Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents FIELD: This invention relates to heterocyclic pharmaceuticals, and more particularly, to 2-arylimino heterocycles, pharmaceutical compositions containing them, and their use in modulating progesterone receptor mediated processes.

BACKGROUND: An agent which binds to the progesterone receptor may be employed for a wide variety of indications, including those shown in the lettered paragraphs below: A1) to enhance bone formation in bone weakening diseases, for the prevention of and/or treatment of osteopenia or osteoporosis (Manzi, et al., J. Soc. Gynecol.

Invest., 1,302 (1994); Scheven, et al., Biochem. Biophys. Res. Commun., 186,54 (1992); Verhaar, et al., Bone, 15,307 (1994); Ontjes, In"Calcium and Phosphorus in Health Diseases", Anderson and Garner (Eds.), CRC Press, 207 (1996); Scheven et al., Biochem. Biophys. Res. Commun., 186,54 (1992)) including corticosteroid-induced osteoporosis (Picardo, et al., Drug Safety 15,347 (1996)), postmenopausal osteoporosis, or Paget's disease; A2) as an agent to enhance fracture healing; B1) as a female contragestive agent, (Cadepond et al., Annu. Rev. Med., 48,129 (1997); Heikinheimo Clin. Pharmacokinet., 33,7 (1997); Li et al., Adv.

Contracept., 11,285 (1995); Spitz et al., Adv. Contracept. 8,1 (1992); Spitz et al., Annu. Rev. Pharmacol. Toxicol., 36,47 (1996)); B2) for prevention of endometrial implantation (Cadepond et al., Annu. Rev.

Med., 48,129 (1997)); B3) for the induction of labor (Heikinheimo Clin. Pharmacokinet., 33,7 (1997); Karalis et al., Ann. N. Y. Acad. Sci., 771,551 (1995)), including the case of foetus mortus (Heikinheimo, Clin. Pharmacokinet., 33,7 (1997); Cadepond et al., Annu. Rev. Med., 48,129 (1997)); B4) for treatment of luteal deficiency (Pretzsh et al., Zentralbl. Gynaekol., 119 (Suppl. 2), 25 (1997); Bezer et al., In"Molecular and Cellular Aspects of Periimplantation Processes", Dey (Ed.), Springer-Verlag, p. 27 (1995)); B5) to enhance recognition and maintanence of pregnancy (Bezer et al., In "Molecular and Cellular Aspects of Periimplantation Processes", Dey (Ed.), Springer-Verlag, p. 27 (1995));

B6) for counteracting preeclampsia, eclampsia of pregnancy and preterm labor (Yallampalli et al., WO 97/34,922); B7) for the treatment of infertility, including promotion of spermatogenesis, the induction of the acrosome reaction, oocyte maturation, and in vitro fertilization of oocytes (Baldi et al., J. Steroid Biochem. Mol. Biol., 53,199 (1995); Baldi et al., Trends Endocrinol. Metab., 6,198 (1995); Blackwell et al., Colloq. INSERM, 236,165 (1995); Blackmore et al., Cell. Signalling, 5, 531 (1993); Cork et al., Zygote, 2,289 (1994); Meizel, Biol. Reprod., 56,569 (1997)); Cl) for treatment of dysmenorrhea (Coll Capdevila et al., Eur. J. Contracept.

Reprod. Health Care, 2,229 (1997); Adashi et al., Keio J. Med., 44,124 (1995)); C2) for treatment of dysfunctional uterine bleeding (Coll Capdevila et al., Eur. J.

Contracept. Reprod. Health Care, 2,229 (1997); Adashi et al., Keio J. Med., 44,124 (1995)); C3) for treatment of ovarian hyperandrogynism (Schaison et al., Androg. Excess Disord. Women, 715 (1997)); C4) for treatment of ovarian hyperaldosteronism (Adashi et al., Keio J. Med., 44, 124 (1995)); C5) for treatment of premenstral syndrome and/or premenstral tension (Mortola, Curr. Opin. Endocrinol. Diabetes, 2,483 (1995)); Adashi et al., Keio J. Med., 44,124 (1995)); C6) for treatment of perimenstrual behavior disorders (Constant et al., Hormone Res., 40,141 (1993)); C7) for treatment of climeracteric disturbance, i. e. menopause transition (Adashi et al., Keio J. Med., 44,124 (1995)) including hot flushes (Sarrel, Int. J.

Fertil. Women's Med., 42,78 (1997); Bäckström et al., Ciba Found. Symp., 121,171 (1995)), mood changes (Backstrom et al., Ciba Found. Symp., 121, 171 (1995)), sleep disturbance (Sarrel, Int. J. Fertil. Women's Med., 42,78 (1997)) and vaginal dryness (Sarrel, Int. J. Fertil. Women's Med., 42,78 (1997)); C8) for enhancement of female sexual receptivity (Dei et al., Eur. J. Contracept.

Reprod. Health Care, 2 (4), 253 (1997); McCarthy et al., Trends Endocrinol.

Metab., 7,327-333 (1996); Mani et al., Horm. Behav., 31,244 (1997)) and male sexual receptivity (Johnson et al., In"Essential Reproduction, 2nd ed., Blackwell Scientific Pub., London pl77 (1984)); C9) for treatment of post menopausal urinary incontinence (Mäkinen et al., Maturitas, 22,233 (1995); Batra et al., J. Urology, 138,1301 (1987));

Ciao) to improve sensory and motor functions (Bäckström et al., Ciba Found.

Symp., 121,171 (1995)); Cll) to improve short term memory (Bäckström et al., Ciba Found. Symp., 121, 171 (1995)); C12) for treatment of postpartum depression (Dalton, Practitioner, 229,507 (1985)); C13) for treatment of genital atrophy (Sarrel, Int. J. Fertil. Women's Med., 42,78 (1997)); C14) for prevention of postsurgical adhesion formation (Ustun, Gynecol. Obstet.

Invest., 46,202 (1998)); C15) for regulation of uterine immune function (Hansen et al., J. Reprod. Fertil., 49 (Suppl.), 69 (1995)); C16) for prevention of myocardial infarction (Sarrel, Int. J. Fertil. Women's Med., 42,78 (1997)); D1) for hormone replacement therapy (Casper et al., J. Soc. Gynecol. Invest., 3, 225 (1996)); E 1) for treatment of cancers, including breast cancer (Cadepond et al., Annu. Rev.

Med., 48,129 (1997); Pike et al., Endocr.-Relat. Cancer, 4,125 (1997)), uterine cancer (Heikinheimo Clin. Pharmacokinet., 33,7 (1997)), ovarian cancer (Pike et al., Endocr.-Relat. Cancer, 4,125 (1997); Hughes, WO 98/10,771), and endometrial cancer (Satyaswaroop, Contrib. Oncol., 50,258 (1995); Pike et al., Endocr.-Relat. Cancer, 4,125 (1997)); E2) for treatment of endometriosis (Cadepond et al., Annu. Rev. Med., 48,129 (1997); Heikinheimo, Clin. Pharmacokinet., 33,7 (1997); Edmonds, Br. J.

Obstet. Gynaecol., 103 (Suppl. 14), 10 (1996); Adashi et al., Keio J. Med., 44,124 (1995)); E3) for treatment of uterine fibroids (Cadepond et al., Annu. Rev. Med., 48,129 (1997); Adashi et al., Keio J. Med., 44,124 (1995)); F 1) for treatment of hirsutism (Orentreich et al., US 4684635; Azziz et al., J. Clin.

Endocrinol. Metab., 80,3406 (1995)); F2) for inhibition of hair growth (Houssay et al., Acta Physiol. Latinoam., 28,11 (1978)); G1) as a male contraceptive (Hargreave et al., Int. Congr., Symp. Semin. Ser., 12, 99 (1997); Meriggiola et al., J. Androl., 18,240 (1997)); G2) as an abortifacient (Michna et al., Pharm. Ztg., 141,11 (1996)); and H1) for the promotion of mylin repair (Baulieu et al., Cell. Mol. Neurobiol., 16, 143 (1996); Baulieu et al., Mult. Scler., 3,105 (1997); Schumaker et al., Dev.

Neurosci., 18,6 (1996); Koenig et al., Science, 268,1500 (1995)).

Currently, progesterone or progestins alone or in combination with estrogens are clinically indicated: for contraception (Merck Manual; Merck & Co. (1992)); for treatment of gastrointestional bleeding due to arteriovenous malformations (Merck Manual; Merck & Co. (1992)); for treatment of recurrent metatarsal stress fractures complicated by oligiomenorrhea or amenorrhea (Merck Manual; Merck & Co.

(1992)); for treatment of premenstral syndrome (PMS, premenstral tension; Merck Manual; Merck & Co. (1992)); for postmenopausal hormone replacement therapy (Merck Manual; Merck & Co. (1992)); for treatment of hot flashes and subsequent insomnia and fatigue during menopause (Merck Manual; Merck & Co. (1992)); for treatment of dysfunctional uterine bleeding when pregnancy is not desired (Merck Manual; Merck & Co. (1992)); and for suppression of endometriosis (Merck Manual; Merck & Co. (1992)), breast cancer (Merck Manual; Merck & Co. (1992)), endometrial cancer (Merck Manual; Merck & Co. (1992)), or luteal insufficiency (Merck Manual; Merck & Co. (1992)). For example, medroxyprogesterone, a progestin, alone or in combination with estrogens is indicated for prevention of osteoporosis, treatment of vulvar and/or vaginal atrophy, treatment of moderate to severe vasomotor symptoms associated with menopause, treatment of secondary amenorrehea, treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, prevention of pregnancy, or as adjunctive therapy and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal carcinoma (Merck Manual; Merck & Co. (1998)).

SUMMARY: This invention provides nonsteroidal 2-arylimino-and 2-heteroarylimino- heterocyclic compounds which have affinity for the progesterone receptor, and therefore can act as progestins and/or antiprogestins thus modulating progesterone receptor mediated processes.

This invention relates to compounds having the formula (I) wherein Ris

aryl of 6-14 carbons; or heteroaryl of 3-10 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene; R'is alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons and containing 1-3 rings; heterocycloalkyl of 4-7 carbons and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O, and S; alkenyl of 2-10 carbons; cycloalkenyl of 5-12 carbons and containing 1-3 rings; or alkynyl of 3-10 carbons; and R3, and R4 are independently selected from the group consisting of H; alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons; alkenyl of 2-10 carbons; cycloalkenyl of 5-12 carbons; aryl of 6-13 carbons; heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S; C02R'; wherein R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons, or halocycloalkyl of 3-6 carbons; halogen; and =O, representing two of the groups R, R3, and R4; X is O or S (O) y; wherein y is 0, 1, or 2; nis2,3,4, or5; p is the sum of non-H substituents R2, R3, and R4; T is a substituent selected from the group consisting of alkyl of 1-4 carbons; alkoxy of 1-4 carbons; aryl of 6-10 carbons; CO2H; CO,; alkenyl of 2-4 carbons;

alkynyl of 2-4 carbons; C (O) C6Hs ; C (O) N (R6) (R'); wherein R6 is H or alkyl of 1-5 carbons; and R'is H or alkyl of 1-5 carbons; S (O) ytR8; wherein y'is 1 or 2; and R8 is alkyl of 1-5 carbons; SOIF; CHO; OH; NO2; CN; halogen; OCF3; N-oxide; O-C (R9) 2-O, the oxygens being connected to adjacent positions on R; and wherein R9 is H, halogen, or alkyl of 1-4 carbons; C (O) NHC (O), the carbons being connected to adjacent positions on R; and C (O) C6H4, the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; t is 1-5; provided that when substituent moiety T is alkyl of 1-4 carbons, alkoxy of 1-4 carbons, aryl of 6-10 carbons, Co2R5, alkenyl of 2-4 carbons, alkynyl of 2-4 carbons, C (O) C6H5, C (O) N (R6) (R'), S (O) ylR8, O-C (R9) 2-O, or C (O) C6H4, then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1-4 carbons; alkoxy of 1-4 carbons; Co2R5; CO2H; C (O) N (R6) (R'); CHO; OH; NO2; CN; halogen; S (O) yR; or =O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level; G is a substituent selected from the group consisting of halogen; OH; OR'; =O, representing two substituents G;

alkyl of 1-4 carbons; alkenyl of 1-4 carbons; cycloalkyl of 3-7 carbons; heterocycloalkyl of 3-5 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; cycloalkenyl of 5-7 carbons; heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; Co2R5; C (O) N (R6) (R'); aryl of 6-10 carbons; heteroaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; NO2; CN; S (O) YR'; S03R'; and SOZN (R6) (R'); g is 0-4, with the exception of halogen, which may be employed up to the perhalo level; provided that when substituent G is alkyl of 1-4 carbons, alkenyl of 1 -4 carbons, cycloalkyl of 3-7 carbons, heterocycloalkyl of 3-5 carbons, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen; Q is a substituent selected from the group consisting of alkyl of 1-4 carbons; haloalkyl of 1-4 carbons; cycloalkyl of 3-8 carbons; alkoxy of 1-8 carbons; alkenyl of 2-5 carbons; cycloalkenyl of 5-8 carbons; aryl of 6-10 carbons;

heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S; Co2R5; =O, representing two substituents Q; OH; halogen; S (O) YR'; SO3R8; and<BR> SO N (R6) (R7); q is 0-4 provided that when substituent Q is aryl or heteroaryl, then Q optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and with the further provisos that: a) two of (Q) qR', (Q) qR2, (Q) qR3, and (Q) qR4 may be joined, and taken together with the atom (s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N, O, and S; b) when n = 2 or 3, at least one of R2, R3, and R4 is other than H; c) when n = 2, and X = O, if t = 1, then T is selected from the list of substituents T above excepting alkyl, and the 4-position of the 1,3- oxazolidine ring must bear a substituent; d) when n = 3 and X = O, if t is equal to or greater than 1, then at least one T is selected from the list of substituents T above, excepting alkyl and alkoxy; e) when n = 2 or 3 and X = O or S, then the sum of non-hydrogen atoms in R', R2, R3, and R4 is at least 5; f) when n = 2, X = O, the 4-position of the 1,3-oxazolidine ring bears a carbonyl group, and R bears halogen at its 2-and 4-positions, then the 5-position of R bears H; g) when n = 2 and X = O, the 4-position of thel, 3-oxazolidine ring may bear a carbonyl only if the 5-position of said ring bears at least one non-H substituent;

h) when n = 2, X = S (O) y, the 4-position of the 1,3-thiazolidine ring bears a carbonyl group, R'is a substituted methyl group, and G is a phenyl group, then said phenyl group bears a secondary substituent; i) when n = 4, X = S, and G is Co2R5, then R5 contains at least two carbons; and pharmaceutically acceptable salts thereof.

The invention also relates to pharmaceutical compositions which include a compound of formula (I) as disclosed above, plus a pharmaceutically acceptable carrier.

As a result of their affinity for the progesterone receptor and their resultant ability to act as progestins and/or antiprogestins, and thus modulate progesterone receptor mediated processes, the compounds of this invention, as well as certain related compounds of the prior art, are believed to be useful for the purposes listed in the background section.

It is to be noted that the definition of the set of compounds for use in the claimed method of treatment (formula II) is broader than the set of compounds defined by formula I, because the treatment method may employ certain compounds of the prior art which have not been recognized previously as being useful for this purpose.

Accordingly, the invention relates further to a method of treating a mammal to achieve an effect, wherein the effect is: A1) enhancement of bone formation in bone weakening diseases for the treatment or prevention of osteopenia or osteoporosis; A2) enhancement of fracture healing; B 1) activity as a female contragestive agent; B2) prevention of endometrial implantation; B3) induction of labor; B4) treatment of luteal deficiency; B5) enhanced recognition and maintanence of pregnancy; B6) counteracting of preeclampsia, eclampsia of pregnancy, and preterm labor; B7) treatment of infertility, including promotion of spermatogenesis, induction of the acrosome reaction, maturation of oocytes, or in vitro fertilization of oocytes; C 1) treatment of dysmenorrhea; C2) treatment of dysfunctional uterine bleeding; C3) treatment of ovarian hyperandrogynism;

C4) treatment of ovarian hyperaldosteronism; C5) alleviation of premenstral syndrome and of premenstral tension; C6) alleviation of perimenstrual behavior disorders; C7) treatment of climeracteric disturbance, including. menopause transition, mood changes, sleep disturbance, and vaginal dryness; C8) enhancement of female sexual receptivity and male sexual receptivity; C9) treatment of post menopausal urinary incontinence; Ciao) improvement of sensory and motor functions; Cl 11) improvement of short term memory; C12) alleviation of postpartum depression; C13) treatment of genital atrophy; C14) prevention of postsurgical adhesion formation; C15) regulation of uterine immune function; C 16) prevention of myocardial infarction; D1) therapy for hormone replacement; El) treatment of cancers, including breast cancer, uterine cancer, ovarian cancer, and endometrial cancer; E2) treatment of endometriosis; E3) treatment of uterine fibroids; F 1) treatment of hirsutism; F2) inhibition of hair growth; Gl) activity as a male contraceptive; G2) activity as an abortifacient; and HI) promotion of mylin repair; which comprises administering to said mammal an effective amount of a compound of the formula (II) wherein Ris aryl of 6-14 carbons; or

heteroaryl of 3-10 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene; R'is alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons and containing 1-3 rings; heterocycloalkyl of 4-7 carbons and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl of 6-10 carbons; heteroaryl of 3-9 carbons and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O, and S; alkenyl of 2-10 carbons; cycloalkenyl of 5-12 carbons and containing 1-3 rings; or alkynyl of 3-10 carbons; R, R3, and R4 are independently selected from the group consisting of H; alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons; alkenyl of 2-10 carbons; cycloalkenyl of 5-12 carbons; aryl of 6-13 carbons; heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S; Co2R5; wherein R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons, or halocycloalkyl of 3-6 carbons; halogen; and =O, representing two of the groups R2, R3, and R4; X is O or S (O) y; wherein y is 0, 1, or 2; nis2,3,4, or5; p is the sum of non-H substituents R2, R3, and R4; s represents the number of double bonds in the ring, and is 0,1, or 2; T is a substituent selected from the group consisting of alkyl of 1-4 carbons; alkoxy of 1-4 carbons; aryl of 6-10 carbons;

C02H; CO2R5; alkenyl of 2-4 carbons; alkynyl of 2-4 carbons; C (O) C6Hs ; C (O) N (R6) (R'); wherein R6 is H or alkyl of 1-5 carbons; and R'is H or alkyl of 1-5 carbons; S (O) ylR8; wherein y'is 1 or 2; and R8 is alkyl of 1-5 carbons; SOIF; CHO; OH; NO2; CN; halogen; OCF3; N-oxide; O-C (R9) 2-O, the oxygens being connected to adjacent positions on R; and wherein R9 is H, halogen, or alkyl of 1-4 carbons; C (O) NHC (O), the carbons being connected to adjacent positions on R; and C (O) C6H4, the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; tis 1-5; provided that when substituent moiety T is alkyl of 1-4 carbons; alkoxy of 1-4 carbons; aryl of 6-10 carbons; Co2R5; alkenyl of 2-4 carbons; alkynyl of 2-4 carbons; C (O) C6H5; C (O) N (R6) (R'); S (O) y. R' ; O-C (R9) 2-O, or C (O) C6H4, then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1-4 carbons; alkoxy of 1-4 carbons; COR'; CO2H; C (O) N (R6) (R'); CHO; OH; NO2; CN; halogen; S (O) yR8; or =O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level; G is a substituent selected from the group consisting of halogen;

OH; OR'; =O, representing two substituents G; alkyl of 1-4 carbons; alkenyl of 1-4 carbons; cycloalkyl of 3-7 carbons; heterocycloalkyl of 3-5 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; cycloalkenyl of 5-7 carbons; heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; CO2R'; C (O) N (R6) (R'); aryl of 6-10 carbons; heteroaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; NO2; CN; S (O) YR'; <BR> <BR> SO3R8; and<BR> <BR> <BR> <BR> <BR> SO N (R6) (R7); g is 0-4, with the exception of halogen, which may be employed up to the perhalo level; provided that when substituent G is alkyl of 1-4 carbons, alkenyl of 1 -4 carbons, cycloalkyl of 3-7 carbons, heterocycloalkyl of 3-5 carbons, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen; Q is a substituent selected from the group consisting of alkyl of 1-4 carbons; haloalkyl of 1-4 carbons; cycloalkyl of 3-8 carbons; alkoxy of 1-8 carbons; alkenyl of 2-5 carbons;

cycloalkenyl of 5-8 carbons; aryl of 6-10 carbons; heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S; Co2R5; =O, representing two substituents Q; OH; halogen; S (O) YR'; SO3R8; and SOZN (R6) (R');<BR> q is 0-4 provided that when substituent Q is aryl or heteroaryl, then Q optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and with the further proviso that two of (Q) qR', (Q) qR2 (Q) qR3, and (Q) qR4 may be joined, and taken together with the atom (s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N, O, and S; and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The compounds of formula (I) have been defined broadly in the summary above.

In the compounds of formula (I), the following group preferences apply: R is preferably phenyl or pyridyl.

R'is preferably alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons and containing 1-3 rings, alkenyl of 2-10 carbons, cycloalkenyl of 5-12 carbons and containing 1-3 rings, or alkynyl of 3-10 carbons. R'is more preferably alkyl of 1- 10 carbons, cycloalkyl of 3-12 carbons and containing 1-3 rings, alkenyl of 2-10 carbons, or cycloalkenyl of 5-12 carbons and containing 1-3 rings.

R2, R3, and R4 are preferably H, alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons, alkenyl of 2-10 carbons, cycloalkenyl of 5-12 carbons, or =O, in which the carbonyl represents two of the groups R2, R3, and R4. R, R3, and R4 are more

preferably H, alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons, alkenyl of 2-10 carbons, or cycloalkenyl of 5-12 carbons.

X is preferably O or S (O) y, wherein y is 0,1, or 2.

The subscript n, representing the number of carbons in the ring, is preferably 2 or 3.

The subscript p, representing the sum of non-H substituents R2, R3, and R4, is preferably 1 or 2.

T is a substituent preferably selected from the group consisting of alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkenyl of 2-4 carbons, alkynyl of 2-4 carbons, NO2, CN, and halogen. T is more preferably alkyl of 1-4 carbons, alkenyl of 2-4 carbons, NO2, CN, or halogen.

The subscript t, representing the number of substituents T, is 1-5, more preferably 1-3.

When substituent moiety T is alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkenyl of 2-4 carbons, or alkynyl of 2-4 carbons, then T optionally may bear secondary substituents preferably selected from the group consisting of alkyl of 1-4 carbons, alkoxy of 1-4 carbons, Co2R5, CO2H, C (O) N (R6) (R'), CHO, OH, NO2, CN, halogen, S (O) yR, and =O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level.

As employed in this application, the term"secondary substituent"means a substituent on a substituent, not"secondary"as used in defining the degree of substitution at a carbon.

As employed in this application, the terms"haloalkyl"and"halocycloalkyl" are employed to refer to groups which may contain halogen atoms in any number up to the per-halo level.

G is preferably selected from the group consisting of halogen, oR5, alkyl of 1 -4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, cycloalkenyl of 5- 7 carbons, aryl of 6-10 carbons, and CN. G is more preferably halogen, alkyl of 1- 4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, cycloalkenyl of 5-7 carbons, or aryl of 6-10 carbons.

The subscript g, representing the number of substituents G, is 0-4, more preferably 0-2, with the exception of halogen, which may be employed up to the perhalo level.

Q is preferably selected from the group consisting of alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-8 carbons, alkoxy of 1-8 carbons, alkenyl of 2-5 carbons, cycloalkenyl of 5-8 carbons, COZRS, =O, OH, halogen, N (R6) (R'), and S (O) yR'. Q is more preferably alkyl of 1-4 carbons, haloalkyl of 1-

4 carbons, cycloalkyl of 3-8 carbons, alkoxy of 1-8 carbons, alkenyl of 2-5 carbons, cycloalkenyl of 5-8 carbons, or halogen.

The present invention also includes pharmaceutically acceptable salts of the compounds of Formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e. g., Li+ Na+ or K+), alkaline earth cations (e. g., Mg+2, Ca+2 or Ba+2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N, N-diethylamine, N, N-dicyclohexylamine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5- diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

A number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to the skilled in the art.

