In certain embodiments, the borylation reagent for step (b) is selected from the group consisting of trimethyl borate, tri ethyl borate, pinacolborane, 2-methoxy-4,4,5,5-tetramethyl- 1 , 3 , 2-di ox ab oral ane, 2-i sopropoxy-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane, B -catecholb orane, and 2-bromo- 1 ,3 ,2-benzodioxaborole. In particular embodiments, the borylation reagent is 2- isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane.

[00314] In certain embodiments, the process for preparing a compound of formula V, or a co- crystal, solvate, salt, or combination, thereof is carried out in the temperature range of from about 40 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -80 °C to about 40 °C. In particular embodiments, the process is carried out in the temperature range of from about -40 °C to about 20 °C.

[00315] In certain embodiments, R 1 is B(0C(Me) 2 C(Me) 2 0).

[00316] In some embodiments, a process for preparing a compound of formula VII:

or a co-crystal, solvate, salt, or combination thereof is provided, compri sing hydrolyzing a compound of formula VII- A:

or a co-crystal, solvate, salt, or combination thereof in the presence of a base and a solvent to provide a compound of formula VII. [00317] In certain embodiments, the base is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, and potassium trimethylsilanoate. In particular embodiments, the base is potassium hydroxide.

[00318] In certain embodiments, the solvent is selected from the group consisting of a chlorinated solvent (e.g., di chi orometh an e), an alcohol (e.g., ethanol, methanol, 1 -propanol, 2- propanol), an ether (e.g., diethyl ether, methyl tert butyl ether, tetrahydrofuran, 2- m ethyl tetr ahy dr of ur an , l,4-dioxane), an aromatic hydrocarbon solvent (e.g., benzene, toluene, xylene), water, and a combination thereof

[00319] In certain embodiments, the solvent is selected from the group consisting of a chlorinated solvent (e.g., di chi oromethan e), an alcohol (e.g., ethanol), an ether (e.g.,

tetrahydrofuran, 2-methyltetrahydrofuran), an aromatic hydrocarbon solvent (e.g., toluene), water, and a combination thereof. In particular embodiments, the solvent is a mixture of dichloromethane and ethanol.

[00320] In particular embodiments, the solvent is a mixture of dichloromethane, water, and, ethanol. In particular embodiments, the solvent is a mixture of water and ethanol.

[00321] In certain embodiments, the process is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the process is carried out in the temperature range of from about 10 °C to about 100 °C. In particular embodiments, the process is carried out in the temperature range of from about 10 °C to about 60 °C.

[00322] In some embodiments, a process for preparing a compound of formula VII- A:

VII-A

or a co-crystal, solvate, salt, or combination thereof is provided, comprising fluorinating a compound of formula 5h-l:

5h-l or a co-crystal, solvate, salt, or combination thereof, wherein n is 1 or 2, with a fluorinating reagent, in a sol vent, and in the presence of an activator, to provide the compound of formula VI1-A or a co-crystal, solvate, salt, or combination thereof.

[00323] In certain embodiments, n is 1. In certain embodiments, n is 2.

[00324] In certain embodiments, the fluorinating reagent is selected from the group consisting of hydrogen fluoride pyridine, calcium fluoride, potassium hydrogenfluori de, tri ethyl amine trihydrofluoride, elemental fluorine, bromine trifluoride, iodine pentafluoride, tetra-A- butyl ammonium dihydrogen tri fluoride, 4-iodotoluene difluoride, and hydrogen fluoride melamine. In particular embodiments, the fluorinating reagent is hydrogen fluoride pyridine.

[00325] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl /er/-butyl ether, tetrahydrofuran, 2 -methyl tetrahy drofuran, 1,4- dioxane), polar aprotic solvents (e.g., acetone, A A/-dimethylformamide, NN- dimethylacetamide, A’-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes), chlorinated solvents (e.g., dichloromethane), and a combination thereof. In certain

embodiments, the solvent is selected from the group consisting of diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, acetone, NN- dimethylform amide, A ? ,A ? -dimethylacetamide, A'-methylpyrrolidinone, benzene, toluene, xylenes, dichloromethane, and a combination thereof. In particular embodiments, the solvent is dichloromethane.

[00326] In certain embodiments, the activator is selected from the group consisting of 1,3- dibromo-5,5-dimethylhydantoin, A-bromosuccinimide, A r -iodosuccinimide, nitrosonium tetrafluorob orate, sulfuryl chloride fluoride, triflic acid, and mercuric fluoride. In particular embodiments, the activator is 1 , 3 -dibromo-5 , 5 -dimethyl hydantoi n.

[00327] In certain embodiments, the process is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -70 °C to about 100 °C. In particular embodiments, the process is carried out in the temperature range of from about -30 °C to about 20 °C.

[00328] In some embodiments, a process for preparing a compound of formula 5h-l:

5h-l or a co-crystal, solvate, salt, or combination thereof!, wherein n is 1 or 2, is provided, comprising combining a compound of formula XIV :

or a co-crystal, solvate, salt, or combination thereof, with a di thiol reagent and a promoter, in a solvent, to provide the compound of formula 5h-l or a co-crystal, solvate, salt, or combination thereof

[00329] In certain embodiments, n is 1. In certain embodiments, n is 2.

[00330] In certain embodiments, the dithiol reagent is 1,2-ethanedithiol or l,2-propanedi thiol. In particular embodiments, the reagent is l,2-ethanedithiol.

[00331] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane), polar aprotic solvents (e.g., acetone, V,V-dimethylformamide, N,N- di m ethyl acetami de, /V-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes), chlorinated solvents (e.g., dichloromethane), and a combination thereof. In certain

embodiments, the solvent is selected from the group consisting of diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxaneacetone, N,N- dimethylformamide, /V,7V-dimethyl acetamide, N-m ethyl pyrroli di none, benzene, toluene, xylenes, dichloromethane, and a combination thereof. In particular embodiments, the solvent is dichloromethane.

[00332] In certain embodiments, the promoter is selected from the group consisting of boron tri fluoride acetic acid complex, -toluenesulfonic acid, iodine, l,3-dibromo-5,5- dimethylhydantoin, copper(II) dodecyl sulfate, ytterbium(III) triflate, yttrium(III) inflate, bismuth(III) triflate, bismuth(III) chloride, tungstophosphoric acid, perchloric acid,

praseodymium triflate, hafnium (IV) triflate, iron(III) chloride, hydrogen chloride, / dodecyl benzenesulfonic acid, BF 3 OEt 2 , BF 3 OMe 2 , BF 3 THF, BF 3 OBu 2 , BF 3 MeOH, BF 3 Me S, and

BF 3 PhQI IBFs 2H 2 0. In particular embodiments, the promotor is boron trifluoride acetic acid complex.

[00333] In certain embodiments, the process is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, the process is carried out in the temperature range of from about 0 °C to about 40 °C.

[00334] In some embodiments, a process for preparing a compound of formula XIV:

XIV or a co-crystal, solvate, salt, or combination thereof is provided, compri sing alkylating a compound of formula XIV-A:

XIV-A or a co-crystal, solvate, salt, or combination thereof, with an alkylating agent in the presence of a base, a solvent, and opti onally a phase transfer catalyst, to provide the compound of formula XIV or a co-crystal, solvate, salt, or combination thereof.

[00335] In certain embodiments, the alkylating agent is selected from the group consisting of ethyl chloroacetate, ethyl iodoacetate, ethyl (methanesulfonyloxy)acetate, ethyl (p - tosyloxy)acetate, ethyl(((trifluoromethyl)sulfonyl)oxy)acetate, and ethyl bromoacetate. In particular embodiments, the alkylating agent is ethyl bromoacetate.

[00336] In certain embodiments, the base is selected from the group consisting of ethyl diisopropylamine, triethylamine, tri -n-propyl amine, tri-n-butylamine, V-methylmorpholine, N- methylpyrrolidine, /V-m ethylpiperi dine, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, potassium ethoxide, sodium fert-butoxide, sodium hydride, lithium hexam ethyl di sil azi de, sodium hexamethyisilazide, and potassium hexam ethyl disilazide. In particular embodiments, the base is ethyl diisopropylamine. [00337] In certain embodiments, the process comprises a phase transfer catalyst.

[00338] In certain embodiments, the phase transfer catalyst is selected from the group consisting of tetra-7V-butyl ammonium hydrogensulfate and tetra-A-butyl am m oni um iodide.

[00339] In certain embodiments, the solvent is selected from the group consisting of an ether ( e.g ., diethyl ether, methyl fe/7-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane), a polar aprotic solvent (e.g., AyV-dimethylform amide, AyV-dimethylacetamide, N- methylpyrrolidinone), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), a chlorinated solvent (e.g., di chi orom ethane), an ester (e.g., ethyl acetate, n-butyl acetate, isopropyl acetate), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutylketone), a nitrile (e.g., acetonitrile), water, and a combination thereof. In particular embodiments, the solvent is acetonitrile.

[00340] In certain embodiments, the process is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, the process is carried out in the temperature range of from about -20 °C to about 30 °C.

[00341] In some embodiments, a process for preparing a compound of formula XIV-A:

XIV-A

or a co-crystal, solvate, salt, or combination thereof is provided, comprising oxidizing a compound of formula 3c:

3c

or a co-crystal, solvate, salt, or combination thereof, with an oxidant, a promoter, a solvent, and a catalyst, to provide the compound of formula XIV-A or a co-crystal, solvate, salt, or combination thereof. [00342] In certain embodiments, the oxidant is selected from the group consisting of tert- butyl hydroperoxide, peracetic acid, hydrogen :, molecular oxygen, air, sodium hypochlorite, sodium chlorite, sodium periodate, potassium peroxymonosulfate, 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone, 1 ,4-benzoquinone, periodic acid, potassium bromate, meta- chloroperoxybenzoic acid (mCPBA or m-CPBA), and magnesium monoperoxypthalate. In particular embodiments, the oxidant is ert-butyl hydroperoxide.

[00343] In certain embodiments, the promoter is selected from the group consi sting of pyridine, bipyridine, neocuproine, 1 , 10-phenanthroline, 2,6-lutidine, 4-picoline, 2-picoline, 3- methylpyridine, Isonicotinamide, nicotinamide, picolinic acid, (2,2,6,6-tetramethylpiperidin-l- yl)oxyl, and didecyldimethylammonium bromide. In particular embodiments, the promoter is pyridine.

[00344] In certain embodiments, the solvent is selected from the group consisting of acetic acid, acetonitrile, n-butyl acetate, isopropyl acetate, ethyl acetate, acetaone, dichloromethane, dimethyl carbonate, tetrahydrofuran, methanol, tert-butanol, di chi or om ethane, sulfolane, water, and a combination thereof. In particular embodiments, the solvent is water.

[00345] In certain embodiments, the catalyst is selected from the group consisting of manganese(II) triflate, copper(II) chloride, (25',2'6'-(-)-[A r ,A r '-Bis(2-pyridylmethyl)]-2,2'- bipyrrolidinebis(acetonitrile)iron(n) hexafluoroantimonate, bismuth, cobalt(II) acetate, manganese(III) acetate, ruthenium(III) chloride, /V-hydroxyphthalimide,

bis(cyclopentadienyl)vanadium(IV) dichloride, and manganese dioxide. In particular embodiments, the catalyst is copper(II) chloride.

[00346] In certain embodiments, the process is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -40 °C to about 100 °C. In particular embodiments, the process is carried out in the temperature range of from about 10 °C to about 50 °C.

[00347] In some embodiments, disclosed herein is a process for preparing a compound of formula 3c:

3c or a co-crystal, solvate, salt, or combination thereof!, comprising: (a) cyclizing a compound of formula 3a:

3a

or a co-crystal, solvate, or combination thereof, with a hydrazine derivative and a promoter, in a solvent, to provide a compound of formula 3b:

3b

or a co-crystal, solvate, salt or combination thereof; and

(b) separating the compound of formul a 3b, or a co-crystal, solvate, salt or combination thereof, to provide the compound of formula 3c, or a co-crystal, solvate, salt, or combination thereof.

[00348] In certain embodiments, the hydrazine derivative in step (a) is selected from the group consisting of anhydrous hydrazine, hydrazine monohydrate, aqueous hydrazine, hydrazine acetate, hydrazine dihydrochloride, hydrazine monohydrochl ori de, hydrazine sulfate, hydrazine hemi sulfate, and hydrazine monohydrobromide. In particular embodiments, the hydrazine derivative in step (a) is hydrazine hydrate.

[00349] In certain embodiments, the solvent in step (a) is selected from the group consisting of water, alcohols (e.g., methanol, ethanol, 1 -propanol, 2-propanol, etc.), ethers (e.g., diethyl ether, methyl tert-buty\ ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane), polar aprotic solvents (e.g., AyV-dimethylformamide, AyV-dimethylacetamide, N- methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes), carboxylic acids (e.g., acetic acid, formic acid, propionic acid, butanoic acid) and a combination thereof. In certain embodiments, the solvent in step (a) is selected from the group consisting of water, methanol, ethanol, 1- or 2-propanol diethyl ether, methyl te/ -butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, AyV-dimethylformamide, AyV-dimethylacetamide, N- methylpyrrolidinone, benzene, toluene, xylenes, carboxylic acids, acetic acid, formic acid, propionic acid, butanoic acid, and a combination thereof. In particular embodiments, the solvent used in step (a) is acetic acid.

[00350] In certain embodiments, the promoter in step (a) is selected from the group consisting of Bronsted acids (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid,), and Lewis acids (e.g., zinc chloride, magnesium chloride, titanium tetrachloride). In certain embodiments, the promoter in step (a) is selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, zinc chloride, magnesium chloride, and titanium tetrachloride.

[00351] In some embodiments, step (a) is carried out at a temperature range of from about 120 °C or less. In certain embodiments, step (a) is carried out at a temperature range of from about -40 to about 120 °C. In particular embodiments, step (a) is carried out at a temperature range of from about 30 to about 70 °C.

[00352] In some embodiments, disclosed herein is a process for preparing a compound of formula 3c:

3c

or a co-crystal, solvate, salt, or combination thereof, comprising:

(b) cyclizing a compound of formula 3a:

3a

or a co-crystal, solvate, or combination thereof, with a hydrazine derivative and a promoter, in a solvent, to provide a compound of formula 3b:

or a co-crystal, solvate, salt or combination thereof; and

(b) chromatographically separating the compound of formula 3b, or a co-crystal, solvate, salt or combination thereof, with a chiral stationary' phase and a solvent to provide the compound of formula 3c, or a co-crystal, solvate, salt, or combination thereof.

[00353] In certain embodiments, the hydrazine derivative in step (a) is selected from the group consisting of anhydrous hydrazine, hydrazine monohydrate, aqueous hydrazine, hydrazine acetate, hydrazine dihydrochloride, hydrazine monohydrochloride, hydrazine sulfate, hydrazine hemi sulfate, and hydrazine monohydrobromide in particular embodiments, the hydrazine derivative in step (a) is hydrazine hydrate.

[00354] In certain embodiments, the solvent in step (a) is selected from the group consisting of water, alcohols (e.g., methanol, ethanol, 1 -propanol, 2-propanol, etc.), ethers (e.g., diethyl ether, methyl /ert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane), polar aprotic solvents (e.g., A^Y-dimethylform amide, V,A ? -dimethylacetamide, N- methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes), carboxylic acids (e.g., acetic acid, formic acid, propionic acid, butanoic acid) and a combination thereof. In certain embodiments, the solvent in step (a) is selected from the group consisting of water, methanol, ethanol, 1- or 2-propanol diethyl ether, methyl /er/-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane, AyV-dimethylformamide, AvV-dimethylacetamide, N- methylpyrrolidinone, benzene, toluene, xylenes, carboxylic acids, acetic acid, formic acid, propionic acid, butanoic acid, and a combination thereof. In particular embodiments, the solvent used in step (a) is acetic acid.

[00355] In certain embodiments, the promoter in step (a) is selected from the group consisting of Bronsted acids (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid,), and Lewis acids (e.g., zinc chloride, magnesium chloride, titanium tetrachloride). In certain embodiments, the promoter in step (a) is selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, zinc chloride, magnesium chloride, and titanium tetrachloride.

[00356] In some embodiments, step (a) is carried out at a temperature range of from about 120 °C or less. In certain embodiments, step (a) is carried out at a temperature range of from about -40 to about 120 °C. In particular embodiments, step (a) is carried out at a temperature range of from about 30 to about 70 °C.

[00357] In certain embodiments, the chiral stationary phase used in step (b) is selected from the group consisting of Chiralpaks AD, AS, AY, AZ, T101, OD, IA, IB, 1C, ID, IE, IF, IG (Chiral Technologies); Lux Celluloses 2, 3, 4 (Phenomenex); and ( R,R ) Whelk-O, (R,R) ULMO, {S,S) Dach DNB (Regis Technologies). In certain embodiments, the chiral stationary phase used in step (b) is selected from the group consisting of Chiralpaks AD, AS, AY, AZ, T101, OD, IA,

IB, IC, ID, IE, IF, IG; Lux Celluloses 2, 3, 4; and (R,R) Whelk-O, (R,R) ULMO, and (S,S) Dach

DNB. In particular embodiments, the chiral stationary phase is Chiralpak IG.

[00358] In certain embodiments, the solvent used in step (b) is selected from the group consisting of hydrocarbons (e.g., hexanes, heptanes, octanes), esters (e.g., ethyl acetate, n -propyl acetate, isopropyl acetate), alcohols (e.g., methanol, ethanol, 1- or 2-propanol), ethers (e.g., diethyl ether, methyl ter/-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane), aromatic solvents (e.g., benzene, toluene, xylenes), chlorinated solvents (e.g., dichlorom ethane, chloroform, 1 ,2-dichloroethane,), acetonitrile, and a combination thereof. In certain

embodiments, the solvent used in step (b) is selected from the group consisting of hexanes, heptanes, octanes, esters, ethyl acetate, n-propyl acetate, isopropyl acetate, methanol, ethanol, 1- or 2 -propanol, diethyl ether, methyl ter /-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, benzene, toluene, xylenes, dichloromethane, chloroform, 1 ,2-dichloroethane, acetonitrile, and a combination thereof. In particular embodiments, the solvent is acetontrile.

[00359] In certain embodiments, step (b) is carried out at a temperature range of from about 50 °C or less. In particular embodiments, step (b) is carried out at a temperature range of from about 10 to about 50 °C.

[00360] In some embodiments, a process for preparing a compound of formula XIV:

XIV

or a co-crystal, solvate, salt, or combination thereof is provided, comprising kinetically resolving a compound of formula XVII:

XVII

or a co-crystal, solvate, or combination thereof, with: a catalyst, a reducing agent, and a solvent, to provide a compound of formula XIV or a co-crystal, solvate, salt or combination thereof.

[00361] In certain embodiments, the catalyst for resolving a compound of formula XVII, or a co-crystal, solvate, or combination thereof, is selected from the group consisting of (R)-(+)-o- tolyl-CBS-oxazaboroli dine, (/?)-( +)-2 -butyl -CB S-oxazaborolidine, ( ?)-(-)-2-methyl -CBS- oxazoborolidine /ra«s-RuCl 2 [(f?)-xylbinap]--[(i?)-diapen], RuBr 2 [(f?)-BINAP], [RuCl(PhH)(i?)- BINAP)]Cl, RuCl(p-cymene)[(S,S)-Ts-DPEN], RuCl(mesitylene)[(S,S)-Ts-DPEN], RuBF 4 (p- cymene)[(S,S)-Ts-DPEN], RuCl(p-cymene)[(S,S)-Fs-DPEN], RuCl(p-cymene)[(R,R)-Teth-Ts- DPEN], and Baker’s yeast. In particular embodiments, the catalyst is (i?)-(-)-2-m ethyl -CB S - oxazoborolidine.

[00362] In certain embodiments, the reducing agent is selected from the group consisting of borane dimethyl sulfide complex, borane tetrahydrofuran complex, borane trimethylamine complex, borane triethylamine complex, borane A^V-diethylaniline complex, catecholborane, hydrogen gas, formic acid/triethylamine, and 2-propanol. In particular embodiments, the reducing agent is borane dimethylsulfide complex.

[00363] In certain embodiments, the solvent is selected from the group consisting of an ether (e.g., diethyl ether, methyl lert- butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane, dimethoxyethane), a hydrocarbon solvent (e.g., n-hexane, n-heptane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), an ester (e.g., ethyl acetate, isobutyl acetate, isopropyl acetate), a chlorinated solvent (e.g., dichloromethane), a nitrile (e.g., acetonitrile), and a combination thereof. In particular embodiments, the solvent is tetrahydrofuran.

[00364] In certain embodiments, the process is carried out at a temperature range of from about 100 °C or less. In certain embodiments, the process is carried out at a temperature range of from about -20 °C to about 100 °C. In particul ar embodiments, the process is carried out at a temperature range of from about 0 °C to about 10 °C.

[00365] In some embodiments, disclosed herein is a process for preparing a compound of formula XIV:

XIV

or a co-crystal, solvate, salt, or combination thereof, comprising:

(c) kinetically resolving a compound of formula XVII:

XVII

or a co-crystal, solvate, or combination thereof, with:

a catalyst,

a reducing agent, and

a solvent,

to provide a first mixture comprising the compound of formula XIV, or a co-crystal, solvate, or combination thereof, and a compound of formula XVIII:

XVIII

or a co-crystal, solvate, salt or combination thereof;

(b) combining the first mixture with an alcohol derivatizing agent (e.g , succinic anhydride), a catalyst (e.g., DMAP), and a solvent to produce a second mixture; and

(c) extracting the second mixture with a base and solvent to provide the compound of formula XIV, or a co-crystal, solvate, salt, or combination thereof.

[00366] In some embodiments, step (c) provides the compound of formula XIV, or a co crystal, solvate, salt, or combination thereof, substantially free of the compound of formula XVIII, or a co-crystal, solvate, or combination thereof. In some embodiments, step (c) removes 99-95% of the compound of formula XVIII, or a co-crystal, solvate, salt, or combination thereof. In some embodiments, step (c) removes 95-85% of the compound of formula XVIII, or a co-crystal, solvate, salt, or combination thereof In some embodiments, step (c) removes 85- 75% of the compound of formula XVIII, or a co-crystal, solvate, salt, or combination thereof.

[00367] In certain embodiments, the solvent used in the resolving step step (a) is selected from the group consisting of an ether (e.g., diethyl ether, methyl te /-butyl ether,

tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane, dimethoxyethane), a hydrocarbon solvent (e.g., n-hexane, n-heptane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), an ester (e.g., ethyl acetate, isobutyl acetate, isopropyl acetate), a chlorinated solvent (e.g., dichloromethane), a nitrile (e.g., acetonitrile), a ketone (e.g., acetone), a polar aprotic solvent (e.g., AvV-dimethylformamide, AyV-di methyl acetamide, /V-m ethylpyrroli di none), and a combination thereof. In particular embodiments, the solvent is tetrahydrofuran.

[00368] In certain embodiments, the catalyst for the resolving step (a) is selected from the group consisting of (7?)-(+)-o-tolyl-CBS-oxazaborolidine, (7?)-(+)-2-butyl-CBS-oxazaborolidine, (i?)-(-)-2-methy 1 -CB S-oxazob oroli dine /ra«s-RuCl 2 [(7i9-xylbinap]-[(i¾)-diapen], RuBr 2 [(/^)- BINAP], [RuCl(PhH)(f?)-BINAP)]Cl, RuCl(p-cymene)[(S,S)-Ts-DPEN],

RuCl(mesitylene)[(S,S)-Ts-DPEN], RuBF 4 (p-cymene)[(S,S)-Ts-DPEN], RuCl(p-cymene)[(S,S)- Fs-DPEN], RuCl(p-cymene)[(R,R)-Teth-Ts-DPEN], and Baker’s yeast. In particular embodiments, the catalyst is (i?)-(-)-2-methyl-CBS-oxazoborolidine.

[00369] In certain embodiments, the reducing agent for the resolving step (a) is selected from the group consisting of b orane · di m ethyl sulfi de complex, borane tetrahydrofuran complex, borane trimethylamine complex, borane triethylamine complex, borane VA-diethylaniline complex, catecholborane, hydrogen gas, formic acid/triethylamine, and 2 -propanol. In particular embodiments, the reducing agent is borane· dimethylsulfide complex.

[00370] In some embodiments, the process of the resolving step (a) is carried out at a temperature range of from about 100 °C or less. In certain embodiments, the process of step (a) is carried out at a temperature range of from about -40 °C to about 100 °C. In particular embodiments, the process of step (a) is carried out at a temperature range of from about 10 °C to about 60 °C.

[00371] In certain embodiments, the process of step (a) is carried out at a temperature range of from about -20 °C to about 100 °C. In particular embodiments, the process of step (a) is carried out at a temperature range of from about 0 °C to about 10 °C.

[00372] In certain embodiments, the alcohol derivatizing agent used in step (b) is selected from the group consisting of succinic anhydride, maleic anhydride, phthalic anhydride, glutaric anhydride, and diglycolic anhydride. In particular embodiments, the alcohol derivatizing agent is succinic anhydride.

[00373] In certain embodiments, the catalyst used in step (b) is selected from the group consisting of 4-(dimethylamino)pyridine, diethylaniline, scandium triflate, silica sulfuric acid, and N -m ethyli m i dazol e . In particular embodiments, the catalyst is 4-(dimethylamino)pyridine (DMAP).

[00374] In certain embodiments, the extraction base used in step (c) is selected from the group consisting of potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and ammonium hydroxide.

In particular embodiments, the extraction base is potassium carbonate.

[00375] In certain embodiments, the extraction solvent in step (c) is selected from the group consisting of an ether (e.g., diethyl ether, methyl ter/-butyl ether, tetrahydrofuran, 2- m ethyl tetr ahy dr of ur an , l,4-dioxane, dimethoxyethane), a hydrocarbon solvent (e.g., n-hexane, n-heptane),an aromatic hydrocarbon solvent (e.g., toluene, xylenes), an ester (e.g., ethyl acetate, isobutyl acetate, isopropyl acetate), a chlorinated solvent (e.g., dichloromethane), water and a combination thereof. In particular embodiments, the extraction solvent is tetrahydrofuran, methyl te 7-butyl ether, and water.

[00376] In certain embodiments, step (b) and step (c) are carried out at a temperature range of from about 100 °C or less. In certain embodiments, step (b) and step (c) are carried out at a temperature range of from about -40 °C to about 100 °C. In particular embodiments, step (b) and step (c) are carried out at a temperature range of from about -10 °C to about 60 °C.

[00377] In some embodiments, a process for preparing a compound of formula XIV:

XIV

or a co-crystal, solvate, or combination thereof is provided, comprising:

(a) oxidizing a compound of formula 5a:

5a or a co-crystal, solvate, or combination thereof, with an oxidant, a base, and a solvent to provide a compound of formula 5b:

5b or a co-crystal, solvate, or combination thereof, wherein each R 3 is independently Ci -6 alkyl that is unsubstituted or substituted with one to five C l-6 alkyl groups;

(b) further oxidizing the compound of formula 5b or a co-crystal, solvate, or combination thereof, with an oxidant, a base, and a solvent, to provide a compound of formula 5c:

R 3 O OR 3

xV

5c or a co-crystal, solvate, or combination thereof;

(c) combining the compound of formula 5c or a co-crystal, solvate, or combination thereof with a trifluoroacetylating agent and a lithium base in a solvent, to provide a compound of formula 3d:

or a co-crystal, solvate, or combination thereof; and

(d) combining the compound of formula 3d or a co-crystal, solvate, or combination thereof with ethyl hydrazinoacetate hydrochloride, an acid and optionally, an additive, to provide the compound of formula XIV, or a co-crystal, solvate, salt, or combination thereof

[00378] In certain embodiments, the oxidant used in step (a) is selected from the group consisting of iodine, thianthrenium tetrafluorob orate, di acetoxyiodob enzene, and potassium iodide/platinum electrode. In particular embodiments, the oxidant used in step (a) is di acetoxyi odob enzene. [00379] In certain embodiments, the base used in step (a) is selected from the group consisting of sodium hydroxide, lithium hydroxide, and potassium hydroxide. In particular embodiments, the base used in step (a) is potassium hydroxide.

[00380] In certain embodiments, the solvent used in step (a) is an alcohol (e.g., methanol, ethanol, 1 -propanol, ethylene glycol). In particular embodiments, the solvent used in step (a) is methanol.

[00381] In certain embodiments, step (a) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, step (a) is carried out in the temperature range of from about -15 °C to about 30 °C.

[00382] In certain embodiments, the oxidant used in step (b) is selected from the group consisting of dimethyl sulfoxide and an activating agent selected from the group consisting of cyanuric chloride, oxalyl chloride, di cy cl ohexyl carb odi imi de, A^’-diisopropylcarbodiimide, N- chlorosuccinimide, benzoic anhydride, methanesulfonic anhydride, tosic anhydride, triflic anhydride, methyl chi orogl yoxyl ate, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, tosyl chloride, benzenesulfonyl chloride, tri chi oroacetonitril e, 2-chi oro- 1,2- dimethylimidazolinium chloride, polyphosphoric acid, PC1 3 , triphenylphosphine di chloride, triphenylphosphine dibromide, POCl 3 , phosphorous pentoxide, acetyl chloride, benzoyl chloride, acetyl bromide, phenyl di chi orophosphate, diphenyl chlorophosphate, diethyl chlorophosphate, and ethoxyacetylene, TEMPO and bleach, chromium tri oxide, Dess-Martin periodinane, 2- iodoxybenzoic acid, and sulfur tri oxide pyridine complex. In particular embodiments, the oxidant used in step (b) is dimethyl sulfoxide and oxalyl chloride.

[00383] In certain embodiments, the base used in step (b) is selected from the group consisting of diisopropyl ethylamine, tri -«-propyl amine, triethylamine, pyridine, and 2,6-lutidine. In particular embodiments, the base used in step (b) is triethylamine.

[00384] In certain embodiments, the solvent used in step (b) is selected from the group consisting of a chlorinated solvent (e.g., di chi orom ethane, 1 ,2-dichloroethane), an aromatic hydrocarbon solvent (e.g., toluene), and a combination thereof In particular embodiments, the solvent used in step (b) is dichloromethane.

[00385] In certain embodiments, step (b) is carried out in the temperature range of from about 50 °C or less. In certain embodiments, step (b) is carried out in the temperature range of from about -80 °C to about 50 °C. In particular embodiments, step (b) is carried out in the

temperature range of from about -60 °C to about - TO °C. [00386] In certain embodiments, R 3 is methyl, ethyl, or propyl. In some embodiments, R 3 is methyl .

[00387] In certain embodiments, the trifluoroacetylating agent used in step (c) is selected from the group consisting of trifluoroacetic anhydride, phenyltrifluoroacetate, methyl trifluoroacetate, ethyl trifluoroacetate, and trifluoroethyl trifluoroacetate. In particular embodiments, the trifluoroacetylating agent is ethyl trifluoroacetate.

[00388] In certain embodiments, the lithium base used in step (c) is selected from the group consisting of lithium hexam ethyl di si 1 azi de, lithium diisopropylamine, lithium

tetramethylpiperidide, lithium methoxide, lithium ethoxide, and lithium fe/7-butoxide. In particular embodiments, the lithium base is lithium hexam ethyl di sil azi de .

[00389] In certain embodiments, the solvent used in step (c) is selected from the group consisting of an ether (e.g., diethyl ether, methyl te/7-butyl ether, tetrahydrofuran, 2- m ethyl tetr ahy dr of ur an , l,4-dioxane, dimethoxyethane), a hydrocarbon solvent (e.g., n-hexane, n-heptane), an aromatic hydrocarbon solvent (e.g., toluene, xylenes), a chlorinated solvent (e.g., di chi orom ethane), a polar aprotic solvent (e.g., /v-d i m et by ! form am I de, N,N- dimethylacetamide, /V-methylpyrrolidinone), a nitrile (e.g., acetonitrile), and a combination thereof. In particular embodiments, the solvent used in step (c) is tetrahydrofuran.

[00390] In certain embodiments, step (c) is carried out in the temperature range of from about 30 °C or less. In certain embodiments, step (c) is carried out in the temperature range of from about 30 °C to about 30 °C. In particular embodiments, step (c) is carried out in the temperature range of from about -80 °C to about 60 °C. In particular embodiments, step (c) is carried out in the temperature range of from about -80 °C to about 30 °C.

[00391] In certain embodiments, step (c) is carried out in the temperature range of from about 60 °C or less hi certain embodiments, step (c) is carried out in the temperature range of from about -80 °C to about 60 °C. In particular embodiments, step (c) is carried out in the temperature range of from about -30 °C to about 30 °C.

[00392] In certain embodiments, the acid used in step (d) is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, hydrogen bromide, methanesulfonic acid, -toluenesulfonic acid, magnesium chloride, zinc chloride, scandium triflate, and bismuth chloride. In particular embodiments, the acid is sulfuric acid.

[00393] In certain embodiments, step (d) comprises an additive. [00394] In certain embodiments, the additive used in step (d) is selected from the group consisting of ethyl orthoacetate, ethyl orthoformate, molecular sieves, and Dean-Stark distillation. In particular embodiments, the additive is ethyl orthoformate.

[00395] In certain embodiments, the solvent used in step (d) is selected from the group consisting of an ether (e.g., diethyl ether, methyl te /-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane), a ketone (e.g., acetone), a polar aprotic solvent (e.g., NN- dimethylform amide, A ? ,A ? -dimethylacetamide, A'-methylpyrrolidinone), an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylenes), an ester (e.g., ethyl acetate, isopropyl acetate), an alcohol (e.g., methanol, ethanol, i sopropanol , ethyl ene glycol, propylene glycol), a chlorinated solvent (e.g., dichloromethane), and a combination thereof. In particular embodiments, the solvent used in step (d) is ethanol.

[00396] In certain embodiments, step (d) is carried out in the temperature range of from about 60 °C or less. In certain embodiments, step (d) is carried out in the temperature range of from about 20 °C to about 60 °C. In particular embodiments, step (d) is carried out in the temperature range of from about -20 °C to about 20 °C.

[00397] In some embodiments, a process for preparing a compound of formula XV:

XV or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula 3d-02:

3d-02 or a co-crystal, solvate, or combination thereof, with a hydrazine source and a solvent to provide a compound of formula XV or a co-crystal, solvate, salt, or combination thereof.

[00398] In certain embodiments, the hydrazine source is selected from the group consisting of hydrazine sulfate, hydrazine hemi sulfate, hydrazine hydrochloride, hydrazine dihydrochloride, hydrazine acetate, hydrazine hydrobromide, hydrazine hydrate, and anhydrous hydrazine. In particular embodiments, the hydrazine source is hydrazine sulfate.

[00399] In certain embodiments, the solvent is selected from the group consisting of alcohol s (e.g., methanol, ethanol, ethylene glycol), ethers (e.g., diethyl ether, methyl fcrt-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane), polar aprotic solvents (e.g., acetone, AyV-dimethylformamide, /V,A r -dimethylacetamide, iV-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes), chlorinated solvents (e.g., di chi orom ethane), and a

combination thereof. In particular embodiments, the solvent is ethylene glycol.

[00400] In certain embodiments, the process is carried out at a temperature range of from about 80 °C or less. In certain embodiments, the process is carried out at a temperature range of from about 0 °C to about 80 °C. In particular embodiments, the process is earned out at a temperature range of from about 20 °C to about 60 °C. In particular embodiments, the process is carried out at a temperature of about 40 °C.

[00401] In some embodiments, a process for preparing a compound of formula XV:

XV

or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula 3k:

3k

or a co-crystal, solvate, salt, or combination thereof, with a reagent to provide the compound of formula XV, or a co-crystal, solvate, salt, or combination thereof.

[00402] In certain embodiments, the reagent is selected from the group consisting of 2,3- di chloro-5,6-dicyano- 1 ,4-benzoquinone (DDQ), ceric ammonium nitrate, hydrogen chloride, hydrogen bromide, methanesulfonic acid (MsOH), triflic acid (TfOH), trifluoroacetic acid (TFA), Pd/C (with ¾, NH 4 HC0 2 , or Et 3 SiH), BC1 3 , BBr 3 , and lithium naphthalenide. In particular embodiments, the reagent is trifluoroacetic acid.

[00403] In certain embodiments, the process is carried out at a temperature range of from about 120 °C or less. In certain embodiments, the process is carried out at a temperature range of from about 0 °C to about 120 °C. In particular embodiments, the process is carried out at a temperature range of from about 40 °C to about 80 °C.

[00404] In some embodiments, a process for preparing a compound of formula 3k:

[00405] or a co-crystal, solvate, salt, or combination thereof is provided, comprism:

combining a compound of formula 3j :

3j

or a co-crystal, solvate, salt, or combination thereof, with a base and a solvent, to provide the compound of formula 3k, or a co-crystal, solvate, salt, or combination thereof.

[00406] In certain embodiments, the base is selected from the group consisting of lithium dii sopropyl ami de, 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex, n-butyl lithium, phenyllithium, phenylmagnesium chloride, i sopropyl m agne si um chloride lithium chloride complex, sec-butylmagnesium chloride lithium chloride complex, n-butyllithium lithium AvV-dimethylaminoethanol complex, and mesityllithium di si 1 azide bases (e.g., lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide). In particular embodiments, the base is lithium diisopropylamide.

[00407] In certain embodiments, the solvent is selected from the group consisting of ethers

(e.g., diethyl ether, methyl to7-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane), aromatic solvents (e.g., benzene, toluene, xylenes), and a combination thereof. In particular embodiments, the solvent is tetrahydrofuran. [00408] In certain embodiments, the process is carried out at a temperature range of from about 50 °C or less. In certain embodiments, the process is carried out at a temperature range of from about -80 °C to about 50 °C. In particular embodiments, the process is carried out at a temperature range of from about -80 °C to about -20 °C.

[00409] In some embodiments, a process for preparing a compound of formula 3j :

or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining a compound of formula 3f:

or a co-crystal, solvate, salt, or combination thereof, with a compound of formula 3i:

31 or a co-crystal, solvate, salt, or combination thereof, a base, a solvent, and a catalyst, to provide the compound of formula 3j, or a co-crystal, solvate, salt, or combination thereof.

[00410] In certain embodiments, the base is selected from the group consisting of cesium fluoride, sodium bicarbonate, potassium phosphate dibasic, sodium carbonate, potassium carbonate, potassium phosphate tribasic, sodium hydroxide, and potassium hydroxide. In particular embodiments, the base is cesium fluoride.

[00411] In certain embodiments, the solvent is selected from the group consisting of combinations of water and ethers (e.g., diethyl ether, l ,4-dioxane, 2 -methyl tetrahydrofuran, dimethoxyethane), hydrocarbon solvents (e.g., toluene, xylenes), dimethylformamide, esters (e.g., isopropyl acetate, isobutyl acetate), and a combination thereof. In particular embodiments, the solvent is dimethylformamide.

[00412] In certain embodiments, the catalyst is selected from the group consisting of palladium catalysts (e.g., palladium(II) acetate/triphenylphosphine, bis(di-/er/-butyl(4- di m ethyl am in opheny 1 ) phosphine) dichloropalladium(II), bi s[(dicy clohexyl)(4- dimethylaminophenyl) phosphine] palladium(II) chloride,

dichlorobis(triphenylphosphine)palladium(II), [ 1 , -bis(diphenylphosphino)

ferrocene]dichloropalladium(II)). In particular embodiments, the catalyst is palladium(II) acetate/triphenylphosphine.

[00413] In certain embodiments, the process is carried out at a temperature range of from about 120 °C or less. In certain embodiments, the process is carried out at a temperature range of from about 20 °C to about 120 °C. In particular embodiments, the process is carried out at a temperature range of from about 40 °C to about 100 °C.

[00414] In some embodiments, a process for preparing a compound of formula 3i-l:

3i-l

or a co-crystal, solvate, salt, or combination thereof, is provided, comprising combining a compound of formula 3h:

or a co-crystal, solvate, salt, or combination thereof, with a borylating reagent, a solvent and, a catalyst, to provide the compound of formula 3i-l, or a co-crystal, solvate, salt, or combination thereof,

wherein each R 7 is independently H, alkyl, or aryl, or both R 7 and the atoms to which they are attached form a 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is optionally substituted with 1-5 Ci alkyl. [00415] In certain embodiments, both R 7 and the atoms to which they are attached form a 5- membered heterocyclyl optionally substituted with 1-5 Ci alkyl. In certain embodiments, both

R and the atoms to which they are attached form a 5-membered heterocyclyl substituted with 1-

4 C alkyl. In certain embodiments, both R 7 and the atoms to which they are attached form a 5- membered heterocyclyl substituted with four methyl groups. In particular embodiments, both both R 7 and the atoms to which they are attached form pinacolboranyl.

[00416] In certain embodiments, the compound of formula 3i-l is a compound of formula 3i:

[00417] In certain embodiments, the borylating reagent is selected from the group consisting of Bis(pinacol ato)diboron, Bis(neopentyl glycolato)diboron, tetrahy droxy dib or on, bis(hexylene glycolato)diboron, and bi s(catechol ato)dib or on . In particular embodiments, the borylating reagent is Bi s(pi nacol ato)dib or on .

[00418] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl /erZ-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran), polar aprotic solvents (e.g., A^ V-dimethylacetamide, f-methy 1 py rroli dinone), aromatic solvents (e.g., benzene, toluene, xylenes), chlorinated solvents (e.g., dichloromethane), alcohols (e.g., methanol, ethanol, isopropanol), esters (e.g., ethyl acetate, isopropyl acetate), and a combination thereof. In particular embodiments, the solvent is dioxane and AvV-dimethylformamide.

[00419] In certain embodiments, the catalyst is selected from the group consisting of palladium catalysts (e.g., [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis(di- te/7-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II), bis[(dicyclohexyl)(4- di m ethyl am in opheny 1 ) phosphine]palladium(II) chloride,

dichlorobis(triphenylphosphine)palladium(II), [ 1 , -bis(diphenylphosphino)ferrocene] di chi oropal 1 adium(II)) . In particular embodiments, the catalyst is [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[00420] In certain embodiments, the process is carried out at a temperature range of from about 130 °C or less. In certain embodiments, the process is carried out at a temperature range of from about 10 °C to about 130 °C. In particular embodiments, the process is carried out at a temperature range of from about 80 °C to about 1 10 °C.

[00421] In some embodiments, a process for preparing a compound of formul a 3i-l:

or a co-crystal, solvate, salt, or combination thereof, is provided, comprising combining a compound of formula 3h:

3h

or a co-crystal, solvate, salt, or combination thereof, with a borylating reagent, an

organometallic reagent and a solvent, to provide the compound of formula 3i-l, or a co-crystal, solvate, salt, or combination thereof,

wherein each R 7 is independently H, alkyl, or aryl, or both R 7 and the atoms to which they are attached form a 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is optionally substituted with 1-5 C l-3 alkyl.

[00422] In certain embodiments, both R 7 and the atoms to which they are attached form a 5- membered heterocyclyl optionally substituted with 1-5 C l-3 alkyl. In certain embodiments, both R and the atoms to which they are attached form a 5 -membered heterocyclyl substituted with 1- 4 Ci -3 alkyl. In certain embodiments, both R 7 and the atoms to which they are attached form a 5- membered heterocyclyl substituted with four methyl groups. In particular embodiments, both both R 7 and the atoms to which they are attached form pinacolboranyl.

[00423] In certain embodiments, the compound of formula 3i-l is a compound of formula 3i:

3i.

[00424] In certain embodiments, the borylating reagent is selected from the group consisting of trialkyl borates (e.g., trimethyl borate, triethyl borate), pinacolborane, 2-isopropoxy-4, 4,5,5- tetram ethyl- 1 ,3 ,2-dioxaborolane, 2-methoxy-4,4, 5, 5-tetram ethyl- 1 , 3 ,2-dioxaboralane, B- catecholborane, and 2-bromo-l,3,2-benzodioxaborole. In particular embodiments, the boiylating reagent is 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane.

[00425] In certain embodiments, the organometallic reagent is selected from the group consisting of lithium metal, magnesium metal, isopropylmagnesium chloride, n-butyHithium, s- butylmagnesium chloride lithium chloride complex, tert-butylmagnesium chloride, and isopropylmagnesium chloride lithium chloride complex. In particular embodiments, the organometallic reagent is isopropylmagnesium chloride.

[00426] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, l,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane), hydrocarbon solvents (e.g., n-hexane, n-heptane, toluene, xylenes), and a combination thereof.

In particular embodiments, the solvent is tetrahydrofuran.

[00427] In certain embodiments, the process is carried out at a temperature range of from about 40 °C or less. In certain embodiments, the process is carried out at a temperature range of from about -80 °C to about 40 °C. In particular embodiments, the process is carried out at a temperature range of from about -20 °C to about 20 °C.

[00428] In some embodiments, a process for preparing a compound of formula 3h:

3h

or a co-crystal, solvate, salt, or combination thereof, is provided, comprising combining a compound of formula 3h:

3g

or a co-crystal, solvate, salt, or combination thereof, with an alkylating agent, a base and a solvent, to provide the compound of formula 3h, or a co-crystal, solvate, salt, or combination thereof.

[00429] In certain embodiments, the alkylating agent is selected from the group consisting of 4-methoxybenzyl chloride, 4-methoxybenzyl bromide, 4-methoxybenzyl-2,2,2- tri chl oroacetimi date, and (4-methoxybenzyl oxy)-4-methylquinoline. In particular embodiments, the alkylating agent is 4-methoxybenzyl chloride.

[00430] In certain embodiments, the base is selected from the group consisting of tertiary amines (e.g., triethylamine, tri -«-propyl amine, tri -«-butyl amine, Y-methylmorpholine, N- methylpyrrolidine, /V-methylpiperidine), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), alkoxide bases (e.g., sodium ethoxide, potassium eth oxide, sodium fert-but oxide), sodium hydride, and disilazide bases (e.g., lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide). In particular embodiments, the base is sodium hydride.

[00431] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane), polar aprotic solvents (e.g., acetone, AyV-dimethylformamide, N,N- dimethylacetamide, A’-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes,), chlorinated solvents (e.g., dichloromethane), and a combination thereof. In particular embodiments, the solvent is dimethylform amide.

[00432] In certain embodiments, the process is carried out at a temperature range of from about 100 °C or less. In certain embodiments, the process is carried out at a temperature range of from about -20 °C to about 100 °C. In particular embodiments, the process is carried out at a temperature range of from about 0 °C to about 40 °C.

[00433] In some embodiments, a process for preparing a compound of formula 3f: or a co-crystal, solvate, salt, or combination thereof!, is provided, comprising amidating a compound of formula 3e:

3e or a co-crystal, solvate, salt, or combination thereof, with a coupling agent and a solvent, to provide the compound of formula 3f, or a co-crystal, solvate, salt, or combination thereof.

[00434] In certain embodiments, the coupling agent is selected from the group consisting of carbonyl diimidazole, oxalyl chloride, thionyl chloride, di cy cl oh exyl carb odii m i de,

diisopropylcarbodiimide, 1 -ethyl -3-(3-dimethylaminopropyl)carbodiimide, isobutyl chloroformate, hexafluorophosphate azabenzotri azole tetramethyl uronium (HATU), hexafluorophosphate benzotri azole tetramethyl uronium (HBTU), (benzotriazol-l- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (Benzotri azol-l- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), tri-w-propylphosphonic anhydride, and 2-chloro-4,6-dimethoxy-l,3,5-triazine. In particular embodiments, the coupling agent is carbonyl diimidazole.

[00435] In certain embodiments, the solvent is selected from the group consisting of ethers (e.g., diethyl ether, methyl er -butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane), aromatic solvents (e.g., benzene, xylenes), polar aprotic solvents (e.g.,/V,A r - dimethylformamide, A V-dimethylacetamide, iV-methylpyrrolidinone), di chi orom ethane, and a combination thereof. In particular embodiments, the solvent is tetrahydrofuran.

[00436] In certain embodiments, the process is carried out at a temperature range of from about 120 °C or less. In certain embodiments, the process is carried out at a temperature range of from about -20 °C to about 120 °C. In particular embodiments, the process is carried out at a temperature range of from about 0 °C to about 40 °C.

[00437] In some embodiments, a process for preparing a compound of formula 3n-l: chiral amine is provided, comprising

(a) combining a compound of formula 3a:

3a or a co-crystal, solvate, or combination thereof, with an acid to to provide a compound of formula 31

31, or a co-crystal, solvate, or combination thereof; and

(b) combining the compound of formula 31 or a co-crystal, solvate, or combinati on thereof, with a chiral amine and a solvent, to provide the compound of formula 3n-l.

[00438] In certain embodiments, the acid used in step (a) is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, and trifluoroacetic acid. In particular embodiments, the acid used in step (a) is hydrochloric acid or sulfuric acid. In particular embodiments, the acid used in step (a) is hydrochloric acid. In particular embodiments, the acid used in step (a) is sulfuric acid.

[00439] In certain embodiments, the chiral amine used in step (b) is selected from the group consisting of quinine, (S)-(-)-a-methylbenzylamine, (R)-(+)-a-methylbenzylamine, (S)-(+)-2- phenylglycinol, (R)-(-)-2-phenylglycinol, (S)-valinol, (R)-valinol, quinidine, quinine , brucine, cinchonine, cinchonidine, (+)-dehydroabi etyl amine, ( 1 R,2 S)-(-)-ephedrine, (l S,2R)-(+)- ephedrine hemihydrate, ( 1 S,2R)-(-)-cis- 1 -amino-2-indanol, (lR,2S)-(-)-cis-l-amino-2-indanol, (S)-(+)-l-cyclohexylethylamine, (R)-(-)-l -cyclohexyl ethylamine, (S)-(-)-l-(l- naphthyl)ethyl amine, (R)-(+)- 1 -( 1 -napthyl)ethylamine, (S)-(+)-2-amino- 1 -butanol, (R)-(-)-2- ami no- 1 -butanol, (S)-2-aminohexane, (R)-2-aminohexane, (i?)-phenyf glycine, and (/?)-( 1- napthyl)ethylamine. In particular embodiments, the chiral amine is quinine.

[00440] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert- butyl ether, tetrahydrofuran, 2- m ethyl tetr ahy dr of ur an , l,4-dioxane), polar aprotic solvents (e.g., acetone, N,N- dimethylformamide, AyV-dimethylacetamide, /V-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes), chlorinated solvents (e.g., dichloromethane), alcohols (e.g., methanol, ethanol, isopropanol), esters (e.g., ethyl acetate, isopropyl acetate), and a combination thereof. In particular embodiments, the solvent used in e.g., step (b) is acetone.

[00441] In certain embodiments, the process is carried out at a temperature range of from about 80 °C or less in certain embodiments, the process is carried out at a temperature range of from about -30 °C to about 80 °C. In particular embodiments, the process is carried out at a temperature range of from about -20 °C to about 60 °C.

[00442] In some embodiments, a process for preparing a compound of formula 5h:

5h

or a co-crystal, solvate, or combination thereof is provided, comprising:

(a) combining a compound of formula 5b-02:

5b-02

or a co-crystal, solvate, or combination thereof, with l,2-ethanedithiol, a solvent, and a promoter, to provide a compound of formula 5d-0l:

5d-01 or a co-crystal, solvate, or combination thereof;

(b) oxidizing the compound of formula 5d-01 or a co-crystal, solvate, or combination thereof, with an oxidant, a base, and a solvent, to provide a compound of formula 5e:

5e or a co-crystal, solvate, or combination thereof;

(c) combining the compound of formula 5e or a co-crystal, solvate, or combination thereof with a trifluoroacetylating agent, a base, and a solvent, to provide a compound of formula 5G-1 :

5f-l or a co-crystal, solvate, or combination thereof, wherein M is selected from the group consisting of alkali metals (e.g., Li, Na, K, Mg, Ca), transition metals (e.g., Zn, Sr), aliphatic ammoniums (e.g., dii sopropyl ammonium, dicycloh exyl ammonium, diethylammonium, tri ethyl am m onium), and aromatic ammoniums (e.g., pyridinium); and

(d) combining the compound of formula 5f-l or a co-crystal, solvate, or combination thereof with ethyl hydrazinoacetate hydrochloride and an acid to provide the compound of formula 5h or a co-crystal, solvate, salt, or combination thereof. [00443] In certain embodiments, the promoter used in step (a) is selected from the group consisting of / oluenesulfonic acid, copper(II) dodecyl sulfate, ytterbium(III) triflate, yttrium(III) triflate, bismuth(III) triflate, bismuth (III) chloride, tungstophosphoric acid, perchloric acid, praseodymium triflate, hafnium(IV) triflate, iron(III) chloride, hydrogen chloride, -dodecyl benzenesulfonic acid, BiCl 3 BF 3 -HOAc, BF 3 OEt 2 , BF 3 OMe 2 , BF 3 THF, BF 3 OBU 2 , BF 3 MeOH, BF 3 Me 2 S, BF 3 PhOH, and BF 3 2H 2 0. In particular embodiments, the promoter used in step (a) is BiCl 3 .

[00444] In certain embodiments, the solvent used in step (a) is ethers (e.g., diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane,), polar aprotic solvents (e.g., acetone, A,A-dimethylformamide, Ay/V-dimethyl acetamide, N- methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes), chlorinated solvents (e.g., dichloromethane), esters (e.g., ethyl acetate, isopropyl acetate), a nitrile (e.g., acetonitrile) and a combination thereof. In particular embodiments, the solvent used in step (a) is

acetonitrile.

[00445] In certain embodiments, step (a) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, step (a) is carried out in the temperature range of from about 0 °C to about 80 °C.

[00446] In certain embodiments, the oxidant used in step (b) is selected from the group consisting of dimethyl sulfoxide (DM SO) and an activating agent (e.g., S0 3 . pyridine complex, oxalyl chloride, cyanuric chloride, dicyclohexylcarbodiimide (DCC), N, N'- Di i sopropyl carb odii m i de (DIC), N-chlorosuccinimide (NCS), benzoic anhydride,

methanesulfonic anhydride, tosic anhydride, triflic anhydride, methyl chloroglyoxylate, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, tosyl chloride, benzenesulfonyl chloride, tri chi oroacetonitril e, 2-chloro-l,2-dimethylimidazolinium chloride, polyphosphoric acid (PPA), PC1 3 , P 2 Os, triphenylphosphine di chloride (TPP Cl 2 ), triphenylphosphine dibromide (TPP Br 2 ), POCl 3 , acetyl chloride, benzoyl chloride, acetyl bromide, phenyl di chi orophosphate, diphenyl chlorophosphate, diethyl chlorophosphate, and ethoxyacetylene), (2, 2,6,6- tetramethylpiperidin-l -yl)oxyl/bleach (TEMPO/b leach), chromium tri oxide, Dess-Martin periodinane, and 2-iodoxybenzoic acid. In particular embodiments, the oxidant used in step (b) is DMSO and S0 3 . pyridine complex.

[00447] In certain embodiments, the base used in step (b) is selected from the group consisting of aliphatic amines (e.g., triethylamine, diisopropylethylamine, tri-w-propylamine), and aromatic amines (e.g., pyridine, 2,6-lutidine). In particular embodiments, the base used in step (b) is triethylamine.

[00448] In certain embodiments, the solvent used in step (b) is dichlorom ethane,

dichloroethane, toluene, DMSO, ethyl acetate, and a combination thereof. In particular embodiments, the solvent used in step (b) is dichloromethane.

[00449] In certain embodiments, step (b) is carried out in the temperature range of from about 80 °C or less. In certain embodiments, step (b) is carried out in the temperature range of from about -80 °C to about 80 °C. In particular embodiments, step (a) is carried out in the temperature range of from about -60 °C to about 60 °C.

[00450] In certain embodiments, M is selected from the group consisting of alkali metals (e.g., Li, Na, K, Mg, Ca), transition metals (e.g., Zn), aliphatic ammonium (e.g.,

diisopropylammonium, dicyclohexylammonium, diethylammonium, triethylammonium), aromatic ammonium (e.g., pyridinium). In certain embodiments, M is an aliphatic ammonium.

In particular embodiments, M is dii sopropyl ammonium .

[00451] In certain embodiments, the trifluoroacetylating agent used in step (c) is selected from the group consisting of ethyl trifluoroacetate, trifluoroacetic anhydride,

phenyltrifluoroacetate, alkyl trifluoroacetates, and 1 -(trifluoroacetyl)imidazole. In particular embodiments, the trifluoroacetylating agent is ethyl trifluoroacetate.

[00452] In certain embodiments, the base used in step (c) is selected from the group consisting of lithium hexamethyldisilazide, lithium diisopropylamine, lithium

tetramethylpiperidide, lithium methoxide, lithium ethoxide, lithium fert-butoxide, alkali metal alkoxides, and alkali metal amides. In particular embodiments, the lithium base is lithium hexamethyldisilazide.

[00453] In certain embodiments, the salt used in step (c) is selected from the group consisting of alkali metals (e.g., Na, K, Mg, Ca), transition metals (e.g., Zn, aliphatic ammoniums (e.g., diisopropylammonium, di cy cl oh exyl amm oni um , di ethyl am m oni um , tri ethyl ammonium), and aromatic ammoniums (e.g., pyridinium). In particular embodiments, the salt is

dii sopropyl ammonium .

[00454] In certain embodiments, the solvent used in step (c) is selected from the group consisting of ethers (e.g., diethyl ether, l,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, methyl tert-butyl ether), hydrocarbon solvents (e.g., «-hexane, «-heptane, toluene, xylenes), di chl or om ethane, acetonitrile, and a combination thereof. In particular embodiments, the solvent used in step (c) is tetrahydrofuran. [00455] In certain embodiments, the acid used in step (d) is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, hydrogen bromide, methanesulfonic acid, ?-toluenesulfonic acid, benzenesulfonic acid, tri fl uoromethan esul foni c acid, and BF 3 2HOAc. In particular embodiments, the acid is sulfuric acid. In particular embodiments, the acid is hydrochloric acid.