The present invention encompasses any racemic or optically active forms of compounds described in Formula I which possess progesterone receptor binding activity.

The most preferred 2-imino-1,3-thiazolidines and ring expanded homologues of 2-imino-1,3-thiazolidines of the invention are the following: <BR> <BR> (4S)-2- (2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-thi azolidine;<BR> <BR> <BR> (4S)-2- (2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidin e;<BR> <BR> <BR> (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(trifluoro methyl)-1,3- thiazolidine; <BR> <BR> <BR> (4S)-2- (2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isobutyl-1,3-t hiazolidine;<BR> <BR> <BR> (4S)-2- (2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-thi azolidine;<BR> <BR> <BR> (4S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isoprop yl-1,3-thiazolidine;<BR> <BR> <BR> (4R)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropylt etrahydro-2H-1,3- thiazine; (4S)-2-(4-nitro-1-naphthylimino)-3-cyclopentyl-4-((1 R)-1-hydroxyethyl)-1,3- thiazolidine; 2- (4-cyano-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspir o(4-cyano-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspi ro [4.4] nonane; 2- (4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane;

2- (4-cyanophenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; 2- (4-cyano-2-methylphenylimino)-1-isobutyl-3-thia-1-azaspiro [4.4] nonane; 2- (4-cyano-2, 3-dimethylphenylimino)-1-isobutyl-3-thia-1-azaspiro [4.4] nonane; 2- (4-cyano-2-methylphenylimino)-1- (1-ethyl-1-propyl)-3-thia-1- azaspiro [4.4] nonane; 2- (4-cyano-1-naphthylimino)-1-isobutyl-3-thia-1-azaspiro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino)-1- (prop-2-en-1-yl)-3-thia-1-azaspiro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino)-1-isopropyl-3-thia-1-azaspiro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspir o [4.4] nonane; 2- (3-methyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspir o(3-methyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspi ro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino)-1-cyclohexyl-3-thia-1-azaspiro [4.4] nonane; 2- (2, 3-dimethyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspi ro(2, 3-dimethyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspi ro [4.4] nonane; and 2- (4-cyano-2, 3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro(4-cya no-2, 3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

The most preferred thiazolidin-4-ones of the invention are the following: 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-o ne;<BR> 2- (3-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-o ne;<BR> 2- (2-methyl-4-nitrophenylimino)-3-benzyl-1, 3-thiazolidin-4-one;<BR> 2- (3-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidin-4-one ; 2- (2-methyl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1,(2-meth yl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1, 3-thiazolidin-4-one; 2- (3-methyl-4-nitrophenylimino)-3- (2-methyl-1-butyl)-1,3-thiazolidin-4-one;<BR> 2-(2-methyl-4-nitrophenylimino)-3-(1-cyclohexyl-1-ethyl)-1, 3-thiazolidin-4-one;(2-methyl-4-nitrophenylimino)-3-(1-cyclo hexyl-1-ethyl)-1, 3-thiazolidin-4-one <BR> 2- (3-methyl-4-nitrophenylimino)-3- ( 1-cyclohexyl-1-ethyl)-1,3-thiazolidin-4-one;<BR> 2- (2-methyl-4-nitrophenylimino)-3- (2-ethyl-1-butyl)-1,3-thiazolidin-4-one; 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-5-methylene-1, 3-thiazolidin-4-one; and 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-5-methyl-1,3-thiazo lidin-4-one.

The most preferred oxazolidines of the invention are the following: 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-4, 4-dimethyl-1,3-oxazolidine; 1-cyclopentyl-2- (4-cyano-2-ethylphenylimino)-3-oxa-1-azaspiro [4.4] nonane; 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro(2-methyl-4-ni trophenylimino)-3-oxa-1-azaspiro [4.4] nonane; and 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro(2-methyl-4-ni trophenylimino)-3-oxa-1-azaspiro [4.4] nonane.

The therapeutic agents of the invention may be employed alone or concurrently with other therapies. For example, when employed as in A1 or A2, the agent may be used in combination with a calcium source, vitamin D or analogues of

vitamin D, and/or antiresorptive therapies such as estrogen replacement therapy, treatment with a fluoride source, treatment with calcitonin or a calcitonin analogue, or treatment with a bisphosphonate such as alendronate. When employed as in Bl through B7, the agent may be used with therapies such as estrogen replacement therapy. When employed as in Cl through C16, E1 through E3, or Fl or F2, the agent may be used concurrently with therapies such as estrogen replacement therapy and/or a gonadotropin-releasing hormone agonist. When employed as in Gl or G2, the agent may be used concurrently with therapies such as an androgen.

The method of the invention is intended to be employed for treatment of progesterone receptor mediated conditions in both humans and other mammals.

The compounds may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations. The term'administered by injection'includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired, other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein

the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used.

Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.

Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid formulations, e. g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti- oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.

Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides,

for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.

Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, for example: Chien;"Transdermal Controlled Systemic Medications" ; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94/04157 3Mar94). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.

Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.

Suitable penetration enhancing materials for transdermal delivery systems are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C8-C, g fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C8-C, 8 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric

acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated Cg-C, g fatty alcohols, saturated or unsaturated Cg-C, 8 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.

Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene coploymers, and natural and synthetic rubbers.

Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.

For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.

The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg.

The daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.

It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition

undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.

The entire disclosures of all applications, patents and publications cited above and below are hereby incorporated by reference.

The compounds of Formula I may be prepared by use of known chemical reactions and procedures, from known compounds (or from starting materials which, in turn, are producible from known compounds) through the preparative methods shown below as well as by other reactions and procedures known to the skilled in the art. Nevertheless, the following general preparative methods are presented to aid practitioners in synthesizing the compounds of the invention, with more detailed particular examples being presented in the experimental section. The examples are for illustrative purposes only and are not intended, nor should they be construed, to limit the invention in any way.

LIST OF ABBREVIATIONS AND ACRYONYMS As employed herein, the following terms have the indicated meanings.

AcOH acetic acid anh anhydrous BOC tert-butoxycarbonyl conc concentrated dec decomposition DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DIBAL diisobutylaluminum hydride DME 1,2-dimethoxyethane DMF N, N-dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EtOH ethanol (100%) Et2O diethyl ether Et3N triethylamine KMnO4 potassium permanganate MagnosilZ MgSiO3 xH2O m-CPBA 3-chloroperoxybenzoic acid

MeOH methanol pet. ether petroleum ether (boiling range 30-60 °C) THF tetrahydrofuran TFA trifluoroacetic acid GENERAL PREPARATIVE METHODS Aryl amines, aryl isocyanates, aryl isothiocyanates, unsymmetrical aryl thioureas, aryl isocyanate dichlorides and 2-arylimino-1,3-heterocycles may be synthesized utilizing known methodology (Katritzky, et al. Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984). March. Advanced Organic Chemistry, 3rd Ed.; John Wiley: New York (1985)). For example, aryl isocyanates (2) are available from the reaction of phosgene, or a phosgene equivalent, such as carbonyl diimidazole, diphosgene or triphosgene, and aryl isothiocyanates (3) are available from reaction of an aryl amine with thiophosgene or a thiophosgene equivalent, such as thiocarbonyl diimidazole (Scheme I). Also, many aryl isocyanates and aryl isothiocyanates are commercially available. Reaction of an aryl isothiocyanate with a primary amine then affords thiourea 4 (Hahn et al. Han'guk Nonghwa Hakhoechi 1997, 40,139; Durr US Patent 4,079,144; Enders US Patent 4,148,799).

Scheme I As shown in Scheme II, thioureas react with a-haloketones, e. g. a- bromoketone 5, to afford, after dehydration, the thiazoline (6) (Hahn et al. Hanguk Nonghwa Hakhoechi 1997, 40,139; Durr US Patent 4,079,144; Enders US Patent 4,148,799).

Scheme II

Similarly, thioureas react with a-haloacid halides (Giri et al. Asian J. Chem.

Lakhan et al. Agric. Biol. Chem. a-haloacids (Dogam et al. Spectrosc. Lett. 1983,16, Seada et Seada et 7 Indian J. Heterocycl. Chem. 1993,3, 81), and a-haloesters (Seada et al. Indian J. Heterocycl. Chem. to afford 4-thiazolidinones (10).

Scheme III

Aryl isothiocyanates (3) also react with allylamines (Tsoi et al. Zh. Org.

Khim. and propargylamines (Azerbaev et al. Khim. Geterotsikl. Soedin. 1972,471) to form the corresponding thioureas, which on acid treatment afford the 5-substituted thiazolidines (Scheme IV).

Scheme IV

Aryl isothiocyanates may also be reacted with hydroxylamines (17) to form N-hydroxyalkylthiourea 18 (Scheme V). Treatment of the thiourea with acid then leads to 2-imino-1,3-heterocycle 19 (Jen et al. J. Med. Chem. ; Tyukhteneva et al. Khim. Geterotsikl. Soedin. Olszenko-Piontkowa et al. Org. Prep. Proced. Int. 11971, 3,27). Reaction of hydroxyalkylthiourea 18 with SOC12 affords cloroalkyl analogue 20, which on treatment with base will cyclize to afford heterocycle 19 (Cherbuliez et al. Helv. Chim. Acta Felix et al. US Patent 4,806,653).

Scheme V

Alternatively, as shown in Scheme VI, treatment of N-hydroxyalkylthiourea 18 with either HgO or an alkylating agent, such as methyl iodide followed by base affords the corresponding oxygen-containing heterocycle (Jen et al. J. Med. Chem.

Ignatova et al. Khim. Geterotsikl. Soedin. 1974,354).

Scheme VI Chloroalkyl isothiocyanates have been reported to react with arylamines to afford the corresponding sulfur 2-phenylimino-1,3-heterocycle (Sagner et al. US Patent 3,651,053; Ibid US Patent 3,737,536).

Scheme VII Aryl amines react with a formylating source, such as formic acetic anhydride, to form formanilide 25, which may then be oxidatively converted to the aryl

isocyanide dichloride (Ferchland et al. DE 3,134,134; for a review, see: Kuehle et al. Angew. Chem. Aryl isocyanide dichlorides (26) react with hydroxylamines (27) to give oxygen-containing 2-phenylimino-1,3-heterocycle 30 (Wollweber US Patent 3,787,575; Ibid US Patent 3,686,199) and with hydroxylamide 28 to give thiazolidinone 31. In addition, aryl isoyanide dichlorides have been shown to react with aminomercaptans (29) to give the sulfur-containing 2- phenylimino-1,3-heterocycle 32 (Thibault French Patent 1,510,015).

Scheme VIII

Treatment of hydroxylamines with CS in the presence of base will generate the 1,3-thiaza-2-thione (Scheme IX). It has been reported that thione 34 reacts with SOC'2 to give hydroscopically labile imidate 35, which on treatment with an aryl amine affords the sulfur-containing 2-imino-1,3-heterocycle (Hanefeld et al. Arch.

Pharm. Ibid 1988,321,199).

Scheme IX sain HOwN _ SJ4N, R SOC12 S N+ R1 ArNH2 Jt R basa 33 34 35 36

Both oxygen-containing and sulfur-containing 2-imino-1,3-heterocycles may be further elaborated. Thus, for example, as shown in Scheme X, treatment of N3- unsubstituted 2-phenylimino-1,3-heterocycles with electrophiles, typically in the

precense of base, affords the N3-substituted product (Ambartsumova et al. Chem. Heterocycl. Compd. 1997,33,475; Mizrakh et al. Khim. Geterotsikl. Soedin. 1990, 563; Olszenko-Piontkowa et al. Org. Prep. Proced. Int. 11971,3,27).

Scheme X

In addition, as shown in Scheme XI, sulfur-containing 2-imino-1,3- heterocycles may be oxidized to the sulfoxide or sulfone (Chizhevskayaet al. Khim.

Geterotsikl. Soedin. 1971,96; Pandey et al. J. Indian Chem. Soc.

Scheme XI

DETAILED EXPERIMENTAL PROCEDURES Detailed examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In the tables of compounds to follow, the synthesis of each compound is referenced back to these exemplary preparative steps.

EXAMPLES All reactions were carried out in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification.

Unless otherwise stated, the term'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg. Bulb-to-bulb concentrations were conducted using an Aldrich Kugelrohr apparatus, and in these cases temperatures refer to oven temperatures. All temperatures are reported uncorrected in degrees Celcius (°C). Unless otherwise indicated, all parts and percentages are by volume.

Thin-layer chromatography (TLC) was performed on WhatmanZ pre-coated glass- backed silica gel 60A F-254 250 um plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science'silica gel. Rotary chromatography was performed using pre-cast SiO2 plates (Alltech) from Harrison Research Chromatotron.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected.

Fourier transform infrared sprectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.

Proton ('H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (8 0. 00) or residual protonated solvent (CHCl3 8 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard. Carbon ('3C) NMR spectra were measured with a General Electric GN- Omega 300 (75 MHz) spectrometer with solvent (CDCl3 8 77.0; MeOD-d3; 8 49.0; DMSO-d6 8 39.5) as standard.

Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were obtained as electron impact (EI), chemical ionization (CI), or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 °C. Electron impact ionization was performed with

electron energy of 70 eV and a trap current of 300 uA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment, were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (lxl04 torr to 2.5x10'" torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared (-1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan.

HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett- Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time according to the number of ions in the source. Gas chromatography-ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV).

Elemental analyses were conducted by Robertson Microlit Labs, Madison NJ.

NMR spectra, LRMS, elemental analyses, and HRMS of the compounds were consistant with the assigned structures.

Examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In the tables of compounds to follow, the synthesis of each compound is referenced back to these exemplary preparative steps.

A. Synthesis of Imine Precursors Ala. General method of synthesis of anilines from nitrobenzenes. Synthesis of 4-cyano-2-methylaniline.

4-Cyano-2-methylaniline was synthesized as previously described (J. Med.

Chem. (1991), 34,3295): To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.34 mmol) in acetic acid (20 L) was added dropwise a solution of SnC12 (9.6 g, 49.38 mmol) in conc. HCl (20 mL). After stirring for 3 h, the mixture was added carefully to a saturated NH40H solution (120 mL) at 0 °C. The resulting mixture was extracted with EtOAc (4x30 mL). The combined organic layers were sequentially washed with

H20 (30 mL) and a saturated NaCl solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc/hex) to give 4-cyano-2-methylaniline as a white solid (1.48 g, 92%): TLC (30% EtOAc in hexane) RfO. 23. This material was used without further purification.

A2a. General method for the synthesis of isothiocyanates. Synthesis of 4- nitro-2-n-propyl isothiocyanate.

Step 1 To a solution of 2-n-propylaniline (8.91 g, 66 mmol) and Et3N (14 mL, 106 mmol) in CH2Cl2 (60 mL) was added acetic anhydride (10.9 mL, 99 mmol) dropwise.

The resulting mixture was allowed to stir at room temp. overnight, then was treated with a IN HCl solution (40 mL). The acidic mixture was extracted with CH2C12 (2x30 mL). The combined organic layers were sequentially washed with H20 (40 mL), a 1N NaOH solution (40 mL), H20 (40 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The resulting powder was purified by crystalization (EtOAc) to give 2-n-propylacetanilide as white needles (7.85 g, 67%). TLC (30% EtOAc/hex) Rf0.37.

Step 2 To a solution of 2-n-propylacetanilide (1.15 g, 6.50 mmol) in TFA (20 mL) at -5 °C was added NaNO2 (0.55 g, 6.50 mmol). The mixture was allowed to stir at-5 °C for 3 h, then was treated with H2O (30 mL). The resulting aqueous solution was extracted with EtOAc (3x20 mL). The combined organic layers were washed with a 1N NaOH solution (30 mL), H20 (30 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in a conc. HCl solution (30 mL) and heated at 100 °C overnight. The resulting mixture was cooled to 0 °C with an ice bath, then was carefully adjusted to pH 10 with a 50% NaOH solution. The basic mixture was extracted with EtOAc (4x30 mL).

The combined organic layers were sequentially washed with H20 (30 mL) and a saturated NaCI solution (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc/hex) to give

2-n-propyl-4-nitroacetanilide as a yellow solid (0.56 g, 48%): TLC (20% EtOAc/hex) Rf 0.47.

Step 3 To a solution of 2-propyl-4-nitroacetanilide (0.56 g, 0.31 mmol) in toluene (30 mL) was added thiophosgene (0.24 mL, 0.31 mmol) dropwise. The mixture was heated at the reflux temp. overnight, then cooled to room temp. and concentrated under reduced pressure. The residue was purified by flash chromatography (1% EtOAc/hex) to give 2-propyl-4-nitrophenyl isothiocyanate as a yellow oil (0.65 g, 95%): TLC (20% EtOAc/hex) RfO. 82.

A2b. General method for the synthesis of isothiocyanates. Synthesis of 4-cyano- 2-ethylphenyl isothiocyanate.

To a solution of 4-amino-3-ethylbenzonitrile, (75 g, 0.51 mol) in toluene (1 L) was added thiophosgene, (43 mL, 0.56 mol, 1.1 equiv.) slowly via syringe. Within 5 min. a viscous slurry formed. The reaction mixture was heated to the reflux temp. and the viscosity diminished. The reaction mixture was heated at the reflux temp. for 5 h then allowed to cool to room temp. The resulting mixture was concentrated under reduced pressure and the residue was treated with CH2Cl2 (600 mL) and concentrated under reduced pressure to give 4-cyano-2-ethylphenyl isothiocyanate as a light tan crystalline solid (98 g, 100%):'H NMR (DMSO-d6) 8 1.18 (t, J=7.4 Hz, 3H), 2.69 (q, J=7.4 Hz, 2H), Hz, 1H), 7.75 (d, J=7.0 Hz, 2H), 7.84 (s, 1H); MS (CI-MS) m/z 189 ( (M+H) +).

A2c. General method for the synthesis of isothiocyanates. Synthesis of 2,4- dimethyl-3-cyano-5-pyridyl isothiocyanate.

A suspension of 6-amino-3-cyano-2,4-dimethylpyridine (0.1 g, 0.68 mmol) in CH2Cl2 (1 mL) was added to a vigorously stirred mixture of CaCO3 (0.41 g, 4.11

mmol) in a 1: 2 water: CH2Cl2 mixture (9 mL total) at room temp. The reaction mixture was cooled to 0 °C and thiophosgene (0.09 g, 0.78 mmol) was added dropwise. The resulting mixture was allowed to warm to room temp and was stirred overnight. The resulting aqueous layer was back-extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with water (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2,10% EtOAc/hex) to give 2,4-dimethyl-3-cyano-6-pyridyl isothiocyanate (0.12 g, 91%): CI-MS m/z 190 ( (M+H) +).

A2d. General method for the synthesis of isothiocyanates. Synthesis of 2,3- dimethyl-4-nitrophenyl isothiocyanate.

To a solution of 2,3-dimethyl-4-nitroaniline (0.5 g, 1.0 equiv.) in toluene (50 mL) was added thiophosgene (0.3 mL, 1.3 equiv.) and the reaction mixture was heated at the reflux temp. overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (25% CH Cl2/hex) to afford 2,3-dimethyl-4-nitrophenyl isothiocyanate as a light yellow solid (0.30 g, 48%):'H NMR (CDCl3) 8 2.39 (s, 3H), 2.41 (s, 3H), 7.20 (d, J=8.4 Hz, 1H); CI-MS m/z 200 ( (M+H) +).

A2e. General method for the synthesis of isothiocyanates. Synthesis of 2,3- dimethyl-6-nitrophenyl isothiocyanate.

To a solution of 2,3-dimethyl-6-nitroaniline (3.0 g, 1.0 equiv.) in toluene (150 mL) was added thiophosgene (2.5 mL, 1.8 equiv.) and the reaction mixture was heated at the reflux temp. overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (10% CHZCl2/hex) to afford 2,3-dimethyl-6-nitrophenyl isothiocyanate as a light yellow solid (3.63 g, 95%):'H NMR (CDC13) 8 2.39 (s, 3H), 2.40 (s, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H).

A3a. General method of synthesis of aryl isonitrile dichlorides. Synthesis of 4-cyano-2-ethylphenyl isocyanide dichloride.

Step 1 Acetic anhydride (235 mL, 2.5 mol, 2.6 equiv.) was added to formic acid (118 mL 3.1 mol, 3.2 equiv.) and the resulting solution was heated at 60 °C for 2 h.

After the reaction had cooled to room temp., a solution of 4-amino-3- ethylbenzonitrile (140 g, 0.96 mol) in anh. THF (700 mL) was added at such a rate that the reaction temp. did not exceed 45 °C (approximately 20 min.). When the resulting solution had cooled to room temp. it was concentrated under reduced pressure, treated with EtOH (600 mL), and concentrated again under reduced pressure to afford 4-cyano-2-ethylformanilide as a light tan solid (167 g, 100%):'H <BR> <BR> NMR (CDCl3) 8 1.13 (t, J=7.3 Hz, 3H), 2.48 (q, J=7.3 Hz, 2H), 7.65 (d, J=8.5 Hz, 1H), 8 35 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 9.89 (br s, 1H).

Step 2 To a solution of 4-cyano-2-ethylformanilide (167 g, 0.96 mol, 1.0 equiv.) in SOC12 (525 mL, 6.05 mol, 6.3 equiv.) which had been cooled to 0 °C with an ice bath was added sulfuryl chloride, (112 mL, 1.4 mol, 1.4 equiv.) via syringe. The cooling bath was then removed and the reaction was heated at 50 °C overnight. The resulting mixture was concentrated under reduced pressure, treated with CH2Cl2 (600 mL), and concentrated again under reduced pressure. The residue was dissolved in Et2O (800 mL) and filtered through a pad of Magnosil'to give 4-cyano-2-ethylphenyl isocyanide dichloride as an oil (210 g, 96%):'H NMR (CDCl3) 8 1.13 (t, J=7.3 Hz, 3H), 2.49 (q, 2H, J = 7.3 Hz), 7.15 (d, J=8.2 Hz, 1H), 8.35-8.40 (m, 2H).

A3b. General method of synthesis of aryl isonitrile dichlorides. Synthesis of 2-methyl-4-nitrophenyl isocyanide dichloride.

Step 1 Acetic anhydride (400 mL, 4.26 mol, 2.6 equiv.) was added to formic acid (200 mL, 5.25 mol, 3.2 equiv.) and the resulting solution was heated at 60 °C for 2.25 h. After cooling to room temp., a solution of 2-methyl-4-nitroaniline (152 g, 1.64 mol, 1.0 equiv.) in anh. THF (1.2 L) was added at such a rate that the reaction temp. did not exceed 45 °C (approximately 30 min.). When the resulting solution had cooled to room temp. it was concentrated to half the volume under reduced pressure and the reaction product was removed by filtration yielding 2-methyl-4- <BR> <BR> nitroformanilide as a light tan solid (295g, 100%):'H NMR (CDCl3) 8 2.31 (s, 3H) 8.03 (m, 2H), 8.24 (d, J=8.8 Hz, 1H), 8.39 (br s, 1H), 9.94 (br s, 1H).

Step 2 SOCS2 (525 mL, 6.05 mol, 6.3 equiv.) was added to 2-methyl-4- nitroformanilide (167 g, 0.96 mol) and the resulting solution was cooled to 0 °C.

Sulfuryl chloride, (112 mL, 1.4 mol, 1.4 equiv.) was added via syringe, the cooling bath was removed and the reaction was heated at 60 °C for 4 h, then allowed cool to room temp. overnight. The reaction mixture was concentrated to half the volume under reduced pressure and the resulting slurry was filtered. The solids were washed with a 50% EtO/hex solution to yield 2-methyl-4-nitrophenyl isocyanide dichloride as a yellow solid (323 g, 85%):'H NMR (CDCl3) 8 2.19 (s, 3H), 7.20 (d, J=8.5Hz, 1H), 8.15 (d, J=8.5Hz, 1H), 8.2 (s, 1H).

A4a. General method for the synthesis of nitroanilines from anilines.

Synthesis of 2, 3-dimethyl-6-nitroaniline and 2,3-dimethyl-4-nitroaniline.

Step 1 To a solution of 2,3-dimethylaniline (1.1 mL, 1.00 equiv.) and Et3N (1.5 mL, 1.30 equiv.) in CH2Cl2 (15 mL) at 0 °C was added acetyl chloride (0.73 mL, 1.25

equiv.) over 30 min.. The reaction mixture was allowed to stir overnight at room temp., then was treated with a 2N HCl solution (10 mL) and CH2Cl2 (25 mL). The resulting mixture was extracted with EtOAc (3x25 mL). The combined organics were washed with a 2N HCl solution (2x25 mL), water (2x25 mL), a saturated NaHC03 solution (2x25 mL) and a saturated NaCI solution (2x25 mL), dried (Na2SO4), and concentrated under reduced pressure to give 2,3-dimethylacetanilide as a white solid (1.25 g, 93%):'H NMR (CDCl3) 8 2.05 (s, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 6.95 (d, J=7.5 Hz, 1H) 7.02 (app t, J=7.5 Hz, 1H), Hz, 1H).

Step 2 To a solution of 2,3-dimethylacetanilide (14.0 g, 1.0 equiv.) in conc. H2SO4 (35 mL) at 0 °C was added HN03 (5.1 mL, 1.25 equiv) over 30 min. The resulting mixture was allowed to stir at room temp. for 15 min., then was treated with ice water (500 mL) to form a yellow precipitate. The solids were removed and washed with water to afford a 1: 1 mixture of 2,3-dimethyl-6-nitroacetanilide and 2,3- dimethyl-4-nitroacetanilide (16.0 g, 90%):'H NMR (CDCl3) 8 2.15 (s, 1.5H), 2.22 (s, 1.5H), 2.37 (s, 1.5H), 2.38 (s, 1.5H), 2.41 (s, 1.5H), 5.93 (br s, 1H), 7.15 (d, J=8.7 Hz, 0.5H), 7.63 (d, J=8,7 Hz, 0.5H), 7.76 (d, J=8.1 Hz, 1H). This mixture was used in the next step without further purification.

Step 3 To a solution of the mixture of nitroacetanilides (16.0 g, 1.0 equiv.) was added a 60% H2SO4 solution (150 mL). The solution was heated at the reflux temp. for 1 h, then cooled to room temp. and treated with a 2N NaOH solution in ice water (100 mL). The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with a saturated NaHC03 solution (2x50 mL) and a saturated NaCl solution (2x50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (10% CH2Cl2/hex) to afford 2,3-dimethyl-6-nitroaniline (5.5 g, 43%), followed by 2,3- dimethyl-4-nitroaniline (1.5 g, 12%). 2,3-Dimethyl-6-nitroaniline (5.5 g, 43%):'H NMR (CDCL) 8 2.05 (s, 3H), 2.20 (s, 3H), 6.15 (br s, 2H), 6.45 (d, J=8.7 Hz, 1H),

7.63 (d, J=9.0 Hz, 1H);'H NMR (DMSO-d6) 8 2.10 (s, 3H), 2.30 (s, 3H), 6.50 (d, J=8.7 Hz, 1H), 7.15 (br s, 2H), 7.75 (d, J=9.0 Hz, 1H). 2,3-Dimethyl-4-nitroaniline: 'H NMR (CDCl3) 8 2.10 (s, 3H), 2.45 (s, 3H), 4.05 (br s, 2H), 6.45 (d, J=9.0 Hz, 1H), 7.65 (d, J=8.7 Hz, 1H);'H NMR (DMSO-d6) 8 2.00 (s, 3H), 2.35 (s, 3H), 6.12 (br s, 2H), 6.53 (d, J=9.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H).

A5a. General method for the synthesis of iodoanilines. Synthesis of 4-iodo-2-n- propylaniline.

To a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of NaHC03 (5.0 g, 59.5 mmol) in H2O (25 mL). Iodine (8.4 g, 33.3 mmol) was added portionwise over 70 min. while maintaining the temp. at 10 °C, then the mixture was allowed to stir at 10 °C for 30 min. The resulting mixture was diluted with H20 (30 mL) and extracted with EtOAc (4x40 mL). The combined organic layers were sequentially washed with a 5% Na2S203 solution (30 mL) and a saturated NaHC03 solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4- iodo-2-n-propylaniline (9.4 g, 98%): TLC (20% EtOAc/hex) Rf 0.43. This material was used in the next step without further purification.

B. Methods for Forming Precursors to 2-Iminoheterocycles Bla. General method for the synthesis of ethanolamines via reduction of amino acid derivatives. Synthesis of 1-amino-1- (hydroxymethyl) cyclohexane.

Step 1 To a solution of 1-aminocyclohexane-1-carboxylic acid (10.0 g, 70.0 mmol) in a 1M NaOH solution (100 mL) was added benzyl chloroformate (12.0 ml, 84.0 mmol). The reaction mixture was stirred for 2 h while maintaining pH 9 by addition of a 1M NaOH solution as necessary. The resulting solution was washed with Et2O (2x100 mL), then the aqueous layer was adjusted to pH 0 with a conc. HCl solution and the solution was extracted with EtOAc (3x150 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to yield 1- (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid (17.3 g, 89%): TLC (25% EtOAc/hex) Ru 0. 07.

Step 2 To a solution of 1-(benzyloxycarbonylamino) cyclohexane-1-carboxylic acid (4.16 g, 15.0 mmol) and N-methylmorpholine (1.81 mL, 16.5 mmol) in DME (15 mL) at 4 °C was slowly added isobutyl chloroformate (2.14 mL, 16.5 mmol) and the reaction mixture was stirred for 5 min, then filtered into a pre-cooled (4 °C) flask.

Sodium borohydride (0.85 g, 22.5 mmol) in water (7 mL) was added followed immediately by water (500 mL). The reaction was then warmed to 20 °C and stirred for 30 min. The reaction mixture was extracted with CH2C12 and concentrated under reduced pressure to yield 1-(benzyloxycarbonylamino)-1- (hydroxymethyl) cyclohexane (4.0 g, 100%): TLC (25% EtOAc/hex) Rf0.11.

Step 3 A slurry of 1- (benzyloxycarbonylamino)-1-(hydroxymethyl) cyclohexane (4.0 g, 15 mmol) and 10% Pd/C (0.40 g) in MeOH (75 ml) was stirred under H2 (1 atm.) for 1 h, then treated with Celite. The resulting mixture was filtered and concentrated under reduced pressure to give 1-amino-1- (hydroxymethyl) cyclohexane.

Blb. General method for the synthesis of ethanolamines via reduction of amino acid derivatives. Synthesis of (1S)-1- (hydroxymethyl)-3- methylbutylamine.

Step 1 To a suspension of (L)-leucine, (315 g, 2.4 mol) in MeOH (3.2 L) at-15 °C was added SOC12 (315 mL, 4.32 mol, 1.8 equiv.) dropwise at such a rate that the temp. of the reaction did not exceed 5 °C. After the addition was complete, the reaction mixture was allowed to warm to room temp. and was stirred overnight. The

resulting mixture was concentrated under reduced pressure and Et2O (3 L) was slowly added to the residue to produce a precipitate. The mixture was cooled with an ice bath, then treated with additional MeOH (3 L) relatively rapidly. After 1 h at 0 °C, the crystals were collected and dried to give (L)-leucine methyl ester HCl salt as <BR> <BR> a white crystalline solid (394 g, 86%): mp 147-149 °C ;'H-NMR (CD30D) 8 0.78- 0.98 (m, 6h), 1.58-1.72 (m, 3H), 3.76 (s, 3H), 3.92 (t, J=7.3 Hz, 1H).

Step 2 To a mixture of (L)-leucine methyl ester HC1 salt (254 g, 1.4 mol), NaHC03, (118 g, 1.4 mol, 1.0 equiv.) and water (1.8 L) in EtOH (1.8 L) at 5°C was added NaBH4, (159 g, 4.2 mol, 3.0 equiv.) in portions at such a rate that the reaction temp. did not exceed 15°C (approximately 70 min). After the addition of NaBH4 was complete, the ice bath was removed and the reaction was heated to the reflux temp. overnight. The resulting mixture was cooled to room temp. with the aid of an ice bath. The resulting slurry was filtered and the solids were washed with EtOH (750 mL). The combined filtrates were concentrated to approximately 950 mL under reduced pressure. The residue was diluted with EtOAc (2.5 L) and extracted with a 1N NaOH solution (2x1 L). The aqueous layer was back-extracted with EtOAc (2x750 mL). The combined organics were dried (MgSO4) and concentrated under reduced pressure to yield (lS)-1- (hydroxymethyl)-3-methylbutylamine as a pale yellow oil (112 g, 65%):'H NMR (CDC13) 8 0.88-0.93 (m, 6H), 1.17 (t, J=7.7 Hz, 2H), 1.68-1.80 (m, 2H), 1.82 (br s, 2H), 2.86-2.91 (m, 1H), 3.22 (dd, J=10.7,8.1 Hz, 1H), 3.6 Hz, 1H).

Bic. General method for the synthesis of ethanolamines via reduction of amino acid derivatives. Synthesis of 1-hydroxymethylcyclopentanamine Step 1 To a suspension of 1-aminocyclopentanecarboxylic acid, (675 g, 5.23 mol, 1.0 equiv.) in MeOH (6.5 L) held at-15 °C with an ice/MeOH bath was added SOC12 (687 mL, 9.4 mol, 1.8 equiv.), dropwise at such a rate that the reaction temp. did not exceed 7 °C. After the addition was complete, cooling was removed, the reaction was allowed to stir at room temp. overnight, then was concentrated under reduced

pressure. The residue was treated with CH2Cl2 (1 L) and concentrated under reduced pressure to afford methyl 1-aminocyclopentanecarboxylate HC1 salt as a white solid (938 g, 100%):'H NMR (CD30D) d 1.87-1.94 (m, 8H), 3.83 (s, 3H); NMR (DMSO- d6) 8 1.67-1.71 (m, 2H), 1.83-1.98 (m, 4H), 2.06-2.14 (m, 2H), 3.73 (s, 3H), 8.81 (br s 3H). This material was used in the next step without further purification.

Step 2 A solution of methyl 1-aminocyclopentanecarboxylate HC1 salt (310 g, 1.73 mol) in a solution of EtOH (12.5 L) and water (2.5 L) was treated with NaHC03 (145 g, 1.73 mol, 1.0 equiv.). The resulting mixture was then cooled to 5 °C with an ice bath and NaBH4 (196 g, 5.2 mol, 3.0 equiv.) was added in portions at such a rate that the reaction temp. did not exceed 15 °C (approximately 75 min.). After the addition of NaBH4 was complete, the ice bath was removed and the reaction was heated at the reflux temp. overnight, cooled to room temp. with the aid of an ice bath, and filtered. The resulting solids were washed with EtOH (750 mL) and the combined filtrates were concentrated under reduced pressure. The resulting slurry was then treated with EtOAc (2.5 L). The organic layer was washed with a IN NaOH solution (2x750 mL) and the aqueous layer was back-extracted with EtOAc (2x500 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford 1-hydroxymethylcyclopentanamine as a low melting wax (169 g, 85%):'H NMR (CDC13) b 1.38-1.44 (m, 2H), 1.58-1.69 (m, 4H), 1.70-1.84 (m, 2H), 2.11 (br s, 3H), 3.36 (s, 2H). CI-MS m/z 116 ((M+H) +).

B2a. General method for the N-alkylation of ethanolamines via substitution reactions. Synthesis of 2- (isobutylamino)-2- (hydroxymethyl) norbornane.

2-Aminonorbornane-2-carboxylic acid was converted into 2-amino-2- (hydroxymethyl) norbornane as a diastereomeric mixture in a manner analogous to Method Bla. A solution of the amino alcohol (0.31 g, 2.16 mmol) and isobutyl bromide (0.23 ml, 2.16 ml) in DMF (3 mL) was heated at 90 °C for 92 h, then cooled to room temp. and partitioned between EtOAc (100 mL) and a saturated NaHC03 solution (100 mL). The organic layer was washed with a saturated NaCI solution (50 mL), dried (MgSO4), and concentrated under reduced pressure to yield 2-

(isobutylamino)-2- (hydroxymethyl) norbomane as a diastereomeric mixture (0.24 g, 55%): GC-MS m/z 197 (M+).

B2b. General method for the N-alkylation of ethanolamines via substitution reactions. SynthesisofN-hydroxyethyl-N-cyclohex-1-enylmethylamine.

Step 1 To a stirred solution of methyl cyclohex-1-enecarboxylate (4.56 g, 32 mmol) in THF (100 mL) at-78 °C was added DIBAL (1 M in THF, 130 mmol, 130 mL) dropwise. The mixture was allowed to stir at-78 °C for 4 h then treated with a saturated NaHC03 solution (40 mL). The aqueous layer was extracted with EtOAc (4x20 mL) and the combined organic layers were washed with H2O (40 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The residual cyclohex-1-enylmethanol was used directly for the next step without purification: TLC (30% EtOAc/hex) RfO. 44.

Step 2 To a solution of cyclohex-1-enylmethanol (3.58 g, 32 mmol) in CH2CI2 (40 mL) at 0 °C was added PPh3 (36 mmol, 9.39 g) and CBr4 (39 mmol, 12.96 g). The mixture was allowed to stir at room temp. overnight then concentrated under reduced pressure. The residue was diluted with pentane (60 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (5% EtOAc/hex) to give 1-bromomethyl-1-cyclohexene as an oil (3.25 g, 57% over two steps): TLC (30% EtOAc/hex) Rf 0.91.

Step 3 A solution of 1-bromomethyl-1-cyclohexene (3.25 g) and 2-aminoethanol (6 mL) in trichloroethylene (40 mL) was heated at the reflux temp. for 3 d, cooled to room temp., and diluted with a IN NaOH solution (30 mL). The aqueous layer was extracted with CH2C12 (4x20 mL) and the combined organic layers were washed with H20 (30 mL) and a saturated NaCI solution (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by vacuum distillation to give N-hydroxyethyl-N-cyclohex-1-enylmethylamine as a colorless oil (1.78 g, 62%): bp 92-94 °C (6 mmHg).

B3a. General method for the N-alkylation of ethanolamines via reductive alkylation. Synthesis of (R)-N-isobutylserine methyl ester HCI salt.

To a suspension of (D)-serine methyl ester HC1 salt (2.13 g, 13.7 mmol) in 1,2-dichloroethane was added isobutyraldehyde (1.5 mL, 16.4 mmol) and sodium triacetoxyborohydride (4.3 g, 20.5 mmol). The reaction mixture was stirred at room temp. for 24 h, then partitioned between Et2O (100 mL) and a saturated NaHC03 solution (100 mL). The organic layer was washed with a saturated NaHC03 solution (3x100 mL), dried (MgSO4), and treated with a 1M HCl solution in ether (25 mL).

The resulting mixture was concentrated under reduced pressure to yield (R)-N- isobutylserine methyl ester HC1 salt (2.27 g, 79%): NMR (DMSO-d6) 8 0.94 (dd, J=6.7,3.0 Hz, 6H); 1.97-2.11 (m, 1H); 2.76-2.91 (m, 1H); 3.76 (s, 3H); 3.86 (dd, J=12.1,4.1 Hz, 1H), 3.99 (dd, J=12.4,3.2 Hz, 1H), 4.13-4.21 (m, 1H).

B4a. General method for the N-alkylation of ethanolamines via 2-alkyl-1,3- oxazolidine formation followed by reduction. Synthesis of 1- (cyclohexylamino)-1-(hydroxymethyl) cyclopentane.

Step 1 To a solution of 1-amino-1- (hydroxymethyl) cyclopentane (Method Bic; 1.44 g, 12.54 mmol) in CH2Cl2 (10 mL) at 4 °C was added TFA (0.097 mL, 1.25 mmol), cyclohexanone (1.30 mL, 12.54 mmol) and sodium sulfate (2 g) and the reaction was warmed to 20 °C. The reaction was stirred for 72 h and was sequentially washed with water (10 mL) and a saturated NaHC03 solution (20 mL), dried (MgSO4), and concentrated under reduced pressure to give 14-aza-7-oxadispiro [4.2.5.1] tetradecane (2.38 g, 97%): GC-MS m/z 195 (M+).

Step 2

To a solution of LiAlH4 (0.93 g, 24.4 mmol) and AlCl3 (3.24 g, 24.4 mmol) in THF at 4 °C was added dropwise a solution of 14-aza-7- oxadispiro [4.2.5.1] tetradecane (2.38 g, 12,2 mmol) in THF (15 mL). The resulting mixture was warmed to 20 °C and stirred for 45 min., then cooled to 4 °C. Water (5 mL) was slowly added to quench the reaction and a IN NaOH solution (85 mL) was added to dissolve the resulting solids. The resulting solution was extracted with Et2O (200 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield 1- (cyclohexylamino)-1-(hydroxymethyl) cyclopentane 1.89 g (79%): GC-MS m/z 197 (M+).

B4b. General method for the N-alkylation of ethanolamines via 2-alkyl, 3- oxazolidine formation followed by reduction. Synthesis of N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine.

Step 1 A mixture of 2-amino-2-methyl-1-propanol (15.0 g, 0.168 mol), cyclopentanone (14.9 mL, 0.168 mol, 1.0 equiv.) and p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol, 0.05 equiv.) in toluene (300 mL) was stirred at the reflux temp. overnight. The reaction mixture was then cooled to room temp., diluted with EtOAc (500 mL), then washed with a saturated NaHC03 (250 mL), dried (Na2SO4), and concentrated under reduced pressure to yield 4-aza-3,3-dimethyl-1- oxaspiro [4.4] nonane as a pale yellow oil (15.5 g, 60%):'H NMR (CDC13) 8 1.12 (s, 6H), 1.65 (m, 5H), 1.80 (m, 2H), 1.97 (m, 2H), 3.45 (s, 2H).

Step 2 To a solution of 4-aza-3, 3-dimethyl-1-oxaspiro [4.4] nonane (15.5 g, 0.10 mol) in EtOH (85 mL) at 0 °C was then added NaBH4 (5.47 g, 0.145 mol, 1.45 equiv.) at a rate that the reaction temp. did not exceed 10 °C (approximately 1 h). The reaction mixture was then allowed to warm to room temp. and stirred for 18 h. The resulting mixture was treated with water (100 mL) and concentrated to a paste under reduced pressure. MeOH (100 mL) was added and the mixture was reconcentrated under reduced pressure. The residue was treated with EtOAc (300 mL) and water (150 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure

to yield N-cyclopentyl- (1, 1-dimethyl-2-hydroxyethyl) amine as a pale yellow oil (13.0 g, 83%):'H NMR (CDCl3) 8 1.07 (s, 6H), 1.24 (m, 3H), 1.50 (m, 2H), 1.65 (m, 2H), 1.87 (m, 2H), 3.0 (m, 1H), 3.22 (s, 2H); CI-MS m/z 158 ( (M+H) +).

B4c. General method for the N-alkylation of ethanolamines via 2-alkyl, 3- oxazolidine formation followed by reduction. Synthesis of (2S)-4-methyl- 2-(isobutylamino) pentan-1-ol.

Step 1 A solution of (lS)-1-(hydroxymethyl)-3-methylbutylamine (Method B I b; 152 g, 1.3 mol) and isobutyraldehyde (118 mL, 1.3 mol, 1.0 equiv.) in toluene (1.5 L) was heated at the reflux temp. until the theoretical amount of water had been collected in a Dean-Stark trap (23.4 mL). The reaction mixture was concentrated by distillation to approximately 700 mL. The resulting mixture was cooled to room temp. and was concentrated under reduced pressure to a constant weight to give (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine as a pale yellow oil (223 g, 100%):'H NMR (CDC13) 8 0.88-0.99 (m, 12H), 1.18-1.35 (m, 1H), 1.42-1.56 (m, 1H), 1.61- 1.79 (m, 4H), 3.08 (t, J=7.4 Hz 1H), 3.20-3.34 (m, 1H), 3.85 (t, J=7.4 Hz, 1H), 4.18 (dd, J = 7.3,3.4 Hz, 1H).

Step 2 To a solution of (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine (223g, 1.3 mol) in EtOH (1.1 L) cooled to-13 °C with an ice/MeOH bath was added NaBH4 (70.3 g, 1.82 mol) in portions at such a rate that the reaction temp. did not exceed 10 °C (approximately 2 h). The reaction mixture was allowed to warm to room temp., stirred overnight, then filtered through a coarse sintered glass funnel. The resulting solids were washed with EtOH. The combined filtrate was concentrated under reduced pressure and the residue was treated with EtOAc (2 L) and water (1 L). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield (2S)-4-methyl-2- (isobutylamino) pentan-l-ol as a viscous pale yellow oil (192 g, <BR> <BR> 85%):'H NMR (CDCl3) 8 0.90-0.96 (m, 12H), 1.18-1.24 (m, 1H), 1.32-1.39 (m, 1H),

1.58-1.72 (m, 2H), 2.33 (dd, J=11.1,7.0 Hz, 1H), 2.49 (dd, J=11.1,7.0 Hz, 1H), 2.63-2.67 (m, 1H), 3.19 (dd, J=10.3,6.2 Hz, 1H), 3.60 (dd, J=10.3,6.2 Hz, 1H).

B4d. General method for the N-alkylation of ethanolamines via 2-alkyl, 3- oxazolidine formation followed by reduction. Synthesis of 1- (cyclopentylamino)-1-(hydroxymethyl) cyclopentane.

Step 1.

A solution of 1-hydroxymethylcyclopentanamine (Method Blc; 263 g, 2.3 mol) and cyclopentanone (220 mL, 1.3 mol, 1.1 equiv.) in toluene (2.7 L) was heated at the reflux temp. with azeotropic removal of water until the theoretical amount of water had been collected (41.4 mL). The reaction mixture was concentrated to 700 mL by simple distillation, then cooled to room temp. and concentrated to constant weight under reduced pressure to give 6-aza-12-oxadispiro [4.1.4.2] tridecane (414 g, 100%) as a pale yellow oil:'H NMR (CDC'3) 8 1.55-1.89 (m, 17H), 3.60 (s, 2H).

Step 2 To a solution of 6-aza-12-oxadispiro [4.1.4.2] tridecane (124 g, 0.69 mol) dissolved in EtOH (600 mL) held at-13 °C with an ice/MeOH bath was added NaBH4 (38 g, 1.0 mol, 1.45 equiv.) in portions at a rate that the temp. did not exceed 10 °C (approximately 30 min.). The reaction mixture was allowed to warm to room temp. and stirred overnight. The reaction mixture was diluted with water (500 mL) and concentrated under reduced pressure. The residual paste was separated between EtOAc (1 L) and water (600 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield 1-(cyclopentylamino)-1- (hydroxymethyl) cyclopentane as a white powder (107 g, 85%):'H NMR (CDCl3) 8 1.23-1.28 (m, 2H), 1.46-1.57 (m, 8H), 1.58-1.69 (m, 4H), 1.82-1.86 (m, 2H), 2.94- 3.06 (m, 1H,), 3.30 (s, 2H).

B5a. General method for the synthesis of ethanolamines via reaction of amines with epoxides. Synthesis of N (hydroxyethyl) N (2-butyl) amine.

To a solution of sec-butylamine (60 mL, 0.60 mmol) in MeOH (40 mL) at room temp. was added ethylene oxide (10 mL, 0.20 mmol) dropwise via cannula.

The mixture was stirred for 4 h at room temp., then concentrated under reduced pressure. The residue was purified by vacuum distillation to give N (hydroxyethyl)- N (2-butyl) amine as a colorless oil (16.4 g, 70%): bp 109-112 °C (6 mmHg).

B5b. General method for the synthesis of ethanolamines via reaction of amines with epoxides. Synthesis of N- (3-phenyl-2-hydroxypropyl)-N-isobutylamine 2,3-Epoxypropyl benzene (10 g, 74.5 mmol) and isobutylamine (5.4 g, 74.5 mmol) were mixed then treated with water (2 mL). The mixture was stirred overnight at 110 °C, then distilled to yield N- (3-phenyl-2-hydroxypropyl)-N-isobutylamine (6.5 g): bp 115-117 °C (1 mmHg).

B6a. General method for the synthesis of propanolamines via Arndt Eisert homologation of amino acids followed by reduction. Synthesis of (R)-3- (tert-butylamino)-4-methylpentanol.