[00456] In certain embodiments, the solvent used in step (d) is selected from the group consisting of ethanol, esters (e.g., ethyl acetate, isopropyl acetate), ether (e.g., tetrahydrofuran, 2-methyl tertrahydrofuran, l,4-dioxane), aprotic solvent (e.g., acetonitrile, NN- dimethylformamide, 7V,A r -dimethylacetamide, iV-methylpyrrolidinone), aromatic solvent (e.g., benzene, toluene, xylenes), chlorinated solvents (e.g., di chi orom ethane) and a combination thereof. In particular embodiments, the solvent used in step (d) is ethanol.

[00457] In certain embodiments, step (d) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (d) is carried out in the temperature range of from about 20 °C to about 100 °C. In particular embodiments, step (d) is carried out in the temperature range of from about 0 °C to about 40 °C.

[00458] In some embodiments, a process for preparing a compound of formula 5h:

5h

or a co-crystal, solvate, or combination thereof is provided, comprising:

(a) condensing a compound of formula 5f-la:

or a co-crystal, solvate, or combination thereof, wherein M 1 is selected from the group consisting alkali metals (e.g., Li, Na, K, Mg, Ca), transition metals (e.g., Zn, Sr), aliphatic ammonium (e.g., diisopropylammonium, di cy cl ohexyl ammonium, di ethyl ammonium, triethylammonium), aromatic ammonium (e.g., pyridinium), with a hydrazine derivative, a solvent, and a promoter, to provide a compound of formula 5g:

5g

or a co-crystal, solvate, or combination thereof;

(b) alkylating the compound of formula 5g or a co-crystal, solvate, or combination thereof, with an alkylating agent, a base, a solvent, and optionally a phase transfer catalyst, to provide the compound of formula 5h or a co-crystal, solvate, salt, or combination thereof

[00459] In certain embodiments, M 1 is selected from the group consi sting of alkali metals (e.g., Li, Na, K, Mg, Ca), transition metals (e.g., Zn, Sr), aliphatic amines (e.g.,

diisopropylammonium, dicyclohexylamine, diethylamine, triethylamine), and aromatic ammonium (e.g., pyridinium). In particular embodiments, M 1 is an alkali metal. In particular embodiments, M 1 is Lithium.

[00460] In certain embodiments, the hydrazine derivative used in step (a) is selected from the group consisting of anhydrous hydrazine, hydrazine monohydrate, hydrazine acetate, hydrazine dihydrochloride, hydrazine hydrate (e.g., hydrazine monohydrochloride), hydrazine sulfate, hydrazine hemi sulfate, and hydrazine m onohy drobrom i de . In particular embodiments, the hydrazine derivative used in step (a) is hydrazine hydrate.

[00461] In certain embodiments, the promoter used in step (a) is selected from the group consisting of carboxylic acids (e.g., formic acid, propionic acid, butanoic acid, acetic acid), Bronsted acids (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, toluenesulfonic acid), and Lewis acids (e.g., zinc chloride, magnesium chloride, titanium tetrachloride). In certain embodiments, the promoter used in step (a) is a carboxylic acid. In particular embodimens, the promoter used in step (a) is acetic acid.

[00462] In certain embodiments, the solvent used in step (a) is selected from the group consisting of water, alcohols (e.g., methanol, ethanol, 1- or 2-propanol), ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane), polar aprotic solvents (e.g., A,A-dimethylformamide, A^V-dimethylacetamide, N- methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes), alkyl carboxylic acid (e.g., formic acid, acetic acid, propanic acid, butanoic acid) and a combination thereof. In particular embodiments, the solvent used in step (a) is water .

[00463] In certain embodiments, step (a) is carried out in the temperature range of from about 120 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about 0 °C to about 120 °C. In particular embodiments, step (a) is carried out in the temperature range of from about 20 °C to about 100 °C.

[00464] In certain embodiments, the alkylating agent used in step (b) is selected from the group consisting of ethyl bromoacetate, ethyl chloroacetate, ethyl iodoacetate, ethyl

(methanesulfonyloxy)acetate, ethyl (p-tosyloxy)acetate, and ethyl

(((trifIuoromethyl)sulfonyl)oxy)acetate. In particular embodiments, the alkylating agent used in step (b) is ethyl bromoacetate.

[00465] In certain embodiments, the base used in step (b) is selected from the group consisting of tertiary amines (e.g., triethylamine, tri -n-propyl amine, tri-n-butylamine, N- methylmorpholine, /V-methylpyrrolidine, /V-methylpiperidine), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), alkoxide bases (e.g., sodium ethoxide, potassium ethoxide, sodium ter /-but oxide, potassium fe 7-butoxide, lithum fe/7-butoxide), sodium hydride, disilazide bases (e.g., sodium hexamethyldisilazide, lithium

hexam ethyl di si 1 azi de, sodium hexamethylsilazide, potassium hexamethyldisilazide), and a combination thereof. In particular embodiments, the base used in step (b) is sodium

h ex amethyldisilazide.

[00466] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ethers (e.g., diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane), polar aprotic solvents (e.g., A^-dimethylformamide, N,N- dimethylacetamide, A’-methylpyrrolidinone, acetonitrile), aromatic solvents (e.g., benzene, toluene, xylenes), chlorinated solvents (e.g., dichloromethane), esters (e.g., ethyl acetate, isopropyl acetate, //-butyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), alcohols (e.g., methanol, ethanol), water, and a combination thereof. In particular embodiments, the solvent used in step (b) is tetrahydrofuran.

[00467] In certain embodiments, step (b) comprises a phase transfer catalyst. In certain embodiments, the phase transfer catalyst used in step (b) is selected from the group consisting of tetra-alkylammonium salts. In particular embodiments, the tetra-alkylammonium salt is tetra-AA butyl ammonium hydrogensulfate and/or tetra-A'-buty 1 ammonium iodide.

[00468] In certain embodiments, step (b) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (b) is carried out in the temperature range of from about 20 °C to about 100 °C. In particular embodiments, step (b) is carried out in the temperature range of from about -20 °C to about 50 °C.

[00469] In some embodiments, a process for preparing a compound of formula 5e:

or a co-crystal, solvate, or combination thereof is provided, comprisin: (a) oxidizing a compound of formula 5a:

or a co-crystal, solvate, or combination thereof, with an oxidant, a base, and a solvent to provide a compound of formula 4a

4a or a co-crystal, solvate, or combination thereof;

(b) combining the compound of formula 4a or a co-crystal, solvate, or combination thereof, with l,2-ethanedithiol, a solvent, and a catalyst, to provide a compound of formula 5i:

5i

or a co-crystal, solvate, or combination thereof; and

(c) hydrolyzing the compound of formula 5i or a co-crystal, solvate, or combination thereof, with an acid, a solvent, and a promoter, to provide the compound of formula 5e or a co- crystal, solvate, salt, or combination thereof

[00470] In certain embodiments, the oxidant used in step (a) is selected from the group consisting of alkyl nitrites (e.g., isopentyl nitrite, «-butyl nitrite, tert-butyl nitrite, ethyl nitrite), nitrite salts (e.g., sodium nitrite, potassium nitrite), nitrosyl chloride, nitrosyl sulfate, and nitrosonium salts (e.g., tetraflu orob orate, hydrogen sulfate). In certain embodiments, the oxidant used in step (a) is selected from the group consisting of isopentyl nitrite, «-butyl nitrite, tert- butyl nitrite, ethyl nitrite, sodium nitrite, potassium nitrite, nitrosyl chloride, nitrosyl sulfate, tetrafluorob orate, and hydrogen sulfate. In particular embodiments, the oxidant used in step (a) is tert-butyl nitrite.

[00471] In certain embodiments, the base used in step (a) is selected from the group consisting of alkali metal alkoxides (e.g., potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium isopropoxide, sodium ethoxide, sodium methoxide), alkali metal hydrides (e.g., sodium hydride), amide bases (e.g., lithium tetram ethyl pi p eri di de, lithium

hexamethyldisilazide), and phosphazenes. In certain embodiments, the base used in step (a) is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, lithium tert- butoxide, sodium isopropoxide, sodium ethoxide, sodium methoxide, sodium hydride, lithium tetramethylpiperidide, lithium hexamethyldisilazide, and phosphazenes. In particular embodiments, the base used in step (a) is potassium tert-butoxide.

[00472] In certain embodiments, the solvent used in step (a) is selected from the group consisting of tetrahydrofuran, ethers (e.g., diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyltetrahydrofuran, l,4-dioxane), polar aprotic solvents (e.g., L T ,N- dimethylform amide, A ? ,A ? -dimethylacetamide, Ά'-methylpyrrolidinone), halogenated solvents (e.g., dichloromethane), alcohols (methanol, ethanol, isopropanol), sulfolane, and a combination thereof. In certain embodiments, the solvent used in step (a) is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, 2- methyltetrahydrofuran, l,4-dioxane, A(A-dimethylformamide, A A'-dimethylacetamide, N- methylpyrrolidinone, di chl orom ethane, methanol, ethanol, isopropanol, sulfolane, and a combination thereof. In particular embodiments, the solvent used in step (a) is tetrahydrofuran.

[00473] In certain embodiments, step (a) is carried out in the temperature range of from about 70 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about -78 °C to about 70 °C. In particular embodiments, step (a) is earned out in the temperature range of from about -10 °C to about 10 °C.

[00474] In certain embodiments, the catalyst used in step (b) is selected from the group consisting of mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid), sulfonic acids (e.g., ara-toluenesulfonic acid monohydrate, methanesulfonic acid, benzenesulfonic acid), trifluoroacetic acid, phosphoric acid, iodine, 1 , 3 -dibromo-5 , 5 -dimethylhydantoin, copper(II) dodecyl sul fate, y tterbium(III) triflate, yttrium (III) triflate, bismuth(III) trill ate, bismuth(III) chloride, tungstophosphoric acid, perchloric acid, praseodymium triflate, hafnium (IV) triflate, iron(III) chloride, hydrogen chloride, -dodecyl benzenesulfonic acid,

BF 3 OEt 2 , BF 3 OMe 2, BF 3 THF, BF 3 OBu 2 , BF 3 MeOH, BF 3 Me 2 S, BF 3 PhOH, and

BF 3 2H 2 0. In certain embodiments, the catalyst used in step (b) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, ara-toluenesulfonic acid monohydrate, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, phosphoric acid, iodine, l,3-dibromo-5,5-dimethylhydantoin, copper(II) dodecyl sulfate, ytterbium(III) triflate, yttrium(III) triflate, bismuth(III) triflate, bismuth(III) chloride, tungstophosphoric acid, perchloric acid, praseodymium triflate, hafnium(IV) triflate, iron(III) chloride, hydrogen chloride, /?-dodecyl benzenesulfonic acid, BF 3 OEt 2 , BF OMe , BF 3 THF, BF OBu ,

BF 3 MeOH, BF 3 Me 2 S, BF 3 PhOH, and BF 3 2H 2 0. In particular embodiments, the catalyst used in step (b) is ara-toluenesulfonic acid monohydrate.

[00475] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ethers (e.g., diethyl ether, methyl tert-buiy\ ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane,), aromatic solvents (e.g., benzene, xylenes), polar aprotic solvents (e.g., L',A-di m et h y 1 form am i d e, A^V-dimethylacetamide, N- methylpyrrolidinone), acetonitrile, halogen ated solvents (e.g., dichloromethane, dichloroethane), carboxylic acids (e.g., acetic acid, propionic acid), sulfolane and a combination thereof. In particular embodiments, the solvent used in step (b) is a carboxylic acid. In certain

embodiments, the solvent used in step (b) is selected from the group consisting of diethyl ether, methyl /er/-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane, benzene, xylenes, A(A r -dimethylformamide, A/,A r -dimethyiacetamide, N- methylpyrrolidinone, acetonitrile, dichloromethane, dichloroethane, acetic acid, propionic acid, sulfolane, and a combination thereof. In particular embodiments, the solvent used in step (b) is acetic acid.

[00476] In certain embodiments, step (b) is carried out in the temperature range of from about 80 °C or less. In parti cular embodiments, step (b) is carried out in the temperature range of from about 0 °C to about 80 °C.

[00477] In certain embodiments, the acid used in step (c) is selected from the group consisting of mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid monohydrate), trifluoroacetic acid, phosphoric acid, levulinic acid, glyoxylic acid, alkali metal bisulfites (e.g., sodium bisulfite, sodium metabi sulfite, potassium bisulfite), and sodium dithionite. In certain embodiments, the acid used in step (c) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, para- toluenesulfonic acid monohydrate, trifluoroacetic acid, phosphoric acid, levulinic acid, glyoxylic acid, sodium bisulfite, sodium metabi sulfite, potassium bisulfite, and sodium dithionite. In certain embodiments, the acid used in step (c) is a sulfonic acid. In particular embodiments, the acid used in step (c) is para-toluenesulfonic acid monohydrate.

[00478] In certain embodiments, the solvent used in step (c) is selected from the group consisting of ethers (e.g., diethyl ether, methyl fert-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane), aromatic solvents (e.g., benzene, xylenes), polar aprotic solvents (e.g., A V-dimethylform amide, AyV-dimethylacetamide, A^-methylpyrrolidinone), acetonitrile, halogen ated solvents (e.g., dichloromethane, dichloroethane), ketones (e.g., methyl ethyl ketone, acetone, methyl isobutyl ketone), aldehydes (e.g., formaldehyde/formalin, acetaldehyde, isobutyraldehyde), water, and a combination thereof. In certain embodiments, the solvent used in step (c) is selected from the group consisting of diethyl ether, methyl fer/-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, l,4-dioxane, benzene, xylenesA 7 ,A r - dimethylformamide, A r ,A " -dimethylacetamide, AAmethylpyrrolidinone, acetonitrile,

di chi orom ethane, dichloroethane, methyl ethyl ketone, acetone, methyl isobutyl ketone, formaldehyde/formalin, acetaldehyde, isobutyraldehyde, water, and a combination thereof. In particular embodiments, the solvent used in step (c) is methyl ethyl ketone and water.

[00479] In certain embodiments, step (c) is carried out in the temperature range of from about 100 °C or less. In particular embodiments, step (c) is carried out in the temperature range of from about 20 °C to about 100 °C. [00480] In some embodiments, a process for preparing a compound of formula 5a:

5a or a co-crystal, solvate, or combination thereof is provided, comprising combining a compound of formula 4e:

4e

or a co-crystal, solvate, salt, or combination thereof, with a catalyst, an acid, a base, a solvent, and optionally an additive to provide the compound of formula 5a, or a co-crystal, solvate, or combination thereof, wherein X 1 is selected from the group consisting of tosyloxy, chloro, bromo, iodo, mesyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2,4,6-triisopropylbenzenesufonyloxy, acetoxy, trichloroacetoxy, and trifluoroacetoxy.

[00481] In certain embodiments, X 1 is tosyloxy.

[00482] In certain embodiments, the catalyst is selected from the group consisting of (8 a, 95)- 6'-methoxycinchonan-9-amine trihydrochloride, cinchona alkaloid derivatives, amino acids (e.g. D- or L-phenylglycine, D- or L-cyclopentylglycine, D- or L-proline) primary amines (e.g., 1- phenyl ethyl amine), secondary amines (e.g., 2-methyl pyrroli di ne, 2,5-dimethylpyrrolidine), and aldolase. In certain embodiments, the catalyst is selected from the group consisting of (8a,95)- 6'-methoxycinchonan-9-amine trihydrochloride, cinchona alkaloid derivatives, D- or L- phenylglycine, D- or L-cyclopentylglycine, D- or L-proline, 1 -phenyl ethylamine, 2- methylpyrrolidine, 2, 5 -di m ethylpyrrolidine, and aldolase. In particular embodiments, the catalyst is (8a,95)-6'-methoxycinchonan-9-amine trihydrochloride.

[00483] In certain embodiments, the acid is selected from the group consisting of carboxylic acids (e.g., acetic acid, trifluoroacetic acid, trichloroacetic acid, tartaric acid), sulfonic acids (e.g., camphorsulfonic acid), sulfuric acid, phosphonic acids, phosphoric acid, and triflic acid. In certain embodiments, the acid is selected from the group consisting of acetic acid, trifluoroacetic acid, trichloroacetic acid, tartaric acid, camphorsulfonic acid, sulfuric acid, phosphonic acids, phosphoric acid, and triflic acid. In particular embodiments, the acid is trifluoroacetic acid.

[00484] In certain embodiments, the base is selected from the group consisting of

carboxylates (e.g., lithium acetate, sodium acetate, potassium acetate, lithium benzoate, sodium benzoate), carbonates (e.g., lithium bicarbonate, lithium carbonate, sodium bicarbonate, sodium carbonate), sulfates (e.g., lithium sulfate, sodium sulfate), phosphates (e.g., sodium phosphates, potassium phosphate), and organic amines (e.g., imidazole, triethylamine, DABCO). In certain embodiments, the base is selected from the group consisting of lithium acetate, sodium acetate, potassium acetate, lithium benzoate, sodium benzoate, lithium bicarbonate, lithium carbonate, sodium bicarbonate, sodium carbonate, lithium sulfate, sodium sulfate, sodium phosphates, potassium phosphate, imidazole, triethylamine, and DABCO. In particular embodiments, the base is lithium acetate.

[00485] In certain embodiments, the solvent is selected from the group consisting of alcohols (e.g., methanol, ethanol, 2-propanol), esters (e.g., ethyl acetate, butyl acetate, isobutyl acetate), ethers (e.g., diethyl ether, methyl terf-hutyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylenes), polar aprotic solvents (e.g., LnU-dimethylformamide, N, Y-dimethyl acetamide, /V-methylpyrrolidinone, dimethyl sulfoxide), chlorinated solvents (e.g., di chi oromethane, dichloroethane, chloroform), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), water, and a combination thereof. In certain embodiments, the solvent is selected from the group consisting of methanol, ethanol, 2- propanol, ethyl acetate, butyl acetate, isobutyl acetate, diethyl ether, methyl fcrt-butyl ether, 2- methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, toluene, benzene, xylenes, N,N- dimethylformamide, AyV-dimethylacetamide, /V-methylpyrrolidinone, dimethylsulfoxide, di chi oromethane, dichloroethane, chloroform, acetonitrile, propionitrile, butyronitrile, water, and a combination thereof. In particular embodiments, the solvent is 2-methyltetrahydrofuran and water. In particular embodiments, the solvent is 2-methyl tetrahydrofuran .

[00486] In certain embodiments, the process comprises an additive. In certain embodiments, the additive is an alcohol. In certain embodiments, the additive is selected from the group consisting of methanol, ethanol, 1 -propanol, 2-propanol, and water. In particular embodiments, the additive is water.

[00487] In certain embodiments, the process is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -40 °C to about 120 °C. In particular embodiments, the process is carried out in the temperature range of from about 0 °C to about 40 °C. In particular embodiments, the process is carried out at about 20 °C.

[00488] In some embodiments, a process for preparing a compound of formul a V-02:

V-02

or a co-crystal, solvate, salt, or combination thereof is provided, comprising

(a) combining a compound of formula 6d:

6d

or a co-crystal, solvate, salt, or combination thereof, with a formyl source, a base and a solvent to provide a compound of formula 6a:

6a

or a co-crystal, solvate, salt, or combination thereof;

(b) combining the compound of formula 6a or a co-crystal, solvate, salt, or combination thereof, with a reagent, a dehydrating reagent, and a solvent to provide a compound of formula

6b:

6b

or a co-crystal, solvate, salt, or combination thereof;

(c) combining the compound of formula 6b or a co-crystal, solvate, salt, or combination thereof, with a hydrazine source and a sol vent to provi de a compound of formula 6c:

6c

or a co-crystal, solvate, salt, or combination thereof;

(d) combining the compound of formula 6c or a co-crystal, solvate, salt, or combination thereof, with an alkylating reagent, a base, a solvent, and, optionally an alkylating additive, to provide a compound of formula V-A:

V-A

or a co-crystal, solvate, salt, or combination thereof; and

(e) combining the compound of formula V-A or a co-crystal, solvate, salt, or

combination thereof, with a boron coupling agent, a base, a palladium catalyst and a solvent to provide the compound of formula V-02, or a co-crystal, solvate, salt, or combination thereof.

[00489] In certain embodiments, the formyl source used in step (a) is selected from the group consisting of carbon monoxide and hydrogen chloride; hydrogen cyanide and hydrogen chloride; metal cyanide and hydrogen chloride; phosphorus oxychloride; N,N-di m ethylformami de;

hexamine acetic acid; dichloromethyl methyl ether; and form amide. In particular embodiments, the formyl source used in step (a) is N,N-dimethylformamide. [00490] In certain embodiments, the base used in step (a) is selected from the group consisting of sodium, lithium, or potassium bis(trimethylsilyl)amide, sodium or potassium diisopropylamide, lithium tetramethylpiperi di de, and lithium or sodium amide. In particular embodiments, the base used in step (a) is lithium diisopropyl amide. In particular embodiments, the based used in step (a) is lithium di isopropyl amide that is prepared in situ from

diisopropylamine and n-butyl lithium.

[00491] In certain embodiments, the solvent used in step (a) is selected from the group consisting of ethers (e.g., diethyl ether, methyl / <? r/-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylenes), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform,), non-polar solvents (e.g., hexanes, heptane, cyclohexane), and a combination thereof. In particular embodiments, the solvent used in step (a) is tetrahydrofuran.

[00492] In certain embodiments, step (a) is carried out in the temperature range of from about 60 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about -80 °C to about 60 °C. In particular embodiments, step (a) is carried out in the temperature range of from about -30°C to about 40 °C.

[00493] In certain embodiments, the reagent used in step (b) is selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine-O-sulfonic acid, sodium azide, trifluoromethanesulfonic acid, and propylphosphonic anhydride. In particular embodiments, the reagent used in step (b) is hydroxylamine hydrochloride.

[00494] In certain embodiments, the dehydrating reagent used in step (b) is selected from the group consisting of aceti c anhydride, acids (e.g., formic acid, hydrochloric acid, sulfuric acids, citric acids, phosphoric acids), copper(II) acetate, and cyanuric chloride/dimethylform amide. In particular embodiments, the base used in step (b) is acetic anhydride.

[00495] In certain embodiments, the solvent used in step (b) is selected from the group consisting of acids (e.g., acetic acid, formic acid), polar solvents (e.g., dimethyl sulfoxide, N,N- dimethylform amide, N,N-di m ethyl acetam i de, N-methyl-2-pyrrolidone, acetonitrile, water, tert- butyl alcohol), non-polar solvents (e.g., toluene), and a combination thereof. In particular embodiments, the solvent used in step (b) is acetic acid.

[00496] In certain embodiments, step (b) is carried out in the temperature range of from about 95 °C or less. In certain embodiments, step (b) is carried out in the temperature range of from about 20 °C to about 95 °C. In particular embodiments, step (b) is carried out in the temperature range of from about 40° C to about 70 °C. [00497] In certain embodiments, the hydrazine source used in step (c) is selected from the group consisting of hydrazine, hydrazine hydrochloride, hydrazine hydrobromide, hydrazine sulfate, and hydrazine acetate. In particular embodiments, the hydrazine source used in step (c) is hydrazine hydrate.

[00498] In certain embodiments, the solvent used in step (c) is selected from the group consisting of alcohols (e.g., ethanol, methanol, isopropanol), water and a combination thereof. In particular embodiments, the solvent used in step (c) is water and isopropanol.

[00499] In certain embodiments, step (c) is carried out in the temperature range of from about 85 °C or less. In particular embodiments, step (c) is carried out in the temperature range of from about 75 °C to about 85 °C.

[00500] In certain embodiments, the alkylating reagent used in step (d) is selected from the group consisting of 2,2,2-trifluoroethyl trifluoromethanesulfonate, 2,2,2-trifluoroethyl tri chloromethanesulfonate, 1 , 1,1 -trifluoro-2 -i odoeth ane, 2-bromo- 1, 1,1 -trifluoroethane, 1,1, 1 - trifluoro-2-chloroethane, 2,2,2-trifluoroethyl methanesulfonate, and 2,2,2-trifluoroethyl p- toluenesulfonate. In particular embodiments, the reagent used in step (d) is 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[00501] In certain embodimnets, step (d) comprises an alkylating additive. In certain embodiments, the alkylating additive used in step (d) is selected from the group consisting of symmetrical quaternary ammonium salts (e.g., tetrabutylammonium bromide,

tetraeth yl ammonium bromide, tetr abutyl ammoni um hydrogen sulfate), non-symmetrical quaternary ammonium salts (e.g., benzyltrimethylammonium chloride,

benzyltrimethylammonium bromide, benzyltrimethylammonium iodide,

benzyltriethylammonium chloride, benzyltri ethylammonium bromide, b enzyltri ethyl am m onium iodide, b enzyl tributyl ammonium chloride, benzyltributylammonium bromide,

b enzyl tri butyl am m onium iodide, phenyltrimethylammonium chloride,

phenyltrimethylammonium bromide, phenyltrimethylammonium iodide,

decyl trimethyl ammonium bromide), lithium chloride, and phosphonium salts (e.g.,

methyltriphenoxyphosphonium iodide, tetrabutylphosphonium bromide).

[00502] In certain embodiments, the base used in step (d) is selected from the group consisting of cesium carbonate, lithium bases (e.g., lithium hydroxide, lithium phosphate, lithium carbonate, lithium ethoxide, lithium methoxide, lithium trifluoromethanesulfonate), sodium bases (e.g., sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, sodium te/7-butoxide, sodium methoxide, sodium ethoxide, sodium pivalate, sodium propionate, sodium hydride), potassium bases (e.g., potassium phosphate, potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium /ert-butoxide, potassium phosphate dibasic, potassium phosphate monobasic, potassium acetate, potassium piva!ate), calcium bases (e.g., calcium hydroxide, calcium carbonate), amine bases (e.g., triethylamine, N,N- di i sopropylehtyl amine, N-methylmorpholine, 1 ,8-diazabicyc!o[5.4.0]undec-7-ene, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, pyridine, l-methy!imidazo!e, imidazole, 2,6-lutidine, 4-methyl morpholine, 2,6-ditertbutylpyridine), and barium bases (e.g., barium hydroxide, barium carbonate,). In particular embodiments, the base used in step (d) is a potassium base. In particular embodiments, the base used in step (d) is potassium phosphate.

[00503] In certain embodiments, the solvent used in step (d) is selected from the group consisting of polar aprotic solvent (e.g., N,N-di m ethylformami de, N-methyl-2-pyrrolidone, N,N- dimethylacetamide, pyridine, dimethyl sulfoxide, sulfolane), ketone solvents (e.g., acetone, methyl ethey ketone, methyl isobutyl ketone), hydrocarbon solvents (e.g., toluene, heptane, hexane), alcohol solvents (e.g., methanol, ethanol, isopropyl alcohol, tert- amyl alcohol, tert- butyl alcohol, 1- butanol, «-butanol), ether solvents (e.g., tetrahydrofuran, 2- methyltetrahydrofuran, methyl fert-butyl ether), acetate solvents (e.g., ethyl acetate, isopropyl acetate), acetonitrile, di chi or om ethane, and a combination thereof. In particular embodiments, the solvent used in step (d) is a polar aprotic solvent. In particular embodiments, the solvent used in step (d) is N,N-dimethylform amide.

[00504] In certain embodiments, step (d) is carried out in the temperature range of from about 60 °C or less. In certain embodiments, step (d) is carried out in the temperature range of from about -20°C to about 60 °C. In particular embodiments, step (d) is carried out in the temperature range of from about 0°C to about 40 °C. In particular embodiments, step (d) is carried out at about 20 °C.

[00505] In certain embodiments, the boron coupling agent used in step (e) is selected from the group consisting of bis(pinacolato)diboron, bis(neopentyl glycolato)diboron, bisboronic acid, and bis(ethylene glycolato diboron). In particular embodiments, the boron coupling agent used in step (e) is bis(pinacolato)diboron.

[00506] In certain embodiments, the base used in step (e) is selected from the group consisting of cesium acetate, potassium propionate, sodium propionate, potassium acetate, sodium acetate, cesium acetate, potassium propionate, sodium propionate, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, potassium phosphate dibasic, potassium phosphate tribasic, sodium hydroxide, potassium hydroxide,

di cyclohexyl amine, A-methyimorpholine, tri ethyl amine, and diisopropyl ethylamine. In particular embodiments, the base used in step (e) is potassium acetate.

[00507] In certain embodiments, the palladium catalyst used in step (e) is selected from the group consisting of bis(di-/ert-butyl(4-dimethylaminophenyl)phosphine)dichloropa lladium(II), bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium (II) chloride,

dichlorobis(triphenylphosphine)palladium(II), [ 1 , G - bis(diphenylphosphino)ferrocene]dichloropalladium(II), [ 1 ,2- bis(diphenylphosphino)ethane]dichloropalladium(II), and dichloro[9, 9-dimethyl -4,5- bis(diphenylphosphino)xanthene]palladium(II). In certain embodiments, the palladium catalyst used in step (e) is palladium(II) precatalyst (e.g., palladium (II) chloride, palladium(II) acetate, palladium(II) trifluoroacetate) or palladium(O) precatalyst (e.g.,

bis(dibenzylideneacetone)palladium(0)) and further comprises a phosphine ligand (e.g., tri cy cl ohexyl phosphine, triphenylphosphine,

cyclohexyl diphenylphosphine, dicyclohexylphenylphosphine). In particular embodiments, the palladium catalyst used in step (e) is bis(triphenylphosphine)palladium (II) di chloride.

[00508] In certain embodiments, the solvent used in step (e) is selected from the group consisting of ethers (e.g., 1 ,4-dioxane, 2-methyltetrahydrofuran, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, xylenes), esters (e.g., ethyl acetate, isopropyl acetate, propyl acetate, isobutyl acetate), alcohols (e.g., ethanol, isopropanol), and polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidine), and a combination thereof. In particular embodiments, the solvent used in step (e) is toluene and N,N- di m ethylformami de.

[00509] In certain embodiments, step (e) is carried out in the temperature range of from about 120 °C or less. In certain embodiments, step (e) is carried out in the temperature range of from about 20°C to about 120 °C. In particular embodiments, step (e) is carried out in the temperature range of from about 95 °C to about 105 °C.

[00510] In some embodiments, a process for preparing a compound of formula lb-02: l b-02 or a co-crystal, solvate, salt, or combination thereof is provided, comprising: (a) combining the compound of formula Ij :

lj

or a co-crystal, solvate, salt, or combination thereof, with an oxidant, a base, a solvent, and optionally a catalyst or optionally an additive, to provide a compound of formula Hi:

Ih or a co-crystal, solvate, salt, or combination thereof;

(b) hydrolyzing the compound of formula lh or a co-crystal, solvate, salt, or combination thereof, with a reagent and a sol vent, to provide a compound of formula la:

°g k

Be '

la

or a co-crystal, solvate, salt, or combination thereof; (c) combining the compound of formula la or a co-crystal, solvate, salt, or combination thereof, with a bisulfite source and a solvent, to provide a compound of formula li:

li or a co-crystal, solvate, salt, or combination thereof, wherein M 2 is K or Na + ; and

(d) combining the compound of formula li or a co-crystal, solvate, salt, or combination thereof, with benzhyhydrylamine, a base, and a solvent, to provide the compound of formula lb- 02 or a co-crystal, solvate, salt, or combination thereof.

[00511] In certain embodiments, the oxidant used in step (a) is selected from the group consisting of alkyl nitrites (e.g. /.vo-arnyl nitrite, «-butyl nitrite, «-propyl nitrite, tert- butyl nitrite). In particular embodiments, the oxidant used in step (a) is ferf-butyl nitrite.

[00512] In certain embodiments, the base used in step (a) is selected from the group consisting of metal alkoxides (e.g., sodium tert-butoxide, sodium methoxide, sodium iso- propoxide, potassium fert-butoxide, potassium Aopropoxide, sodium ethoxide) and metal amides (e.g., potassium amide, sodium amide, LDA). In particular embodiments, the base used in step (a) is potassium fert-butoxide.

[00513] In certain embodiments, the solvent used in step (a) is selected from the group consisting of tetrahydrofuran, ethers (e.g., MTBE, diethyl ether, CPME), nitriles (e.g., acetonitrile), DMSO, and a combination thereof. In particular embodiments, the solvent used in step (a) is tetrahydrofuran.

[00514] In certain embodiments, step (a) comprises a catalyst or an additive. In certain embodiments, the catalyst or additive used in step (a) is selected from the group consisting of benzoic acid and copper salts (e.g. copper di acetate).

[00515] In certain embodiments, step (a) does not comprise a catalyst or an additive.

[00516] In certain embodiments, step (a) is carried out in the temperature range of from about 40 °C or less. In certain embodiments, step (a) is carried out in the temperature range of from about -20 °C to about 40 °C. In particular embodiments, step (a) is carried out in the temperature range of from about 0°C to about 10 °C. [00517] In certain embodiments, the reagent used in step (b) is selected from the group consisting of glyoxylic acid, pyruvic acid, sodium dithionite, sodium bisulfite, potassium metabisulfite, 3 -methoxypropi oni c acid, sodium nitrite, nitrosyl chloride, /e/7-butyl nitrite, and potassium persulfate. In particular embodiments, the reagent used in step (b) is glyoxylic acid.

[00518] In certain embodiments, the solvent used in step (b) is selected from the group consisting of ketones (e.g. acetone, methyl ethyl ketone (MEK)) alcohols (e.g. methanol, ethanol), THF, water, and a combination thereof. In particular embodiments, the solvent used in step (b) is water.

[00519] In certain embodiments, step (b) is carried out in the temperature range of from about 100 °C or less. In certain embodiments, step (b) is carried out in the temperature range of from about 0 °C to about 100 °C. In particular embodiments, step (b) is carried out in the temperature range of from about 50°C to about 90 °C.

[00520] In certain embodiments, the bisulfite source used in step (c) is selected from the group consisting of potassium metabi sulfite and sodium bisulfite. In particular embodiments, the bisulfite source used in step (c) is potassium metabisulfite.

[00521] In certain embodiments, the solvent used in step (c) is selected from the group consisting of alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butanol), ethers (e.g. MTBE, THE, 2-methyltetrahydrofuran, CPME, diethyl ether, diisopropyl ether), water, and a combination thereof. In particular embodiments, the solvent used in step (c) is water and isopropanol.

[00522] In certain embodiments, step (c) is carried out in the temperature range of from about 60 °C or less. In certain embodiments, step (c) is carried out in the temperature range of from about 0°C to about 60 °C. In particular embodiments, step (c) is carried out in the temperature range of from about 20°C to about 30 °C.

[00523] In certain embodiments, the base used in step (d) is selected from the group consisting of hydroxides (e.g., potassium hydroxide, sodium hydroxide), bi carbonates (e.g., potassium or sodium bicarbonate), carbonates (e.g. potassium or sodium carbonates), and phosphates (e.g. potassium or sodium phosphate, mono- bi- or tribasic). In particular

embodiments, the base used in step (d) is potassium hydroxide.

[00524] In certain embodiments, the solvent used in step (d) is selected from the group consisting of ethers (e.g., diethyl ether, methyl /er/-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, l,4-dioxane), polar aprotic solvents (e.g., iV,A dimethylformamide, N,N- dimethylacetamide, JV-methylpyrrolidinone), aromatic solvents (e.g., benzene, xylenes), chlorinated solvents (e.g., di chl oromethane), water, and a combination thereof. In particular embodiments, the solvent used in step (d) is water and 2-m ethyltetrahydrofuran.

[00525] In certain embodiments, step (d) is carried out in the temperature range of from about 120 °C or less. In certain embodiments, step (d) is carried out in the temperature range of from about -20°C to about 120 °C. In particular embodiments, step (d) is carried out in the

temperature range of from about 20°C to about 80 °C.

[00526] In some embodiments, a process for preparing a compound of formula IX:

IX or a co-crystal, solvate, salt, or combination thereof is provided, comprising combining 3- Chloro-3 -methylbut- 1 -yne (3 -CMB):

3-CMB with a reagent, a ligand, a solvent, an acid, and a catalyst, to provide the compound of formula IX or a co-crystal, solvate, salt, or combination thereof.

[00527] In certain embodiments, the reagent is selected from the group consisting of sodium methanesulfmate, lithium methanesulfmate, and potassium methanesulfmate. In particular embodiments, the reagent is sodium methanesulfmate.

[00528] In certain embodiments, the ligand is selected from the group consisting of

N,N,N',N'-Tetramethylethylenediarnme (TMEDA), L-proline, DMAP, 2,2’-bipyridine, TEA, DIPEA, pyridine, ethylenediamine, 1 2-diaminocyclohexane, and N, N’ -dimethyl cy cl ohexane- 1, 2-diamine. In particular embodiments, the ligand is N,N,N',N'-Tetramethylethylenediamine.

[00529] In certain embodiments, the catalyst is selected from the group consisting of CuCl,

CuCl 2 , CuBr, Cul, C11SO 4, CuO, Cu 2 0, Cu(OAc), Cu(OAc) 2 , Fed , FeBr 3 , CuBr 2 , Cu(N0 3 ) 2 l ed ¾, and Fe(N0 3 ) 3 -9H 2 0. In particular embodiments, the catalyst is copper (II) acetate. [00530] In certain embodiments, the solvent is selected from the group consisting of esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate), ethers (e.g., diethyl ether, methyl / -butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, l,4-dioxane), aromatic solvents (e.g., toluene, benzene, xylenes), polar aprotic solvents (e.g., A’,A ? -dimethylfomiamide, NN-d\ m ethyl acetami de, /V-methylpyrrolidinone, dimethyl sul foxide), polar protic solvents (e.g., methanol, ethanol, 2-propanol, /-butyl alcohol, sec-butyl alcohol, /-amyl alcohol), chlorinated solvents (e.g., dichloromethane, dichloroethane, chloroform), nitriles (e.g., propionitrile, butyronitrile), ketones (e.g., acetone, 2-butanone, methyl isobutyl ketone), and a combination thereof. In particular embodiments, the solvent is isopropyl acetate.

[00531] In certain embodiments, the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, ammonium chloride, ammonium hydroxide, phosphoric acid, acetic acid, and citric acid. In certain embodiments, the acid is an aqueous acid. In certain

embodiments, the acid is selected from the group consisting of 5% aqueous sulfuric acid, 5% aqueous hydrochloric acid, 10% aqueous ammonium chloride, 10% aqueous ammonium hydroxide, 5% aqueous phosphoric acid, 5% aqueous acetic acid, and 5% aqueous citric acid. In particular embodiments, the acid is 5% aqueous sulfuric acid.

[00532] In certain embodiments, the process is carried out in the temperature range of from about 120 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -20 °C to about 120 °C. In particul ar embodiments, the process is carried out in the temperature range of from about 20 °C to about 60 °C. In particular embodiments, the process is carried out at about 40 °C.

[00533] In some embodiments, a process for preparing a compound of formula X:

or a co-crystal, solvate, salt, or combination thereof is provided, comprising contacting a compound of formula VIII:

an enantiomer of the compound of formula VIII, or a mixture of the compound of formula VIII and the enantiomer of the compound of formula VIII, or a co-crystal, solvate, salt, or combination of any of the foregoing, with an aldehyde, a solvent, and one reagent selected from the group consisting of a metal catalyst and a base, to provide the compound of formula X, or a co-crystal, solvate, salt, or combination thereof.

[00534] In certain embodiments, the process comprises contacting the compound of formula VIII, the enantiomer of the compound of formula VIII, or a mixture of the compound of the compound of formula VIII and the enantiomer of the compound of formula VIII, or a co- crystal, solvate, salt, or combination of any of the foregoing, with an aldehyde, a solvent, and a metal catalyst to provide the compound of formul a X. In certain embodiments, the process comprises contacting the compound of formula VIII, the enantiomer of the compound of formula VIII, or a mixture of the compound of the compound of formula VIII and the enantiomer of the compound of formula VIII, or a co-crystal, solvate, salt, or combination of any of the foregoing, with an aldehyde, a solvent, and a base to provide the compound of formula X.

[00535] In certain embodiments, the aldehyde is selected from the group consisting of aromatic aldehydes (e.g., benzaldehyde, 2,4-dichlorobenzaldehyde, 2-methoxybenzaldehyde, 4- (dimethylamino)benzaldehyde, 2-(dimethylamino)benzaldehyde, 2-hydroxy-5- methoxybenzaldehyde, 2 -h y droxy- 5 -nitrob enzal dehy de, 5-chloro-2-hydroxybenzaldehyde, 4- hydroxybenzaldehyde, 2-hydroxybenzaldehyde, 3 , 5 -di chl oro-2-hy droxyb en zal dehy de, 3- hy droxyb enzal dehy de, 2-hydroxy-3-nitrobenzaldehyde); heteroaromatic aldehydes (e.g., 2- formylpyridine, 3 -(trifluorom ethyl )pi colinal dehyde, 4-chl oropicolinaldehyde, nicotinaldehyde, quinolone-4-carbaldehyde, quinolone-2-carbaldehyde); and aliphatic aldehydes (e.g., formaldehyde, ethyl glyoxylate, glyoxylic acid). In particular embodiments, the aldehyde is 2- formylpyridine. [00536] In certain embodiments, the metal catalyst is selected from the group consisting of zinc salts (e.g., zinc(II) oxide, zinc(II) acetate, zinc(II) trifluoromethanesulfonate, zinc(II) trif!uoroacetate, zinc(II) chloride, zinc (P) stearate, zinc (II) neodecanoate, zinc (II)

tetrafluoroborate); nickel salts (e g., nickel (II) acetate, nickel(II) chloride, nickel (P) triflate); indium salts (e.g., indium (III) acetate); copper salts (e.g., copper(II) acetate); cobalt salts (e.g., cobalt(II) acetate); and manganese salts (e.g., manganese(II) acetate). In particular embodiments, the metal catalyst is zinc(II) acetate.

[00537] In certain embodiments, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, DBU, DBN, DABCO,

tetramethylguanidine, BEMP, and l-/er/-Butyl-4,4,4-tris(dimethylamino)-2,2- bis[tris(dimethylamino)-phosphoranylidenamino]-2k 5 ,4> 5 -catenadi(phosphazene) (t-Bu-P4).

[00538] In certain embodiments, the solvent is selected from the group consisting of esters (e.g., ethyl acetate, isopropyl acetate), ethers (e.g. ,tetrahy drofuran, 2-methyl tertrahydrofuran, 1,4-dioxane), aprotic solvents (e.g., acetonitrile, A,A-dimethylformamide, NN- di m ethyl acetami de, A-methylpyrrolidinone), aromatic solvents (e.g., benzene, toluene, xylenes), chlorinated solvents (e . g. , di chi orom ethane), alcohols (e.g., methanol, ethanol, isopropanol) and a combination thereof. In particular embodiments, the solvent is toluene.

[00539] In certain embodiments, the process is carried out in the temperature range of from about 100 °C or less. In certain embodiments, the process is carried out in the temperature range of from about -20 °C to about 100 °C. In particular embodiments, the process is carried out in the temperature range of from about 20 °C to about 80 °C. In particular embodiments, the process is carried out at about 60 °C.

[00540] Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative solvents may be used, such as other ethers (e.g., diethyl ether, methyl fe/7-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane), aromatic hydrocarbon solvents (e.g., toluene, benzene, xylenes), nitriles (e.g., propionitrile, butyronitrile, acetonitrile), esters (e.g., ethyl acetate, n-butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate), polar aprotic solvents (e.g., N, /V-di iri ethyl form ami de, A^V-di m ethyl acetam i de, A-rnethyl pyrrol i di none, dimethylsulfoxide), alcohols (e.g., methanol, ethanol, 1 -propanol, isopropanol, ter/-amyl alcohol, n-butanol, sec-butanol), chlorinated solvents (e.g., di chi orom ethane, dichloroethane, chloroform), hydrocarbon solvents (e.g., n-hexane, cyclohexane, n-heptane), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutylketone), and water. The reactions may also be performed with a combination of the aforementioned solvents or without solvent. Further, temperatures ranging from about -80 °C to about 130 °C may employed.

[00541] In some embodiments, a compound of formula VI:

or a co-crystal, solvate, or combination thereof is provided.

[00542] In some embodiments, a compound of formula VIII:

VIII

or a co-crystal, solvate, salt or combination thereof is provided.

[00543] In certain embodiments, the compound of formula VIII is a compound of formula

VIII-02:

or a co-crystal, solvate, or combination thereof, wherein HX is a chiral or achiral acid.

[00544] In certain embodiments, HX is a chiral acid. In particular embodiments, HX is selected from the group consisting of L-lactic acid, L-(+)-tartaric acid, L-aspartic acid, L- glutamic acid, L-(-)-malic acid, D-glucuronic acid, (1 R, 35)-(+)-camphoric acid, (LS)-(+)- camphor- 10-sulfonic acid, (R)-(+)-A r -(l -phenyl ethyi)succinamic acid, carb ob enzyl oxy-L- proline, dibenzoyl -L-tartari c acid, (R)-(+)-3 -methyl adipic acid, (+)-menthyloxy acetic acid, (-)- pyroglutamic acid,(--)-n-acetyl-L-leucine, /V-Boc-D-leucine, V-(+)-BOC-phenylalanine, (--)- quinic acid, (+)-«-acetyl -L-phen yl al anin e, (+)-V-BOC-isoleucine, L-(-)-acetyl glutamic acid, (- )-acetyl mandelic acid, (f?)-(--)-citramalic acid, (-)-camphanic acid, and (A)-mandelic acid. In some embodiments, HX is (A)-mandelic acid. In some embodiments, HX is V-Boc-D-leucine.

[00545] In certain embodiments, HX is an achiral acid (i.e., a compound of formula VIII-04). In particular embodiments, HX is selected from the group consisting of sulfuric acid, methanesulfonic acid, /?-toluenesulfonic acid, and phosphoric acid. In some embodiments, HX is methanesulfonic acid.

[00546] In some embodiments, a compound of formula IV:

IV

or a co-crystal, solvate, salt, or combination thereof is provided.

[00547] In certain embodiments, a compound of formula III:

III

or a co-crystal, solvate, salt, or combination thereof is provided.

[00548] In certain embodiments, the compound of formula III is:

III-03

or a co-crystal or solvate or combination thereof.

[00549] In certain embodiments, the compound of formula III is:

10-04

or a co-crystal thereof.

[00550] In certain embodiments, the compound of formula III is:

10-05

or a co-crystal thereof.

[00551] In certain embodiments, a compound of formula II:

or a co-crystal, solvate, salt, or combination thereof is provided.

EXAMPLES

[00552] Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow. The following examples are merely illustrative, and not intended to limit this disclosure in any way. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and carried forth in the next synthetic step.

I. Synthesis of Starting Materials and Intermediates

Example la: Preparation of (S)-l-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan- 1-amine (VIII-02), or a co-crystal, solvate, salt, or combination thereof, and starting materials and/or intermediates therein

X VIII-02

wherein R 4 and R 5 are each independently hydrogen, methyl, phenyl, benzyl,

4-nitrobenzyl, 4-chlorobenzyl, 4-brornobenzy!amine, or 4-methoxybenzyl Synthesis of 3.6-dibromopicolinaldehyde (la)

la

[00553] A dry reaction flask with magnetic stir-bar was charged with 2, 5 -dibrom opy ridi ne (1.0 g). The flask was inerted under nitrogen, THF (4.2 mL) was added, and the thin slurry agitated . Separately, a dry' glass reactor was charged with 2, 2,6,6- tetramethy!piperidinyfmagnesium chloride, lithium chloride complex (TMPMgChLiCi) (5.8 mL, 6.3 mmol). The TMPMgCLLiCl solution was agitated and cooled to about -20 °C. The 2,5-dibromopyridine solution was added to the TMPMgChLiCl solution over about 30 min, maintaining a temperature below about -18 °C. Upon completing the addition, the flask was rinsed forward to the reactor with three additional portions of THF (1 mL x 2), and aged at about -20 for about 1 hour. A solution of A( V-dimethyiformamide (1.6 mL, 20 mmol) in THF (1.6 mL) was added to the reactor over about 15 min. The reaction mixture was aged for a further 15 min. and quenched by the addition of a solution of acetic acid (1.9 mL, 34 mmol) in water (10 mL) over about 20 minutes, maintaining a temperature of no more than about 0 °C. To the reactor was added isopropyl acetate (10 mL) and the reaction mixture was warmed to about 20 °C. After aging for 30 min, the mixture was filtered through diatomaceous earth and the reactor rinsed with a mixture of isopropyl acetate (10 mL), saturated aqueous ammonium chloride (10 mL) and 0.2 M aqueous hydrochloric acid (10 mL). The reactor rinse was filtered and the pH of the combined reaction mixture was adjusted to about 8-9 by the addition of a 10% aqueous sodium hydroxide solution (about 6 mL). The mixture was filtered a second time to remove magnesium salts and transferred to a separatory funnel . The phases were separated and the aqueous phase was extracted with isopropyl acetate (3 x 10 mL). The combined organic extracts were washed with 50% saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, and filtered. The solution was concentrated to dryness by rotary evaporation and purified by chromatography (eluting with 0-100% ethyl acetate in heptane) to afford 3,6- dibromopicolinaldehyde (la) as a solid. 1H NMR (400 MHz, DMSO- e) d 9.94 (q, J= 0.6 Hz, 1H), 8.19 (dq, j= 8.4, 0.6 Hz, 1H), 7.82 (dt, j= 8.4, 0.7 Hz, IH). 13 C NMR (101 MHz, DMSO- d 6 ) d 189.33, 148.59, 145.66, 140.17, 133.19, 120.27. Synthesis of 3.6-dibromopicolinaldehyde (la)

[00554] A solution of 2,5-dibromo-6-methylpyridine (8.03 g) in THF (81 mL) was cooled to about 0 °C. To this solution was charged fcrt-butyl nitrite (4.33 g), followed by a dropwise addition of potassium /e/ -butoxide (28 mL,l.5 equiv, 20 wt% solution in THF). The reaction mixture was agitated at about 0 °C until the reaction was complete. The reaction mixture was diluted with THF (24 mL), and quenched with ammonium chloride (6.38 g, 1 19 mmol) in water (43 mL). The reaction mixture was distilled under vacuum to approximately 55 mL to afford a shirty, which was filtered and washed twice with water (2x 24 mL) to afford lh. 1 H NMR (400 MHz, DMSO- ) d 11.69 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H).

[00555] A solution of glyoxylic acid (407 L, 50 wt% in water) was heated to about 80 °C and in portions was charged with lh (40.69 kg, 145.4 mol) . Reaction mixture was held at this temperature until the reaction was complete. The reaction mixture was cooled to about 20 °C, filtered, and the filter cake was washed with water until the filtrate had a pH > 5, to afford la. 1H NMR (400 MHz, DMSO-i/ 6 ) d 9.95 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 1H).

Synthesis of (E)-N-benzhvdryl-l- dibromopyridin-2-yl)methanimine (lb-02)

la lb-02

[00556] Compound la (5.0 g, 18.0 mmol) in toluene (20 mL) was heated to about 50 °C and benzhydrylamine (3.47 g, 18.9 mmol) was charged in one portion and agitated at this

temperature until the reaction was deemed complete. Methanol (61 mL) was charged and the reaction mixture was distilled to a volume of approximately 25 mL. Methanol (40 mL) was charged and the reaction mixture was distilled to a volume of approximately 30 mL. The resulting slurry was filtered and rinsed with two portions of methanol (15 mL each) and dried under vacuum to afford lb-02. [00557] Alternatively, compound la (10.0 g, 37.8 mmol) in 2-methyltetrahydrofuran (50 mL) was heated to about 50 °C and benzhydrylamine (7.28 g, 39.7 mmol) was charged dropwise. The reaction was agitated at this temperature until it was deemed complete. The reaction mixture was distilled to a volume of approximately 30 mL. To the reaction mixture was charged heptane (100 mL) and lb-02 seed (59.3 mg, 0.138 mmol). The resulting slurry was filtered, rinsed with two portions of heptane (2x 20 mL), and dried under vacuum to afford lb-02. 1H NMR (400 MHz, DMSO-d6) d 8.73 (s, 1 H), 8.12 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, I H), 7.44 - 7.40 (m,

4H), 7.38 - 7.32 (m, 4H), 7.28 - 7.22 (m, 2H), 5.88 (s, 1H).

Synthesis of ( ' E)-N-benzhvdryl-l-( ' 3.6-dibromopyridin-2-yl)methanimine (lb-02)

la li-1 lb-02

[00558] la (2.00 g) was combined with isopropanol (7.6 mL) and agitated at ambient temperature. To this mixture was added potassium metabi sulfite (0.96 g) in water (3.8 mL), dropwise. This mixture was agitated for at least 90 minutes and the resulting slurry was filtered. The filter cake was rinsed twice with isopropanol (6 mL then 12 mL) to afford li-1. l H NMR (400 MHz, DMSO-d6) d 7.92 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 5.48 - 5.38 (m, 2H).

[00559] li-1 (1.00 g) was combined with 2-methyltetrahydrofuran (3.5 ml.) and agitated at ambient temperature. To this slurry was charged potassium hydroxide (443.8 mg, 7.91 mmol) in water (4 mL) and the biphasic mixture was agitated for 2 hours. The layers were separated and the aqueous layer was extracted with an additional portion of 2-methyltetrahydrofuran (3.5 mL). To the combined organics was charged benzhydrylamine (0.47 mL, 2.7 mmol). The reaction mixture was concentrated in vacuo (-300 mbar, 45 °C bath) to a volume of approximately 3 mL. Heptane (7 mL) was charged and the mixture was agitated. The resulting slurry was filtered to afford lb-02 l H NMR (400 MHz, DMSO-d6) d 8.73 (s, 1 H), 8.12 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.44 - 7.40 (m, 4H), 7.38 - 7.32 (m, 4H), 7.28 - 7.22 (m, 2H), 5.88 (s, 1H). Synthesis of (E)-N-benzhvdryl-l-(3.6-dibromopyridin-2-yl)methanimine (lb-02)

la lb-02

[00560] Compound la (1.0 g) was added to a reactor, and toluene (6 0 mL) was added to the reactor. The mixture was agitated. Aminodiphenylmethane (0.73 g, 1.05 equiv.) was added to the reaction mixture. The jacket was heated to about 60 °C, and the mixture was allowed to age for about 1 hour. After about one hour, the mixture was carried forward to the next step. 1H NMR (400 MHz, DMSO-d6) d 8.68 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 4H), 7.40 - 7.34 (m, 7H), 7.29 (td, J = 6.9, 6.5, 1.7 Hz, 5H), 7.22 - 7.16 (m, 3H), 5.81 (s, 1 H).

Synthesis of N-(l -(3.6-dibromopyridin-2-yl)-2-( 3 5-difluorophenyl)ethyl )- 1.1- diphenylmethanimine (ld-02)

lb-02 ld-02

[00561] A solution of lb-02 in toluene (1.0 g in 3.8 mL) was stirred in a reactor at about 60 °C. Tetrabutyl ammoni um bromide (0. 08 g, 0.10 equiv.) was added, 3,5-difluorobenzylbromide (0.60 g, 1.20 equiv.) was added, and potassium hydroxide (50% in water, 1.3 g, 5 equiv.) was added. The mixture was aged for about 4 hours and sampled for conversion. When the reaction was complete, the aqueous phase was removed, and water (3.1 mL) was added to the reactor. Contents were agitated and phases were allowed to settle. The aqueous phase was removed, and the toluene solution of ld-02 was carried forward to the next step. 1H NMR (400 MHz, Chloroform-d) d 7.78 (dd, J = 8.6, 1.0 Hz, 1H), 7.64 - 7.60 (m, 2H), 7 59 - 7.53 (m, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.47 (s, OH), 7.45 (s, OH), 7.43 (d, J = 0.7 Hz, OH), 7.41 - 7.34 (m, 3H), 7.33 (t, J = 1.4 Hz, 1H), 7.28 (t, J = 7.3 Hz, 2H), 7.22 (s, OH), 7.18 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 7.7, 1.7 Hz, 2H), 6.55 (dt, J = 9.0, 2.3 Hz, 1 H), 6.50 (dd, J = 7.0, 4.9 Hz, 3H), 5.26 (s, OH), 5.16 (t, J = 6.9 Hz, 1H), 3.32 (dd, J = 13.2, 6.6 Hz, 1H), 3.16 (dd, J = 13.1, 7.2 Hz, 1H). Synthesis of l-(3 6-dibromopyridin-2-yl)-2-(3.5-difluorophenyl)ethan-l-amine (X) from N-(l- (3.6-dibromopyridin-2-yl -2-(3.5-difluorophenyl)ethyl )- 1.1 -diphenylmethani mine (ld-02)

ld-02 X

[00562] A solution of ld-02 in toluene (1.0 g in 3.0 mL) was stirred in a reactor at about 60 °C. Sulfuric acid (0.93 g, 5 equiv.) was diluted into water (3.5 mL), and added to the reactor. The mixture was aged for about 4 hours. When the reaction was complete, the aqueous phase was removed. The aqueous phase was recharged to the reactor, and heptane (2.5 mL) was added. The mixture was agitated and agitation stopped and layers allowed to settle. The aqueous phase was removed, and heptane was discharged to waste. Toluene (5.0 mL) and potassium hydroxide (50% in water, 2.1 g, 10 equiv.) was added to the reactor. The aqueous acidic solution was added to the reactor. The mixture was agitated for about 10 minutes, and agitation stopped and phases allowed to settle. The aqueous phase was discharged to waste. Water (2.5 mL) was added to the reactor, and the mixture was agitated for about 5 minutes, and agitation was stopped and the phases were allowed to settle. The aqueous phase was discharged to waste. The toluene solution of 1 -(3 ,6-dibromopyridin-2-yl)-2-(3 , 5 -di fluorophenyl )ethan - 1 - amine (X) was carried forward to the next step. 1H NMR (400 MHz, Chloroform-d) d 7.60 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.74 - 6.67 (m, 2H), 6.66 - 6.58 (m, 1H), 4.57 - 4.45 (m, 1H), 3.02 (dd, J = 13.5, 5.2 Hz, 1H), 2.72 (dd, J = 13.5, 8.6 Hz, 1H), 1.77 (s, 3H).