Step 1 To a solution of N- (tert-butoxycarbonyl)- (L)-valine (4.32 g, 19.9 mmol) and N-methylmorpholine (2.3 mL, 20.9 mmol) in DME (30 mL) at-10 °C was added isobutyl chloroformate (2.27 mL, 21.0 mmol). The resulting mixture was stirred at room temp. for 15 min, then filtered, and the solids were washed with cold DME.

The filtrate was cooled to-10 °C, then treated with a solution of CH2N2 in Et2O until a yellow color persisted, the resulting mixture was warmed to 20 °C and stirred at that temp. for 45 min., then the mixture was concentrated under reduced pressure.

The residue was purified by chromatography (SiO2, gradient from hexane to 30 % EtOAc/hex) to yield (S)-3-(tert-butoxycarbonylamino)-1-diazo-4-methylpentan-2- one (1.82 g, 38%): TLC (10% EtOAc/hex) Rif0.11.

Step 2 A solution of (S)-3-(tert-butoxycarbonylamino)-1-diazo-4-methylpentan-2- one (1.83 g, 7.6 mmol) in MeOH (100 mL) was heated at the reflux temp. and a filtered solution of silver benzoate in Et3N (0.50 g silver benzoate in 5 mL Et3N, 0.5 mL) was added. After the initial gas evolution stopped (ca. 0.5 minute) additional silver solution (0.5 mL) was added. This process was repeated until the addition of silver salt caused no more gas to be evolved. The resulting mixture was cooled to 20 °C, treated with Celitei and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtO (100 mL) and was sequentially washed with a IN HCl solution (100 mL), a saturated NaHC03 solution (100 mL), and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced <BR> <BR> <BR> pressure to give methyl (R)-3- (tert- butoxycarbonylamino)-4-methylpentanoate (1.63 g, 87%): TLC (10% EtOAc/hex) RfO. 29.

Step 3 Methyl (R)-3- (tert-butoxycarbonylamino)-4-methylpentanoate (1.62 g, 6.6 mmol) was treated with lithium borohydride in a manner analogous to Method B8a, Step 2 to afford (R)-3-(tert-butoxycarbonylamino)-4-methylpentanol (93%).

B7a. General method for the synthesis of chloroethylamines. Synthesis of (1S)-1-(chloromethyl)-3-methylbutanammonium chloride.

A solution of (lS)-1-(hydroxymethyl)-3-methylbutylamine (Method Blb; 5.40g, 46.1 mmol) in CH2Cl2 (200 mL) was cooled over an ice bath and saturated with HC1 gas. SOC12 (4.0 mL, 55.3 mmol) was added, the reaction was heated at the reflux temp. for 2.5 h, then cooled to room temp. and concentrated under reduced pressure. The residue was triturated with Et20 to yield (lS)-1-(chloromethyl)-3- methylbutanammonium chloride (5.67 g, 71%): EI-MS m/z 136 ((M+H) +).

B7b. General method for the synthesis of chloroethylamines. Synthesis of 1- (chloromethyl)-1-(cyclohexylamino) cyclopentane HCI salt.

A 4M HCl solution (p-dioxane, 40 mL) containing 1-(cyclohexylamino)-1- (hydroxymethyl) cyclopentane (Method B4a; 1.9 g, 9.6 mmol) and SOCS2 (0.84 mL, 11.5 mmol) was heated to 70 °C for 18 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure to yield crude 1-(chloromethyl)-1- (cyclohexylamino) cyclopentane HCl salt (2.84 g), which was used in the next step without further purification.

B7c. General method for the synthesis of chloroethylamines. Synthesis of N-(1- S)- (1- (chloromethyl)-3-methylbutyl)-N-(isobutyl) amine HCl salt.

To a solution of (2S)-4-methyl-2-(isobutylamino) pentan-1-ol (Method B4c; 256 g, 1.5 mol) and toluene (2.5 L) was added SOC12 (167 mL) over 15 min. After the addition of SOCS2 was complete the reaction was heated at 90 °C overnight. The reaction solution was then cooled to room temp. and concentrated under reduced pressure. The dark oily residue was dissolved in CH2C12 (2 L) and concentrated under reduced pressure. The red-brown residue was dissolved in Et2O (1 L), and hexane (750 mL) was added dropwise over a period of 8 h. The resulting slurry was stirred overnight, filtered, and washed with a 40% EtOAc/hex solution to give N-(1- S)- (1- (chloromethyl)-3-methylbutyl)-N (isobutyl) amine HCl salt as a dark brown solid (276 g):'H NMR (CDCl3) 8 0.93-1.00 (m, 6H), 1.10-1.12 (m, 6H), 1.85 (m, 4H), 2.24-2.34 (m, 2H), 2.80-2.88 (m, 1H), 2.90-3.02 (m, 1H), 3.50-3.57 (m, 1H), 3.96 (dd, J=12.9,5.6 Hz, 1H), 4.10 (dd, J=13.2,3.6 Hz, 1H).

B7d. General method for the synthesis of chloroethylamines. Synthesis of 1- (chloromethyl)-1-(cyclopentylamino) cyclopentane HCl salt.

To a solution of 1-(cyclopentylamino)-1-(hydroxymethyl) cyclopentane (Method Bic; 140 g, 0.76 mol, 1.0 equiv.) in toluene (1.4 L). was added SOC12 (84 mL) over a period of 15 min. After the addition of SOC12 was complete the reaction mixture, which had already warmed to 40 °C, was heated at 60 °C overnight. The resulting solution was cooled to room temp. and treated with HCl (4N in p-dioxane, 100 mL), and the reaction was heated to 60 °C for 3 h then stirred at room temp. overnight. The resulting mixture was concentrated to half of the original volume under reduced pressure, at which time a precipitate began to form. The resulting slurry was diluted with Et20 and allowed stir for 4 h. The resulting precipitate was filtered and washed with Et2O (2x50 mL) to yield 1-(chloromethyl)-1- (cyclopentylamino) cyclopentane HCl salt as an off-white powder (125 g, 70%):'H NMR (CDCL) 8 1.53-1.66 (m, 4H), 1.76-1.94 (m, 2H) 1.95-2.22 (m, 10H), 2.28-2.34 (m, 2H), 3.40 (s, 2H), 3.63-3.73 (m, 1H).

B7e. General method for the synthesis of chloroethylamines. Synthesis of 1- chloromethylcyclopentanamine HCI salt To a solution of 1-hydroxymethylcyclopentanamine HC1 salt (Method Bic; 20 g, 0.17 mol) in anh. p-dioxane (65 mL) was added HC1 (4M in p-dioxane; 65 mL, 0.26 mol). The resulting solution was stirred for 20 min. at room temp., then SOC12 (22.7 g, 0.19 mol) was added dropwise. The reaction mixture was heated at 80 °C for 2 d, cooled to room temp., and concentrated under reduced pressure to give 1- chloromethylcyclopentanamine HC1 salt (29g, 100%): CI-MS m/z 171 ( (M+H) +).

B8a. General method for the synthesis of 2-aminoethylsulfonate esters.

Synthesis of (lR, 2R)-1- (methanesulfonyloxymethyl)-2- (tert- butoxy) propaneammonium chloride.

Step 1 A solution of (L)-(lS, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt (2.15 g, 4.4 mmol) in CH2C12 (50 mL) was treated with a solution of CH2N2 in Et2O until a yellow color persisted. The resulting solution was

concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed sequentially with a IN HC1 solution (2x100 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure to yield (lS, 2R)-N (benzyloxycarbonyl)-O-tert-butylthreonine methyl ester (1.44 g, 100%): TLC (25% EtOAc/hex) RfO. 54.

Step 2 To a solution of (I S, 2R)-N- (benzyloxycarbonyl)-O-tert-butylthreonine methyl ester (1.4 g, 4.4 mmol) in Et2O (20 mL) was added a saturated solution of LiBH4 in Et2O (9 mL) and the reaction mixture was heated at the reflux temp. for 2 h., then cooled to 20 °C. Water (5 mL) was added to the resulting mixture, then a 1N HC1 solution was added until no more gas evolved. The ether layer was washed with a saturated NaCl solution (50 mL), dried (MgS04), and concentrated under reduced pressure to yield (lR, 2R)-N-(benzyloxycarbonyl)-1-(hydroxymethyl)-2-(tert- butoxy) propanamine (1.69 g, 99%): TLC (25% EtOAc/hex) RfO. 20.

Step 3 To a solution of (lR, 2R)-N-(benzyloxycarbonyl)-1-(hydroxymethyl)-2-(tert- butoxy) propanamine (1.6 g, 5.4 mmol) in anh. pyridine (30 mL) at 4 °C was added methanesulfonyl chloride (0.75 mL, 9.7 mmol) dropwise. The reaction was stirred for 5.5 h, then was diluted with EtOAc (200 mL) and washed with a 1N HC1 solution (4x200 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield ( R, 2R)-N (benzyloxycarbonyl)-l- (methanesulfonyloxymethyl)-2- (tert-butoxy) propanamine as an oil (2.03 g, 100%): TLC (25% EtOAc/hex) Rf0. 31.

Step 4 To a solution of (lR, 2R)-N-(benzyloxycarbonyl)-1- (methanesulfonyloxymethyl)-2- (tert-butoxy) propanamine (2.03 g, 5.5 mmol) in MeOH (50 mL) was added a 4M HC1 solution (dioxane; 1.5 mL, 6.0 mmol) and 10% Pd/C (0.20 g). The resulting slurry was stirred under H2 (1 atm.) for 2 h, then treated with Celite, filtered and concentrated under reduced pressure to yield (lR, 2R)-l- (methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride (1.6 g, 100%).

B8b. General method for the synthesis of 2-aminoethylsulfonate esters.

Synthesis of N-(2-tosyloxyethyl)-2-methylprop-2-en-1-ammonium trifluoroacetate.

Step 1 To a solution of N- (tert-butoxycarbonyl) glycine tert-butyl ester (3.97 g, 17.2 mmol) in DMF (70 mL) at 0 °C was added sodium hexamethyldisilazide (3.78 g, 20.6 mmol) and the resulting mixture was stirred for 25 min., then allowed to warm to room temp. The resulting solution was treated with 3-bromo-2-methylpropene (2.60 mL, 25.7 mmol), stirred at room temp. for 10 min., and diluted with EtOAc (300 mL). The EtOAc solution was sequentially washed with water (4x500 mL) and a saturated NaCl solution (4x500 mL), dried (MgSO4), and concentrated under reduced pressure to afford N-(tert-butoxycarbonyl)-N (2-methylprop-2-enyl) glycine tert-butyl ester (4.03 g, 82%): TLC (10% EtOAc/hex) Rf0. 51.

Step 2 A solution of N- (tert-butoxycarbonyl)-N (2-methylprop-2-enyl) glycine tert- butyl ester (0.26 g, 0.93 mmol) in Et2O (3 mL) was treated with lithium borohydride (0.011 g), then stirred at room temp. overnight. To the resulting mixture was added water (2 mL), then a IN HC1 was added dropwise until gas evolution stopped. The organic phase was washed with a saturated NaHC03 solution (20 mL), dried (MgS04), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 10% EtOAc/hex to 50% EtOAc/hex) to give N- (tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methylpro p-2-ene (0.113 g, 57%): TLC (10% EtOAc/hex) Rif 0.66.

Step 3 To a solution of N-(tert-butoxycarbonyl)-N (2-hydroxyethyl)-1-amino-2- methylprop-2-ene (21.1 g, 98 mmol) in Et2O (800 mL) at-78 °C was slowly added potassium tert-butoxide (1M in tert-butanol, 103 mL, 103 mmol). The reaction mixture was allowed to warm briefly to-45 °C, then was cooled to-78 °C, and treated with a solution of p-toluenesulfonyl chloride (18.7 g, 98.0 mmol) in Eut20 (100 mL). The resulting mixture was then warmed to-45 °C and treated with water (500 mL). The organic phase was washed with a saturated NaCl solution (800 mL), dried (MgSO4), and concentrated under reduced pressure to give N-(tert- butoxycarbonyl)-N- (2-tosyloxyethyl)-1-amino-2-methylprop-2-ene(2-tosyloxyethyl )-1-amino-2-methylprop-2-ene (36.4 g, 101%): TLC (25% EtOAc/hex) Rf0.56.

Step 4 Solid N-(tert-butoxycarbonyl)-N (2-tosyloxyethyl)-1-amino-2-methylprop-2- ene (15 g, 55.7 mmol) was cooled to 0 °C and dissolved in TFA (200 mL). The reaction mixture was allowed to warm to room temp., then was concentrated under reduced pressure. The residual oil was crystallized using Et2O (500 mL) to afford N- (2-tosyloxyethyl)-2-methylprop-2-en-1-ammonium trifluoroacetate (16.7 g, 78%).

B9a. General method for the synthesis of 3-chloropropyl-and 4- chlorobutylamines. Synthesis of N-isobutyl-3-chloropropylamine HCI salt.

Step 1 To a solution of 3-aminopropanol (91 g, 65.4 mmol) in toluene (100 mL) was added isobutraldehyde (9.0 mL, 99.1 mmol, 1.5 equiv.) and MgS04 (7.5 g) to generate an exotherm. The slurry was stirred for 30 min. and an additional portion of

MgSO4 was added (7.5 g), and the slurry was stirred overnight. The resulting mixture was filtered and concentrated under reduced pressure. The condensate was again concentrated under reduced pressure and the two residues were combined to afford 2-isopropyltetrahydro-1,3-oxazine as a colorless oil (5.18 g, 61%):'H NMR <BR> <BR> <BR> (CDC13) 8 0.84-0.88 (m, 6H), 1.24-1.29 (m, 1H), 1.51-1.66 (m, 3H), 2.77-2.87 (m, 1H), 3.07-3.13 (m, 1H), 3.60-3.76 (m, 2H), 4.00-4.05 (m, 1H).

Step 2 To a solution of 2-isopropyltetrahydro-1,3-oxazole (4.94 g, 38.2 mmol) in abs. EtOH (100 mL) at 0 °C was added NaBH4 (2.17 g (57.4 mmol, 1.5 equiv.) in small portions over 15 min. and the resulting mixture was stirred at room temp. overnight. The resulting mixture was concentrated under reduced pressure, then treated with EtOAc (150 mL) and water (100 mL) (CAUTION: gas evolution), and stirred at room temp for 30 min. The resulting organic layer was washed with a saturated NaCl solution. The combined aqueous layers were back-extracted with EtOAc (150 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford N-isobutyl-3-hydroxypropylamine as a <BR> <BR> colorless oil (5.04 g, 100%):'H NMR (CDC13) 8 0.84 (d, J=6.6 Hz, 6H), 1.60-1.71 (m, 3H), 2.36 (d, J=6.6 Hz, 2H), 2.80 (dd, J=5.9,5.9 Hz, 2H), 3.10-3.30 (br s, 2H), 3.74 (dd,, J=5.5,5.5 Hz, 2H);'3C NMR (CDC13) 8 20.5,28.1,30.6,50.0,57.8,64.1.

Step 3 To a solution of N-isobutyl-3-hydroxypropylamine (1.01 g, 7.70 mmol) in toluene (100 mL) was added SOC12 (1.37 g, 11.6 mmol, 1.5 equiv.) and the resulting mixture was stirred at room temp. for 4 h. The resulting slurry was concentrated under reduced pressure to afford N-isobutyl-3-chloropropylamine HCl salt:'H NMR (CDCl3) 8 1.12 (s, 9H), 1.28 (t, J=7.0 Hz, 3H), 4.24 (q, J=7.0 Hz, 2H), 4.55 (s, 1H), 5.00 (s, 2H); 13C NMR (CDCl3) 8 13.9,27.8,38.2,61.5,67.1,67.3,117.0,167.1, 180.7; CI-LRMS mlz (rel abundance) 150 ((M+H) +, 100%).

BlOa. General method for the synthesis of 2-chlorothiazolidinium salts.

Synthesis of (4S)-2-chloro-3,4-diisobutyl-4, 5-dihydro-1, 3-thiazolinium chloride.

Step 1 To a mixture of (2S)-4-methyl-2- (isobutylamino) pentan-l-ol HCI salt (Method B4c; 0.21 g, 1.0 mmol) and CS (0.30 mL, 5.0 mmol, 5.0 equiv.) in 2- butanone (20 mL) was added Cs2CO3 (0.72 g, 2.20 mmol, 2.2 equiv.) and the resulting mixture was heated at the reflux temp. overnight. The resulting orange solution was concentrated under reduced pressure and the residue was triturated with EtOAc (25 mL). The remaining solids were washed with EtOAc (25 mL), and the combined EtOAc phases were concentrated under reduced pressure. The residue was absorbed onto SiO2 and purified by MPLC (Biotage 40 S silica gel column; 5% EtOAc/hex) to give (4S)-3,4-diisobutyl-1,3-thiazolidin-2-thione as a yellow oil (0.11 g, 52%).

Step 2 A solution of (4S)-3,4-diisobutyl-1,3-thiazolidin-2-thione (5.0 g, 21.6 mmol) in SOC12 (31 mL, 0.43 mol) and was heated at 70 °C for 2.5 h, then was cooled to room temp. and concentrated under reduced pressure to afford (4S)-2-chloro-3,4- chloride as a semisolid:'H NMR 8 0.99- 1.10 (m, 12H), (m, 1H), 1.72-1.84 (m, 1H), 2.00-2.10 (m, 1H), 2.17-2.29 (br m, 1H), 3.61-3.68 (m, 1H), 3.86-3.95 (br m, 2H), 4.50-4.57 (m, 1H), 4.97-5.06 (br m, 1H). This material was dissolved in dichloroethane (180 mL) to make a 0.12 M stock solution (assuming quantitative conversion to the thiazolidinium chloride).

C. Methods for the Synthesis of Imino Heterocycles Cla. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S)- 2- (2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine.

To a mixture of (lS)-1-(chloromethyl)-3-methylbutanammonium chloride (Method B7a; 1.14 g, 3.71 mmol) and 2-methyl-4-nitrophenyl isothiocyanate (0.72 g, 3.71 mmol) suspended in CH2Cl2 (15 mL) was added Et3N (1.08 mL, 7.78 mmol) via syringe. The resulting solution was stirred for 18 h at room temp. The reaction mixture was washed with a saturated NaHC03 solution and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 10% EtOAc/hex to 30% EtOAc/hex) to afford (4S)-2-(2-methyl-4- nitrophenylimino)-4-isobutyl-1,3-thiazolidine (0.91 g, 47%): TLC (25% EtOAc/hex) Rf 0.46.

Clb. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S)- 2- (4-cyano-2-ethylphenylimino)-3, 4-diisobutyl-1,3-thiazolidine HCI salt.

To a solution of N-(1-S)-(1-(chloromethyl)-3-methylbutyl)-N-(isobutyl) amine HC1 salt (Method B7c; 95 g, 0.41 mol, 1.08 equiv.) in CH2Cl2 (1.1 L) at 15 °C was added 4-cyano-2-ethylphenyl isothiocyanate (Method A2b; 72 g, 0.38 mol) followed by diisopropylethylamine, (200 mL, 1.15 mol, 3.0 equiv.) generating a slight exotherm. When the reaction had cooled back to room temp., the ice bath was removed and the reaction was stirred at room temp. for 4 h. The reaction was then diluted with CH2Cl2 (500 mL), washed with a 1N NaOH solution (3x500 mL), dried (MgSO4) and concentrated under reduced pressure. The residual dark oil (132 g) was dissolved in CH2Cl2 (50 mL) and filtered through a plug of silica gel (5 g SiO2/g crude product) with the aid of a 5% EtOAc/hexane solution to give an oil (120 g), which was dissolved in EtOAc (400 mL) and slowly treated with an HCl solution (1M in Et20,500 mL) to give (4S)-2- (4-cyano-2-ethylphenylimino)-3,4-diisobutyl-

1,3-thiazolidine HCI salt as a white solid (95 g, 66%):'H NMR (CDC13) 8 0.96 (d, J=5.9 Hz, 3H), 1.02 (d, J=6.3 Hz, 3H), 1.12 (m, 6H), 1.23 (t, J=7.7 Hz, 3H), 1.46- 1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q, J=7.7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J=11.4,7.7 Hz, 1H), 4.18-4.25 (m, 1H), 5.02 (dd, J=14.3,8.1 Hz, 1H), 7.32 (d, J=8.1 Hz 1H), 7.51 (dd, 1H,. 7=8.1,1.8 Hz, 1H), Hz, 1H).

Clc. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S)- 2- (2-chloro-4-cyano-6-methylphenylimino)-4-isobutyl-1, 3-thiazolidine.

To a slurry of 2-chloro-4-cyano-6-methylphenyl isothiocyanate (0.10 g, 0.50 mmol) and poly (4-vinylpyridine) (0.030 g) in CH2C12 was added a solution of (lS)-1- (chloromethyl)-3-methylbutanammonium chloride (Method B7a; 0.086 g, 0.50 mol, 1.0 equiv) in DMF (2 mL) and the resulting mixture was stirred at 55 °C for 16 h, then concentrated under reduced pressure. The residue was purified by column chromatography (30 g, gradient from 10% EtOAc/hex to 20% EtOAc/hex) to give (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-4-isobutyl-1,3 -thiazolidine (0.052 g, 34%).

Cld. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S)- 2- (4-chloro-2- (trifluoromethyl) phenylimino)-3-isobutyl-1,3-thiazolidine.

N (Hydroxyethyl)-N-isobutylamine was converted into N (chloroethyl)-N- isobutylammonium chloride in a manner analogous to Method B7c. To a slurry of N (chloroethyl)-N-isobutylammonium chloride (0.10 mmol, 0.10 M) and poly (4- vinylpyridine) (0.030 g) in DMF (1.0 mL) was added a 4-chloro-2- (trifluoromethyl) phenyl isothiocyanate solution (0.25 M in THF, 0.40 mL, 0.10

mmol) and the resulting mixture was heated at 55 °C for 16 h in a sand bath. The resulting slurry was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (C-18 column, gradient from 0.1% TFA/20% CH3CN/79.9% water to 0.1% TFA/99.9% CH3CN) to furnish (4S)-2- (4-chloro-2- (trifluoromethyl) phenylimino)-3-isobutyl-1,3-thiazolidine (0.020 g, 59%).

Cle. General method for the synthesis of 2-imino-1, 3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2- (2, 4-dimethyl- 3-cyano-6-pyridylimino)-3-thia-1-azaspiro [4.4] nonane.

To a solution of 1-chloromethylcyclopentanamine HCl salt (Method B7e; 0.25 g, 1.32 mmol) and 2,4-dimethyl-3-cyano-5-pyridyl isothiocyanate (Method A2c; 0.23 g, 1.32 mmol) in anh. 1,2-dichloroethane (10 mL) was added Et3N (1 mL) dropwise via syringe. The resulting mixture was heated at 50 °C overnight, then cooled to room temp., and treated with a saturated NaHC03 solution. The resulting mixture was extracted with CH2Cl2 (3x25 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2,40% EtOAc/hex) to give 2- (2,4-dimethyl-3-cyano-6- pyridylimino)-3-thia-1-azaspiro [4.4] nonane (0.192 g, 51%): CI-MS m/z 287 ( (M+H) +).

Clf. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2- (3- quinolylimino)-3, 5-diisobutyl-1,3-thiazolidine.

3-Quinoline isothiocyanate was prepared in a manner analogous to Method A2c. To a solution of 3-quinoline isothiocyanate (0.1 g, 0.54 mmol) and N- (I-S)- (l- (chloromethyl)-3-methylbutyl)-N-(isobutyl) amine HC1 salt (Method B7c; 0.113g, 0.54 mmol) in anh. CH2Cl2 (2 mL) was added diisopropylethylamine (0.208 g, 1.61 mmol) dropwise. The resulting mixture was allowed to stir at room temp. overnight, then was concentrated under reduced pressure. The residue was purified by chromatography (SiO2,30% EtOAc/hex) to give 2- (3-quinolylimino)-3,5-diisobutyl- 1,3-thiazolidine (0.02 g, 0.9%): ES-MS m/z 342 ( (M+H) +).

C2a. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2- (2-methyl-4- nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane.