Synthesis of (S)-l-(3.6-dibromopyridin-2-yl)-2-(3.5-difluorophenyl)ethan- l-amine (R)-2- hydroxy-2-phenyl acetate (VIH-03)

X VIII-03

[00563] A solution of X in toluene (1.0 g in 7.1 mL) was stirred in a reactor at about 60 °C. The mixture was distilled to minimum volumes (2.9 mL), and methyl /tr /-butyl ether was added (7.1 mL). (i?)-(-)-Mandelic acid (0.41 g, 1 equiv.) was added, and the mixture was cooled to about 0 °C. The newly formed slurry was filtered, providing (S)-l-(3,6-dibromopyridin-2-yl)-2- (3 , 5 -difluorophenyl)ethan- 1 -ami ne (R)-2-hydroxy-2-phenylacetate (VIII-03). ] H NMR (400 MHz, DMSO-d6) d 7.93 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 7.3 Hz, 2H), 7.28 - 7.14 (m, 4H), 7.01 (tt, J = 9.4, 2.3 Hz, 1H), 6.79 (d, J = 7.4 Hz, 3H), 4.77 (s, I H), 4.55 (d, J = 6.6 Hz, 1H), 3.02 (s, 1H), 2.92 (d, J = 6.7 Hz, 2H), 1.05 (s, 2H).

Synthesis of -(3.6-dibromopyridin-2-yl)-2-(3.5-difluorophenyl)ethan-l -amine N-acetyl-D-

Leucine (VIII-04)

X VIII-04

[00564] A reactor was charged with X (15.0 g), A-ac etyl -D -1 eucine (8.28 g) and zinc oxide (0.31 1 g). Toluene (375 mL) was charged to the reactor followed by 2 -pyri dinecarb oxal d ehy de (183 pL). The mixture was aged at about 55 °C for about 6 hrs. and then held at about 35 °C for about 4 days. The mixture was cooled to about 0 °C and held for about 17 hrs. The product was isolated by filtration and the filter cake was washed with cold toluene (2 x 75 mL). The filter cake was re-charged to the reactor. Ethanol (150 mL) was added and the mixture distilled to remove residual toluene. Once the toluene was removed, the reactor volume was adjusted with ethanol to about 90 mL and the mixture was cooled to about 25 °C. Water (210 mL) was added over approximately 10 min. and the mixture aged for approximately 12 hrs. The slurry was filtered and the solids were dried to afford VIII-04. 1H NMR (400 MHz, DMSO-7 6 ) d 8.03 (d, J = 8.0 Hz, H i ). 7.95 (d, j= 8.3 Hz, 1H), 7 49 (d, 7 8.3 Hz, 1H), 7.03 (tt, j= 9.5, 2.4 Hz, 1H),

6.87 (dtd, j= 8.4, 6.2, 2.2 Hz, 2H), 5.49 (s, 3H), 4.42 (dd, j= 7.9, 5.9 Hz, 1H), 4.18 (q, j= 7.8 Hz, 1H), 2.93 (dd, j= 13.3, 5.9 Hz, 1H), 2.85 (dd, j= 13.2, 8.0 Hz, 1H), 1.83 (s, 3H), 1.71 - 1.54 (m, I H), 1.47 (dd, j= 8.4, 6.2 Hz, 2H), 0.88 (d, j= 6.6 Hz, 3H), 0.83 (d, j= 6.5 Hz, 3H). 13 C NMR (101 MHz, DMSO- ) d 174.72, 169.03, 162.07 (dd, j= 245.5, 13.3 Hz), 161.79, 143.51, 142.82 (t, 7 = 9.4 Hz), 139.72, 128.39, 1 19.30, 1 13.36 - 11 1.39 (m), 101.73 (t, 7 = 25.7 Hz), 55.19, 50.69, 41.74 (d, 7= 2.3 Hz), 40.51, 24.36, 22.91, 22.44, 21.46. Example lb: Preparation of alternative starting materials and intermediates for use in the formation of (S)-l-(3,6-dibromopyridin-2-yl)-2~(3,5~difliiorophenyl)ethan -l-amine (VIII), or a co-crystal, solvate, salt, or combination thereof

Synthesis of 1 -(3.6-dibromopyridin-2-yl)-2-(3.5 -difluorophenvDethan- 1 -ol (XII)

XI XII

[00565] A stainless steel autoclave equipped with a glass inner tube was charged with compound XI (1.00 g) and (A)-RuCY-XylBINAP (16 mg, 0.05 equiv.) EtOH (1.0 mL) and IP A (1.0 mL) followed by fert-BuOK (1.0 M solution in THE, 0.51 mL, 0.2 equiv.) were added to the autoclave. After being purged by Hi, the autoclave was charged with 3 MPa (=435 psi) of H 2 . The mixture was stirred at about 20 °C for about 10 h. To the mixture, cone. HC1 aqueous solution was added and pH was adjusted to 2. l H NMR (400 MHz, CDC13): d 7.72 ( d, J= 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.80 -6.72 (m, 2H), 6.68 (tt, J= 9.2, 2.4 Hz, 1H), 5.16 (dd, J = 8.2, 3.4 Hz, 1H), 3.60 (br, 1H), 3.12 (dd, j= 13.8, 3.4 Hz, 1H), 2.81 (dd, j= 13.8, 8.2 Hz,

1H). 13C NMR (100 MHz, CDC13): d 162.8 (dd, J= 246.4, 12.9 Hz), 160.1, 143.0, 141.3 (t, j = 9.1 Hz), 139.8, 128.7 (t, J= 35.7 Hz), 117.9, 112.3 (m), 102.1 (t, ./= 25.0 Hz), 72.0, 43.0. 19F NMR (376 MHz, CDC13): d -112.1 (m).

Synthesis of N-(T-(3.6-dibromopyridin-2-yl)-2-(3.5-difluorophenyl)ethyl)- l5-chloranimine (X- 02)

XIII X-02

[00566] Compound XIII (.0 g) was dissolved in THF (4.2 mL) and was cooled over an ice bath. Diphenylphosphoryl azide (0.66 mL, 1.2 equiv.) was added followed by DBU (0.46 mL, 1.2 equiv.) over about 25 min at below about 4 °C. The dark mixture was aged about 1 hour, and the cooling bath was removed. After about 2.5 hours age at RT, some starting material was still present so more diphenylphosphoryl azide (0.15 equiv.) and DBU (0.15 equiv.) were added after cooling over an ice bath. After about 2 hours, more diphenylphosphoryl azide (0.08 equiv.) and DBU (0.08 equiv.) were added. The reaction mixture was allowed to age overnight for about 16 h to allow the conversion to azide intermediate complete. The reaction mixture was cooled over an ice bath and triphenylphosphine (1.0 g, 1.5 equiv.) was added over about 15 min at about 6 °C). The cooling bath was removed after about 10 min and the reaction mixture was agitated for additional about 2.5 hours. To this reaction mixture was added water (0.18 mL, 4 equivalents) and the resulting mixture was aged for about 15 hours at room temperature. The mixture was diluted with EtOAc (5.0 mL) and was washed with water (4.2 mL + 2.0 mL). The aqueous layer was back extracted with EtOAc (4.0 mL) and the EtOAc layer was washed with water (1.0 mL). The organic layers were combined, concentrated via rotary evaporation and evaporated with EtOAc (4 x 4.0 mL) to dry. The residue was dissolved to a 50 ml solution in EtOAc, and cooled over an ice bath to become slurry. To the cold slurry 4N HCl/dioxane (0.76 mL, 1.2 equiv.) was added and the slurry was aged about 2 hours at room temperature. The solid product was filtered and the filter cake was rinsed with EtOAc and dried at about 35 to 50 °C under vacuum to give X-02.

[00567] Recrystallization: A portion of the above obtained X-02 (1.0 g) was mixed with EtOAc (10 mL) and was heated to 65 °C to afford thick slurry. The slurry was aged at about 65 °C for about 2 hours, and overnight at room temperature. The solids were filtered with recycling the mother liquor to help transfer the solids. The filter cake was rinsed with EtOAc, and dried overnight at about 50 °C vacuum to afford X-02. 1H NMR (300 MHz, DMSO-d) d 8.78 (br s, 3 H), 8.06-8.02 (m, 1 H), 7.64-7.61 (m, 1 H), 7.15-7.08 (m, 1 H), 6.83-6.78 (m, 2 H), 4.87-4.82 (m, 1 H), 3.35-3.25 (m, 1 H), 3.17-3.05 (m, 1 H). 19 F NMR (282.2 MHz, Chloroform-d) d - 109.9-110.1 (m).

Synthesis of l-(3.6-dibromopyridin-2-yl)-2-f3.5-difluorophenyl)ethyl methanesulfonate (XIII-

XIII XIII-A

[00568] Compound XIII (1.0 g) and DMAP (0.1 equiv.) were dissolved in THF (4.5 mL) and cooled over an ice bath. Triethylamine (Et 3 N) (0.39 mL, 1.1 equiv.) was added followed by methanesulfonyl chloride (218 pL, 1.1 equiv ). The cooling bath was removed, and the mixture was aged about 1.5 hours at room temperature. The reaction mixture was cooled over an ice bath and quenched with water (10 mL). The mixture was diluted with EtOAc and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic phase was dried (Na S0 ) and was passed through silica gel with EtOAc. The filtrate was

concentrated to afford the mesylate (XIII-A). 1H NMR (300 MHz, Chloroform-d) d 7.72-7.66 (m, 1 H), 7.38-7.32 (m, 1 H), 6.78-6.63 (m, 3 H), 6.17-6.13 (m, 1 H), 3.40-3.25 (m, 2 H), 2.87 (s, 3 H). 19 F NMR (282.2 MHz, Chloroform-d) d -109.3—109.5 (m).

Synthesis of l-(3.6-dibromopyridin-2-yl)-2-(3.5-difluorophenyl)ethan-l-am ine (X) from 1 -(3.6- dibromopyridin-2-yl)-2- 3.5 -difluorophenvDethyl methanesulfonate (XIII-A)

XIII-A X

[00569] A glass pressure bottle was charged with the mesylate (XIII-A) (1.0 g), 28-30% ammonium hydroxide (19 mL) and MeOH (4.7 mL). The mixture was sealed and heated at about 70 °C for about 16 hours, and extracted with 2-MeTHF/ EtOAc. The organic layer was dried (Na 2 S0 4 ) and purified by silica gel chromatography (10-60% EtOAc/hexanes) to afford racemic amine X. 1H NMR (300 MHz, Chloroform-d) d 7.70-7.60 (m, 1 H), 7.30-7.20 (m, 1 H), 6.78-6.60 (m, 3 H), 4.46-4.58 (m, 1 H), 3.00-3.16 (m, 1 H), 2.70-2.80 (m, 1 H). 19 F NMR (282.2 MHz, Chloroform-d) d -110.3 110.4 (m).

Synthesis of (Z)-N-( l -(3.6-dibrornopyridin-2-yl )-2-(3.5-di fluorophenyl Kinyl 'acetamide (If)

XI le If

[00570] A glass reactor was charged with XI (1.0 g). Ethanol (5.0 mL) was added, and the shirty was agitated while hydroxyl amine hydrochloride (0.88 g) was charged. Pyridine (1.0 L) was added and the mixture heated at about 55-65 °C for about two hours. The mixture was cooled to about 20 °C, transferred to a flask, and concentrated to approximately 75 mL by rotary evaporation. The concentrate was returned to the reactor, rinsing through with isopropyl acetate (5.0 mL). Residue remaining in the flask was carefully (gas evolution) rinsed into the reactor with saturated aqueous sodium bicarbonate (5.0 mL). The bi -phasic mixture was agitated, the phases separated, and the organic extract washed with water (3.2 mL) and saturated sodium chloride (3.2 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness by rotary evaporation to yield le which was used without further purification.

[00571] A glass reactor was charged with iron powder (<10 micron, 0.30 g mmol) followed by acetic acid (1.6 mL) and acetic anhydride (0.72 mL). The slurry was de-gassed by holding the reactor contents under vacuum until bubbling was observed, and back-filled with nitrogen (3 cycles). The mixture was heated at 115-120 °C for 2 hours and cooled to 40 °C. Compound le from the previous step in isopropyl acetate (2.0 mL) was added over 30 min. Upon completing the addition, the temperature was raised to 45-65 °C and the mixture aged for about 2 hours. A slurry of diatomaceous earth (1.0 g) in isopropyl acetate (2.0 mL) was added, followed by toluene (2.0 mL). The slurry was filtered, hot, through a Buchner funnel and the reactor and filter cake were washed with warm isopropyl acetate (3 x 1.8 mL). The filtrate was transferred to a reactor and the solution washed with 0.5% aqueous sodium chloride (4.2 mL). Water (3.1 mL) was added to the reactor and the mixture was cooled to about 5 °C. The pH was adjusted to 7-9 with the addition of 50 wt% aqueous sodium hydroxide; following separation, the organic extract was warmed to room temperature and washed with aqueous 1% (w/w) sodium chloride NaCl (3.6 mL). The organic extract was discharged to a flask and dried over anhydrous sodium sulfate (ca. 0.8 g), filtered through diatomaceous earth, and concentrated to approximately 4 mL at 100 mniHg and 45 °C water bath. The warm solution was returned to the reactor, rinsing forward with isopropyl acetate to a produce a total volume of approximately 5.2 mL. This solution was heated further to 50 °C with agitation, cooled to about 35 °C, and seeded with pure If (0.006 g). Heptane (9.6 mL) was added over a period of about 4 hours, the solution was cooled to about 10 °C, and the product was isolated by filtration. The filter cake was washed with 33.3% iPAc in heptane (4.0 mL) and dried in a vacuum oven at 40 °C with nitrogen sweep for approximately 24 hours. Compound If, a mixture of geometric isomers (approximately 94:6 ratio) was isolated. Major isomer: 1H NMR (400 MHz, DMSO-<7 6 ) d 9.96 (s, 1H), 8.04 (d, J = 8.4 Liz, 1H), 7.66 (d, ./ 8.4 Hz, 1H), 7.05 (s, 1H), 6.97 (tt, ./ 9.2, 2.2 Hz, 1H), 6.40 - 6.31 (m,

2H), 1.97 (s, 3H). 13 C NMR (101 MHz, DMSO- ) d 168.37, 162.04 (dd, J= 245.1, 13.9 Hz), 154.47, 143.63, 139.45, 139.40 - 139.18 (m), 135.99, 129.44, 120.66, 113.80, 1 1 1.23 - 109.68 (m), 101.77 (t, J= 26.0 Hz), 23.49.

Synthesis of (SVN-(l-(3.6-dibromopyridin-2-yl)-2-(3.5-difluorophenyl)ethv Oacetamide (lg)

If lg

[00572] Preparation of catalyst solution: A flask was charged with [IrCl(cod)((S)-segphos)] (1 10 mg) and the internal atmosphere was replaced with N 2 . EtOAc (200 mL) was added to the flask and the mixture was stirred until the catalyst solid was dissolved.

[00573] A stainless steel autoclave was charged with compound If (1.0 mg). EtOAc (16 mL) and followed by the catalyst solution prepared above (4.0 mL, 0.001 equiv.) were added to the autoclave. After being purged by H 2 , the autoclave was charged with 3 MPa (º435 psi) of ¾. The mixture was stirred at about 130 °C for about 6 hours and cooled to room temperature and H 2 was vented out. The reaction mixture was purified by silica gel column chromatography (EtOAc/Hexane = 1/4 to 1/1) to afford lg. 1H NMR (400 MHz, CD2C12): d 7.70 ( d, J= 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, H i ), 6.68 (tt, j = 9.2, 2.4 Hz, 1H), 6.64 -6 58 (m, 2H), 6.49 (brd, j = 8.0 Hz, 1H), 5.74 (ddt, J= 8.0, 7.2, 6.4 Hz, 1H), 3.10 (dd, J= 13.6, 6.4 Hz, 1H), 2.99 (dd, J = 13.6, 7.2 Hz), 1.95 (s, 3H). 13C NMR (100 MHz, CD2C12): d 169.5, 163.3 (dd, J = 246.0, 12.9 Hz), 159.1, 143.6, 141.4 (1 ,7= 9.1 Hz), 140.7, 129.1, 119.9, 112.9 (m), 102.6 (t, ,/= 25.1 Hz), 53.0, 41.3, 23.6. 19F NMR (376 MHz, CD2C12): d -111.3 (m). Synthesis of (S)- 1 -( 3.6-dibromopyridin-2-yl)-2-( 3.5 -difluorophenvDethan- 1 -amine (VIII) from l-(3.6-dibromopyridin-2-yl)-2-(3.5-difluorophenvDethan-l-one (XI). Method 1

XI VIII

[00574] A glass-lined reactor was charged with isopropylamine (about 18 g) and

triethanolamine (3.8 g). Water (231 mL) was added and the pH was adjusted to about 7.5 by the addition of concentrated hydrochloric acid. A portion of the buffer solution (23 mL) was removed. The transaminase enzyme (2.5 g) was added to the reactor as a suspension in buffer solution (12 mL), followed by addition of pyridoxal phosphate monohydrate (50 mg) as a solution in buffer solution (12 mL). A solution of XI (1.0 g) in dim ethyl sulfoxide (23 mL) was added to the reactor and the mixture was heated at about 35 °C for about 48 hours with constant nitrogen sparging of the solution. The reaction mixture was cooled to about 20 °C the unpurified amine was removed by filtration. The filter cake was washed with water (3 x 7.7 mL) and the product was dried at about 60 °C under vacuum with nitrogen sweep to afford VIII.

Synthesis of (S)-l-(3.6-dibromopyridin-2-yl)-2-(3.5-difluorophenyl)ethan- l-amine (VIII) from l-(3.6-dibromopyridin-2-yl)-2-(3.5-difluorophenyl)ethan-l-on e (XI). Method 2

1 NH /M OH

XI VIII

[00575] A stainless steel reactor was charged with XI (1.0 g) and -toluenesulfonic acid (0.49 g). Ammonia (7 M in methanol, 3.7 mL) was added and the vessel was sealed and heated at about 60 °C for about 18 hours. The mixture was cooled to about 20 °C and sparged for about 30 min to remove excess ammonia. A solution of diacetato[(/?)-5,5'-bis(diphenylphosphino)- 4,4 '-bi- 1 ,3 -benzodioxole]ruthenium(II) (0.10 g) in methanol (0.5 mL) was added to the reactor, which was sealed and heated at about 60 °C under a hydrogen atmosphere (400 psi) for a further about 6-10 hours. Upon cooling to about 20 °C the mixture was filtered through a plug of silica, rinsing with additional methanol (5.0 mL). Concentration of the filtrate by rotary evaporation affords VIII. Example lc: Preparation of 1 -(3,6-dibromopyridin-2-yI)-2-(3,5-difluorophenyI)ethan-l - amine (X) by racemization of (S)~l~(3,6~dibromopyridin~2~yI)~2-(3,5-difIuoropheny!)ethan~ 1-amine (VIII)

VIII X

[00576] A vial was charged with zinc acetate (25 mol %), enantioenriched VIII (1.0 g, 92:8 enantiomer ratio), toluene (10 mL), and 2-formylpyridine (5 mol %). The vial was wanned to about 60 °C and stirred for about 4 h.

Example 2: Preparation of (S)-l-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l- yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethan-l-amine (VI)

VIII-03 VI

[00577] A glass-lined reactor was charged with (S)- 1 -(3 ,6-dibromopyridin-2-yl)-2-(3 , 5- difluorophenyl)ethan-l-amine (f?)-mandelic acid salt (VIII-03) (1.0 g), 3 -methyl -3- (m ethyl sulfonyl)but- 1 -yne (IX) (about 0.3 g), and dichlorobis(triphenylphosphine)palladium(II) (about 0.39 g). The reactor was evacuated and purged with nitrogen to inert. To this reactor was added 2-methyltetrahydrofuran (6.4 kg) and triethylamine (0.92 kg 5.0 equiv.). The reaction mixture was agitated at about 65-75 °C until the reaction was deemed complete by HPLC analysis. Upon cooling to about 30-40 °C the reaction mixture was discharged to another reactor and the parent reactor was rinsed with 2-methyltetrahydrofuran (4.6 g) and the resulting solution transferred to the receiving reactor. To the reactor was added water (5.0 g) and the biphasic mixture agitated at about 30-40 °C for about 30 min. Agitation was ceased and the mixture was allowed to layer for 30 min. The lower aqueous layer was discharged and the remaining organic solution held for about 15 hours. A solution of A-acetyl-L-cysteine (196 g) and sodium hydroxide (0.80 g) in water (11.8 g) was prepared. To the reactor was added approximately half of the A^-acetyl-L-cysteine solution (6.7 g). The mixture was agitated at about 55-65 °C for about 30 min. The temperature was adjusted to about 30-40 °C and agitation was ceased. After about 30 min had elapsed, the lower aqueous phase was discharged. The remaining alkaline N- acetyl -L-cysteine solution (5.4 kg) was added and the mixture was heated, with agitation, to about 55-65 °C and held for about 30 min. The temperature was adjusted to about 30-40 °C and agitation was ceased. After about 30 min had elapsed, the lower aqueous phase was discharged. To the reactor was added a solution of sodium chloride (0.26 g) in water (4.9 g) and the mixture agitated at about 30-40 °C for about 30 min. Agitation was ceased and the biphasic mixture allowed to layer for about 30 min. The lower aqueous layer was discharged and the contents cooled to about 15-25 °C and held for about 16 hours. The mixture was concentrated at about 55-65 °C. The concentrated solution was cooled to about 30-40 °C and heptane (3.4 kg) was added over about 2 hours. The resulting slurry was cooled to about 20 °C and aged for about 20 h, and filtered. The filter cake was washed with 2- methyltetrahydrofuran/heptane (1 : 1 v/v,2 mL) and the solids dried in a vacuum oven at about 40 °C to yield (S)- 1 -(3 -bromo-6-(3 -m ethyl-3 -(methyl sulfonyl)but- 1 -yn- 1 -yl)pyridin-2-yl)-2-(3 , 5 - difluorophenyl)ethan-l -amine (VI)). 1H NMR (400 MHz, DMSO -d 6 ) d 8.05 (d, J= 8.2 Hz, 1H), 7.42 (d, j= 8.2 Hz, 1H), 7.01 (tt, j= 9.5, 2.4 Hz, 1H), 6.97 - 6.84 (m, 2H), 4.41 (dd, j= 8.5, 5.2 Hz, 1H), 3.20 (s, 3H), 2.93 (dd, J= 13.3, 5.2 Hz, 1H), 2.79 (dd, J= 13.3, 8.5 Hz, 1H), 1.99 (s, 2H), 1.68 (s, 6H). 13 C NMR (101 MHz, DMSO- ) d 162.25, 162.00 (dd, J = 245.2, 13.4 Hz), 143.88 (t, J= 9.4 Hz), 141.09, 139.72, 127.51, 120.08, 112.58 - 112.12 (m), 101.45 (t, 7= 25.7 Hz), 87.94, 84.25, 57.24, 55.90, 42.57, 34.99, 22.19.

Example 2a: Preparation of 3-methyl-3-(methylsulfonyl)but-l-yne (IX)

3-CMB IX

[00578] Sodium methansulfmate (418.1 g), copper (II) acetate (26.6 g), N,N,N',N'-

Tetramethyl ethyl enedi amine (TMEDA, 34.0 g), and isopropyl acetate (2100 L) were added to a reactor and the suspension was agitated at 20 - 25 °C. 3 -Chloro-3 -methylbut- 1 -yne (3-CMB,

300 g) was added slowly to maintain a constant temperature of about 20 - 25 °C. The reaction mixture was then heated to about 30 °C until the reaction was complete. The mixture was cooled to about 20 °C and washed twice with 5% aqueous sulfuric acid (600 mL). The combined aqueous layers were then extracted with isopropyl acetate (600 mL). The combined organic layers were then washed with water (600 mL). The product was then isolated by crystallization from isopropyl acetate (900 mL) and «-heptane (1.8 kg) at about 0 °C. The wet cake was then washed with cold «-heptane to afford IX. 1H NMR (400 MHz, DMSO-<7 6 ) d 3.61 (s, 1H), 3.07 (s, 3H), 1.55 (s, 6H); 13 C NMR (10Q MHz, DMSO) d 82.59, 77.76, 56.95, 34.95, 22.77.

Example 3a: Preparation of (3bS,4aR)-3-(trifluoromethyI)-l,3b,4,4a-tetrahydro-5H- cycIopropa|3,4]cyclopenta[l,2-c]pyrazoI-5-one (XV) from lithium (Z)-2,2,2-trifluoro-l-(3- oxobicyclo[3.1.0]hexan-2-ylidene)ethan-l-oIate (3a)

Synthesis of 3-(trifluoromethyl)-3b.4.4a.5-tetrahvdro-lH-cvclopropai3.41c vclopentaiL2- clpyrazole (3b)

[00579] A reactor was charged with 3a (1.0 g) and AcOH (4.2 ml) and the resulting solution was adjusted to about 20 °C. Hydrazine hydrate (0.29 g, 1.4 equiv.) was added over about 60 min at about 17-25 °C and the reaction mixture was stirred for about 2 hours at about 20-25 °C, warmed up to about 45 to 50 °C over about 30 min, and aged at about 50 °C overnight. Water was slowly (5 mL) added at about 50 °C and product started to crystallize after addition of 5 mL of water. Another 5 mL of water was added at about 50 °C, and the slurry was cooled down to about 20 °C in about one hour and held overnight at about 20 °C. The solids were filtered, washed with water (4X 3 mL), and dried under vacuum at about 30 °C to yield 3b. 1H NMR (400 MHz, Chloroform-d) d 2.99 (dd, J = 17.0, 6.1 Hz, 1H), 2.89 - 2.78 (m, 1H), 2.14 (dddd, J = 9.1 , 7.9, 3.6, 2.5 Hz, 2H), 1.13 (td, J = 7.8, 5.1 Hz, 1H), 0.36 - 0.26 (m, 1H). Isolation of (3bS.4aSV3-(trifluoromethyl)-3bA4a.5-tetrahvdro-lH- cvclopropar3.41cvclopentaiL2-clpyrazole (3c)

3b 3c

[00580] Chiral purification of 3b (1.0 g) was achieved using a 8x50 mm simulated moving bed (SMB) chromatography system and Chiralpak IG (20 m particle size) stationary phase using acetonitrile as a mobile phase to afford 3c. 1H NMR (400 MHz, Chloroform-d) d 3.00 (dd, J = 17.0, 5.7 Hz, 1 H), 2.90 - 2.77 (m, 1H), 2.21 - 2.05 (m, 2H), 1.13 (td, J = 7.8, 5.1 Hz, 1 H), 0.35 - 0.27 (m, 1H).

Synthesis of (3bS.4aR)-3-(trifluoromethyl)-L3b.4.4a-tetrahvdro-5H- cvclopropai3.41cvclopentail.2-c]pyrazol-5-one (XV)

3c XV

[00581] A reactor was charged with water (7 mL) and CuCl 2 · 2H 2 0 (0.09 g, 0.1 equiv). To the reactor was added pyridine (0.42 g, 1 equiv.) and 3c. te 7-Butyl hydroperoxide (70% in water, 5.5 g, 8 equiv.) was added over about 0.5 hour. The reaction mixture was stirred at about 20 °C for about 2.5 days and quenched with aqueous sodium metabi sulfite solution (0.73 g in 2.5 mL water). The quenched reaction mixture was extracted with isopropyl acetate (20 mL), and the aqueous layer was back extracted with isopropyl acetate (2.0 ml). The organic layers were combined and washed with aqueous eth y 1 en edi am i n etetr aaceti c acid (EDTA) solution 0.16 g EDTA 10 ml in water), the aqueous layer was dropped, and the organic layer was further washed with aqueous EDTA solution (0.015 g EDTA in 20 ml water). The washed organic layer was concentrated to dryness. To the residue was added isopropyl acetate (2.0 ml) and heptane (2.0 L). The solution was seeded and stirred overnight at about 20 °C, further diluted with heptane (2.0 mL), and the mixture was concentrated to dryness. The residue was suspended in heptane (4.0 mL) at about 40 °C. The solid was filtered and the filter cake was washed with heptane (1.0 mL) and dried at about 40 °C to yield XV. 1H NMR (400 MHz, Chloroform-d) d 2.84 (dt, J = 6.8, 4.2 Hz, 1H), 2.71 - 2.64 (m, 1H), 1.79 - 1.67 (m, 2H). Example 3b: Preparation of (3bS,4aR)-3-(trifluoromethyI)-l,3b,4,4a-tetrahydro-5H- cyclopropa[3,4]cyclopenta[l,2-c]pyrazoI-5-one (XV) from lithium (Z)-l-((lS,5R)-4,4- dimethoxy-3-oxobicyclo[3.1.0]hexan-2-ylidene)-2,2,2-trifluor oethan-l-olate (3d-02)

3d-02 XV

[00582] Hydrazine sulfate (0.45 g, 0.95 equiv.) and ketal lithium salt 3d-02 (1.0 g) were dissolved in ethylene glycol (9.5 mL), and the solution was heated to about 40 °C for about 16 hours. Reaction was cooled to room temperature and water (9.0 mL) was added. Reaction was polish filtered andThe filtrate was collected and to this receiving flask was added water (10 mL, 2x). Slurry was cooled in ice water bath for about five hours, and filtered. Solids were washed with ice water (10 mL, 2x), deliquored, and dried to afford XV. 1H NMR (400 MHz, CDCf) d 11.83 (bs, 1H), 2.93 - 2.77 (m, 1H), 2.77 - 2.58 (m, 1H), 1.86 - 1.57 (m, 2H). 19 F NMR (376 MHz, CDCfs) d -61.69. 13 C NMR (101 MHz, CDCL) d 188.56, 144.08, 142.92, 121.82, 119.15, 36.28, 31.87, 14.15.

Example 3c: Preparation of (3bS,4aR)-3-(trifiuoroniethy!)-l,3b,4,4a-tetrahydro-5H- cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-5-one (XV) from (lS,2S)-2-iodo-N-methoxy-N- methylcyclopropane-l-carboxamide (3f) and l-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-lH-pyrazole (3i) and preparation of starting materials and/or intermediates therein

Synthesis of -2-iodo-N-methoxy-N-methylcvclopropane-l-carboxamide

3e 3f

[00583] Starting material iodoacid 3e is a mixture of 3e and cyclopropane carboxylic acid (des-iodo 3e) with mole ratio of 3e to des-iodo 3e of 2: 1 by NMR. A mixture of 3e (1.0 g),

N, O-dimethyl hydroxyl amine-HCl (0.46 g) and carbonyl diimidazole (1.72 g) in THF was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with CH2CI2, and concentrated to afford unpurified 3f (1.8 g). The unpurified 3f was purified by column chromatography to afford 3f which was a mixture of Wei nr eb amide 3f and des-iodo-3f (about 80:20 by HPLC).

Synthesis of l-(4-methoxybenzyl)-4-(4.4.5.5-tetramethyl-l.3.2-dioxaborola n-2-yl)-3-

(tri fluorom ethyl VI H-p yr azol e

3g 3h 3i

[00584] To a suspension of NaH (60%, 0.31 g, 1.1 equiv.) in DMF (7.5 mL), a solution of 3g (1.0 g) in DMF (7.5 mL) was added dropwise over about 15 min at about 3 to 7 °C. The reaction mixture was stirred at room temperature for about 1 h and a solution of PMBC1 (1.2 g, 1.05 equiv.) in DMF (4.2 mL) was added dropwise in about 25 min at room temperature. The reaction mixture was stirred at room temperature overnight, poured into water (17 mL), and extracted with diethyl ether (3x17 mL). The ether layers were combined and washed with water (2 x 17 mL) and brine (17 mL), dried over Na 2 S0 4 , and concentrated in vacuo to give unpurified 3h. Unpurified 3h was absorbed in silica gel (4.3 g) and purified by silica gel chromatography (eluting with 5-25% EtOAc in hexanes) to give 3h (1.5 g).

[00585] To solution of iodopyrazole 3h (1.0 g) in THF (8 mL) /-PrMgCl (2M in ether, 1.8 mL, 1.1 equiv.) was added dropwise over about 10 min at below about 5 °C. The resulting solution was stirred at about 0 °C for about 70 min and 2 -m ethoxy-4, 4, 5 , 5 -tetram ethyl- 1,3,2- dioxaborolane (970 mg, 1.81 equiv.) was added at below about 6 °C. The reaction mixture was warmed up to room temperature, quenched by addition of saturated NH 4 C1 (20 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with saturated NH 4 Cl (10 mL) and concentrated to unpurified oil, which was combined with the unpurified oil from a previous batch (prepared using 1 .1 g of 3h), absorbed on silica gel (6 g), and purified via silica gel chromatography (eluting with 5-40% EtOAc/Hexanes,). Boronate 3i was obtained. 1H NMR (300 MHz, Chloroform-d) d 7.60 (s, 1 H), 7.23-7.19 (m, 2 H), 6.90-6.85 (m, 2 H), 5.25 (s, 2 H), 3.81 (m, 3 H), 1.29 (s, 12 H).

Synthesis of (TR.2S)-N-methoxy-2-f 1 -(4-methoxybenzyl)-3-( trifluoromethyl )- 1 H-pyrazol-4-yl)- N-methyl cyclopropane- 1 -carboxamide (3i)

3f 3i 3j

[00586] A mixture of unpurified iodide 3f (1.0 g), boronate 3i (about 2.2 g), CsF (4.5 equiv.), Pd(OAc) 2 (0.1 equiv.), and PPh 3 (0.5 equiv.) in DMF (58 mL) was degassed by bubbling N 2 and heated at about 87 °C for about 15 hours. The reaction mixture was diluted with water, extracted with MTBE, concentrated and the unpurified product was purified by column chromatography to give 3j. 1H NMR (300 MHz, Chloroform-d) d 7.18-7. 14 (m, 3 FI), 6.86-6.82 (m, 2 H), 5.24-5.08 (m, 2 H), 3.77 (s, 3 H), 3.63 (s, 3 H), 3.05 (s, 3 H), 2.37-2.32 (m, 1 H), 1.50- 1.42 (m, 1 H), 1.32-1.21 (m, 2 H).

Synthesis of (3bS.4aR)-l-(4-methoxybenzyl)-3-ftrifluoromethyl)-l .3b.4.4a-tetrahydro-5H- cvclopropa[3.41cvclopentaiE2-c1pyrazol-5-one (3k)

3j 3k

[00587] Compound 3j (1.0 g) was treated with freshly prepared LDA (3.3 eq then 0.7 equiv.) at about -67 °C for about 2.5 hours. The reaction mixture was quenched with saturated NH 4 CI (12.5 mL) and diluted with MTBE (63 mL). The organic layer was washed with brine, concentrated, and purified by column chromatography to give 3k. 1H NMR (300 MHz, Chloroform-d) d 7.36-7.33 (m, 2 H), 6.86-6.83 (m, 2 H), 5.28 (s, 2 H), 3.78 (s, 3 H), 2.73-2.65 (m, 1 H), 2.60-2.53 (1 H), 1.70-1.61 (m, 2 H).

Synthesis of (3b S 4aR)-3 -(trifluorom ethyl)- 1 3b A4a-tetrahydro-5H- cvclopentaf 1.2-c]pyrazol-5-one (XV)

[00588] A mixture of 3k (1.0 g) and TFA (5 mL) was heated at about 75 °C for about 3 hours and concentrated. The residue was dissolved in DCM (50 mL), washed with saturated NaHC0 3 and brine, concentrated, and purified by column chromatography to give XV. 1H NMR (300 MHz, Chloroform-d) d 2.86-2.80 (m, 1 H), 2.68-2.63 (m, 1 H), 1.77-1.65 (m, 2 H).

Example 3d: Resolution of 2-(2,2,2-trifluoroacetyl)bicycIo [3.1.0] hexan-3-one (31) with quinine

[00589] A flask was charged with 31 (1 .0 g), acetone (2.5 ml), and quinine (1.7 g, 0.65 equiv). The mixture was stirred at about 15 to 25 °C for about 18 hours and the solids were isolated by filtration and washed with acetone to provide the quinine salt 3n.

Example 4a: Preparation of ethyl 2-((3bS,4aR)-5-oxo-3-(trifluoromethyl)-3b,4,4a,5- tetrahydro-lH-cyclopropa|3,4]cyclopenta[l,2-c]pyrazol-l-yl)a cetate (XIV) from

(3bS,4aR)-3-(trifluoromethyl)-l,3b,4,4a-tetrahydro-5H-cyc lopropa[3,4]cyclopenta[l,2- c]pyrazol-5-one (XV)

XV XIV [00590] Acetonitrile (5 vol.) was added to a reactor containing XV (1.0 g). N,N- Di i sopropyl ethyl amine (0.80 g, 1.25 equiv.) was added at about 0 °C. Ethyl bromoacetate (0.91 g, 1.1 equiv.) was added over about 1 hour at about 0 °C. The reaction was stirred at about 5 °C for about 30 minutes and warmed to about 10 °C. The reaction was stirred until complete as determined by HPLC, warmed to about 20 °C, and extracted with MTBE (2 vol.) and saturated NaCl (6 vol.). The aqueous layer was removed and the organic phase was concentrated and diluted with EtOH (3 vol.). The reaction was crystallized by the addition of H 2 0 (7.8 vol.) at about 20 °C. The mixture was cooled to about 5 °C over about 2 hours and maintained at about 5 °C for about 0.5 hour. The mixture was filtered at about 5 °C and washed with cold water (4 vol). The product was dried at about 40 °C under vacuum to give XIV. 1H NMR (400 MHz, Chloroform-d) d 4 97 (s, 2H), 4.31 - 4 17 (m, 2H), 2.77 (dddd, ./= 6.4, 5.2, 2.9, 2.3Hz, 1H), 2.65 - 2.55 (m, 1H), 1.74 - 1.64 (m, 2H), 1.34 - 1.19 (m, 5H), 0.94 - 0.84 (m, 1H).

Example 4b: Preparation of ethyl 2-((3bS,4aR)-5-oxo-3-(trifluoromethyl)-3b,4,4a,5- tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)a cetate (XIV) from (1R,5S)- bicyclo [3.1.0] hexan-2-one (4a)

3d -02 XIV

Synthesis of (lR.5R)-2.2-dimethoxybicvclor3. l .01hexan-3-ol (4b-02)

Phi(OAc)2

4a 4b-02

[00591] Potassium hydroxide (KOH) (2 2 g, 3.50 equiv.) and anhydrous methanol (13 ml.) were added to a reactor and the reaction mixture was wanned to about 55 °C and agitated until KOH solids were dissolved completely. The mixture was adjusted to about 0 to 6 °C and compound 4a (1.0 g) was slowly added while maintaining the internal temperature at NMT 6 °C. The reaction mixture was agitated for about 45 min at about 0 to 6 °C. Diacetoxy iodobenzene (PhI(OAc) 2 , 5.0 g, 1.5 equiv.) was added over about 2 hours while maintaining the internal temperature at NMT 6 °C. The reaction mixture was agitated for NLT 1 hour at about 0 to 6 °C. Water (10 g) and heptane (10 mL) were added to the reaction mixture and the biphasic was agitated for NLT 30 min at about 19 to 25 °C The aqueous layer was separated and washed with heptane (10 mL). The combined organic layer was extracted twice with aqueous solution of methanol (MeOH, 10 mL) and water (5 g). The combined aqueous layer was concentrated under vacuum. The aqueous layer was extracted twice with DCM (15 mL and 5 mL). The combined organic layer was concentrated and dried under vacuum. The unpurified compound 4b-02 was obtained. 1H NMR (600 MHz, CDC1 3 ): d 3.98 (d, 1H), 3.45 (s, 3H), 3.25 (s, 3H),

2.40 (s, 1H), 2.21 (m, IH), 1.78 (d, 1H), 1.48 (m, IH), 1.38 (m, 1H), 0.83 (q, IH), 0.58 (m, 1H). 13 C NMR (l50 MHz, CDC1 3 ): d 110.91, 72.19, 51.18, 49.02, 34.08, 21.66, 14.75, 8.37.

Synthesis of (lR 5R)-2 2-dimethoxybicvclor 3 1.01hexan-3-one (4c-02)

4b-02 4c-02

[00592] Oxalyl chloride (0.96 g, 1.20 equiv.) and dichloromethane (10 mL) were added to a reactor and the mixture was cooled to about -78 °C. Dimethyl sulfoxide (DMSO, 1.2 g, 2.4 equiv.) was added over about 30 min while maintaining the internal temperature below about - 60 °C. After agitation for about 5 min, the solution of compound 4b-02 (1.0 g) in

dichloromethane (6 mL) was added over about 30 min while maintaining the internal

temperature below about -60 °C and the reaction mixture was agitated for about 20 min at about -60 °C. Triethylamine (TEA, 3.1 g, 4.8 equiv.) was added over about 40 min at about -60 °C, and the reaction mixture was warmed to about 10 to 20 °C. Water (15 g) was added and the biphasic was agitated about 30 min at about 10 to 20 °C. After phase separation, the aqueous layer was back-extracted with dichloromethane (10 mL). Combined organic layer was concentrated until no distillate was observed. To the residue was added MTBE (1 mL), filtered and evaporated to afford unpurified compound 4c-02. 1H NMR (600 MHz, CDC1 3 ): d 3.45 (s, 3H), 3.27 (s, 3H), 2.79 (ddd, 1H), 2.30 (d, 1H), 1.73 (td, 1H), 1.63 (m, 1H), 0.96 (m, 1H), 0.25 (td, 1H). 13 C NMR (150 MHz, CDC1 3 ): d 207.75, 102.13, 50.93, 50.50, 38.87, 19.15, 9.30, 8.56.

Synthesis of lithium (Z)- 1 -(( 1 S.5R)-4.4-dimethoxy-3 -oxobicvcloi 3.1.0]hexan-2-ylidene)-2.2.2- trifluoroethan- 1 -olate (3d-02)

4c-02 3d-02

[00593] A reactor was charged with compound 4c-02 (1.0 g), ethyl trifluoroacetate

(CF 3 COOEt, 0.91 g, 1.0 equiv.) and tetrahydrofuran (THF, 0.5 mL) and the reaction mixture was cooled to about -10 to 0 °C. The 1M solution of lithium bis(trimethylsilyl)amide

(LiHMDS, 7.0 mL, 1.10 equiv.) was added over about 40 min while maintaining the internal temperature below about 0 °C. The reaction mixture was agitated for about 2 hours at about -10 to 0 °C until the reaction was complete. After then, the reaction mixture was wanned to about 20 °C followed by charging /e/T-butyl methyl ether (MTBE, 10 mL) and water (10 g). After agitating for about 30 min, the organic layer was separated and the aqueous layer was back- extracted twice with mixture of MTBE (6 ml.) and THF (4 mL). The combi ned organic layer was concentrated until no distillate was observed. To the unpurified solids, THF (3 mL) and heptane (15 mL) were added at about 20 °C, and the reaction mixture was cooled to about 0 °C and agitated about 1 hour. The resulting slurry was filtered and wet cake was washed with heptane (7 g) and dried under vacuum at about 40 °C to afford compound 3d-02. 1H NMR (600

MHz, DMSO-de): d 3.31 (s, 3H), 3.27 (s, 3H) 2.01 (m, H), 1.42 (td, 1H), 0.96 (m, 1 H), 0.08 (q, 1H). (600 MHz, CDCk with THF) d 3.44 (s, 3H), 3.24 (s, 3H), 2.26 (m, 1H), 1.48 (m, 1H), 1.04 (q, 1H), 0.25 (m, H). 13 C NMR (150 MHz, DMSO-d 6 ): 193.20, 120.78, 118.86, 105.53,

104.04, 50.66, 49.86, 17.34, 16.20, 13.78.

Synthesis of ethyl 2-((3bS.4aR)-5-oxo-3-(trifluoromethyl)-3b.4.4a.5-tetrahydro- lH- cyclopropa[3.41cvclopentai 1.2-clpyrazol- 1 -vDacetate (XIV)

3d 02 XIV [00594] Compound 3d-02 (1.0 g), ethyl hydrazinoacetate hydrochloride (EHA-HC1, 0.60 g,

1.0 equiv.) and absolute ethanol (EtOH, 15 mL) were added to a reactor and the reaction mixture was cooled to about 0 - 5 °C. Sulfuric acid (H2SO4, 0.19 g, 0.50 equiv.) was added while maintaining the internal temperature below about 5 °C. Tri ethyl orthoformate (0.86 g, 1.50 equiv.) was added and the reaction mixture was agitated at about 0 to 5 °C for about 15 hours. The reaction mixture was warmed to about 20 to 25 °C and water (30 g) was added over about 15 minutes. The content was cooled to about 0 to 5 °C and agitated for about 1 hour. The slurry was filtered and wet cake was washed with water (5 g) and dried under vacuum at about 45 °C to afford XIV 1 H NMR (600 MHz, CDC1 3 ): d 4.97 (s, 1H), 4.23 (qd, 2H), 2.77 (quint. III), 2.60 (quint, 1H), 1.69 (m, 2H), 1.28 (t, 3H). 13 C NMR (150 MHz, CDCl 3 ): d 187.14, 165.98, 143.35, 143.12, 121.37, 1 19.59, 62.34, 51.83, 35.35, 31.72, 14.00, 13.73.

Example 4c: Kinetic resolution of ethyl 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro- lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetate (XVII) to form ethyl 2- ((3bS,4aR)-5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH - cyclopropa[3,4]cyclopenta[l,2-c]pyrazoI-l-yl)acetate (XIV)

XVII XIV XVIII XIV

[00595] Compound XVII (1.0 g), (i?)-2-methyi-CBS-oxazaborolidine (0.0.05 g, 0.05 equiv.), and tetrahydrofuran (11.9 g) were combined and cooled to about 0 to 5 °C. A solution of borane dimethyl sulfide complex (0.14 g, 0.55 equiv.) in tetrahydrofuran (0.67 g) was added to the mixture, and the mixture was agitated at about 0 to 5 °C until the reaction was deemed complete. Methanol (1 mL) was added to the mixture at about 0 to 5 °C over about 1 h, and the mixture was adjusted to about 15 to 25 °C. The mixture was concentrated under vacuum and combined with tetrahydrofuran (2.7 g). The mixture was combined with 4-dimethylaminopyridine (0.18, 0.44 equiv.) and succinic anhydride (0.30 g, 0.87 equiv.) and agitated at about 15 to 25 °C until the reaction was deemed complete. The mixture was combined with lert- butyl methyl ether (5.2 g) and washed with 1 M aqueous HC1 (6.7 g), twice with 5 wt % aqueous potassium carbonate (6.7 g each), and 5 wt % aq. sodium chloride (6.7 g). The organics were concentrated under reduced pressure to an oil which was dissolved in dichloromethane (0.1 g) and purified by flash column chromatography (2.0 g silica gel, 20:80 to 80:20 gradient of ethyl acetate:hexanes). The combined fractions were concentrated under vacuum to give XIV.

Example 4d: Preparation of (lR,5S)-bicyclo[3.1.0]hexan-2-one (4a)

[00596] 4-Tosyloxycyclohexanone (50 mg), (8a,9X)-6'-methoxycinchonan-9-amine trihydrochloride (16 mg), trifluoroacetic acid (28 pL), lithium acetate (49 mg), water (3.4 pL), and 2-methyltetrahydrofuran (0.75 mL) were combined in a vial. The mixture was agitated at about 20 °C until the reaction was complete. 4a was isolated by vacuum distillation. l H NMR (400 MHz, CDCl·,) 2.05 (m, 5H), 1.74 (m, 1H), 1.18 (m, 1H), 0.91 (m, 1H).

Example 5: Synthesis of ethyl 2-((3bS,4aR)-3-(triflnoromethy!)~4,4a~

dihydrospiro[cyclopropa[3,4]cyclopenta[l,2-c]pyrazole-5,2 '-[l,3]dithiolane]-l(3bH)- yl)acetate (5h) from (lR,5R)-2,2-dimethoxybicyclo[3.1.0]hexan-3-ol (4b-02)

Synthesis of (lR 5R)-spirorbicvclor3. l .01hexane-2.2'-rl.31dithiolan1-3-ol

r 0H

4b-02 5d

[00597] A mixture of ketal alcohol 4b-02 (1.0 g), ethanedi thiol (0.91 g), MeCN (7.5 ml) and BiCl 3 (0.30 g) was agitated at r.t. overnight. The solids were removed by filtration and the filtrate was concentrated and the residue was further purified by flash column on silica gel to obtain the two isomers. Major product: 1H NMR (400 MHz, Chloroform-i/) d 3.82 (ddt, J= 6.1, 1.3, 0.6 Hz, 1H), 3.41 - 3.32 (m, 2H), 3.31 -3.23 (m, 1H), 3.14 - 3.06 (m, 1H), 2.71 (s, 1H),

2.33 (dddd, j = 14.0, 6.2, 4.8, 1.4 Hz, 1H), 2.00 (d, j= 13.9 Hz, 1H), 1.79 - 1.72 (m, 1H), 1.54 - 1.46 (m, 1H), 1.04 (dt, j= 5.1 , 3.9 Hz, 1 H), 0.63 - 0.54 (m, 1H). Minor product: 1H NMR (400 MHz, Chloroform -J) d 3.83 (q, J= 9.1 Hz, 1H), 3.43 - 3.34 (m, 2H), 3.33 - 3.25 (m, 2H), 2.35 (d, ./ 1 1.2 Hz, 1H), 2.18 (ddd, J = 12.7, 6.7, 0.4 Hz, 1H), 1.84 (ddd, ./ 8.1, 6.3, 3.7 Hz, 1H),

1.60 - 1.51 (m, 1H), 1.43 - 1.35 (m, 1H), 0.65 (tdt, ./= 8.1, 5.9, 0.8 Hz, 1H), 0.57 (dddd, J= 5.9, 4.2, 3.7, 0.6 Hz, 1H).

Synthesis of -spiro[bicvclor3.1.01hexane-2.2'-n .31dithiolan1-3-one

5d 5e

[00598] To a dried flask was sequentially added dithiolane alcohol 5d (1.0 g), CH2CI2 (25 ml), anhydrous DMSO (8.5 ml), and tri ethyl amine (3.5 ml) and the resulting mixture was aged at room temperature for about 21 hours. The reaction mixture was transferred to a separatory funnel, diluted with CH 2 Cl 2 (30 ml), washed with 1 M HC1 (25 ml), and water (25 ml). The CH2CI2 layer was concentrated to a solid and further purify by flash column chromatography on silica gel eluted with gradient EtOAc/n-heptane (0-20%) to obtain 5e. 1H NMR (400 MHz, Chloroform -d d 3.57 (dddd, J= 10.5, 5.6, 4.3, 0.5 Hz, 1H), 3.49 - 3.41 (m, 1H), 3.39 - 3.28 (m, 2H), 3.10 (ddd, J = 18.3, 5.6, 2.2 Hz, 1H), 2.29 (d, ./ 18.3 Hz, 1H), 1.89 (ddd, j = 8.0, 7.0, 3.9

Hz, 1H), 1.63 (tdd, ./= 7.3, 5.6, 4.1 Hz, 1H), 1.05 (tdd, J= 8.0, 6.3, 2.2 Hz, 1H), 0.21 (dt, ./ = 6.4, 4.0 Hz, 1H). Synthesis of lithium (Z -2.2 2-trifluoro- 1 - 5 SV 3 -oxospirorbicvclol 3.1.0]hexane-2.2'- G 1.3 ldithiolan]-4-ylidene)ethan-l -olate (5f)

[00599] To a flask with dithiolane ketone 5e (1.0 g) under N 2 was added anhydrous THF (8.8 ml), and the mixture was cooled to about -78 °C and followed by addition of LiHMDS (1 M in THF, 7.4 ml) over about 5 min. The resulting mixture was agitated at about -78 °C for about 0.5 hours, and ethyl trifluoroacetate (0.88 ml) was added. The resulting mixture was agitated at about -78 °C for about 10 minutes, at about 0 °C for about 1 hour, and at room temperature overnight. THF was removed under reduced pressure and the residue was crystallized in n-heptane (about 18 ml). The solid product was isolated by filtration, and the filter cake was rinsed with n-heptane (4.1 ml), and dried at about 50 °C under vacuum to provide 5f. 1H NMR (400 MHz, Acetonitrile^) d 6.98 (s, OH), 5.20 (s, OH), 3.60 - 3.50 (m, 2H), 3.46 - 3.36 (m, 2H), 2.28 - 2.20 (m, 1 H), 1.80 (ddd, J= 8.3, 7.2, 4.1 Hz, 1 H), 1.39 (s, 1 H), 1.03 (ddd, J= 8.3, 6.7, 4.8 Hz, 1H), 0.17 (ddd, J= 4.7, 4.2, 3.6 Hz, 1H).

Synthesis of (3b S.4aR)-3 -(trifluorom ethyl)- 1 4.4a-

tetrahvdrospiro[cvciopropa[3.41cvclopentaiT .2-clpyrazole-5 2'-[l 31dithiolane1 (5g)

5f 5g

[00600] To flask containing the dithiolane lithium salt 5f (1.0 g) was added water (10 ml), hydrazine hydrate (0.88 ml) and acetic acid (10 ml). The reaction mixture was heated at about 35 °C for about 2 hours, and at about 55 °C for about 2 hours. Water was removed under reduced pressure and the residue was diluted with acetic acid (20 ml) and heated at about 55 °C for about 0.5 hour and held at room temperature overnight. The reaction mixture was further heated at about 65 °C for about 20 hours, and cooled down and concentrated to remove volatile components by rotavap. The residue was triturated with water (50 ml) at about 0 °C and the solid residue was isolated and further washed with ice-cold water (2x10 ml). The solids were further dried to afford unpurified 5g. 1H NMR (400 MHz, Chloroform -<i) d 3.65 - 3.46 (m, 4H), 2.60 (dddd, J= 8.3, 5.6, 4.2, 0.7 Hz, 1H), 2.47 - 2.38 (m, 1H), 1.33 (dddd, ./= 8.2, 7.4, 5.7, 0.7 Hz, H i ), 0.66 (dddd, J = 5.7, 4.3, 3.6, 0.7 Hz, H i )

Synthesis of ethyl 2-((3bS.4aR)-3-(trifluoromethyl -4.4a- dihydrospiroi cvclopropai 3.4]cvclopentai 1.2-clpyrazole-5.2'-[ 1.3 lciithi plane]- 1 ( 3bH)-yl)acetate

(5h) from (3bS.4aR)-3-(trifluoromethyl)-l .3b.4.4a- tetrahvdrospiro[cyclopropar3.41cvclopentai 2-clpyrazole-5.2'-[ 31dithiolanel (5g)

[00601] A reactor was charged with dithiolane pyrazole 5g (1.0 g) and THF (15 ml). The contents were adjusted to about 0 to -5 °C and followed by addition of ethyl bromoacetate (0.44 ml, 1.1 equiv.). To the resulting mixture NaHMDS (2 M, 2.0 ml, 1.1 equiv.) was added over about 10 min via syringe pump at about -2.5 to 0 °C and the mixture was held for about 3 hours, a second portion of ethyl bromoacetate (0.050 ml, 0.12 equiv.) was added, and the mixture was aged for about 1 hour. The reaction mixture was quenched by excess water (2 ml) to form 5h.

Synthesis of ethyl 2-((3bS.4aR)-3-(trifluoromethyl -4.4a- dihvdiOspiro[cvclopropai3.41cyclopentaih2-clpyrazole-5 2'-[ 31dithiolanel-l(3bHVyl)acetate from lithium (Z)-2.2.2-trifluoro-l -((lR.5S)-3-oxospiro[bicvclor3. l .01hexane-2.2'-

G 1.31dithiolanl-4-ylidene)ethan-l-olate

[00602] A 100 ml flask was charged with ethanol (5 ml). The contents were cooled to about 0 °C and acetyl chloride (1.1 g, 4.0 equiv.) was added over about 10 min. The mixture was agitated at about 0 °C for about 20 minutes and at room temperature for about 20 minutes. To the freshly prepared HC1 ethanol solution was added EHA.HCl (0.68 g, 1.2 equiv.) and dithiolane lithium salt 5f (1.0 g). The reaction mixture was heated at about 40 °C for about 22 hours. Ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate (5 ml) and water (5 ml). The aqueous layer was discarded, and the organic layer was sequentially washed with aqueous NaHC0 3 (5%, 5 ml) and brine (5%, 5 ml) and 5h was obtained in the EtOAc layer. 1H NMR (400 MHz, DMSO-t 6) d 5.14 - 4.97 (m, 2H), 4.14 (qd, J = 7.1, 1.0 Hz, 2H), 3.67 - 3.35 (m, 41 i f 2.69 (ddd, ./ 8.2, 5.6, 4.2 Liz, 1 1 if 2.44 (ddd, ./ 7.2,

5.5, 3.5 Hz, 1H), 1.37 - 1.29 (m, 1H), 1.21 - 1.14 (m, 3H), 0.44 (ddd, j= 5.3, 4.2, 3.6 Hz, 1H).

Synthesis of ethyl 2-( -3-(trifluoromethyl)-4.4a-

dihydrospirol cvclopropaf 3 4]cvcl opental 1.2-c1pyrazole-5.2'-[ 1.3 Idi thiol anel-1 (3bH)-vDacetate fSfa) from (lR.5RVspiro[bicvclo[3. l .01hexane-2.2'-[L31dithiolanl-3-one (5e)

5e 5f-01 5h

[00603] 5e (756 mg) was charged to a vessel and dissolved in 2-m ethyltetrahydrofuran (7.6 niL). To this solution was charged ethyl trifluoroacetate (0.57 g) and the resulting solution was cooled to about 0 °C. Lithium hex am ethyl di si 1 azi de (1.0 M solution in THF, 4.5 g) was charged over about 60 minutes and reaction was agitated until complete. A solution of sulfuric acid (2.0 g) in water (5.6 mL) was charged, then the reaction was warmed to about 20 °C and agitated for about 20 minutes. Layers were separated and aqueous layer was extracted twice with 2- methyltetrahydrofuran (5.3 mL). Combined organic layer was concentrated to about 0.4 mL and A V-diisopropylamine (0.5 g) was charged. The product was crystallized by the addition of heptane (11 ml). The slurry was filtered and the filter cake was washed with heptane, then deliquored thoroughly, and dried to afford 5f-01. 1H NMR (400 MHz, Acetonitrile-^) d 7.84 (m, 2H), 3.58 (d, J = 8.7 Hz, 2H), 3.47 - 3.27 (m, 4H), 2.20 (s, 1H), 1.81 - 1.68 (m, 1H), 1.24 (dd, J= 6.5, 0.6 Hz, 12H), 0.99 (q, J= 6.5 Hz, I H), 0.13 (s, I H).