To a solution of 1-amino-1- (hydroxymethyl) cyclopentane (Method B 1 c; 20.7 g, 180 mmol) and HCl (4M in p-dioxane, 400 mL) was added SOC12 (15.7 mL, 216 mmol) and the resulting solution was heated at 100 °C for 18 h. The reaction mixture was concentrated under reduced pressure, then treated with 2-methyl-4- nitrophenyl isothiocyanate (31.4 g, 162 mmol) and 1,2-dichloroethane (400 ml), followed by N-methylmorpholine (49 mL, 449 mmol). The resulting mixture was heated at 70 °C for 18 h, cooled to room temp. and concentrated under reduced pressure. The residue was treated with hot EtOAc, filtered and concentrated under reduced pressure. The residue was recrystallized (MeOH) to yield 2- (2-methyl-4- nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane (38.3 g, 81%): TLC (25% EtOAc/hex) Rf 0.27.

C2b. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 1-isobutyl-2- (2-methyl-4- nitrophenylimino)-3-thia-1-azaspiro [4.5] decane.

1-Amino-1- (hydroxymethyl) cyclohexane (Method Bla) was dissolved in p- dioxane (80 mL) then treated with SOC12 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to give 2- (2-methyl-4- nitrophenylimino)-3-thia-1-azaspiro [4.5] decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to yield 1-isobutyl-2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.5] decane (0.026 g, 2%): TLC (20% EtOAc/hex) RfO. 69.

C2c. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2- (2-methyl-4- nitrophenylimino)-3-isobutylspiro [1,3-thiazolidine-4,2'- bicyclo [2.2.1] heptane].

2- (Isobutylamino)-2- (hydroxymethyl) norbomane (Method B2a; 0.24 g, 1.2 mmol) was treated with SOCIz followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to yield 2- (2-methyl-4-nitrophenylimino)-3- (2- isobutylspiro [1,3-thiazolidine-4,2'-bicyclo [2.2.1] heptane] as an oil (0.022 g, 5%): TLC (25% EtOAc/hex) Rf 0.72.

C2d. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 3-isobutyl-4-methylene-2- (2- methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one and (4S)-3-isobutyl-4- carbomethoxy-2- (2-methyl-4-nitrophenylimino)-1, 3-thiazolidine HCI salt.

(R)-N-Isobutylserine methyl ester HCl salt (Method B3a; 2.28 g, 10.8 mmol) was treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a. The resulting material was purified by column chromatography (SiO2, gradient from hexane to 10% EtOAc/hex) to give 3-isobutyl- 4-methylene-2- (2-methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one (0.028 g, 10%) followed by (S)-3-isobutyl-4-carboniethoxy-2- (2-methyl-4-nitrophenylimino)-1,3- thiazolidine HCl salt (0.192 g, 56%). 3-Isobutyl-4-methylene-2- (2-methyl-4- nitrophenylimino)-1,3-thiazolidin-5-one: TLC (25% EtOAc/hex) Rf 0.40. (S)-3- isobutyl-4-carbomethoxy-2- (2-methyl-4-nitrophenylimino)-1,3-thiazolidine HCl salt: TLC (free base, 25% EtOAc/hex) Rf 0.50.

C2e. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 1-cyclohexyl-2- (2-methyl-4- nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane.

1-(Cyclohexylamino)-1-(hydroxymethyl) cyclopentane(Cyclohexylamino)-1-(hydroxymethyl) cyclopentane (Method B4a; 1.89 g, 9.59 mmol) was reacted with SOCS2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to yield 1-cyclohexyl-2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane (0.44 g, 17%): CI-MS m/z 374 ( (M+H) +).

C2f. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2- (2-methyl-4- nitrophenylimino)-3-isobutyl-4,4-dimethyl-1,3-thiazolidine.

N-Isobutyl-1, 1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a. HCl was bubbled into a solution of N-isobutyl-1,1- dimethyl-2-hydroxyethanamine (1.45 g, 10 mmol) in toluene (20 mL) until saturation. SOC'2 (10 mmol) was added to the solution dropwise at room temp., stirred at room temp. for 1 h and at 50 °C, for 1 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in CHCl3 (20 mL). To the resulting solution was added 2-methyl-4-nitro-phenyl isothiocyanate (1.94 g, 10 mmol), then a solution of Et3N (10 mmol) in CHCl3 (10 mL) was added dropwise at room temp. The resulting mixture was heated at the reflux temp. for 3 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), and the resulting solution was sequentially washed with a 10% aq. NaOH solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (9% EtOAc/pet. ether) and the resulting solids were recrystallized (pet. ether) to give 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-4,4-dimethyl-1,3-th iazolidine (0.6 g, 63%): mp 97 °C. When appropriate, the product was converted into the HCl salt by dissolving the free base (5 mmol) in EtO (50 mL) and treating this solution with a 2N ethereal HCl solution until no more solid precipitated. The resulting slurry was filtered and the resulting solids were washed with Et2O (25 mL) followed by EtOAc (25 mL).

C3a. General method for the synthesis of 2-imino-1, 3-thiazolidine homologues via conversion of hydroxyalkylamines into chloroalkylamines followed by reaction with isothiocyanates. Synthesis of (R)-4-isopropyl-2- (2- methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-1,3-thiazine.

(R)-3- (tert- Butoxycarbonylamino)-4-methylpentanol (Method B6a) was reacted with SOC12 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner

analogous to Method C2a to afford (R)-4-isopropyl-2- (2-methyl-4- nitrophenylimino)-2,3,4,5-tetrahydro-1,3-thiazine (100%).

C4a. General method for the synthesis of 2-imino-1,3-oxazolidines via reaction of 2-chloroethylamines with isocyanates. Synthesis of 1-cyclohexyl-2- (2- methyl-4-nitrophenylimino)-3-oxa-1-azaspiro [4.4] nonane.

To a solution of 1- (chloromethyl)-1- (cyclohexylamino) cyclopentane HCl salt (Method B7b; 1.06 g, 4.2 mmol) and 2-methyl-4-nitrophenyl isocyanate (0.75 g, 4.2 mmol) in 1,2-dichloroethane (10 mL) was added N-methylmorpholine (0.92 mL, 8.4 mmol). The resulting mixture was heated to 50 °C for 18 h, then cooled to 20 °C and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from hexane to 10% EtOAc/hex) to yield 1-cyclohexyl-2- (2-methyl- 4-nitrophenylimino)-3-oxa-1-azaspiro [4.4] nonane (0.021 g, 1.4%): CI-MS mlz 358 ( (M+H) +).

C5a. General method for the synthesis of 2-iminoheterocycles via reaction of aminoethylsulfonate esters with isocyanates or isothiocyanates.

Synthesis of 2- (2-methyl-4-nitrophenylimino)-3- (2-methylprop-2-enyl)- 1,3-oxazolidine.

To a solution of N-(2-tosyloxyethyl)-2-methylprop-2-en-1-ammonium trifluoroacetate (Method B8b, Step 4 ; 0.21 g, 0.548 mmol) inp-dioxane (5 mL) was added 2-methyl-4-nitrophenyl isocyanate (0.0955 g, 0.536 mmol), followed by Et3N (0.080 mL, 1.15 mmol). The resulting mixture was stirred at 37 °C overnight, cooled to room temp., and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL) and washed with water (50 mL). The organic layer was extracted with a 2N HCl solution. The aqueous layer was made basic with a IN NaOH solution, and was extracted with CH2Cl2 (50 mL). The organic phase was dried

(Na2SO4) and concentrated under reduced pressure to give 2- (2-methyl-4- nitrophenylimino)-3- (2-methylprop-2-enyl)-1,3-oxazolidine as a yellow oil (0.020 g, 14%) CI-MS m/z 276 ( (M+H) +).

C5b. General method for the synthesis of 2-iminoheterocycles via reaction of aminoethylsulfonate esters with isocyanates or isothiocyanates.

Synthesis of (4S)-4-(1 (R)-terf-butoxyethyl)-3-isobutyl-2-(2-methyl-4- nitrophenylimino)-1,3-thiazolidine.

(1 R, 2R)-1-(Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride (Method B8a; 1.5 g, 5.5 mmol) was reacted with 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to that described in Method Cla to afford 4 (S)- (1 (R)-tert-butoxyethyl)-2-(2-methyl-4-nitrophenylimino)-1,3-th iazolidine (1.2 g, 67%). The (45)-2- (2-methyl-4-nitrophenylimino)-4- (1 (R)-tert-butoxyethyl)-1,3- thiazolidine was reacted with isobutyl bromide in a manner analogous to Method D2a to yield (4S)-4-(l (R)-tert-butoxyethyl)-3-isobutyl-2-(2-methyl-4- nitrophenylimino)-1,3-thiazolidine (0. 26 g, 56%): TLC (25% EtOAc/hex) Rf0.67.

C6a. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of chloroethylamines into 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of (4S)-2- (4-cyano-2-

To a solution of sodium hydrogen sulfide (69 g, 1.2 mol, 2.2 equiv.) in water (500 mL) was added N (l-S)- (1- (chloromethyl)-3-methylbutyl)-N (isobutyl) amine HCl salt (Method B7c; 126 g, 0.55 mol, 1.0 equiv.). The resulting mixture was stirred at room temp. for 8 h, then 4-cyano-2-ethylphenyl isocyanide dichloride

(Method A3a; 125 g, 0.5 mol, 1.0 equiv.) was added followed by isopropyl alcohol (500 mL). The resulting mixture was stirred at room temp. for 1 h, then a 3.6M K2CO3 solution (305 mL, 2.0 equiv., 1.1 mol) was added and the mixture was stirred at room temp. overnight. The resulting organic layer was concentrated under reduced pressure and the residue treated with EtOAc (2 L). The organic layer was washed with water (2x500 mL), dried (MgS04) and concentrated under reduced pressure to give a dark oil (160 g). The oil was dissolved in CH2Cl2 (150 mL) and passed through a silica gel plug (3 g SiO2/1 g crude product) with the aid of a 5% EtOAc/hex solution to afford an oil containing the desired product and some residual isocyanide dichloride (134 g). The oil was dissolved in EtOAc (500 mL) and treated with HCl (IN in Et20,500 mL). The resulting (4S)-2- (4-cyano-2-ethylphenylimino)- HCl salt was removed by filtration (147 g, 70%):'H NMR (CDCl3) 8 0.96 (d, J=5.9 Hz, 3H), 1.02 (d, J=6.3 Hz, 3H), 1.12 (m, 6H), 1.23 (t, J=7.7 Hz, 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q, J=7.7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J=11.4,7.7 Hz, 1H), 4.18-4.25 (m, 1H), 5.02 (dd, J=14.3,8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.1,1.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H).

C6b. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of chloroethylamines into 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of 1-cyclopentyl-2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane HCI salt.

To a solution of sodium hydrogen sulfide (31 g, 0.55 mol, 2.2 equiv.) in water (250 mL) was added 1- (chloromethyl)-1-(cyclopentylamino) cyclopentane HCl salt.

(Method B7d; 60 g, 0.25 mol, 1.0 equiv.) The reaction mixture was stirred at room temp. for 8 h then 2-methyl-4-nitrophenyl isocyanide dichloride (Method A3b; 125 g, 0.25 mol, 1.0 equiv.) was added followed by isopropyl alcohol (300 mL). The reaction mixture was stirred at room temp. for 1 h, then a 3.6M K2CO3 solution (305 mL, 2.0 equiv., 0.5 mol) was added. The reaction was stirred at room temp. overnight. The resulting upper aqueous organic layer was separated and concentrated under reduced pressure and the residue was treated with EtOAc (1 L). The resulting

organic layer was washed with water (2x200mL), dried (MgS04) and concentrated under reduced pressure. The residual oil (86 g) was dissolved in CH2Cl2 (50 mL) and filtered through a plug of silica gel (3 g SiO2/1 g crude product) with the aid of a 5% EtOAc/hex solution to afford an oil (34 g) containing the desired product and some residual isocyanide dichloride. This oil was dissolved in EtOAc (300 mL) and with HCl (IN in Et2O, 1.5 L). The resulting solids were removed by filtration to give 1- cyclopentyl-2- (2-methyl-4-nitrophenylimino)-3-thia-l-azaspiro [4.4] nonane HCl salt as a white powder (36.8 g):'H NMR (CD30D) 8 1.40-1.55 (m, 2H), 1.55-1.68 (m, 2H) 1.68-1.80 (m, 8H), 1.80-2.00 (m, 4H), 2.16 (s, 3H), 3.16 (s, 2H), 3.60-3.70 (m, 1H) 6.70 (br s, 1H), 6.93 (d, J=8.4 Hz, 1H), 7.96-8.04 (m, 1H), 8.03 (d, J=3 Hz, 1H).

C6c. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of hydroxyethylamines into 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of 1-cyclopentyl-2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane.

Step 1 To a 0 °C solution of Ph3P (27.9 g, 0.107 mol, 1.3 equiv.) in anh. THF (400 mL) were successively added diisopropyl azodicarboxylate (21.5 g, 0.107 mol, 1.3 equiv.) and 1-cyclopentylamino-1- (hydroxymethyl) cyclopentane (Method B4d; 15.0 g, 0.082 mol). The resulting slurry was stirred for 30 min., then was treated with thiolacetic acid (7.6 mL, 0.107 mol, 1.3 equiv.). The resulting yellow solution was stirred for 15 min. and concentrated under reduced pressure to about 100 mL. The residue was dissolved in EtOAc (200 mL) and the resulting solution was extracted with a IN HC1 solution (5x125 mL). The combined aqueous layers were washed with EtOAc (2x200 mL), neutralized with K2CO3 to pH 7.0-7.5, then extracted with EtOAc (5x200 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. The residue was dried in vacuo to afford 1- cyclopentylamino-1-(thioacetylmethyl)(thioacetylmethyl) cyclopentane as a yellow oil (19.1 g): TLC (10% EtOAc/hexanes) Rif 0.16;'H NMR (CDCL) 8 1.20-1.87 (m, 16H), 2.34 (s, 3H), 2.92-3.02 (m, 1H), 3.15 (s, 2H); 3C NMR (CDCL) 8 23.9,25.2,29.3,36.4,40.1, 55.8,73.0,169.8; CI-LRMS m/z (rel abundance) 242 ((M+H) +, 100%).

Step 2 A solution of 1-cyclopentylamino-1- (thioacetylmethyl) cyclopentane (19.1 g) in a 0.33 M KOH solution in 9: 1 MeOH: H20 (273 mL, 0.090 mol, 1.1 equiv.) was stirred for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was dried in vacuo for to afford crude 1-cyclopentylamino-1- (thiomethyl) cyclopentane as a yellow oil: TLC (10% EtOAc/hexanes) Rf 0.18 (streak);'H NMR (CD30D) 8 1.32-1.71 (m, 14H), 1.87-1.94 (m, 2H), 2.67 (s, 2H), 3.07-3.14 (m, 1H); FAB-LRMS m/z (rel abundance) 200 ((M+H) +, 19%). This material was used immediately in the next step without further purification Step 3 A solution of crude 1-cyclopentylamino-1- (thiomethyl) cyclopentane anh.

CH2Cl2 (100 mL) at 0 °C was treated with a slurry of crude 2-methyl-4-nitrophenyl isocyanide dichloride (Method A3b; 19.1 g, 0.082 mol, 1.0 equiv. based on 1- cyclopentylamino-l- (thioacetylmethyl) cyclopentane) in CH2Cl2 (200 mL) followed by Et3N (30 mL, 0.215 mol, 2.6 equiv.), and the reaction mixture was allowed to warm to room temp. and stirred for 2 d. N, N-Dimethylethylenediamine (92 g, 0.023 mol, 0.3 equiv.) was added and the reaction mixture was stirred for 1 h. Silica gel (50 g) was added and the resulting mixture was concentrated under reduced pressure.

The residue was dried in vacuo overnight and purified by flash chromatography (l lx10 cm SiO2,5% EtOAc/hex) to afford 1-cyclopentyl-2- (2-methyl-4- nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane as a yellow granular solid (17.8 g, <BR> <BR> 60% overall): mp 120-121 °C; TLC (10% EtOAc/hexanes) Rf 0.45;'H NMR (CDCL) 8 1.47-1.91 (m, 14H), 2.22 (s, 3H), 2.46-2.55 (m, 2H), 3.03 (s, 2H), 3.66 (pent, J=8.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 7.95-8.03 (m, 2H); 13C NMR (CDCl3) 8 18.3,24.3,25.6,28.5,36.0,40.6,56.7,75.3,120.6,122.3,125.3,13 2.0,142.3, 155.1,157.4; LC-LRMS m/z (rel abundance) 360 ((M+H) +, 100%). Anal. Calcd. For Cl9H25N302S : C, 63.48; H, 7.01; N, 11.69. Found: C, 63.48; H, 6.89; N, 11.76.

C7a. General method for the synthesis of 2-imino-1, 3-oxazolidines via reaction of hydroxyethylamines with aryl isocyanate dichlorides. Synthesis of 2- (4-cyano-2-ethylphenylimino)-3-cyclopentyl-4, 4-dimethyl-1,3- oxazolidine.

A solution of N-cyclopentyl- (1, 1-dimethyl-2-hydroxyethyl) amine (Method B4b; 0.12 g, 0.69 mmol) in THF (2.5 mL) was added dropwise via syringe to a slurry of NaH (95%, 0.05 g, 1.2 mmol) in THF (5 mL) room temp. The reaction mixture was stirred 15 min, then a solution of 4-cyano-2-ethylphenyl isocyanate dichloride (Method A3a; 0.15 g, 0.63 mmol) in THF (2.5 mL) was added dropwise via syringe.

The resulting mixture was stirred overnight, then treated with a 5% citric acid solution (10 mL), followed by EtOAc (25 mL). The organic phase was sequentially washed with 5% citric acid solution (20 mL), H2O (20 mL) and a saturated NaCl solution (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2,5% EtOAc/hex) to give 2- (4-cyano- as a yellow solid (0.09 g, 43%): mp 112-114 °C; TLC (15% EtOAc/hex) Rf0.60;'H NMR (CDCl3) 8 1.16 (t, J=7.5 Hz, 3H), 1.32 (s, 6H), 1.49-1.61 (m, 2H), 1.71-1.81 (m, 2H), 1.82-1.92 (m, 2H), 2.38-2.50 (m, 2H), 2.61 (q, J=7.6 Hz, 2H), 3.52-3.58 (m, 1H), 3.97 (s, 2H), 7.04 (d, J=8.3 Hz, 1H), 1.8 Hz, 1H), 7.40 (d, J=1.8 Hz, 1H); CI-MS m/z (rel abundance) 312 ((M+H) +, 100%). HRMS Cacld for C,H23N3O3 : 311.1998.

Found: 311.1991.

C7b. General method for the synthesis of 2-imino-1,3-oxazolidines via reaction of hydroxyethylamines with aryl isocyanate dichlorides. Synthesis of (4S)-2- (4-cyano-2-ethylphenylimino)-3, 4-diisobutyl-1,3-oxazolidine.

A solution of 4-cyano-2-ethylphenyl isocyanide dichloride (Method A3a; 0.42 g, 1.83 mmol, 1.2 equiv.) and (2S)-4-methyl-2-(isobutylamino) pentan-1-ol (Method B4c; 0.26 g, 1.52 mmol) in THF (5 mL) was added Et3N (0.5 mL). The resulting mixture was stirred at room temp. for 1 h, then was treated with 2- (dimethylamino) ethylamine (0.5 mL). This mixture was stirred at room temp. for 1 h, then concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 5% EtOAc/hex to 10% EtOAc/hex) to give (4S)-2- as a yellow oil (0.15 g): TLC (10% EtOAc/hex) Ru 0.35;'H NMR (CDCl3) 8 0.81-1.00 (m, 12H), 1.14 (t, J=4.8Hz, 3H), 1.25-1.43 (m, 2H), 1.53-1.70 (m, 2H), 2.57 (sept, J=7.5 Hz, 1H), 2.58 (q, J=7.5 Hz, 2H), 3.01 (dd, J=14.0,6.3 Hz, 1H), 3.33 (dd, J=13.6,8.8 Hz, 1H), 3.73- 3.83 (m, 1H), 3.94 (app t, J=7.5 Hz, 1H), 4.37 (app t, J=7.9 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 7.33 (dd, J=8.1,1.8 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3) 8 13.8,19.9,20.3,21.8,23.6,24.7,24.9,26.7,40.6,50.1,55.3,70.1, 104.1,120.2, 123.4,129.9,131.8,138.4,151.4,152.9; HPLC ES-MS m/z 328 ((M+H) +, 100%).

C8a. General method for the synthesis of 2-inimo-4-oxoheterocycle synthesis via reaction of an isothiocyanate with an amine, followed by reaction with a haloacid halide. Synthesis of 2- (2-methyl-4-nitrophenylimino)-3- isobutyl-1,3-thiazolidin-4-one.

To a solution of 2-methyl-4-nitrophenyl isothiocyanate (0.190 g, 1.0 mmol) in DMF (5.3 mL) was added isobutylamine (0.4 M solution in DMF, 5.3 mL) and the reaction mixture was allowed to stir for 4 h at which time TLC analysis (hexane: EtOAc 3: 1) indicated consumption of the isothiocyanate. To the resulting mixture was added chloroacetic acid (0.8 M solution in DMF, 4.0 mL) followed by N-methylmorpholine (0.7 mL, 6.4 mmol). The reaction mixture was stirred at 80 °C for 18 h, then was partitioned between water (10 mL) and EtOAc (25 mL). The aqueous phase was back-extracted with EtOAc (2x10 mL). The combined organic layers were washed with a saturated NaCl solution (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by MPLC (Biotage 40 S silica gel column, gradient from 5% EtOAc/hex to 33% EtOAc/hex) to afford 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-o ne as a pale yellow oil (0.52 g, 85%).

C9a. General method for the synthesis of 2-imino-1,3-thiazolidines by reaction of hydroxyethylamines with isothiocyanates followed by acid catalyzed ring closure. Synthesis of 2- (2, 6-dichlorophenylimino)-3- cyclohexyl-4, 4-dimethyl-1,3-thiazolidine.

N-Cyclohexyl-1, 1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a. A solution of 2,6-dichlorophenyl isothiocyanate (1. 2 g, 6.0 mmol) and N-cyclohexyl-1, 1-dimethyl-2-hydroxyethanamine (l. Og, 6.0 mmol) in CH2Cl2 (10 mL) was stirred for 20 h at room temp. The resulting mixture was concentrated under reduced pressure, then treated with a 33% HCl solution (15 mL).

The resulting mixture was heated at the reflux temp. for 1 h, cooled to room temp. and neutralized with a 45% NaOH solution. The resulting slurry was filtered, and the resulting solids were washed with water (20 mL), then recrystallized (EtOH) to yield 2- (2,6-dichlorophenylimino)-3-cyclohexyl-4,4-dimethyl-1,3-thia zolidine (0.70 g, 33%): mp 134 °C. When appropriate, the product was converted into the HCl salt by dissolving the free base (5 mmol) in Et2O (50 mL) and treating this solution with a 2N ethereal HCl solution until no more solid precipitated. The resulting slurry was filtered and the resulting solids were washed with Et2O (25 mL) followed by EtOAc (25 mL).

ClOa. General method for the reaction of 2-chlorothiazolinium salts with anilines. Synthesis of 2- (2- (N-phenylcarbamoyl) phenylimino)-3,4- diisobutyl-1, 3-thiazolidine.

A solution of 2- (N-phenylcarbamoyl) aniline (0.097 g, 0.36 mmol, 1.0 equiv.) and Et3N (0.5 mL, 3.6 mmol, 10 equiv.) in p-dioxane (5 mL) was added to a solution

of (4S)-2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride in dichloroethane (Method BlOa; 0.12 M, 0.5 mL, 0.36 mmol). The resulting mixture was heated at 70 °C overnight, then was cooled to room temp., and diluted with EtOAc (25 mL). the EtOAc mixture was sequentially washed with water (2x25 mL) and a saturated NaCl solution (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was absorbed onto SiO2, and purified by MPLC (Biotage 40 S silica gel column; 5% EtOAc/hex) to give 2- (2- (N phenylcarbamoyl) (0.090 g, 61%).

Clla. General method for synthesis of 2-imino-1,3-thiazolidin-5-ones via reaction of amino acid esters with isothiocyanates. Synthesis of 2- (2- methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-5-one.