[00604] Acetyl chloride (1.02 g) was charged to a cooled reaction vessel containing ethanol (5.0 mL) at about 0 °C, then warmed to about 20 °C and agitated for about 30 minutes. In a separate vessel, 5f-01 (1.00 g), ethyl hydrazinoacetate hydrochloride (0.48 g), and lithium chloride (0.39 g) were combined, and the acetyl chloride/ethanol solution was charged to this mixture, followed by tri ethyl orthoformate (1.16 g). The mixture was heated to about 45 °C and agitated until reaction was complete. The reaction was then concentrated to 2 volumes and dichlorom ethane (5.0 mL) was added followed by water (5.0 mL). Layers were separated and organic layer was washed with 5 wt % aqueous sodium bicarbonate followed by 10 wt % aqueous sodium chloride to afford a solution of 5h in dichlorom ethane that was carried forward into the subsequent step. 1H NMR (400 MHz, DMSO-d 6 ) d 5.27 - 4.79 (m, 2H), 4.14 (qd, J = 7.1, 1.1 Hz, 2H), 3.70 - 3.42 (m, 4H), 2.68 (dtd, J = 8.0, 6.4, 5.9, 4.4 Hz, 1H), 2.44 (ddd, J = 7.2, 5.5, 3.6 Hz, 1H), 1.32 (ddd, J = 8.2, 7.2, 5.4 Hz, 1H), 1.18 (t, J = 7.1 Hz, 31 1 ), 0.44 (dt, J = 5.4, 3.9 Hz, 1H); 13 C NMR (101 MHz, DMSO-d6) d 167.14, 148.36, 133.80 (q, J = 38.3 Hz), 128.77 (m), 121.54 (q, J = 268.4 Hz), 65.33, 61.79, 51.14, 41.30, 40.98, 40.49, 23.57, 15.52, 14.33; 19 F NMR (376 MHz, DMSO-d6) d -60.31.

Synthesis of (lR.5R)-spirorbicvclor3. l .01hexane-2.2'-rL31dithiolan]-3-one (5e) from (1R.5R)- spiro[bicvcloi3.1 .01hexane-2.2'-f L31dithiolanl-3-one (5e) from (l R 5S )-bicvclo[3. l .Olhexan-2- one (4a)

5i 5e

[00605] Tert-butyl nitrite (1.31 g) was charged to a vessel containing 4a (1.00 g, 1.0 equiv) and tetrahydrofuran (5.0 mL) at about 20 °C. Potassium tert-butoxide (6.1 g, 1.7M in

tetrahydrofuran) was charged over not less than 30 minutes. The mixture was then agitated until the reaction was complete. The reaction was quenched with aqueous citric acid (2.00 g in 10.00 g water) and extracted with dichloromethane (10.0 mL, 3x). This solution was partially concentrated and the product was isolated by the addition of heptane (6.0 mL). The slurry was filtered and the filter cake was washed with heptane (2.0 mL), then deliquored thoroughly to afford 4d 1H NMR (400 MHz, DMSO-iL) d 12.26 (s, 1H), 2.73 (d, J= 18.5 Hz, 1H), 2.63 (ddd, J= 18.6, 5.3, 2.0 Hz, 1H), 2.17 - 2.01 (m, 2H), 1.34 (dddd, J = 9.2, 7.1, 4.9, 2.0 Hz, 1H), 0.77 (td, .7 = 4.6, 3.4 Hz, 1H).

[00606] l ,2-Ethanedithiol (0.41 g) was charged to a vessel containing a solution of 4d (0.50 g, 4.0 mmol) in glacial acetic acid (2.5 mL) at about 20 °C. L’ara-toluenesulfonic acid monohydrate (0.15 g) was added and the mixture was agitated until the reaction was complete. The product was isolated by the addition of water (2 mL). The slurry was filtered and the filter cake was washed with water, then deliquored thoroughly to afford 5i. 1H NMR (400 MHz, DMSO-i¾) d 10.93 (s, 1H), 3.63 - 3.51 (m, 2H), 3.51 - 3.42 (m, 1H), 3.39 - 3.31 (m, 1H), 2.83 (d, ./ 17.4 Hz, 1 H), 2.59 - 2.52 (m, 1H), 1.87 (ddd, J= 8.0, 6.2, 3.7 Hz, 1H), 1.65 (dddd, ./

7.7, 6.2, 5.2, 3.9 Hz, 1 H), 0.93 (tdd, J= 7.6, 5.5, 1.7 Hz, 1H), 0.02 (dt, ,/= 5.5, 3.8 Hz, 1 H).

[00607] Para-toluenesulfonic acid (0.90 g) was charged to a vessel containing a suspension of 5i (0.50 g, 2.5 mmol) in methyl ethyl ketone (2.5 mL) and water (2.5 mL). The mixture was agitated at about 85 °C until the reaction was complete. The product was isolated from the reaction mixture by cooling to about 20 °C, adding water (2.50 mL), and cooling to about 0 °C. The slurry was filtered and the filter cake was washed with water, then deliquored thoroughly to afford 5e. 1H NMR (400 MHz, DMSO- ) d 3.55 - 3.37 (m, 3H), 3.28 - 3.13 (m, 1H), 3.03 (ddd, J= 18.5, 5.6, 2.2 Hz, 1H), 2.20 (d, J= 18.5 Hz, 1H), 1.84 (ddd, J= 8.0, 7.0, 3.8 Hz, 1H), 1.66 (tdd, J = 7.2, 5.6, 4.1 Hz, 1H), 1.03 (tdd, J= 7.9, 5.9, 2.1 Hz, 1H), 0.06 (dt, J = 6.0, 4.0 Hz, 1H).

Example 6: Preparation of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5- tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)a cetic add (VII) from ethyl 2- ((3bS,4aR)-5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH - cyclopropa[3,4]cyclopenta[l,2-c]pyrazoI-l-yl)acetate (XIV)

Synthesis of ethyl 2-((3bS.4aR)-3-(trifluoromethyl)-4.4a- dihvdiOspiro[cvclopropai3.41cyclopentaiL2-clpyrazole-5.2'-[l .31dithiolanel-l(3bH)-yl)acetate (5h) from ethyl 2-((3bS.4aR)-5-oxo-3-(trifluoromethyl)-3b.4.4a.5-tetrahvdro- lH- cyclopropa[3.41cvclopentai 1.2-c]pyrazol- 1 -vDacetate (XIV)

XIV 5h [00608] Dichloromethane (27 g) was added to a reactor containing XIV (1.0 g) and cooled to about 10 °C. To this was added l,2-ethanedithiol (0.18 g, 1.2 equiv.). To this was added boron tri fluoride acetic acid complex (3.3 g, 2.5 equivalents) over about 25 minutes, and the reaction mixture was agitated at about 20 °C until complete. A solution of calcium chloride dihydrate (0.80g, 0.78 equiv) in 0.10 N hydrochloric acid (16 g) was added over about 1 hour at about 10 °C, and the mixture was agitated for about 90 minutes at about 20 °C. The organic layer was washed successively with water (8 g) and sodium bicarbonate solution (5 w1/wt%). The organic layer was concentrated to afford 5h. 1H NMR (400 MHz, DMSO-<7 6 ) 5 5.27 - 4.79 (m, 2H),

4.14 (qd, j = 7. 1, 1.1 Hz, 2FI), 3.70 - 3.42 (m, 4H), 2.68 (dtd, ./ = 8.0, 6.4, 5.9, 4.4 Hz, 1H), 2.44 (ddd, J= 7.2, 5.5, 3.6 Hz, 1H), 1.32 (ddd, J= 8.2, 7.2, 5.4 Hz, 1H), 1.18 (t, ,/= 7.1 Hz, 3H), 0.44 (dt, j= 5.4, 3.9 Hz, 1H). 13 C NMR (101 MHz, DMSO- ) 5 167. 14, 148.36, 133.80 (q, ./ 38.3 Hz), 128.77 (m), 121.54 (q, ,/= 268.4 Hz), 65.33, 61.79, 51.14, 41.30, 40.98, 40.49, 23.57,

15.52, 14.33. 19 F NMR (376 MHz, DMSO- ) d -60.31.

Synthesis of ethyl 2-(f3bS.4aR)-5.5-difluoro-3-(trifluoromethyl)-3b.4-4a.5-tetr ahvdro-lH- cyclopropa[3.41cvclopentai 1.2-clpyrazol- 1 -yQacetate (VII-A)

5h VII-A

[00609] Dichloromethane (26 g) was added to a reactor containing l,3-dibromo-5,5- dimethylhydantoin (DBDMH, 2.4 g, 3.1 equiv.) and cooled to about -10 °C. To this was added 70% hydrofluoric acid/pyridine complex (1.3 g, 17 equiv.), followed by a solution of 5h (1.0 g) in dichloromethane (3 g). The reaction was agitated at about 0 °C until complete. A solution of potassium hydroxide (3.7 g, 25 equivalents) and potassium sulfite (1 .9 g, 4 equiv.) in water (24 g) was added, maintaining an internal temperature of about 5 °C, and agitated for about 30 minutes at about 20 °C. Layers were separated and organic layer was washed with hydrochloric acid (1.1 g, 4 equiv.) in water (9.6 g). The organic layer was concentrated to afford VII-A. 1H NMR (400 MHz, DMSC s) 5 5.31 - 5.04 (m, 2H), 4.17 (q, J= 7.1 Hz, 2H), 2.78 - 2.57 (m,

2H), 1.47 (dddd, J= 8.5, 7.1, 5.5, 1.4 Hz, 1H), 1.19 (t, j= 7.1 Hz, 3H), 1.04 (tdt, ./= 5.3, 4.0,

1.8 Hz, 1H). 13 C NMR (101 MHz, DMSG- ) 5 166.79, 143.15 (t, ./ 29.4 Hz), 134.65 (q, ./

39.0 Hz), 132.99, 121.05 (q, ,7= 268.4 Hz), 120.52 (t, .7= 243 3 Hz), 62.09, 52.49, 27.95 (dd, ./ = 34.7, 29.0 Hz), 23.82 (d, J= 2.6 Hz), 14.25, 12.14 (t, J= 3.1 Hz). 19 F NMR (376 MHz, DMSO- d 6 ) 5 -60.47, -79.68 (dd, ./= 253.5, 13.2 Hz), -103.09 (dd, j= 253.3, 9.8 Hz). Synthesis of 2-((3bS.4aR)-5.5-difluoro-3-(trifluoiOmethyl)-3bA4a.5-tetrah vdiO-lH- cvciopropa[3.41cvclQpenta clpyrazol-l-vi )acetic acid (VII)

VII-A VII

[00610] A reactor was charged with a solution of VII-A (1.0 g) in dichloromethane (18 g) and cooled to about 5 °C. To this was added ethanol (1.5 g), followed by potassium hydroxide (45 wt/wt%, 0.74 g, 2.0 equiv.). The reaction mixture was agitated at about 20 °C until complete. Water (3.7 g) was added and the reaction mixture was agitated for about 30 minutes. Organic layer was removed and reaction was cooled to about 10 °C. Dichloromethane (18 g) was added, followed by 2N hydrochloric acid (3.3 g, 2,2 equiv.). Reaction was warmed to about 20 °C and agitated for 10 minutes. Layers were separated and aqueous phase was washed with dichloromethane (18 g). Organic layers were combined and concentrated on rotary evaporator to afford VII. 1H NMR (400 MHz, DMSO-i¾) d 13.50 (s, 1H), 5.14 - 4.81 (m, 2H), 2.82 - 2.56 (m, 2H), 1.46 (dddd, J = 8.5, 7.1 , 5.5, 1.4 Hz, 1H), 1.08 - 1.00 (m, 1H). 13 C NMR (101 MHz, DMSO- e) d 168.16, 143.05 (t, J= 29.4 Hz), 134.40 (q, ./= 38.9 Hz), 132.80, 121.11 (q, ./ = 268.4 Hz), 120.55 (t, ./ 243.3 Hz), 52.54, 27.97 (dd, J = 34.7, 29.0 Hz), 23.81 (d, J= 2.5 Hz), 12.13 (t, ./= 3.1 Hz). 19 F NMR (376 MHz, DMSO- ) d -60.39 (d, J= 1.4 Hz), -79.83 (dd, J = 253.2, 13.1 Hz), -102.97 (dd, = 253.2, 9.8 Hz).

Example 7: Preparation of 4~ch!oro-7-(4,4,5,5-tetramethyi~l,3,2-dioxaborolan~2-y!)-l- (2,2,2-trifluoroethyl)-lH-indazoI-3-amine (V-02) and its mesylated derivatives

Synthesis of 4-chloro-7-bromo-l-(2.2.2-trifluoroethyl)-lH-indazol-3-amine (V-A)

[00611] To a reactor was added tetrahydrofuran (THF, 275 kg) and diisopropyl amine (DIP A, 30 kg) and the mixture was cooled to about -35 °C. nButyl lithium (2.5 mol/L in hexanes, 74 kg) was charged slowly keeping the reaction temperature less than -30 °C. The mixture was agitated at-35 °C until the reaction was complete. 1 -brom o-4-chl oro-2-fluorobenzene (52 kg) was charged keeping reaction temperature less than 30 °C and the mixture was agitated at -35°C until reaction was complete. N,N-dimethylform amide (DMF, 36 kg) was charged keeping reaction temperature less than -30 °C and the mixture was agitated at about -35 °C until reaction was complete. Hydrochloric acid (HO, 18 mass% in water, 147 kg) was charged keeping reaction temperature less than -5 °C. The reaction was warmed to about 0 °C, water (312 kg) was added, and the reaction was extracted with methyl tert-butyl ether (MTBE, 770 kg). The organic was warmed to about 20 °C and washed with brine (NaCl, 23.5 mass% in water, 1404 kg). The mixture was distilled to about 3-4 volumes and heptane was charged (354 kg). The product was isolated by distillation to 3-4 volumes. The slurry was filtered and washed with heptane (141 kg) and dried to afford 6a. 1H NMR (400 MHz, DMSO-i/ 6 ) d 10.23 (d, J= 1.2 Hz, 1H), 8.00 (dd, j = 8.7, 1.4 Hz, 1H), 7.44 (dd, j= 8.7, 1.4 Hz, 1H).

[00612] 6a (98.5 kg) was charged to a reactor containing acetic anhydride (105 kg) and acetic acid (621 kg) at 20 °C. The mixture was heated to about 45 °C and hydroxyl amine

hydrochloride (31.5 kg) was charged. The reaction was heated to about 75 °C and agitated until the reaction was complete. The product was isolated from the reaction mixture by adding water (788 kg) at about 45 °C. The mixture was cooled to about 25 °C and then the slurry was filtered. The filtered cake was washed with water (197 kg,). The cake was dried to afford 6b. 1H NMR (400 MHz, DMSO- ) 5 8.11 (dd, , 7= 8.8, 1.4 Hz, 1H), 7.58 (dd, ./= 8.8, 1.4 Hz, 1H).

[00613] To a reactor was charged 6b (84 kg), isopropanol (318 kg), and water (285 kg).

Hydrazine hydrate (20 wt% in water, 178 kg) was charged and the mixture was heated to about 80 °C until the reaction was complete. The product was isolated by cooling the reaction to about 25 °C. The slurry was filtered and the filtered cake was washed with a mixture of isopropanol (127 kg) and water (168 kg). The wet solids were recharged to the reactor and water (838 g) was added. The mixture was agitated at about 25 °C and then filtered and washed with water (168 g, 2 rel). The cake was dried to afford 6c 1H NMR (400 MHz, DMSO- ) d 12.20 (s, 1H), 7 41 (d, ./ 7.9 Hz, III), 6.84 (d, ./ 7 9 Hz, 1H), 5.31 (s, 2H).

[00614] 6c (75 kg) was charged to a reactor containing N,N-dimethylformamide (75 kg). Potassium phosphate (99.8 kg) was charged to the reactor at about 25 °C and the mixture was agitated. 2,2,2-trifluoroethyl trifluoromethanesulfonate (74.3 kg) was charged at about 25 °C and the mixture was agitated until the reaction was complete. Water (375 kg) was charged and the mixture was agitated at about 20 °C. The slurry was filtered and washed with water (150 kg). N,N-dimethylformamide (424 kg) and the wet solid were charged to a reactor at about 20 °C.

The mixture was agitated at about 45 °C. 5 % hydrochloric acid (450 kg) was charged drop-wise to the mixture at about 45 °C. The mixture was cooled to about 25 °C. The slurry was filtered and washed with water (375 g). Water (375 kg) and the filtered solid were charged to a reactor at about 20 °C. The mixture was agitated for about 1 hour at about 20 °C. The slurry was filtered and washed with water (375 kg). The cake was dried to afford V-A. 1H NMR (400 MHz, DMSO- ) d 7 57 (d, ./ 8.1 Hz, III), 6.98 (d, ./ 8 1 Hz, 1H), 5.70 (s, 2H), 5.32 (q, J= 8.6 Hz,

2H).

Synthesis of 4-chloro-7-(4A5.5-tetramethyl-l.3.2-dioxaborolan-2-vP-l-(2.2 .2-trifluoroethyl)- lH-indazol-3-amine (V-02)

y-A V-02

[00615] A reactor containing tetrahydrofuran (27 g) and V-A (1.0 g) was cooled to about 0 °C. Chlorotrimethylsilane (7.6 g, 2.3 equiv) was added, followed by the slow addition of lithium bis(trimethylsilyl)amide (5.7 g, 1 M in THF, 2.1 equiv.). The mixture was stirred at about 0 °C until bistrimethylsilane protection was complete. The solution was washed with ammonium chloride in water (10 wt%, 52 g), toluene (44 g) was added, and the biphasic mixture was filtered through celite. The organic and aqueous phases were separated and the aqueous phase was washed with toluene (44 g). The organics were combined, washed with brine (58 g), and azeotropically distilled . The solution was cooled to about 0 °C, i sopropy 1 m agnesium chloride lithium chloride complex (2.7 g, 1.3 M in THF, 1.2 equiv.) was added and the reaction was stirred at about 0 °C until lithium halogen exchange was complete. Isopropoxyboronic acid pinacol ester (6.8 g, 1.2 equiv.) was added and the reaction was stirred at about 0°C until botylation was complete. At about 0 °C, The reaction was quenched with aqueous hydrochloric acid (52 g, 1 M), acetonitrile (16 g) was added, and the mixture was stirred until tri ethyl silane deprotection was complete. The solution was extracted with ethyl acetate (45 g) and the organic was washed twice with brine (2 x 58 g). The solution was concentrated to low volumes (26 g), dim ethylformami de (47 g) was added, and the solution was concentrated again (51 g). The product was crystallized by the addition of water (50 g). The slurry was filtered and filter cake was washed with heptane (14 g). The solids were dried to afford V-02. ! H NMR (400 MHz, DMSO-d6) d 7.70 (dd, J = 7.6, 1.0 Hz, 1H), 7.07 (dd, J = 7.6, 1.0 Hz, 1H), 5.58 (s, 2H), 5.46 (q, J = 9.1Hz, 2H), 1.32 (s, 12H).

Synthesis of 4-chloro-7-i4A5.5-tetramethyl-l.3.2-dioxaborolan-2-vO-l- trifiuoroethyl -

lH-indazol-3-amine (V-02)

V-A V-02

[00616] To a reactor was charged V-A (30 kg), bis(pinacolato)diboron (27.9 kg),

bis(triphenylphosphine)palladium (II) di chloride (0.9 kg, 1.5 mol%), N,N-di m ethylformami de (56 kg, 2 rel. vol.) and toluene (157 kg, 6 rel vol.). The mixture was heated to about 105 °C until the reaction was complete. The mixture was cooled to about 25 °C, filtered through celite (15 kg, 0.5 rel. wt.) and rinsed forward with ethyl acetate (270 kg, 10 rel vol.). PSA-17 palladium scavenger (3 kg, 10 wt%) was added and the mixture was stirred at about 45 °C. The mixture was filtered and the cake was washed with ethyl acetate (54 kg, 2 rel. vol.). The mixture was washed twice with lithium chloride (180 kg, 6 rel. vol.) and once with brine (NaCl, 23.5 mass% in water, 180 kg, 6 rel. vol.). The mixture was then concentrated to about 5-6 rel. vol. under vacuum, heated to about 45 °C then cooled to about 25 °C. Heptane (102 kg, 5 rel. vol.) was charged and the mixture was concentrated to about 4-5 rel. vol. The product was isolated by charging heptane (41 kg, 2 rel. vol.) and cooling the mixture to about 0 °C. The shirty was filtered and washed with heptane (41 kg, 2 rel. vol.). The wet solids were recharged to the reactor with ethyl acetate (27 kg, 1 rel. vol.) and heptane (82 kg, 4 rel. vol.), heated to about 65 °C, and then cooled to about 5 °C. The slurry was filtered and washed with heptane (41 kg, 2 rel. vol.). The cake was dried to afford V-02. 1H NMR (400 MHz, DMSO-d6) d 7.70 (dd, J = 7.6, 1.0 Hz, 1H), 7.07 (dd, J = 7.6, 1.0 Hz, 1H), 5.58 (s, 2H), 5.46 (q, J = 9.1Hz, 2H), 1.32 (s, 12h).

Synthesis of N-(4-chloro-7-(4.4.5.5-tetramethyl-L3.2-dioxaborolan-2-vD-l -(2.2.2- trifluoroethyl)-lH-indazol-3-yl)-N-(methylsulfonyl methanesulfonamide (V-04)

[00617] To a 100 mL reactor was added V-02 (5.00 g), 2-methyltetrahydrofuran (50 mL), and triethylamine (11.1 mL). The mixture was cooled to about 10 °C and methanesulfonyl chloride (2.58 mL, 33.3 mmol) was added to the mixture. The mixture was agitated at about 10 °C until reaction was complete. The mixture was concentrated to dryness and the residue was purified by column chromatography to afford V-04. 1H NMR (400 MHz, DMSO-i¾) d 7.96 (d, J = 7.7 Hz, 1H), 7.50 (d, ./= 7.6 Hz, 1H), 5.95 (q, J= 8.8 Hz, 2H), 3.66 (s, 6H), 1.37 (s, 12H).

Synthesis of N-(4-chloro-7-(4A5.5-tetramethyl-L3..2-dioxaborolan-2-ylVl -(2.2.2- trifluoroethyl)-lH-indazol-3-yl)methanesulfonamide (V-03)

V-03 [00618] To a 100 mL reactor was added V-02 (5.00 g), 2-methyltetrahydrofuran (50 mL), and triethylamine (11.1 mL, 79.6 mmol). The mixture was cooled to about 10 °C and

methanesulfonyl chloride (2.58 mL) was added to the mixture. The mixture was agitated at about 10 °C until reaction was complete. To the mixture was added 2-methyltetrahydrofuran (21.5 g) and sodium hydroxide (0.43 g) and the mixture was agitated at about 25 °C until the reaction was complete. To the resulting solution was added 2-methyltetrahydrofuran (21.5 g), water (25 g) and acetic acid to achieve a pH of less than 7. The lower aqueous layer was then removed and the organic layer was washed with brine (5 wt%, 7.8g). The organic layer was then concentrated to dryness and the residue was purified by column chromatography to afford V-03. 1H NMR (400 MHz, DMSO- ) d 9.96 (s, 1H), 7.86 (d, J= 7.6 Hz, 1H), 7.34 (d, J= 7.6 Hz, H i), 5.80 (q, j= 8.9 Hz, 2H), 3 22 (s, 3H), 1.36 (s, 12H).

Synthesis of N-(7-bromo-4-chl oro- 1 -(2 2.2-trifluoroethyl - lH-indazol -3 -yl VN-

(methylsulfonyl)methanesulfonamide (V-06)

[00619] To a reactor was added V-A (3 g), 2-methyltetrahydrofuran (25.8 g), and

triethylamine (7.6 mL). The mixture was cooled to about 10 °C, methanesulfonyl chloride (1.8 mL) was added, and the mixture was stirred until reaction was complete. The reaction mixture was washed with aqueous sodium chloride (30 mL) and the organic layer was evaporated to dryness. The residue was purified by column chromatography to afford V-06. 1H NMR (400 MHz, DMSO-^6) d 7.83 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 8.1 Hz, 1H), 5.79 (q, J= 8.5 Hz, 2H), 3.62 (s, 6H). Synthesis of N-(7-bromo-4-chloro-l-(2.2.2-trifluoroethyl)-lH-indazol-3-yl )methanesulfonamide (V-05)

V-5

[00620] To a reactor was added V-02 (3 g), 2-methyltetrahydrofuran (30 mL), and triethylamine (7.6 mL). The mixture was cooled to about 10 °C, methanesulfonyl chloride (1.8 mL) was added, and the mixture was stirred until reaction was complete. The reaction mixture was washed with aqueous sodium chloride (30 mL) and the organic portion was concentrated to dryness.

[00621] To the resulting mixture (2.7g) was added 2-methyltetrahydrofuran (15 mL) and sodium hydroxide (1M in water, 15 mL). The mixture was stirred at about 20 °C until the reaction was complete. The aqueous layer was removed and the organic was washed with acetic acid (0.7M in water, 10 mL) and sodium chloride (5 wt% in water, 10 mL).The organic layer was then concentrated to dryness and the residue was purified by column chromatography to afford V-05. 1H NMR (400 MHz, DMSO-i¾) d 10.03 (s, 1H), 7.71 (dd, J= 8.0, 1.6 Hz, 1H), 7.20 (dd, j= 8.1, 1.6 Hz, 1H), 5.64 (q, j= 8.7 Hz, 3H), 3.19 (2, 3H). Synthesis of N-(4-chloro-7-(4.4.5.5-tetramethyl-L3.2-dioxaborolan-2-yl)-l -(2.2.2- trifluoroethyl)-lH-indazol-3-yl)-N-(methylsulfonyl)methanesu lfonamide (V-04)

V-06 V-04

[00622] To a reactor was charged V-06 (148 mg), bis(pinacolato)diboron (93 mg), potassium acetate (90 mg) and bis(triphenylphosphine)palladium (II) chloride (4.3 mg, 1.5 mol%). N,N- dimethylformamide (0.2 mL) and toluene (0.6 mL) were added and the reaction was heated to about 105 °C until completion. V-04 was formed. 1H NMR (400 MHz, DMSO-6¾) d 7.96 (d, J = 7.7 Hz, 1H), 7.50 (d, ,/= 7.6 Hz, 1H), 5.95 (q, ,/= 8.8 Hz, 2H), 3.66 (s, 6H), 1.37 (s, 12H).

Synthesis of N-(4-chloro-7-(4A5.5-tetramethyl-l.3.2-dioxaborolan-2-yl)-l -(2.2.2- trifluoroethyl)- 1 H-i ndazol -3 -yl)m ethanesulfonami de (V-03)

V-05 V-03

[00623] To a reactor was charged V-05 (124 mg), bis(pinacolato)diboron (93 mg), potassium acetate (90 mg) and bis(triphenylphosphine)palladium (II) chloride (4.3 mg, 1.5 mol%). N,N- dimethylform amide (0.2 mL.) and toluene (0.6 mL, 6 rel. vol.) were added and the reaction was heated to about 105 °C until completion. V-03 was formed. 1H NMR (400 MHz, DMSO-de) d

9.96 (s, 1 H), 7.86 (d, ./ 7.6 Hz, 1H), 7.34 (d, ./ 7.6 Liz, H i ). 5.80 (q, j= 8.9 Hz, 2H), 3.22 (s,

3H), 1.36 (s, 12H). II. Synthesis of the Compound of Formula

Example 8: Preparation of N-((S)-l-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l- yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5 ,5-difluoro-3-(trifluoromethyl)- 3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyra zol-l-yI)acetamide (IV)

Synthesis of N-((SV 1 -(3 -bromo-6-(3-m ethyl-3 -(methylsulfonyl)but- 1 -vn- 1 -vDpyri din-2 -yl)-2- (3.5-difluorophenyl)ethyl)-2-((3bS.4aR)-S.5-difluoro-3-(trif luoromethvn-3b.4.4a.5-tetrahvdro- lH-cvclopropai 3 41cyclopentar 1 2-clpyrazol- 1 -vDacetamide (IV) from (S)-l-(3-bromo-6-(3- methyl-3-(methylsulfbnyl)but-l-vn-l -yl)pyridin-2-yl)-2-(3.5-difluorophenyl)ethan-l -amine (VI) Method 1

[00624] «-Propyl phosphonic anhydride (T3P, 3 1 g, 1.5 equiv.) was slowly added to a reactor containing amine VI (1.5 g), acid VII (1.0 g, 1.1 equiv.), triethylamine (Et 3 N, 0.5 g, 1.5 equiv.), and acetonitrile (MeCN, 8.0 g). The mixture was agitated at about 20 °C until the reaction was complete. The product was crystallized from the reaction mixture with DMF (0.63 g), and water (15 g). The slurry was filtered and the filter cake was washed with a mixture of acetonitrile and water (2 x 2.5 g). The cake was dried to afford IV 1H NMR (400 MHz, DMSO- ) 59.19 (d, J = 8 3 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.50 (d, ./ 8.3 Hz, 1H), 7.07 (si, ./ 9.4, 2.4 Hz, 1H),

6.96 - 6.87 (m, 2H), 5.52 (td), j= 8.8, 5.3 Hz, 1 H), 4.93 - 4.73 (m, 2H), 3.22 (s, 3H), 3.11 - 2.90 (m, 2H), 2.66 - 2.52 (m, 2H), 1.69 (s, 6H), 1.45 - 1.36 (m, 1H), 1.02 - 0.93 (m, 1H). 13 C NMR (100 MHz, DMSO-d 6 ): 5 164.42, 163.62, 163.49, 161 .17, 161.04, 158.19, 142.92, 142.20, 142.10, 142.01, 141.63, 140.23, 134.11, 133.73, 132.14, 128.66, 122.23, 120.49, 119.56, 1 12.49, 112.25, 104.75, 102.25, 88.62, 84.20, 57.44, 53.85, 53.03, 35.21, 23.41, 22.46, 22.40, 1 1.79.