A solution of N-isobutylglycine ethyl ester (0.41 g, 2.57 mmol) in water (5 mL) was treated with Et3N (0.71 mL, 5.15 mmol), followed by a solution of 2- methyl-4-nitrophenyl isothiocyanate (0.50 g, 2.57 mmol) in acetone (5 mL). The resulting mixture waxs heated at 40 °C for 2 h, then cooled to room temperature and concentrated under reduced pressure. The residue was separated between water (25 mL) and ethyl acetate (25 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford 2- (2-methyl-4-nitrophenylimino)-3- isobutyl-1,3-thiazolidin-5-one (0.16 g, 88%): mp 152 °C.

D. General Methods for the Interconversion of Iminoheterocycles Dla. General method for the neutralization of iminoheterocycle salts.

Synthesis of (4S)-2-(4-cyano-2-ethylphenylimino)-3, 4-diisobutyl-1,3- thiazolidine.

To a mixture of (4S)-2- (4-cyano-2-ethylphenylimino)-3, 4-diisobutyl-1,3- thiazolidine HCl salt (Method C6a; 304 g, 0.8 mol), water (1 L) and EtOAc (1.4 L) was added NaHC03 (150 g, 1.78 mol, 2.2 equiv.). The resulting mixture was stirred for 1 h. The organic layer was dried (MgS04) and concentrated under reduced pressure. The resulting viscous oil was treated with EtOH and concentrated under reduced pressure twice to afford (4S)-2- (4-cyano-2-ethylphenylimino)-3,4- diisobutyl-1,3-thiazolidine as a low melting solid (264 g, 96%): mp 50 °C; [a] D = +2.4, (c 1.0, CH30H);'H NMR (CDC13) 80.92-0.99 (m, 12H), 1.13 (t, J=7.4 Hz, 3H), 1.47-1.52 (m, 1H), (m, 2H), 2.07-2.11 (m, 1H), 2.54 (q, J=7.4 Hz, 2H), 2.84-2.90 (m, 2H), 3.28 (dd, J=10.6,6.6 Hz, 1H), 3.68 (dd, J=13.6,8.1, Hz, 1H), 3.81-3.87 (m, 1H), 6.85 (d, J=7.9 Hz, 1H), 7.36-7.42 (m, 2H); CI-MS m/z 344 ( (M+H) +).

Dlb. General method for the neutralization of iminoheterocycle salts.

Synthesis of 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1- azaspiro [4.4] nonane.

To 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino)-3-thia-1- azaspiro [4.4] nonane HCl salt (Method C6b; 52.4 g, 0.132 mol) dissolved in a mixture of water (300 mL) and EtOAc (500 mL) was added NaHC03 (15 g, 0.178 mol, 1.3 equiv.). The mixture was stirred for 1 h and the resulting organic layer was dried (MgSO4) concentrated under reduced pressure. The resulting light yellow solid was treated with EtOH (lOOmL), and concentrated under reduced pressure twice to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane (46 g, 97%): mp 111-112 °C;'H NMR (CDC13) 8 1.49-1.53 (m, 2H), 1.63-1.80 (m, 8H), 1.81-1.91 (m, 4H), 2.21 (s, 3H), 3.02 (s, 2H), 3.60-3.70 (m, 1H), 6.87 (d, J=8.5 Hz, 1H), 8.02 (m, 2H); CI-MS m/z 360 ((M+H) +).

D2a. General method for the ring-nitrogen alkylation of 2-imino heterocycles.

Synthesis of (4S)-2- (2-methyl-4-nitrophenylimino)-3, 4-diisobutyl-1,3- thiazolidine HCI salt.

A slurry of (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazoli dine (Method Cla; 0.10 g, 0.34 mmol), isobutyl bromide (0.11 mL, 1.03 mmol) and Cs2CO3 (0.12 g, 0.38 mmol) in DMF (2 mL) was heated at 90 °C for 18 h, then cooled to 20 °C, diluted with EtOAc (50 mL) and washed with water (2x200 mL).

The organic phase was dried (MgS04), concentrated under reduced pressure, and the residue was purified by chromatography (SiO2, gradient from 100% hex to 10% EtOAc/hex). The resulting material was dissolved in CH2Cl2 (10 mL), treated with an HCl solution (1M in Et2O, 2 mL), then concentrated under reduced pressure to afford (4S)-2- (2-methyl-4-nitrophenylimino)-3, 4-diisobutyl-1, 3-thiazolidine HCl salt (0.088 g, 68%): TLC (free base, 20% EtOAc/hex) Rf0.74.

D2b. General method for the ring-nitrogen alkylation of 2-imino heterocycles.

Synthesis of 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1- azaspiro [4. 4] nonane.

A solution of 2- (2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane (Method C2a; 33.2 g, 114 mmol) in DMF (1 L) was treated with NaOH (690 g, 17.3 mol) and cyclopentyl bromide (865 mL, 6.3 mol) and the resulting mixture was stirred at 20-40 °C for 18 h, then cooled to 4 °C, and treated with water (1.5 L). A conc. HC1 solution was added to adjust the pH to 0, and the mixture was extracted with EtOAc (80 mL). The organic phase was washed with a IN HCl solution (1 L), dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in CPLCL : (500 mL) and filtered through a pad of silica gel (9x4 cm). Hexane was added to the resulting solution and volatiles were slowly removed by partial vacuum until crystals formed. The solids were collected to yield 1-cyclopentyl-2- (2-methyl- 4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane as yellow crystals (10.9 g, 26%): mp 118-9 °C; TLC (5% EtOAc/hex) RfO. 34.

D2c. General method for the ring-nitrogen alkylation of 2-imino heterocycles.

Synthesis of (4R)-3-isobutyl-4-isopropyl-2- (2-methyl-4- nitrophenylimino) tetrahydro-2H-1,3-thiazine.

(R)-4-Isopropyl-2- (2-methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-1,3- thiazine Method C3a) was reacted with isobutyl bromide in a manner analogous to Method D2a to yield (4R)-3-isobutyl-4-isopropyl-2- (2-methyl-4- nitrophenylimino) tetrahydro-2H-1,3-thiazine (0.081 g, 32%). TLC (33% EtOAc/hex) Rf0.76.

D2d. General method for the ring-nitrogen alkylation of 2-imino heterocycles.

2- (2-Methyl-4-nitrophenylimino)-3-propanoyl-1, 3-thiazolidine.

To a solution of 2- (2-methyl-4-nitrophenylimino)-1,3-thiazolidine (prepared in a manner analogous to that described in Method Cla; 0.084 g, 0.35 mmol) in CH2Cl2 (5 mL) was added propionyl chloride (0.033 g, 0.35 mmol) and Et3N (0.049 mL, 0.35 mmol). The mixture was allowed to stir at room temp for 1 h, then was diluted with CH2Cl2 (40 mL). The resulting solution was sequentially washed with H2O (10 mL) and a saturated NaCl solution (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc/hex) to give 2- (2-methyl-4-nitrophenylimino)-3-propanoyl-1,3- thiazolidine (0.036 g, 35%): FAB-MS m/z 294 ((M+H) +).

D2e. General method for the ring-nitrogen alkylation of 2-imino heterocycles.

Synthesis of 1- (cyclohexylmethyl)-2- (2-methyl-4-nitrophenylimino)-3- thia-1-azaspiro [4.4] nonane.

To a solution of 2-(2-methyl-4-nitrophenylimino)-3-thia-1- azaspiro [4.4] nonane (Method C2a; 0.1 Og, 0.3432 mmol) and bromomethylcyclohexane (1.00 mL) in DMF (1.00 mL) was added NaOH (approx.

0.13 g). The resulting mixture was stirred at 45 °C for 2 d during which it turned from deep red to bright orange. The reaction mixture was then cooled to room temp., filtered and concentrated under reduced pressure. The residual oil was purified by chromatography (SiO2; 5% EtOAc/hex) to afford 1- (cyclohexylmethyl)-2- (2-methyl- 4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane (0.042 g, 32%) mp 85-7 °C.

D2f. General method for the ring-nitrogen alkylation of 2-imino heterocycles.

Synthesis of (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-3,4- diisobutyl-1,3-thiazolidine trifluoroacetate salt.

To a solution of (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-4-isobutyl- 1,3-thiazolidine (Method Clc; 0.050 g, 0.16 mmol) in DMF (1.0 mL) was added NaH (0.0045 g, 1.1 equiv.), and the resulting mixture was stirred at room temp. for 5 min. Isobutyl bromide (0.053 mL, 3 equiv.) was then added and the resulting mixture was stirred at 98 °C for 4 h. The reaction mixture was filtered, then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (C-18 column, gradient from 0.1% TFA/20% CH3CN/79.9% water to 0.1% TFA/99.9% CH3CN) to furnish (4S)-2- (2-chloro-4-cyano-6- trifluoroacetate salt (0.030 g, 52% yield).

D2g. General method for the ring-nitrogen alkylation of 2-imino heterocycles.

Synthesis of 2- (2-methyl-4-nitrophenylimino)-3- (2-methyl-prop-2-enyl)- HBr salt.

2- (2-methyl-4-nitrophenylimino)-4, 4-dimethyl-1,3-thiazolidine was prepared in a manner analogous to that described in Method Cla. To a suspension of 2- (2- (1.5 mmol) in toluene (10 mL) was added 2-methylprop-2-en-1-yl bromide (4.5 mmol) and the reaction mixture was heated at the reflux temp. for 3 h at which time the reaction was judged complete by TLC. The resulting precipitate was filtered at 50 °C. The collected solids were washed with toluene (20 mL) and CH2C12 (20 mL) to yield 2- (2-methyl-4- nitrophenylimino)-3- (2-methyl-prop-2-enyl)-4, 4-dimethyl-l, 3-thiazolidine HBr salt (1.14 g, 77%): mp 229 °C.

D2h. General method for the ring-nitrogen alkylation of 2-imino heterocycles.

Synthesis of 2- (2, 4-dimethyl-3-cyano-6-pyridylimino)-1-isobutyl-3-thia-1- azaspiro [4.4] nonane.

To a solution of 2-(2, 4-dimethyl-3-cyano-6-pyridylimino)-3-thia-1- azaspiro [4.4] nonane (Method Cle; 0.192 g, 0.669 mmol) and isobutyl bromide (0.5 mL) in anh. DMF (0.5 mL) was added NaH (95%; 0.62 g, 6.69 mmol) portionwise.

The resulting mixture was heated at 50 °C for 3 h, then treated with MeOH (approximately 0.5 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 20% EtOAc/hex to 100% CH2C12) to give 2-(2, 4-dimethyl-3-cyano-6-pyridylimino)-1-isobutyl-3-thia-1- azaspiro [4.4] nonane (0.04 g, 17%): CI-MS m/z 343 ( (M+H) +).

D3a. General method for the deprotection of tert-butoxycarbamoyl-protected alcohols. Synthesis of (4S)-4- (l (R)-hydroxyethyl)-3-isobutyl-2- (2-methyl- 4-nitrophenylimino)-1,3-thiazolidine.

A solution of TFA (8 mL) was cooled to 4 °C and added to solid (4S)-4- (1(R)-tert-butoxyethyl)-3-isobutyl-2- (2-methyl-4-nitrophenylimino)-1,3-thiazolidine (Method C5b; 0.16 g, 0.42 mmol) via cannula. The resulting solution was warmed to 20 °C and stirred at that temp. for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between Et2O (100 mL) and a saturated NaHC03 solution (100 mL). The ether layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; gradient from hexane to 10% EtOAc/hex) to yield (4S)-4- (l (R)-hydroxyethyl)- 3-isobutyl-2- (2-methyl-4-nitrophenylimino)-1,3-thiazolidine (0.13 g, 90%): TLC (25% EtOAc/hex) Rf 0.13.

D4a. General method for the synthesis of 2-imino-1, 3-thiazolidine 3-oxides and 2-imino-1,3-thiazolidine 3,3-dioxides via oxidation of 2-imino-1, 3- thiazolidines. Synthesis of 1-cyclopentyl-2- (2-methyl-4- nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane 3-oxide and 1- cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1- azaspiro [4.4] nonane 3,3-dioxide.

A solution of 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1- azaspiro [4.4] nonane (Method D2b; 0.041 g, 0.11 mmol) and m-chloroperbenzoic acid (approximately 80%, 0.040 g, 0.19 mmol) in CH2C12 (5 mL) was stirred for 30 min., then washed with a saturated NaHC03, dried (MgS04), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from hexane to 30% EtOAc/hex) to yield 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)- 3-thia-1-azaspiro [4.4] nonane 3,3-dioxide (0.030 g, 67%) followed by 1-cyclopentyl- 2- (2-methyl-4-nitrophenylimino)-3-thia-l-azaspiro [4.4] nonane 3-oxide (0.011 g, 26%). 1-Cyclopentyl-2- (2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane

3,3-dioxide: TLC (25% EtOAc/hex) Rf 0.27.1-Cyclopentyl-2- (2-methyl-4- nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane 3-oxide: TLC (25% EtOAc/hex) Rf 0.10. <BR> <BR> <P>D5a. General method for the reduction of heterocycles containing ketones or aldehydes. Synthesis of 2- (2-methyl-4-nitrophenylimino)-3- (3,3- dimethyl-2-hydroxybutyl)-1,3-thiazolidine.

2- (2-Methyl-4-nitrophenylimino)-1,3-thiazolidine was prepared in a manner analogous to that described in method C2a and was alkylated with 1-bromo-3,3- dimethyl-2-butanone in a manner analogous to that described in Method D2a to give 2- (2-methyl-4-nitrophenylimino)-3- (3, 3-dimethyl-2-oxobutyl)-1,3-thiazolidine. To a solution of 2- (2-methyl-4-nitrophenylimino)-3- (3, 3-dimethyl-2-oxobutyl)-1,3- thiazolidine (0.022 g, 0.065 mmol) in MeOH (2 mL) was added NaBH4 (0.0096 g, 0.26 mmol) in portions. The resulting mixture was stirred at room temp for 4 h, then was separated between EtOAc (10 mL) and H20 (5 mL) and the aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were sequentially washed with H2O (15 mL), a saturated NaCl solution (15 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/hexane) to yield 2- (2-methyl-4-nitrophenylimino)-3- (3,3-dimethyl-2- hydroxybutyl)-1,3-thiazolidine (0.024 g, 92%): FAB-MS m/z 338 ((M+H) +).

D6a. General method for the interconversion of carboxylic acid derivatives.

Synthesis of (4S)-2- (4-carbamoyl-2-methylphenylimino)-3, 4-diisobutyl- 1,3-thiazolidine.

Step 1

To a solution of (4S)-2- (4-methoxycarbonyl-2-methylphenylimino)-3,4- diisobutyl-1,3-thiazolidine (prepared in a manner analogous to that described in Method D2a; 0.035 g, 0.097 mmol) in a mixture of MeOH (1.5 mL) and H20 (1.5 mL) was added LiOH (0.016 g, 0.39 mmol). The resulting mixture was stirred for 2 d at room temp., then was concentrated under reduced pressure. The residue was adjusted to pH 1 with a 1% HCl solution, then extracted with EtOAc (4x10 mL). The combined organic layers were sequentially washed with H20 (15 mL), a saturated NaCl solution (15 mL), and dried (Na2SO4). Concentration under reduced pressure gave (4S)-2- (4-carboxy-2-methylphenylimino)-3, 4-diisobutyl-1,3-thiazolidine (0.034 g, 100%): TLC (40% EtOAc/hex) Rf 0.08. This material was used in the next step without further purification.

Step 2 To a solution of (4S)-2- (4-carboxy-2-methylphenylimino)-3, 4-diisobutyl-1,3- thiazolidine (0.035 g, 0.10 mmol) in CH2C12 (5 mL) was added carbonyl diimidazole (0.047 g, 0.29 mmol). The mixture was allowed to stir at room temp. for 2 h, then anh NH3 (approximately 30 drops) was condensed into the solution at-78 °C. The resulting mixture was warmed to room temp. overnight, then treated with H2O (20 mL). The aqueous layer was extracted with CH2C12 (3x20 mL), sequentially washed with H20 (20 mL) and a saturated NaCl solution (20 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (40% EtOAc/hexane) to give (4S)-2- (4-carbarnoyl-2- as a white solid (0.027 g, 73%): mp 130-131 °C.

D6b. General method for the interconversion of carboxylic acid derivatives.

Synthesis of 2-(2-ethyl-4-(N-methylcarbamoyl) phenylimino)-1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

To a solution of 2- (4-carboxy-2-ethylphenylimino)-l-cyclopentyl-3-thia-l- azaspiro [4.4] nonane (Method D9a; 0.58 g, 0.167 mmol) in CHCl3 (5 mL) was added SOC12 (0.06 mL, 0.83 mmol). The reaction mixture was heated at the reflux temp. for 3 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (3 mL) and treated with methylamine (2.0M in THF, 4 mL). The reaction mixture was stirred at room temp. for 2 h, then treated with a 1N NaOH solution (10 mL).

The resulting mixture was extracted with CH2C12 (3x20 mL), and the combined organic layers were washed with a saturated NaC1 solution (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc/hexane) to give 2- (2-ethyl-4- (N-methylcarbamoyl) phenylimino)- 1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (36 g, 56%): TLC (30% EtOAc/hex) Rf 0.44.

D7a. General method for the synthesis of cyanoarylimines from iodoarylimines. Synthesis of 2- (4-cyano-2-propylphenylimino)-3-thia-l- azaspiro [4.4] nonane.

4-Iodo-2-n-propylaniline was converted into 4-iodo-2-n-propylphenyl isothiocyanate in a manner analogous to Method A2b. Concurrently, 1-amino-1- (hydroxymethyl) cyclopentane was converted to the chloromethyl analogue, then reacted with the isothiocyanate in a manner analogous to Method C2a to give 2- (4- iodo-2-propylphenylimino)-3-thia-1-azaspiro [4.4] nonane. A slurry of 2- (4-iodo-2- propylphenylimino)-3-thia-1-azaspiro [4.4] nonane (0.54 g, 1.35 mmol) and CuCN (0.24 g, 2.70 mmol) in DMF (4 mL) was heated at 140 °C overnight. The resulting mixture was cooled to room temp, concentrated under reduced pressure and purified by flash chromatography (10% EtOAc/hex) to give 2- (4-cyano-2-

propylphenylimino)-3-thia-1-azaspiro [4.4] nonane as a white solid (0.26 g, 65%): TLC (30% EtOAc/hex) Rf0.37.

D8a. General method for the synthesis of phenylacetylenes. Synthesis of 2- (2,3-dimethyl-4-ethynylphenylimino)-1-isobutyl-3-thia-1- azaspiro [4.4] nonane.

Step 1 4-Iodo-2,3-dimethylaniline was converted into 4-iodo-2,3-dimethylphenyl isothiocyanate in a manner analogous to Method A2b. 2- (2,3-Dimethyl-4- iodophenylimino)-3-thia-1-azaspiro [4.4] nonane was prepared in a manner analogous to that described in Method C2a, then was alkylated with isobutyl bromide in a manner analogous to that described in Method D2a. A mixture of the iodophenyl compound (0.009 g, 0.021 mmol), (trimethylsilyl) acetylene (30 mL, 0.21 mmol), Pd (PPh3) 2Cl2 (0.005 g) and Cul (0.012 g, 0.063 mmol) in Et3N (2 mL) was stirred at room temp. for 18 h. The resulting slurry was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (2% EtOAc/hex) to give 2-(2, 3-dimethyl-4-(2-trimethylsilyl-1-ethynyl) phenylimino)- 1-isobutyl-3-thia-1-azaspiro [4.4] nonane (0.005 g, 59%).

Step 2 A mixture of 2- (2, 3-dimethyl-4- (2-trimethylsilyl-l-ethynyl) phenylimino)-l- isobutyl-3-thia-1-azaspiro [4.4] nonane (0.005 g, 0.0125 mmol) and NaOH (0.006 g, 0.15 mmol) in MeOH (2 mL) was stirred overnight at room temp. The reaction mixture was diluted with CH2Cl2 (20 mL), filtered, and the filtrate was concentrated under reduced pressure. Thre residue was purified by preparative TLC (2%

EtOAc/hex) to give 2- (2, 3-dimethyl-4-ethynylphenylimino)-1-isobutyl-3-thia-1- azaspiro [4.4] nonane (0.003.2 g, 78%): TLC (20% EtOAc/hex) RfO. 70.

D9a. General method for the synthesis of benzoic acids via hydrolysis of benzonitriles. Synthesis of 2- (4-carboxy-2-ethylphenylimino)-l- cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

2- (4-Cyano-2-ethylphenylimino)-3-thia-l-azaspiro [4.4] nonane was prepared in a manner analogous to Method C2a and the thiazolidine was alkylated in a manner analogous to Method D2b to give 2- (4-cyano-2-ethylphenylimino)-l-cyclopentyl-3- thia-1-azaspiro [4.4] nonane. A solution of 2- (4-cyano-2-ethylphenylimino)-l- cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.32 g, 9.42 mmol) in conc. HC1 (15 mL) was heated at 100 °C overnight, then was cooled to room temp. to give a white precipitate. The resulting mixture was adjusted to pH 6.5 with a IN NaOH solution" then extracted with CH2Cl2 (4x40 mL). The combined organic layers were sequentially washed with water (30 mL) and a saturated NaCl solution (30 mL), dried (Na2SO4) and concentrated under reduced pressure. to give 2- (4-carboxy-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane as a white solid (0.34 g, 100%): mp 208-209 °C.

DlOa. General method for the conversion of carboxylic acids into ketones.

Synthesis of 2- (4-acetyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane.

To a solution of the 2- (4-carboxy-2-ethylphenylimino)-l-cyclopentyl-3-thia- l-azaspiro [4.4] nonane (Method D9a; 0.046 g, 0.128 mmol) in THF (10 mL) at-78 °C was added methyllithium (1.4 M in EtO, 0.91 mL, 1.28 mmol). The reaction

mixture was while allowed to gradually warm to room temp., then was stirred overnight. Trimethylsilyl chloride (0.5 mL) was added and the mixture was stirred at room temp. for 2 h, then a IN HCl solution (2 mL) was added. The mixture was stirred for 0.5 h, then was treated with a saturated NaHC03 solution (10 mL). The resulting mixture was extracted with EtOAc (4x20 mL), and the combined organic layers were washed with a saturated NaCl solution (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative TLC (10% EtOAc/hex) to give 2- (4-acetyl-2-ethylphenylimino)-l-cyclopentyl-3-thia-l- azaspiro [4.4] nonane as a white solid (0.032 g, 73%): mp 114-115 °C.

Dlla. General method for the conversion of nitriles into aldehydes. Synthesis of 2- (2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane.

2- (4-Cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane was prepared in a manner analogous to Method C2a and the thiazolidine was alkylated in a manner analogous to Method D2b to give 2- (4-cyano-2-ethylphenylimino)-l-cyclopentyl-3- thia-1-azaspiro [4.4] nonane. To a solution of 2- (4-cyano-2-ethylphenylimino)-l- cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.21 g, 0.60 mmol) in anh. toluene (20 mL) at-78C was added DIBAL (1. OM in toluene, 1.20 mL, 1.20 mmol). The reaction mixture was stirred at-78 °C for 3 h, then EtOAc (3 mL) was added at-78 °C, stirring was continued for 0.5 h, and wet silica gel (5% water, 2 g) was added. The reaction mixture was warmed to room temp., stirred for 3 h, then filtered through a pad of through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (30% EtOAc/hex) to give 2- (2-ethyl-4- formylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane as a white solid (0.16 g, 75%): mp 104-105°C.

D12a. General methods for the chain homologation of aldehydes or ketones.

Synthesis of 2-(2-ethyl-4-((1E)-2-ethoxycarbonylvinyl) phenylimino)-1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

To a solution of 2- (2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane (Method Dlla; 0.053 g, 0.149 mmol) in CH3CN was added LiCI (0.0076 g, 0.182 mmol) followed by DBU (0.025 g, 0.167 mmol) and triethyl phosphonoacetate (0.041 g, 0.182 mmol). The reaction mixture was stirred at room temp. for 18 h, then concentrated under reduced pressure. The residue was purified by flash chromatography (3% EtOAc/hex) to give 2- (2-ethyl-4- ( (lE)-2- ethoxycarbonylvinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane as a colorless oil (0.029 g, 48%): TLC (30% EtOAc/hex) Rf0.68.

D12b. General methods for the chain homologation of aldehydes or ketones.

Synthesis of 2-(2-ethyl-4-((1E)-2-nitrovinyl) phenylimino)-1-cyclopentyl- 3-thia-1-azaspiro [4.4] nonane.

To a solution of 2- (2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane (Method Dlla; 0.041 g, 0.115 mmol) in CH2C12 (10 mL) was added MeNO2 (2 drops) and piperidine (4 drops). The reaction mixture was heated at the reflux temp. overnight, thern cooled to room temp. and concentration under reduced pressure. The residue was purified by flash chromatography (3% EtOAc/hex) to give 2- (2-ethyl-4- ( (1E)-2-nitrovinyl) phenylimino)-1-cyclopentyl-3- thia-1-azaspiro [4.4] nonane as a red solid (0.022 g, 48%): mp 141-142 °C.

D12c. General methods for the chain homologation of aldehydes or ketones.

Synthesis of 2-(2-ethyl-4-(2, 2-dicyanovinyl) phenylimino)-1-cyclopentyl-3- thia-1-azaspiro [4.4] nonane.

To a solution of 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane (Method Dlla; 0.037 g, 0.104 mmol) in EtOH (10 mL) was added malononitrile (0.007 g, 0.104 mmol) and piperidine (4 drops). The reaction mixture was stirred at room temp. for 2 h, then concentrated under reduced pressure.

The residue was purified by preparative TLC (20% EtOAc/hex) to give 2- (2-ethyl-4- (2,2-dicyanovinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane as a yellow solid (0.012 g, 28%): mp 135-136 °C.

D12d. General methods for the chain homologation of aldehydes or ketones.

Synthesis of 2-(2-ethyl-4-(2-cyanovinyl) phenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane.

To a solution of KOH (0.024 g, 0.36 mmol) in CH3CN (20 ml) at the reflux temp. was added 2- (2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane (Method Dlla; 0.127 g, 0.36 mmol). The reaction mixture was heated at the reflux temp. for 4 h, cooled to room temp., and concentrated under reduced pressure The residue was diluted with water (15 mL) and extracted with CH2Cl2 (3x15 mL). The combined organic layers were washed with a saturated NaCl solution and dried (Na2SO4). The resulting material was purified by preparative TLC (30% EtOAc/hex) to give 2- (2-ethyl-4- (2-cyanovinyl) phenylimino)-l-cyclopentyl-3- thia-1-azaspiro [4.4] nonane as 1: 3 cis/trans mixture of isomers (0.050 g): TLC (30% EtOAc/hex) Rf0.56.

D13a. General method for the alkylation of chloromethyl side chains. Synthesis of 2- (2-methyl-4-nitrophenylimino)-4- (N-methylaminomethyl)-1,3- thiazolidine.

To a solution of methylamine in methanol (2.0M, 5 mL) was added 2- (2- methyl-4-nitrophenylimino)-4- (chloromethyl)-1,3-thiazolidine (prepared in a manner analogous to that described in Method C2a; 0.040 g, 0.140 mmol) and the resulting mixture was stirred at room temp for 72 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (5% MeOH/CH2Cl2) to give 2-(2-methyl-4-nitrophenylimino)-4-(N- methylaminomethyl)-1,3-thiazolidine as a solid (0.014 g, 35%).

D14a. Acid-catalyzed rearrangement of carbon-carbon double bonds.

Synthesis of 2- (4-nitrophenylimino)-3- (2-methylprop-l-en-1-yl)-1,3- thiazolidine.

2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give 2- (4-nitrophenyl)-1,3-thiazolidine.

The thiazolidine was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2- (4-nitrophenylimino)-3- (2-methylprop-2-en-1-yl)-1,3-thiazolidine. A mixture of 2- (4-nitrophenylimino)-3- (2-methylprop-2-en-1-yl)-1, 3-thiazolidine (0.20 g) in poly (phosphoric acid) (0.4 mL) was heated at 80 °C for 5 h. The reaction mixture was then dissolved in 0 °C water (20 mL) with the aid of sonication. The aqueous mixture was adjusted to pH 12 with a 1N NaOH solution, then extracted with EtOAc (3 x 25 mL). The combined organic phases were dried (K2CO3) and concentrated under reduced pressure. The residue (0.21 g) was purified by preparative HPLC to afford 2- (4-nitrophenylimino)-3- (2-methylprop-1-en-1-yl)-1,3- thiazolidine.

SPECIFIC COMPOUND PREPARATIONS Descriptions of the detailed preparative steps used to prepare the specific compounds listed in Tables 1-4 are provided below. Many of the compounds listed

in the Tables can be synthesized following a variety of methods. The specific examples below are therefore provided by way of illustration only and should not be construed to limit the scope of the invention in any way.

Entry 1 2-Chloroethylamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2-methyl-4-nitrophenylimino)-1, 3-thiazolidine.

Entry 2 2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give 2- (4-nitrophenylimino)-1,3- thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2- (4-nitrophenylimino)-3-isobutyl-1,3-thiazolidine.

Entry 3 2-Chloroethylammomum chloride (k ; ntry l) was reacted with 2-methyl-4-mtrophenyl isothiocyanate, which was reacted with isobutyl bromide according to Method D2a to give 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidine.

Entry 4 2-Chloroethylammonium chloride (Entry 1) was reacted with 2,3-dichlorophenyl isothiocyanate according to Method Cla to give 2- (2, 3-dichlorophenylimino)-1,3- thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2- (2, 3-dichlorophenylimino)-3-isobutyl-1,3-thiazolidine.

Entry 5

N-Chloroethyl-N'-isobutylammonuim chloride (prepared as described in Method B7c) was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to method Cld to give 2- (2-methoxy-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidine.

Entry 6 N-Chloroethyl-N'-isobutylammonuimchloride (prepared as described in Method B7c) was reacted with 4-cyanophenyl isothiocyanate according to method Cld to give 2- (4-cyanophenylimino)-3-isobutyl-1,3-thiazolidine.

Entry7 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-5-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2- (2-methyl-5- nitrophenylimino)-3-isobutyl-1,3-thiazolidine HCl salt.

Entry 8 N-Chloroethyl-N'-isobutylammonuimchloride (prepared as described in Method B7c) was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to method Cld to give 2- (4-cyano-2-ethylphenylimino)-3-isobutyl-1,3-thiazolidine.

Entry 9

N-Chloroethyl-N'-isobutylammonium chloride (prepared as described in Method B7c) was reacted with 4-chloro-2- (trifluoromethyl) phenyl isothiocyanate according to method Cld to give 2- (4-chloro-2- (trifluoromethyl) phenylimino)-3-isobutyl-1,3- thiazolidine.

Entry 10 2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2- (4- nitrophenylimino)-3- (2-methylprop-2-en-1-yl)-1,3-thiazolidine. The 3-allyl-1,3- thiazolidine was rearranged according to Method D14a to give 2- (4- nitrophenylimino)-3-(2-methylprop-1-en-1-yl)-1,(2-methylprop -1-en-1-yl)-1, 3-thiazolidine.

Entry 11 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (2-methylprop-2-en-1-yl)-1,3-thiazolidine.

Entry 12 2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2- (4- nitrophenylimino)-3- (2-methylprop-2-en-1-yl)-1,3-thiazolidine.

Entry 13

2-Chloroethylammonium chloride (Entry 1) was reacted with 3,4-dichlorophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2- (3,4- dichlorophenylimino)-3- (2-methylprop-2-en-1-yl)-1,3-thiazolidine.

Entry 14 N-(2-Hydroxyethyl)-N-(2-methylbutyl)(2-Hydroxyethyl)-N-(2-me thylbutyl) amine was reacted with SOCI2 according to Method B7a to give N- (2-chloroethyl)-N-(2-methylbutyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give to give 2- (2-methyl-4-nitrophenylimino)-3- (2-methyl-l- butyl)-1, 3-thiazolidine.

Entry 15 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 4-bromobut-1-ene according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3-(but-1-en-4-yl)-1,(but-1-en-4-yl)-1, 3-thiazolidine.

Entry 16 2-Chloroethylammonium _ CN! Me N Mu chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromobut-2-yne according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (but-2-yn-1-yl)-1, 3-thiazolidine.

Entry 17

2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 2-ethylbutyl bromide according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (2-ethyl-I-butyl)-1,3-thiazolidine.

Entry 18 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 2-methylbutyl bromide according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (2-methyl-1-butyl)-1,3-thiazolidine.

Entry 19 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-nonyl bromide according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (1-nonyl)-1, 3-thiazolidine.

Entry 20 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 2,2-dimethylpropyl bromide according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (2, 2-dimethylpropyl)-1, 3-thiazolidine.

Entry 21

2-Butylamine was converted to N- (2-hydroxyethyl)-N-(2-butyl) amine according to Method B5a. The amine was reacted with SOC12 according to Method B7a to give N-(2-chloroethyl)-N-(2-butyl)(2-chloroethyl)-N-(2-butyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give to give 2- (2-methyl-4-nitrophenylimino)-3- (2-butyl)-1,3-thiazolidine.

Entry 22 3-Pentylamine was converted to N (2-hydroxyethyl)-N-(3-pentyl) amine according to Method B5a. The amine was reacted with SOC12 according to Method B7a to give N (2-chloroethyl)-N-(3-pentyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give to give 2- (2-methyl-4-nitrophenylimino)-3- (3-pentyl)-1,3-thiazolidine.

Entry 23 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-heptyl bromide according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (l-heptyl)-1,3-thiazolidine.

Entry 24 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 8-bromo-1-octene according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3-(oct-1-en-8-yl)-1,(oct-1-en-8-yl)-1, 3-thiazolidine.

Entry 25

2-Propyl-1-hydroxypentane was converted to 1-bromo-2-propylpentane according to Method B2b, Step 2.2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromo-2-propylpentane according to Method D2a to give 2-(2-methyl-4-nitrophenylimino)-3-(2-propyl-1-pentyl)-1,3-th iazolidine.

Entry 26 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1,1-dicyclopropylbut-1-en-4-yl bromide according to Method D2a to give 2- (2- methyl-4-nitrophenylimino)-3- (1, 1-dicyclopropylbut-1-en-4-yl)-1,3-thiazolidine.

Entry 27 2,6-Wichloro-4-nitrophenyl isothiocyanate was reacted with Z-butylamine tollowed by chloroacetic acid according to Method C8a to afford 2- (2,6-dichloro-4- nitrophenylimino)-3- (2-butyl)-1,3-thiazolidin-4-one.

Entry 28 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with (E/Z)-1,3-dibromopropene according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (bromoprop-1-en-3-yl)-1,3-thiazolidine as an E-/Z-mixture.

The mixture was separated using preparative TLC to afford 2- (2-methyl-4- nitrophenylimino)-3- ((Z)-bromoprop-1-en-3-yl)-1,((Z)-bromoprop-1-en-3-yl)-1, 3-thiazolidine.

Entry 29 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with (E)-1,3-dichloropropene according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3-((E)-chloroprop-1-en-3-yl)-1,((E)-chloro prop-1-en-3-yl)-1, 3-thiazolidine.

Entry 30 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 3-chloro-1-propyne according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (prop-1-yn-3-yl)-1,3-thiazolidine.

Entry 31 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with (E/Z)-1,3-dibromopropene according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (bromoprop-1-en-3-yl)-1,3-thiazolidine as an E-/Z-mixture. The mixture was separated using preparative TLC to afford 2- (2-methyl-4- nitrophenylimino)-3-((E)-bromoprop-1-en-3-yl)-1,((E)-bromopr op-1-en-3-yl)-1, 3-thiazolidine.

Entry 32

2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with ethyl (Z)-4-chloro-3-ethoxybut-2-enoate according to Method D2a to give 2- (2- methyl-4-nitrophenylimino)-3- (1-ethoxycarbonyl-2-ethoxyprop-1-en-3-yl)-1,3- thiazolidine.

Entry 33 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with methyl 4-bromobutanoate according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (1-methoxycarbonyl-3-propyl)-1,3-thiazolidine.

Entry 34 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with methyl chloroacetate according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (1-methoxycarbonylmethyl)-1,3-thiazolidine.

Entry 35 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with a-chloroacetophenone according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (1-oxo-1-phenyl-2-ethyl)-1,3-thiazolidine. The ketone was reduced according to Method D5a to give 2- (2-methyl-4-nitrophenylimino)-3- (1- hydroxy-1-phenyl-2-ethyl)-1,3-thiazolidine.

Entry 36

2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to give 2- (2- methyl-4-nitrophenylimino)-3- (2-oxo-3, 3-dimethyl-1-butyl)-1,(2-oxo-3, 3-dimethyl-1-butyl)-1, 3-thiazolidine.

Method 37 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-chloro-2-butanone according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (2-oxo-1-butyl)-1,3-thiazolidine.

Method 38 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-chloro-2-butanone according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (2-oxo-1-butyl)-1,3-thiazolidine. The ketone was reducded according to Method D5a to give 2- (2-methyl-4-nitrophenylimino)-3- (2-hydroxy-l- butyl)-1,3-thiazolidine.

Method 39 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to give 2- (2-

methyl-4-nitrophenylimino)-3-(2-oxo-3, 3-dimethyl-1-butyl)-1,(2-oxo-3, 3-dimethyl-1-butyl)-1, 3-thiazolidine. The ketone was reduced according to Method D5a to give 2- (2-methyl-4- nitrophenylimino)-3- (2-hydroxy-3, 3-dimethyl-1-butyl)-1,3-thiazolidine.

Entry 40 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 5-bromo-2-pentanone according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (2-oxo-5-pentanyl)-1,3-thiazolidine.

Entry 41 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1,1,3-trichloro-1-propene according to Method D2a to give 2- (2-methyl-4- nitrophenylimino)-3- (1, 1-dichloroprop-1-en-3-yl)-1,3-thiazolidine.

Entry 42 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with propionyl chloride according to Method D2d to give 2- (2-methyl-4- nitrophenylimino)-3- (1-oxo-1-propyl)-1,3-thiazolidine.

Entry 43

2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with (E)-l-chloro-5-methoxy-2-pentene according to Method D2a to give 2- (2- methyl-4-nitrophenylimino)-3-((E)-5-methoxypent-2-en-1-yl)-1 ,((E)-5-methoxypent-2-en-1-yl)-1, 3-thiazolidine.

Entry 44

2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-1-oxaspiro [4.4] nonane. The oxazolidine was reduced according to method B4b, Step 2 to afford N cyclopentyl-N (2-hydroxyethyl) amine.

The alcohol was reacted with SOC'2 according to Method B7c to afford N cyclopentyl-N (2-chloroethyl) amine. The amine was reacted with 2-methyl-4- nitrophenyl isothiocyanate according to Method Cld to afford 2- (2-methyl-4- nitrophenylimino)-3- (cyclopentyl)-1,3-thiazolidine.

Entry 45

2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-1-oxaspiro [4.4] nonane. The oxazolidine was reduced according to method B4b, Step 2 to afford N cyclopentyl-N (2-hydroxyethyl) amine.

The alcohol was reacted with SOC'2 according to Method B7c to afford N cyclopentyl-N (2-chloroethyl) amine. The amine was reacted with 2-methoxy-4- nitrophenyl isothiocyanate according to Method Cld to afford 2- (2-methoxy-4- nitrophenylimino)-3- (cyclopentyl)-1,3-thiazolidine.

Entry 46

2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-1-oxaspiro [4.4] nonane. The oxazolidine was reduced according to method B4b, Step 2 to afford N cyclopentyl-N (2-hydroxyethyl) amine.

The alcohol was reacted with SOCS2 according to Method B7c to afford N- cyclopentyl-N (2-chloroethyl) amine. The amine was reacted with 2,3- dichlorophenyl isothiocyanate according to Method Cld to afford 2- (2,3- dichlorophenylimino)-3-cyclopentyl-1,3-thiazolidine.

Entry 47

Cyclohex-2-en-1-one was reduced according to Method B2b, Step 1 to afford cyclohex-2-en-1-ol. The alcohol was converted to the 3-bromo-1-cyclohexene according to Method B2b, Step 2. The halide was converted to N-(cyclohex-2-en-1- yl)-N-(2-hydroxyethyl)(2-hydroxyethyl) amine according to Method B2b, Step 3. The alcohol was reacted with SOC12 according to Method B7a to afford N-(cyclohex-2-en-1-yl)-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2- methyl-4-nitrophenyl isothiocyanate according to method Cla to afford 2- (2-methyl- 4-nitrophenylimino)-3- (cyclohex-2-en-1-yl)-1,3-thiazolidine.

Entry 48

2-Hydroxyethylamine and cyclohexanone were reacted according to Method B4a, Step 1 to afford 4-aza-1-oxaspiro [4.5] decane. The oxazolidine was reduced according to method B4a, Step 2 to afford N-cyclohexyl-N-(2-hydroxyethyl) amine.

The alcohol was reacted with SOC'2 according to Method B7c to afford N- cyclohexyl-N-(2-chloroethyl)(2-chloroethyl) amine. The amine was reacted with 2-methoxy-4- nitrophenyl isothiocyanate according to Method Cld to afford 2- (2-methyl-4- nitrophenylimino)-3-cyclohexyl-1,3-thiazolidine.

Entry 49

N-(2-Hydroxyethyl)(2-Hydroxyethyl) aniline was reacted with SOC12 according to Method B7a to give N-2-chloroethyl) anilinium chloride. The chloroethylamine was reacted with 2- methyl-4-nitrophenyl isothiocyanate according to Method Cla to afford 2- (2-methyl- 4-nitrophenylimino)-3-phenyl-1,3-thiazolidine.

Entry 50

2-Hydroxyethylamine was reacted with cycloheptyl bromide according to Method B2a to give N cycloheptyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCl2 according to Method B7c to give N cycloheptyl-N (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino)-3-cycloheptyl-1,3- thiazolidine.

Entry 51

2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N cyclooctyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N cyclooctyl-N (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino)-3-cyclooctyl-1,3- thiazolidine.

Entry 52

2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to give N cyclooctyl-N (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2- (2-methoxy-4-nitrophenylimino)-3-cyclooctyl-1,3- thiazolidine.

Entry 53

2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N cyclooctyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N cyclooctyl-N (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino)-3-cyclooctyl-1,3-thiazolidine.

Entry 54

2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N cyclopropylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N-cyclopropylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3- dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino)-3- (cyclopropylmethyl)-1,3-thiazolidine.

Entry 55

2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N cyclopropylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N-cyclopropylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl- 4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino)-3- (cyclopropylmethyl)-1,3-thiazolidine.

Entry 56 2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N cyclopropylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N-cyclopropylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,4- dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino)-3- (cyclopropylmethyl)-1,3-thiazolidine.

Entry 57 2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N cyclopropylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCIz according to Method B7c to give N-cyclopropylmethyl-N-(2-

chloroethyl) ammonium chloride. The chloroethylamine was reacted with 3,4- dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimino)-3- (cyclopropylmethyl)-1,3-thiazolidine.

Entry 58 2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N cyclobutylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,2- dichlorophenyl isothiocyanate to give 2- (2,2-dichlorophenylimino)-3- (cyclobutylmethyl)-1,3-thiazolidine.

Entry 59 2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,4- dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino)-3- (cyclobutylmethyl)-1,3-thiazolidine.

Entry 60 2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N cyclobutylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 3,4- dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimino)-3- (cyclobutylmethyl)-1,3-thiazolidine.

Entry 61

2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N cyclobutylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC'2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3- dimethylphenyl isothiocyanate to give 2- (2,3-dimethylphenylimino)-3- (cyclobutylmethyl)-1,3-thiazolidine.

Entry 62

2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N cyclobutylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 3-chloro- 2-methylphenyl isothiocyanate to give 2- (3-chloro-2-methylphenylimino)-3- (cyclobutylmethyl)-1,3-thiazolidine.

Entry 63

2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N cyclopentylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3- dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino)-3- (cyclopentylmethyl)-1, 3-thiazolidine.

Entry 64

2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N cyclopentylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCIz according to Method B7c to give N-cyclopentylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 3,4- dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimino)-3- (cyclopentylmethyl)-1,3-thiazolidine.

Entry 65

2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N cyclopentylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N-cyclopentylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl- 4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino)-3- (cyclopentylmethyl)-1,3-thiazolidine.

Entry 66

2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N-cyclopentylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,4- dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino)-3- (cyclopentylmethyl)-1,3-thiazolidine.

Entry 67

2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N cyclopentylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N-cyclopentylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3- dimethylphenyl isothiocyanate to give 2- (2,3-dimethylphenylimino)-3- (cyclopentylmethyl)-1,3-thiazolidine.

Entry 68

2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N cyclopentylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N-cyclopentylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 3-chloro- 2-methylphenyl isothiocyanate to give 2- (3-chloro-2-methylphenylimino)-3- (cyclopentylmethyl)-1,3-thiazolidine.

Entry 69

2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N cyclohexylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N-cyclohexylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3- dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino)-3- (cyclohexylmethyl)-1,3-thiazolidine.

Entry 70

2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N cyclohexylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N-cyclohexylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl- 4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino)-3- (cyclohexylmethyl)-1,3-thiazolidine.

Entry 71

2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N cyclohexylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCIz according to Method B7c to give N-cyclohexylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2- methoxy-4-nitrophenyl isothiocyanate to give 2- (2-methoxy-4-nitrophenylimino)-3- (cyclohexylmethyl)-1,3-thiazolidine.

Entry 72

1-Cyclohexyl-1-ethylamine was converted to N-(2-hydroxyethyl)-N-(1-cyclohexyl-1- ethyl) amine according to Method B5a. The alcohol was reacted with SOCS2 according to Method B7a to give N-(2-chloroethyl)-N-(1-cyclohexyl-1- ethyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl-4- nitrophenyl isothiocyanate according to Method Cla to give 2- (2-methyl-4- nitrophenylimino)-3- (1-cyclohexyl-1-ethyl)-1,3-thiazolidine.

Entry 73 Z-Hydroxyethyamme was reacted witn nenzyinromide accordmg to Metnoa ta to give N benzyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N benzyl-N (2-chloroethyl) ammonium chloride.

The chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2- (3-chloro-2-methylphenylimino)-3-benzyl-1,3-thiazolidine.

Entry 74 2-Hydroxyetriylamme was reacted with benzyl bromide according to Method tsza to give N benzyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N benzyl-N (2-chloroethyl) ammonium chloride.

The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.

Entry 75 2-Hyaroxyemyiamine was reactea wltn nenzyinromme accorcung to Metnoa >a to give N benzyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N-benzyl-N (2-chloroethyl) ammonium chloride.

The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.

Entry 76 2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N benzyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N benzyl-N (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidine.

Entry 77

2-Hydroxyethylamme was reacted with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOC'2 according to Method B7c to give N benzyl-N (2-chloroethyl) ammonium chloride.

The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- Entry 78

2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N- (4-chlorobenzyl)-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N (2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 4-cyano-2- ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino)-3- (4- chlorobenzyl)-1,3-thiazolidine.

Entry 79

2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N- (4-chlorobenzyl)-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS ; according to Method B7c to give N-(4-chlorobenzyl)-N (2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-chloro- 4-cyanophenyl isothiocyanate to give 2- (2-chloro-4-cyanophenylimino)-3- (4- chlorobenzyl)-1,3-thiazolidine.

Entry 80

2-Hydroxyethylam1ne was reacted with cycloheptylmethyl bromide according to Method B2a to give N cycloheptylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N-cycloheptylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl- 4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino)-3- (cycloheptylmethyl)-1,3-thiazolidine.

Entry 81

2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N cycloheptylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N-cycloheptylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2- methoxy-4-nitrophenyl isothiocyanate to give 2- (2-methoxy-4-nitrophenylimino)-3- (cycloheptylmethyl)-1,3-thiazolidine.

Entry 82

2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N cycloheptylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOC12 according to Method B7c to give N-cycloheptylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3- dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino)-3- (cycloheptylmethyl)-1,3-thiazolidine.