Synthesis of N- -l -(3-bromo-6-(3-m ethyl-3-(m ethylsulfonyl)but-l -yn-l-vDpyri din-2 -yl)-2-

(3.5-difluorophenyl)ethyl)-2-((3bS.4aR)-5.5-difluoro-3-(t rifluoromethvn-3b.4.4a.5-tetrahvdro- 1 H-cyclopropa[3.41cvclopentarl.2-clpyrazol-l -vDacetamide (IV) from (S)-l-(3-bromo-6-(3- methyl-3 -(methyl sulfonvDbut- 1 -vn- 1 -yl )pyridin-2-yl)-2-( 3.5 -difluorophenyDethan- 1 -amine (VI) Method 2

[00625] V-methylmorpholine (NMM, 0.51 g, 2.3 equiv.) was added to a vessel containing amine VI (1.0 g), acid VII (1.0 g), 1 -hydroxybenzotri azole hydrate (HOB†. · H 2 0, 0. 17 g, 0.5 equiv.), N-(3-dimethyiaminopropyi)-N'-ethy carbodiimide (EDO · HC1, 0.52 g, 1.25 equiv.), and acetonitrile (MeCN, 7.8 g). The mixture was agitated at about 20 °C until the reaction was complete. The product was crystallized from the reaction mixture with DMF (2.8 g), and water (10 g). The slurry was filtered and the filter cake was washed with a mixture of acetonitrile and water. The cake was dried to afford IV. ! H NMR (400 MHz, DMSO- g) 69.19 (d, J = 8.3 Hz, 1H), 8.12 (d, J= 8.3 Hz, 1H), 7.50 (d, J= 8.3 Hz, 1H), 7.07 (tt, J= 9.4, 2.4 Hz, 1H), 6.96 - 6.87 (m, 2H), 5.52 (td), J= 8.8, 5.3 Hz, 1 H), 4.93 - 4.73 (m, 2H), 3.22 (s, 3H), 3.11 - 2.90 (m, 2H), 2.66 - 2.52 (m, 2H), 1.69 (s, 6H), 1.45 - 1.36 (m, 1H), 1.02 - 0.93 (m, 1H). !3 C NMR (l0Q MHz, DMSO-de): 6 164.42, 163.62, 163.49, 161.17, 161.04, 158.19, 142.92, 142.20, 142. 10, 142.01, 141.63, 140.23, 134.11, 133.73, 132.14, 128.66, 122.23, 120.49, 119.56, 112.49, 112.25, 104.75, 102.25, 88.62, 84.20, 57.44, 53.85, 53.03, 35.21, 23.41, 22.46, 22.40, 11.79.

Example 9: Preparation of N~((S)-l~(3-(3-amino-4-ch!oro-i-(2,2,2-trif!iioroethyl)-lH- indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)py ridin-2-yI)-2-(3,5- difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoro methyl)-3b,4,4a,5-tetrahydro- lH-cydopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide (III)

Synthesis of compound III-03

IV III-03

[00626] To a reactor was added IV (1 .0 g), potassium bicarbonate (0.43 g, 1.3 equiv), dichlorobis(tricyclohexylphosphine)palladium(II) (28 mg, 2.5mol%), V-02 (0.67 g), butyl acetate (7.3 g) and water (2.1 g). The reactor was inerted and the mixture was agitated at about 85 °C (75-90 °C) until the reaction was complete. The mixture was cooled to about 40 °C and passed through celite (0.52 g). The celite cake was rinsed with butyl acetate (1.8 g). The filtrate and rinse were combined and this solution was washed twice with a mixture of N-acetyl-L- cysteine (0.31 g) dissolved in water (5.2 g) and sodium hydroxide in water (5 wt%, 5.4 g). The organics were washed twice with sodium chloride in water (5 wt%, 1 1 g). The solution was azeotropically distilled into 1 -propanol (3.3 g). To the propanol solution at about 50 °C was added methanesulfonic acid (0.31 g, 2.25 equiv.) and the product was crystallized using dibutyl ether (5.1 g). The slurry was cooled to about 10 °C, filtered, and the filter cake was washed with a 5: 1 mixture of propanol in dibutyl ether (1.6 g). The solids were dried to afford TIT-03 1H

NMR (400 MHz, DMSO-d6) d 9.19 (d, J = 8.3 Hz, 2H), 7.84 - 7.69 (m, 4H), 7.11 (d, J = 7.7 Hz, 2H), 7.07 - 6.95 (m, 3H), 6.82 (d, J = 7.7 Hz, 2H), 6.54 - 6.40 (m, 4H), 4.90 (d, J = 16.4 Hz, 2H), 4.76 - 4.60 (m, 4H), 4.15 (dq, J = 16.6, 8.4 Hz, 2H), 3.75 (dt, J = 16.3, 8.7 Hz, 2H), 3.25 (s, 7H), 2.99 - 2.86 (m, 4H), 2.63 - 2.50 (m, 3H), 2.41 (s, 14H), 1.73 (d, J = 2.1 Hz, 13H), 0.93 (dd, J = 6.1, 3 9 Hz, 2H).

Synthesis of N-((S -l -(3-(3-amino-4-chloro-l-(2.2.2-trifluoroethyl -l H-indazol-7-yl -6-(3- methyl-3 -(methyl sulfonvDbut- 1 -vn- 1 -yl)pyridin-2-yl)-2- -difluorophenyDethyl)- 2-

((3bS.4aR)-5.5-difluoro-3-(trifluoromethyl -3b.4.4a.5-tetrahydro-lH- cyclopropal 3.41cvclopenta[ 1 2-clpyrazol- 1 -vDacetamide (III)

[00627] Aqueous sodium hydroxide (0.2 M; 2.2 equivalents; 9.2 g) was added to a reactor containing ΪH-03 (1.0 g) in MeTHF (8.3 g) at about 20 °C. The biphasic mixture was agitated for about 15 min, and the aqueous layer was removed. The organic layer was washed four times with 2.0 wt% aqueous sodium chloride (9.8 g) and was distilled. The solution containing III was used directly in the II process below. A sample was concentrated to dryness for analysis.

1H NMR (400 MHz, CDC1 3 ): d 7.44 ( m, 1H), 7.39 (br, 1H), 7.18 (m, 1H), 6.90 (m, 1H), 6.65 (m 1H), 4.10 (m, 2H), 3.72 (m, 4H), 2.78 (m 2H), 2.56 (br, 4H), 1 .31 (s, 9H). !3 C NMR (100 MHz, DMSO-d 6 ): d 176.88, 158.95, 141,06, 129.55, 112.79, 109.56, 106.83, 66.66, 65.73, 57.45,

54.12, 39.53, 27.63. Example 10: Preparation of N-((S)-l-(3-(4-chloro-3-(N-

(methyIsulfonyI)methylsuIfonamido)-l-(2,2,2-trifluoroethy l)-lH-indazol-7-yl)-6-(3-methyl- 3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluor ophenyl)ethyl)-2-((3bS,4aR)- 5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyc lopropa[3,4]cyclopenta[l,2- c]pyrazol-l-yl)acetamide (II)

III II

[00628] Methanesulfonyl chloride (0.32 g, 2.5 equivalents) was added to a reactor containing III (1.0 g), triethylamine (0.69 g, 6.0 equivalents), and MeTHF (1 1 g) at about 10 °C. The mixture was agitated at about 10 °C until the reaction was complete. The reaction mixture was washed with water (6.4 g) for about 15 minutes, and warmed to about 20 °C. The layers were separated and the organic layer was washed for about 15 minutes with 10 wt% aqueous sodium chloride (6.9 g). The layers were separated and the organic layer was used directly in the next step. An aliquot was concentrated to dryness for analysis. 1H NMR (400 MHz, 5 6 -DMSO; 9: 1 mixture of atropi somers): d 9.20 (d, J= 7.9 Hz 1 H), 8.99* (d, J= 8.6 Hz, 1 H), 7.96* (d, J= 7.9 Hz, l H), 7.83 (d, ./ 8.0 Hz, 1 H), 7.80* (d, ./ 7 9 Hz, 1 H), 7.76 (d, J - 8.0 Hz, 1 H), 7.45 (d,

.7 = 7.7 Hz, 1 H), 7.41 * (d, J= 7.8 Hz, 1 H), 7.31 * (d, J= 7.8 Hz, 1 H), 7.02 (tt, J= 9.4, 2.1 Hz,

I H), 6.92* (s, 1 H), 6.91 (d, j= 7.7 Hz, 1 H), 6.48 (m, 2 H), 4.92* (s, 1 H), 4.88 (d, j= 16.4 Hz, 1 H), 4.79* (d, j= 16.8 Hz, 1 H), 4.73* (d, j= 16.4 Hz, 1 H), 4.71 * (m, 1 H), 4.69 (m, 1 H), 4.62* (s, 1 H), 4.60 (m, 1 H), 4.38* (dq, j= 16.4, 8.2 Hz, 1 H), 4.12 (dq, j= 16.7, 8.4 Hz, 1 H), 3.68* (s, 3 H), 3.66* (s, 3 H), 3.63 (s, 3 H), 3.58 (s, 3 H), 3.26 (s, 3 H), 3.12* (dd, 7 = 13.8, 10.5 Hz, 1 H), 3.05 (dd, j= 13.5, 5.8 Hz, 1 H), 2.97 (dd, j= 13.5, 8.5 Hz, 1 H), 2.78* (dd, j= 13.7, 3.9 Hz, 1 H), 2.59 (m, 1 H), 2.53 (m, 1 H), 1.75 (s), 1.75 (s, 6 H), 1 .39 (m, 1 H), 0.98 (m, 1 H). l3 C NMR (100 MHz, DMSO-de, 9: 1 mixture of atropi somers): d 164.5, 163.6*, 162.1 (dd, ,7 = 246.3, 13.4 Hz), 162.0* (dd, j= 246.1, 13.3 Hz), 158.7, 158.4*, 142.7 (t, J = 29.3 Hz), 142.3, 142.0*, 141.8 (t, ,7= 9.4 Hz), 140.6*, 139.9, 139.7*, 139.3, 135.8*, 135.0, 133.8 (q, j= 39.0 Hz), 132.2*, 132.1 (m), 131.6, 129.6, 129.4*, 126.7, 125.3, 125.2*, 124.1 *, 123.4, 122.8*, 122.7 (q, ,7= 280.9 Hz), 120.7 (q, j= 268.3 Hz), 119.9 (t, j= 243.7 Hz), 1 19.8, 1 19.5*, 119.0*, 118.9, 112.0, 102.2 (t, J= 225.7 Hz), 101.8*, 88.4, 84.5, 57.3, 52.93, 52.86, 52.7, 52.5*, 50.7 (q, J = 33.8 Hz), 50.3*, 42.6*, 42.4, 42.3*, 42.2, 39.51, 39.5, 38.9*, 35.1, 27.5 (dd, ./= 35.0, 28.6 Hz), 23.1, 22.4, 22.3, 11.5. (* signals arising from minor atropisomer)

Example 11: Preparation of N-((S)-l-(3-(4-chIoro-3-(methylsuIfonamido)-l-(2,2,2- trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfon yl)but-l-yn-l-yl)pyridin-2-yl)- 2-(3,5-difluoropheny!)ethyl)-2-((3bS,4aR)-5,5-difluoro~3-(tr ifluoromethy!)-3b,4,4a,5- tetrahydro-l H-cyclopropa[3,4]cydopenta[l,2-c]pyrazoI-l-yl)acetamide (I)

Synthesis of sodium (4-chloro-7-(2-((S)-l-(2-((3bS.4aRV5.5-difluoro-3-(trifluoro methyl)- 3b.4.4a 5-tetrahvdro-lH-cvclopropai3.41cvclopentan .2-clpyrazol-l-vnacetamido)-2-(3 5- difluorophenyl )ethyl)-6-(3 -methyl-3 -(methyl sulfonvDbut- 1 -vn- 1 -vDpyri din-3 -yl )- 1 -(2.2.2- trifluoroethyl)-lH-indazol-3-yl)(methylsulfonyl)amide (1-02)

II 1-02

[00629] Sodium hydroxide (1 M, 2.9 g, 3.0 equiv.) was added to a reactor containing II (1.0 g) and 2-methyltetrahydrofuran (8.4 g) at about 35 °C. The mixture was agitated until the reaction was deemed complete. The reaction mixture was adjusted to between about 20 and 40 °C and the bottom layer was removed. The organic layer was washed with water (2.9 g) for about 15 minutes, and the bottom layer was removed. The organic solvent was swapped for ethanol and the solution was concentrated to about 5 volumes and the temperature was adjusted to about 35 °C. «-Heptane (3.4 g) was slowly added, and the mixture was aged for about 12 hours. The solids were collected by filtration, and the filter cake was washed with ethanol/«- heptane (1 : 1). The resultant wet cake was dried under vacuum to afford 1-02. 1H NMR (400 MHz, DMSO-afe) d 9.09 (d, ./ 8.0 Hz, H i ), 8.93 * (d, ./ 8.5 Hz), 7.80 - 7.72* (m), 7.71 (s, 2H), 6.99 (tt, J= 9.5, 2.4 Hz, 1H), 6.94 (d, J= 7.6 Hz, 1H), 6.90* (d, J= 6.3 Hz), 6.69 (d, J = 7.6 Hz, 1H), 6.57 - 6.51 * (m), 6.48 - 6.40 (m, 2H), 4.90 (d, J = 16.5 Hz, 1H), 4.77 (d, ./ 16.4

Hz, 1H), 4.70 (td, j= 8.3, 5.2 Hz, 1 H), 4.63* (d, j= 16.5 Hz), 4.22 (dq, ,/= 16.7, 8.4 Hz, 1H), 3.90 - 3.75 (m, 1H), 3.26 (s, 3H), 2.92 (td, J= 13.8, 8.5 Hz, 2H), 2.83* (s), 2.80 (s, 3H), 2.64 - 2.51 (m, 2H), 1.74 (d, j= 2,2 Hz, 6H), 1.44 - 1.34 (m, 1H), 0.94 (dq, j= 6.0, 3.7 Hz, 1H); 13 C NMR (100 MHz, dmso) d 164.39, 163.43, 163.39, 163.25, 160.94, 160.91, 160.81, 158.93, 158.22, 152.64, 151.94, 142.92, 142.72, 142.63, 142.43, 142.34, 142.19, 142.10, 142.00, 141.43,

141.14, 139.55, 139.36, 133.95, 133.56, 133.17, 132.12, 131.93, 131.68, 129.66, 129.56, 128.17,

127.91, 126.86, 126.76, 125.02, 122.35, 122.21 , 122.08, 122.05, 1 19.93, 1 19.88, 119.38, 118.88,

1 18.18, 117.54, 117.21, 1 17.04, 1 12.18, 112.02, 1 1 1.95, 1 11 .84, 111.78, 102.28, 102.03, 101.81,

88.14, 88.00, 84.69, 84.65, 57.33, 53.22, 52.96, 52.76, 52.44, 40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.97, 38.89, 38.65, 35.10, 35.08, 27.86, 27.56, 27.52, 27.23, 23.19, 22.42, 22.41, 22.30, 22.28, 11.63. * Signals arising from minor atropisomer. l C NMR data is reported for the mixture of atropisomer s.

Synthesis of N-((SVl-(3-(4-chloro-3-(methylsulfonamidoVl-(2.2..2-trifluor oethylVlH-indazol- 7-yl)-6-(3 -methyl-3 -(methyl sulfonyl)but-l-vn-l-yl)pyridin-2-vO-2-(3.5-difluorophenyl)et hyl)-2- ((3bS.4aR¾-5.5-difluoro-3-(trifluoromethyl)-3b.4.4a.5-tetra hvdro-lH- cvclopropai3.41cvclopentail.2-c]pyrazol-l-vOacetamide (I) from sodium (4-chioro-7-(2-((S)-l- (2-((3bS.4aR)-5.5-difluoro-3-(trifluoromethyl)-3b.4.4a.5-tet rahvdro-lH- cvclopropar3.4]cvclopentafT.2-clpyrazol-l -yl)acetamido)-2-(3.5-difluorophenyl)ethyl)-6-(3- methyl-3 -(methyl sulfonvDbut- 1 -vn- 1 -vDpyri din-3 -vi )- 1 -(2.2.2-trifluoroethyl)- 1 H-indazol-3 - yl)(methylsulfonyl)amide (1-02)

1-02 I

[00630] Compound 1-02 (1 .0 g) and glacial acetic acid (2.1 g) were combined at about 20 °C and were agitated until dissolved. The resultant solution was transferred to a reactor containing water (1 5 g) over about 1 hour. The resultant slurry was further agitated for about one hour, and was filtered. The wet cake was washed with water (2 x 5 g), deliquored, and dried at about 60 °C under vacuum to provide I. 1H NMR (400 MHz, 5 6 -DMSO; 5: 1 mixture of atropi somers) d 10.11 * (s), 10.00 (s, 1 H), 9.25 (d, J= 8.0 Hz, 1 H), 8.92* (d, J = 8.4 Hz), 7.90* (d, J= 7.6 Hz), 7.81 (d, J= 8.0 Hz, 1 H), 7.76 (d, = 8.0 Hz, 1 H), 7.32 (d, j= 7.6 Hz, 1 H), 7.23* (d, j = 8.0 Hz), 7.19* (d, j= 8.0 Hz), 7.02 (tt, J= 9.4, 2,4 Hz, 1 H), 6.94* (m), 6.86 (d, j= 7.6 Hz, 1 H), 6.54* (m), 6.48 (m, 2 H), 4.92 (d, J= 16.4 Hz, 1 H), 4.77* (d, J= 16.4 Hz), 4.71 (d, J= 16.4 Hz, 1 H), 4.68* (m), 4.51 (dq, ./ 16.4, 8.3 Hz, 1 H), 4.19* (dq, ./ 16.4, 8.2 Hz), 3.96 (dq, j= 16.8,

8.4 Hz, 1 H), 3.27 (s, 3 H), 3.24* (s), 3.17 (s, 3 H), 3.11 * (dd, J= 13.0, 3.4 Hz), 3.02 (dd, J = 13.6, 5.6 Hz, 1 H), 2.95 (dd, J= 13.8, 8.6 Hz, 1 H), 2.92* (m), 2.60 (m, 1 H), 2.55 (m, 1 H), 1.74 (s, 6 H), 1.40 (m, 1 H), 0.96 (m, 1 H); 13 C NMR (100 MHz, tVDMSQ; 5: 1 mixture of atropisomers) d 164.5, 163.4*, 162.1 (dd, 7 = 246.0, 13.4 Hz), 162.0* (dd, 7 = 246.1, 13.4 Hz), 158.8, 158.1 *, 142.7 (t, 7 = 29.3 Hz), 142.3, 142.1 * (m), 141.9 (t, = 9.5 Hz), 141.7*, 140.2*, 140.0*, 139.8*, 139.5, 139.3, 139.2, 133.8 (q, ,7= 38.7 Hz), 132.0 (m), 131.7*, 131.1, 130.3*, 130.0, 126.8, 126.4, 126.2*, 123.0* (m), 122.9 (q, j = 281.7 Hz), 122.7*, 122.1, 120.7 (q, 7 = 268.3 Hz), 119.9 (t, .7= 243.4 Hz), 119.0, 1 18.7*, 1 17.5*, 117.4, H2.0 (m), 102.1 (t, .7= 25 6 Hz), 101.9* (m), 88.5*, 88.4, 84.5, 57.3, 52.8, 52.7, 52.4*, 50.2 (q, 7= 33.3 Hz), 50.0 (m),

41.4*, 41.2, 39.8, 38.7, 35.1 , 27.5 (dd, 7 = 35.1, 29.0 Hz), 23.2, 22.4, 22.3, 22.2*, 1 1.6. * Signals arising from the minor atropisomer.

[00631] Alternatively, a premixed solution of acetic acid (1.5 g), ethanol (12 g), and water (0.3 g) were combined with Compound 1-02 at 20 °C and were agitated until dissolved. The resultant solution was transferred to a reactor containing water (100 g) over about 30 minutes. The resultant slurry was further agitated for about one hour, and was filtered. The wet cake was washed with water (2 x 25 g), deliquored, and dried at about 60 °C under vacuum to provide I.

Synthesis of N-ffS¾-l-f3-(4-chloro-3-(methylsulfonamidoVl-(2.2.2-trifluo roethyl)-lH-indazol-

7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-vn-l-yl)pyridin -2-yl )-2-(3.5-difluorophenyl)ethvD-2-

((3bS.4aR)-5.5-difluoro-3-(trifluoromethyl)-3bA4a.5-tetra hvdro-lH- cvclopropa[3.41cvcl opentaf 1 2-clpyrazol- 1 -vDacetami de (I) from N-((S)-l-(3-(3-amino-4- chloro-l-(2.2.2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl -3-(methylsulfonyl)but-l-vn-l- yl)pyridin-2-vO-2-(3.5-difluorophenyl)ethyl)-2-((3bS.4aR)-5. 5-difluoro-3-(trifluoromethvO-

3b.4.4a.5-tetrahvdro-lH-cvclopropa[3.41cvclopentail.2-clp yrazol-l-yl)acetamide (III)

[00632] A reactor was charged with III (1.0 g) followed by cyclopentyl methyl ether (2.0 niL). The contents were adjusted to about 80 °C. In a separate reactor, methanesulfonic acid anhydride (0.3g, 1.5 equiv.) was dissolved in cyclopentyl methyl ether (6 mL). The solution was added to the first reactor via a syringe pump over 5 h. Following addition, the reaction mixture was aged for 16 h. The reaction mixture was quenched with water (10 mL). UPLC analysis of the organic phase showed 1 with 94.8% purity. Synthesis ofN-((S)-l-(3-(4-chloro-3-(methylsulfonamido l-(2.2.2-trifluoroethyl)-lH-indazol-

7-vD-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yDpyridin-2 -vD-2- difluorophenyl)ethyl)-2-

((3bS.4aR)-5.5-difluoro-3-(trifluoromethyl)-3b.4.4a.5-tetrah ydro-lH- cvclopropa[3.4]cycl opentaf 1.2-clpyrazol- 1 -vDacetami de (I) from N-((S -l-(3-bromo-6-¾3- methyl-3 -(methyl sulfonvDbut- 1 -vn- 1 -yl)pyridin-2-yl V2-( 3.5 -difluorophenyl)ethyl)-2-

((3bS.4aR)-S.5-difluoro-3-(trifluoromethyl)-3b.4.4a.5-tet rahvdro-lH- cvclopropai 3.41cvclopental 1 2-clpyrazol- 1 -vDacetamide

[00633] To a 40 mL vial was added IV (1 .00 g), potassium bicarbonate (420 mg),

palladium(II) chloride (4.9 mg, 2.0 mol%), cyclohexyl diphenylphosphine (13.4 mg, 3.6 mol%), V-03 (849 mg), 2-methyltetrahydrofuran (8.0 mL) and water (2.0 mL). The vial was inerted and the mixture was agitated at about 68 °C (65-73 °C) until the reaction was complete. The mixture was cooled to about 40 °C and the aqueous layer was removed. The organic layer was washed with aqueous acetic acid (5% w/v, 5.1 g). The organic was then concentrated to dryness and the residue was purified by column chromatography to afford I. 1 H NMR (400 MHz, DMSO- ) d 10.12 (s, 0.2H), 10.00 (s, 1H), 9.25 (d, J= 8.2 Hz, 1H), 8.92 (d, J= 8.6 Hz, OH),

7.90 (d, ./ 7.9 Hz, 0.1H), 7.85 - 7.71 (m, 2H), 7.52-7.50 (m, 0.1H), 7.32 (d, ./ === 7.7 Hz, 1H),

7.21 (q, ,/= 9.6 Hz, 0.4H), 7.11 - 6.97 (m, 1H), 6.94-6.89 (m, 0.2H), 6.86 (d, ./= 7.7 Hz, 1H),

6.55 (d, j= 7.4 Hz, 0.4H), 6.52 - 6.43 (m, 2H), 4.92 (d, j= 16.4 Hz, 1H), 4.81-4.66 (m, 1.5H),

4.64-4.45 (m, 2.4H), 4.28-4.13 (m, 0.2H), 4.08-3.92 (m, 1.6H), 3.32 (s, 0.7H), 3.30-3.22 (m, 4.4H), 3.17 (s, 3H), 3.08-2.89 (m, 2.2H), 2.69 - 2.53 (m, 2.2H), 2.12 (s, 0.2H), 1.99 (s, 1H), 1.91 (s, 0.3H), 1 .80 - 1.70 (m, 6H), 1.48-1.36 (m, 1.2H), 1.23 - 1.12 (m, 1.3H), 0.96 (s, 1 .2H). Synthesis of N-(( S)-l-(3-(4-chloro-3-(methylsulfonamidoVl-f2.2.2-trifluoroeth yr)-lH-indazol-

7-yl -6-(3-methyl-3-(methylsulfonyt but-l-yn-l-yl pyridin-2-vn-2- difluorophenyl ethyl)-2-

((3bS.4aR)-5.5-difluoro-3-(trifluoromethyl -3b.4.4a.5-tetrahvdro-lH- cvclopropaH .4]cvcl opentaf 1.2-clpyrazol- 1 -vDacetami de (I) from N-((S -l-(3-bromo-6-¾3- methyl-3-imethylsulfonyl)but-l-vn-l -yl)pyridin-2-vi)-2-(3.5-difluorophenyl)ethyi)-2-

((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4.4a,5-tet rahvdro-lH- cvclopropai3.41cvclopentail.2-c]pyrazol-l-vnacetamide (IV)

[00634] To a 40 mL vial was added IV (1.00 g), potassium bicarbonate (420 mg), palladium(II) chloride (4.9 mg, 2.0 mol%), cyclohexyl diphenylphosphine (13.4 mg, 3.6 mo!%), V-04 (923 mg), 2-methyltetrahydrofuran (8.0 mL) and water (2.0 mL). The vial was inerted and the mixture was agitated at about 68 °C (65-73 °C) until the reaction was complete. The mixture was cooled to about 40 °C and the aqueous layer was removed. The organic was stirred with aqueous sodium hydroxide (5 % w/w, 6.3 g) at 40 °C until reaction was complete. The organic was washed with aqueous acetic acid (5% w/v, 5.1 g). The organic was then

concentrated to dryness and the residue was purified by column chromatography to afford I. 1H NMR (400 MHz, DMSO-i¾) d 10.12 (s, 0.2H), 10.00 (s, 1H), 9.25 (d, J= 8.2 Hz, 1H), 8.92 (d, J = 8.6 Hz, OH), 7.90 (d, j= 7.9 Hz, 0.1H), 7.85 - 7.71 (m, 2H), 7.52-7.50 (m, 0.1 H), 7.32 (d, j = 7.7 Hz, 1H), 7.21 (q, J= 9.6 Hz, 0.4H), 7.11 - 6.97 (m, 1H), 6.94-6.89 (m, 0.2H), 6.86 (d, J =

7.7 Hz, 1H), 6.55 (d, J = 7.4 Hz, Q.4H), 6.52 - 6.43 (m, 2H), 4.92 (d, J = 16.4 Hz, 1H), 4.81- 4.66 (m, 1.5H), 4.64-4.45 (m, 2.4H), 4.28-4.13 (m, 0.2H), 4.08-3.92 (m, 1.6H), 3.32 (s, 0.7H), 3.30-3.22 (m, 4.4H), 3.17 (s, 3H), 3.08-2.89 (m, 2.2H), 2.69 - 2.53 (m, 2.2H), 2.12 (s, 0.2H), 1.99 (s, 1H), 1.91 (s, 0.3H), 1.80 - 1.70 (m, 6H), 1.48-1.36 (m, 1.2H), 1.23 - 1.12 (m, 1.3H), 0.96 (s, 1.2H).

[00635] All references, including publications, patents, and patent documents were incorporated by reference herein, as though individually incorporated by reference. The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the present disclosure.