Entry 83

2-Hydroxyethylamme was reacted with cycloheptylmethyl bromide according to Method B2a to give N cycloheptylmethyl-N (2-hydroxyethyl) amine. The alcohol was reacted with SOCS2 according to Method B7c to give N-cycloheptylmethyl-N-(2- chloroethyl) ammonium chloride. The chloroethylamine was reacted with 4- cyanophenyl isothiocyanate to give 2- (4-cyanophenylimino)-3- (cycloheptylmethyl)- 1,3-thiazolidine.

Entry 84

Methyl cyclododecanecarboxylate was reduced according to Method B2b, Step 1 to give cyclododecylmethanol. The alcohol was converted to cyclododecylmethylbromide according to Method B2b, Step 2. The halide was reacted with 2-hydroxyethylamine according to Method B2b, Step 3 to give N-(2- hydroxyethyl)-N- (cyclododecylmethyl) amine.(cyclododecylmethyl) amine. The alcohol was reacted with SOC12 according to Method B7a to give N (2-chloroethyl)-N- (cyclododecylmethyl) ammonium chloride. The chloroethylamine was reacted with 2- methyl-4-nitrophenyl isothiocyanate according to Method C 1 a to give 2- (2-methyl-4- nitrophenylimino)-3- (cyclododecylmethyl)-1,3-thiazolidine.

Entry 85

2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2- (2-methyl-4-nitrophenylimino)- 1,3-thiazolidine, which was reacted with 3- (chloromethyl)-6,6- dimethylbicyclo [3.1.1] hept-2-ene according to Method D2a to give 2- (4- nitrophenylimino)-3- ( (6,6-dimethylbicyclo [3.1.1] hept-2-en-3-yl) methyl)-1,3- thiazolidine.

Entry 86

2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2- (2-methyl-4-nitrophenylimino)- 1,3-thiazolidine, which was reacted with 5- (bromomethyl) bicyclo [2.2.1] hept-2-ene according to Method D2a to give 2- (4-nitrophenylimino)-3- ( (bicyclo [2.2.1] hept-2- en-5-yl) methyl)-1,3-thiazolidine.

Entry 87

3-Aminoquinoline was converted to 3-quinoline isothiocyanate according to Method A2c. (1S)-1- (Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (2S)-4-methyl-2- (isobutylamino) pentanol as described in Method B4c, Steps 1-2.

The alcohol was converted to N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride as described in Method B7c. 3-Quinoline isothiocyanate was reacted with N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride according to Method Clf to give 2- (3-quinolylimino)- 3,5-diisobutyl-1,3-thiazolidine.

Entry 88

(1$)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (2$)- 4-methyl-2- (isobutylamino) pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride as described in Method B7c. 4-Nitrophenyl isothiocyanate was reacted with N- (IS)-I- (chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride according to Method Clf to give 2- (4- nitrophenylimino)-3, 5-diisobutyl-1,3-thiazolidine.

Entry 89

(lS)-1- (Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (2S)- 4-methyl-2- (isobutylamino) pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N- (IS)-l- (chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride as described in Method B7c. 4-Cyanophenyl isothiocyanate was reacted with N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride according to Method Clf to give 2- (4- cyanophenylimino)-3,5-diisobutyl-1,3-thiazolidine.

Entry 90 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1$)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4- HCl salt.

Entry 91 (lS)-l-(Hydroxymethyl)-3-methylbutylamine was converted to (lR)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lR)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4R)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2- (2-methyl-4- HCl salt.

Entry 92

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (lR)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-5-nitrophenyl isothiocyanate was reacted with (1 R)-1- (chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4R)-2- (2-methyl- 5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2- (2-methyl-5- nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt.

Entry 93 (15)-l- (Hydroxymethyl)-3-methylbutylamine was converted to (lS)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-5-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2-(2-methyl- 5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-5- HCl salt.

Entry 94 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (lR)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lR)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4R)-2- (2-methyl-

4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (4R)-2- (2-methyl-4- nitrophenylimino)-4-isobutyl-3-methyl-1,3-thiazolidine HCl salt.

Entry 95 (l)-l- (Hydroxymethyl)-3-methylbutylamine was converted to (lS)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (4S)-2- (2-methyl-4- nitrophenylimino)-4-isobutyl-3-methyl-1,3-thiazolidine HCl salt.

Entry 96 (lS)-l- (Hydroxymethyl)-3-methylbutylamine was converted to (lR)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-5-nitrophenyl isothiocyanate was reacted with (lR)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4R)-2- (2-methyl- 5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (4R)-2- (2-methyl-5- nitrophenylimino)-4-isobutyl-3-methyl-1,3-thiazolidine HCl salt.

Entry 97 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (lS)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2- (2-methyl-

4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 1-bromo-2-ethylbutane according to Method D2a to afford (4S)-2- (2-methyl-4- nitrophenylimino)-4-isobutyl-3- (2-ethyl-1-butyl)-1, 3-thiazolidine HCl(2-ethyl-1-butyl)-1, 3-thiazolidine HCl salt.

Entry 98

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium(chloromethyl)-3-methylb utanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to afford (4S)-2- (2- methyl-4-nitrophenylimino)-4-isobutyl-3- (2-oxo-3, 3-dimethyl-1-butyl)-1,3- thiazolidine.

Entry 99

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Ethyl-4-cyanophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2- (2-ethyl-4- cyanophenylimino)-4-isobutyl-3- (2-oxo-3, 3-dimethyl-1-butyl)-1,(2-oxo-3, 3-dimethyl-1-butyl)-1, 3-thiazolidine.

Entry 100

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (15)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4s)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2a to afford (4S)-2- (2-methyl-4- nitrophenylimino)-4-isobutyl-3- (cyclopropylmethyl)-1,3-thiazolidine.

Entry 101

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclobutylmethyl bromide according to Method D2a to afford (4S)-2- (2-methyl-4- nitrophenylimino)-4-isobutyl-3- (cyclobutylmethyl)-1,(cyclobutylmethyl)-1, 3-thiazolidine.

Entry 102

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with

2-chloro-3,3-dimethyl-2-butanone according to Method D2a to give (4S)-2- (2- methyl-4-nitrophenylimino)-4-isobutyl-3- (2-oxo-3, 3-dimethyl-1-butyl)-1,3- thiazolidine. The ketone was reduced according to Method D5a to afford (-2- (2- methyl-4-nitrophenylimino)-4-isobutyl-3- (3, 3-dimethyl-2-hydroxy-l-butyl)-1,3- thiazolidine.

Entry 103 (15)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (15)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2,6- Dimethyl-4-nitroaniline was converted into 2,6-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. 2,6-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-3-methylbutanammonium chloride according to Method Cla to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3- thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (2,6-dimethyl-4-nitrophenylimino)-3,4-diisobutyl-1,3- thiazolidine HCl salt.

Entry 104 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a.

2,3-Dichlorophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4s)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 3-bromopentane according to Method D2a to give (4S)-2-(2,3-dichlorophenylimino)- 4-isobutyl-3- (3-pentyl)-1,3-thiazolidine.

Entry 105

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give (4S)-2- (2-methyl-4- nitrophenylimino)-4-isobutyl-3- (5-heptyl)-1,3-thiazolidine.

Entry 106 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (15)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a.

2,3-Dichlorophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (2,3- dichlorophenylimino)-3,4-diisobutyl-1,3-thiazolidine.

Entry 107 (lS)-1- (Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (ils)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- (Trifluoromethyl)-4-nitrophenyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-3-methylbutanammonium chloride according to Method Clc to give (4S)-2- (2- (trifluoromethyl)-4-nitrophenylimino)-4-isobutyl-1,3-thiazol idine trifluoroacetate salt.

Entry 108

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (I S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- (Trifluoromethyl)-4-nitrophenyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-3-methylbutanammonium chloride according to Method Clc to give (4S)-2- (2- (trifluoromethyl)-4-nitrophenylimino)-4-isobutyl-1,3-thiazol idine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2- (2- (trifluoromethyl)-4-nitrophenylimino)-3,4-diisobutyl-1,3-thi azolidine trifluoroacetate salt.

Entry 109 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4- Cyano-2- (trifluoromethyl) phenyl isothiocyanate was reacted with (15)-1- (chloromethyl)-3-methylbutanammonium chloride according to Method Clc to give (4S)-2- (4-cyano-2- (trifluoromethyl) phenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(4-cyano-2-(trifluoromethyl) phenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.

Entry 110

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Chloro-4-cyano-6-methylphenyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-3-methylbutanammonium chloride according to Method Clc to give (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-4-isobutyl-1,3 -thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-3, 4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.

Entry 111 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4- (Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-3-methylbutanammonium chloride according to Method Cla to give (4S)-2- (4- (methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazo lidine.

The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (4- (methoxycarbonyl)-2-methylphenylimino)-3, 4-diisobutyl-1,3-thiazolidine.

Entry 112 (1S)-1- (Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a.

3,5-Dimethyl-4-nitroaniline was converted to 3,5-Dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3.3,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method Cla to give (4S)-2- (3,5-dimethyl-4-nitrophenylimino)- 4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (3,5-dimethyl-4-nitrophenylimino)-3,4- diisobutyl-1,3-thiazolidine.

Entry 113

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4- (Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-3-methylbutanammonium chloride according to Method Cla to give (4S)-2- (4- (methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazo lidine.

The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (4- (methoxycarbonyl)-2-methylphenylimino)-3, 4-diisobutyl-1,3-thiazolidine.

The thiazolidine was saponified according to Method D6a, Step 1 to give (4S)-2-(4- carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine . The acid was coupled with ammonia as described in Method D6a, Step 2 to afford (4S)-2-(4- carbamoyl-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidi ne.

Entry 114 (15)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4- Fluoro-2-methylphenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2-(4-fluoro- 2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (4-fluoro-2- methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.

Entry 115 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-

Chloro-2-methylphenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (-2- (4-Chloro- 2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (4-chloro-2- methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.

Entry 116 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4- Bromo-2-methylphenyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2-(4-bromo- 2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (4-bromo-2- methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.

Entry 117 (l)-1- (Hydroxymethyl)-3-methylbutylamine was reacted with SOCIz followed by 4- cyano-2-ethylphenyl isothiocyanate according to Method C2a to give (5)-2- (4- cyano-2-ethylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (4-cyano-2- ethylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.

Entry 118 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (2S)- 4-methyl-2- (isobutylamino) pentan-l-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride according to Method B7c. 2-Methyl-4-nitrophenyl

isothiocyanate was reacted with N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride to Method Clb to afford (4S)-2- (2-methyl-4- nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine.

Entry 119 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (2S)- 4-methyl-2- (isobutylamino) pentan-1-ol(isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride according to Method B7c. 4-Amino-3-methylpyridine was converted to 3-methyl-4-pyridylisocyanate according to Method A2b. 3-Methyl- 4-pyridyl isothiocyanate was reacted with N-(lS)-1-(chloromethyl)-3-methylbutyl)- N (isobutyl) ammonium chloride to Method Clb to afford (4S)-2- (2-methyl-4- nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine.

Entry 120 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B 1 b. 4-Nitro-1-naphthylamine was converted to 4-nitro- 1-naphthyl isothiocyanate according to Method A2b. 4-Nitro-1-naphthyl isothiocyanate was reacted with (lS)-1- (hydroxymethyl)-3-methylbutylamine to Method C2a to give (4S)-2- (4-nitro-l-naphthylimino)-4-isobutyl-1,3-thiazolidine.

The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-nitro-1-naphthylimino)-3, 4-diisobutyl-1,3-thiazolidine.

Entry 121 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (2S)- 4-methyl-2- (isobutylamino) pentan-1-ol(isobutylamino) pentan-1-ol as described in Method B4c. The resulting

2-hydroxyethylamine was converted to N-(1 S)-1- (chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride according to Method B7c. 4-Nitrophenyl isothiocyanate was reacted with N (lS)-1- (chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride to Method Clf to afford (4S)-2- (4-nitrophenylimino)- 3,4-diisobutyl-1,3-thiazolidine.

Entry 122 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (2S)- 4-methyl-2- (isobutylamino) pentan-1-ol(isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride according to Method B7c. 4-Cyanophenyl isothiocyanate was reacted with N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride to Method Clf to afford (4S)-2- (4-cyanophenylimino)- 3,4-diisobutyl-1,3-thiazolidine.

Entry 123 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (2S)- 4-methyl-2- (isobutylamino) pentan-1-ol(isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride according to Method B7c. 4-Amino-3-methylpyridine was converted to 3-methyl-4-pyridylisocyanate according to Method A2b. 3-Methyl- 4-pyridyl isothiocyanate was reacted with N- (IS)-I- (chloromethyl)-3-methylbutyl)- N (isobutyl) ammonium chloride to Method Clb to afford (4S)-2- (2-methyl-4- The thiazolidine was oxidized according to Method D4a to afford (4S)-2- (2-methyl-4-nitrophenylimino)-3,4- diisobutyl-1,3-thiazolidine 1-oxide.

Entry 124

(15, 25)-1-(Hydroxymethyl)-2-methylbutylamine was converted to (lS, 25)-1- (chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (15, 25)-1-(chloromethyl)-2- methylbutanammonium chloride according to Method Cla to give (45)-2-(2-methyl- 4-nitrophenylimino)-4-((25)-2-butyl)-1,((25)-2-butyl)-1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (45)-2-(2-methyl-4- nitrophenylimino)-4-((25)-2-butyl)-3-isobutyl-1,((25)-2-buty l)-3-isobutyl-1, 3-thiazolidine HCl salt.

Entry 125 N-(tert-Butoxycarbamoyl)- (1 S, 2R)-1- (hydroxymethyl)-2-methylbutylamine(tert-Butoxycarbamoyl)- (1 S, 2R)-1- (hydroxymethyl)-2-methylbutylamine was prepared from N- (tert-butoxycarbamoyl)- (L)-allo-isoleucine as described in Method Bla, Step 2. The carbamate was converted to (1 S, 2R)-1- (chloromethyl)-2- methylbutanammonium chloride as described in Method B7b. 2-Methyl-4- nitrophenyl isothiocyanate was reacted with (1 S, 2R)-1- (chloromethyl)-2- methylbutanammonium chloride to Method Cle to give (45)-2-(2-methyl-4- nitrophenylimino)-4-((2R)-2-butyl)-1, 3-thiazolidine.((2R)-2-butyl)-1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (45)-2-(2-methyl-4- nitrophenylimino)-4- ( (2R)-2-butyl)-3-isobutyl-1,3-thiazolidine HCl salt.

Entry 126 N-(tert-Butoxycarbamoyl)- (l S)-1-cyclohexyl-2-hydroxyethylbutylamine(tert-Butoxycarbamoy l)- (l S)-1-cyclohexyl-2-hydroxyethylbutylamine was prepared from N- (tert-Butoxycarbamoyl)- (L)--cyclohexylglycine according to Method Bla, Step 2. The carbamate was reacted with SOC12 according to Method Blb, and the resulting material was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give (4S)-2- (2-methyl-4- nitrophenylimino)-4-cyclohexyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2- (2-methyl-4- nitrophenylimino)-4-cyclohexyl-3-isobutyl-1,3-thiazolidine HCl salt.

Entry 127 (lS)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-2-methylbutanammonium(chloromethyl)-2-methylb utanammonium chloride as described in Method B7a. 4- Methoxycarbonyl-2-methylphenyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (45)-2-(4- methoxycarbonyl-2-methylphenylimino)-4- (2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (45)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-3 -isobutyl-1,3- thiazolidine.

Entry 128 (lS)-1-Isopropyl-2-hydroxyethylamine was converted to (15)-2-chloro-1- isopropylethylammonium chloride according to Method B7a. 2-Methyl-4- nitrophenyl isothiocyanate was reacted with (S5)-2-chloro-1- isopropylethylammonium chloride according to Method Cla to give (45)-2-(2- methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (45)-2-(2-methyl- 4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine HCl salt.

Entry 129 (1S)-1- (Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 5- Aminoindan-1-one was converted to 1-oxo-5-indanyl isothiocyanate according to Method A2a. The isothiocyanate was reacted with (lS)-1-(chloromethyl)-2-

methylbutanammonium chloride to Method Cla to give (45)-2-(1-oxo-5- indanylimino)-4- (2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (45)-2-(1-oxo-5-indanylimino)- 4- (2-butyl)-3-isobutyl-1,3-thiazolidine.

Entry 130 (15)-l- (Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4- Chloro-3- (trifluoromethyl) aniline was converted to 4-chloro-3- (trifluoromethyl) phenyl isothiocyanate according to Method A2a, Step 3 4-Chloro-3- (trifluoromethyl) phenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-2- methylbutanammonium chloride according to Method Cla to give (45)-2-(4-chloro- 3- (trifluoromethyl) phenylimino)-4- (2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (45)-2-(4-chloro-3- (trifluoromethyl) phenylimino)-4- (2-butyl)-3-isobutyl-1,3-thiazolidine.

Entry 131 (lS)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4- Cyano-3- (trifluoromethyl) aniline was converted to 4-cyano-3- (trifluoromethyl) phenyl isothiocyanate according to A2a, Step 3. The isothiocyanate was reacted with (lS)-1- (chloromethyl)-2-methylbutanammonium chloride according to Method Cla to give (-2- (4-cyano-3- (trifluoromethyl) phenylimino)-4- (2-butyl)- 1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2- (4-cyano-3- (trifluoromethyl) phenylimino)-4- (2-butyl)- 3-isobutyl-1,3-thiazolidine.

Entry 132

(lS)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4- Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. 4-Nitro-1-naphthyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (45)-2-(4- nitro-1-naphthylimino)-4- (2-butyl)-1,(2-butyl)-1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (45)-2-(4-nitro-1- naphthylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.

Entry 133 (lS)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1-(chloromethyl)-2-methylbutanammonium(chloromethyl)-2-methy lbutanammonium chloride as described in Method B7a. 4- Cyano-2-ethylphenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-2- methylbutanammonium chloride to Method Cla to give (4S)-2- (4-cyano-2- ethylphenylimino)-4- (2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2- (4-cyano-2- ethylphenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.

Entry 134 (lS)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4- Cyano-2-methylaniline was synthesized as described in Method Ala. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate as described in Method A2a, Step 3.4-Cyano-2-methylphenyl isothiocyanate was reacted with (lS)-1- (chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (5)-2- (4-

cyano-2-methylphenylimino)-4- (2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (-2- (4-cyano-2- methylphenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.

Entry 135 (lS)-1- (Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-2-methylbutanammonium chloride as described in Method B7a.

2,5-Dimethyl-4-nitrobenzonitrile was converted to 4-cyano-2,5-methylaniline according to Method Ala. The aniline was converted to 4-cyano-2,5-dimethylphenyl isothiocyanate as described in Method A2a, Step 3.4-Cyano-2,5-dimethylphenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (4S)-2- (4-cyano-2, 5-dimethylphenylimino)-4- (2- butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (5)-2- (4-cyano-2,5-dimethylphenylimino)-4- butyl-3-isobutyl-1,3-thiazolidine.

Entry 136 (lS)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-2-methylbutanammonium(chloromethyl)-2-methylb utanammonium chloride as described in Method B7a.

2,5-methylaniline was converted to 2,5-dimethyl-4-nitrophenyl isothiocyanate according to Method A2a. 2,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (15)-l- (chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (4S)-2-(2, 5-dimethyl-4-nitrophenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(2, 5-dimethyl-4-nitrophenylimino)-4-butyl-3-isobutyl-1,3-thiazo lidine.

Entry 137

(lR)-1-Isopropyl-2-hydroxyethylamine was reacted with SOC'2 followed by 2- Methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2- (2- methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2- (2-methyl- 4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine.

Entry 138

(lS)-1-Isopropyl-2-hydroxyethylamine was reacted with SOC12 followed by 2- methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2- (2- methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopentyl bromide according to Method D2a to afford (-2- (2- methyl-4-nitrophenylimino)-4-isopropyl-3-cyclopentyl-1,3-thi azolidine.

Entry 139

(1 S)-1-Benzyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1- benzylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-benzylethylammonium chloride according to Method Cla to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-benzyl- 1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2- (2-methyl-4-nitrophenylimino)-4-benzyl-3-isobutyl- 1,3-thiazolidine HCl salt.

Entry 140

(lS)-1-Phenyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1- phenylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-benzylethylammonium chloride according to Method Cla to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl- 1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-3-isobutyl- 1,3-thiazolidine HCl salt.

Entry 141

2-Piperidenemethanol was made from methyl pipecolinate as described in Method Blb. The 2-hydroxyethylamine was converted to 2-chloromethylpiperidinium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloromethylpiperidinium chloride according according to Method Cla to give 9- (2-methyl-4-nitrophenylimino)-1-aza-8-thiabicyclo [4.3.0] nonane.

Entry 142

2-Pyrrolidinemethanol was made from proline methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to 2-chloromethylpyrrolidinium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloromethylpyrrolidinium chloride according according to Method Cla to give 3- (2-methyl-4-nitrophenylimino)-2,5,6,7,7a-pentahydro-2- thiapyrrolizine.

Entry 143

(1S)-1-(4-Hydroxyphenylmethyl)-2-hydroxyethylamine was made from (L)-tyrosine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4-- (4-hydroxyphenylmethyl)-1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N- ( (IS)-I- (4- hydroxyphenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((1S)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N- isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N- ((1 S)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammoni um((1 S)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammoni um chloride according to Method Clb to give (4S)-2- (2-ethyl-4-cyanophenylimino)-4- (4- hydroxyphenylmethyl)-3-isobutyl-1,3-thiazolidine HCl salt.

Entry 144 (1S)-1-(4-Chlorophenylmethyl)-2-hydroxyethylamine was made from (L)-4- chlorophenylalanine methyl ester as described in Method Blb. The 2- hydroxyethylamine was converted to (4S)-2-isopropyl-4-- (4-chlorophenylmethyl)- 1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N- ((1 S)-1-(4-chlorophenylmethyl)-2-hydroxyethyl)-N-isobutylamine( (1 S)-1-(4-chlorophenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOC12 according to Method B7c to give N-( (1, 5-1- (4-chlorophenylmethyl)-2-chloroethyl)- N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N ( (1S)-1- (4-chlorophenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method Clb to give (4S)-2- (2-ethyl-4-cyanophenylimino)-4- (4-chlorophenylmethyl)-3-isobutyl-1,3-thiazolidine HCl salt.

Entry 145

(1S)-1- (Benzylthiomethyl)-2-hydroxyethylamine was made from (L)-S- benzylcysteine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4--(benzylthiomethyl)-1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((1$)-1- (benzylthiomethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOC12 according to Method B7c to give N-((lS)-1-(benzylthiomethyl)-2-chloroethyl)-N-isobutylammoni um chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N- ( (lS)-l- (benzylthiomethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method Clb to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(benzylthiomethyl)-3- isobutyl-1,3-thiazolidine HCl salt.

Entry 146 (R)-N-isobutylserine methyl ester HCl salt was made from (-serine methyl ester as described in Method B3a. The ester was reacted with SOC12, followed by 2-methyl- 4-nitrophenyl isothiocyanate according to Method C2a to afford (4S)-2-(2-methyl-4- nitrophenylimino)-4- (methoxycarbonyl)-3-isobutyl-1,3-thiazolidine HCl salt.

Entry 147 (S)-N-isobutylserine methyl ester HCl salt was made from (-serine methyl ester as described in Method B3a. The ester was reacted with SOC12, followed by 2-methyl- 4-nitrophenyl isothiocyanate according to Method C2a to afford (4R)-2- (2-methyl-4- nitrophenylimino)-4- (methoxycarbonyl)-3-isobutyl-1,3-thiazolidine HCl salt.

Entry 148

(lR, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)- (IS, 2R)-N- (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R, 2R)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium(tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((lR)-1-tert- butoxyethyl)-3-isobutyl-1,3-thiazolidine.

Entry 149

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(lS, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (lR, 2R)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nikophenylimino)-4-((lR)-1- tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine.

Entry 150

(1 R, 2S)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)-(lS, 2S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (lR, 2S)-1-

Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nikophenylimino)-4-((ls) tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine.

Entry 151

(1 R, 2S)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(lS, 2S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1 R, 2s)- 1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((lS)-1-tert- butoxyethyl)-3-isobutyl-1,3-thiazolidine.

Entry 152

(1R, 2S)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R, 2S)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-cyano-2-methylphenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-cyano-2-methylphenylimino)-4-((lS)- 1-tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine.

Entry 153

(1 R, 25)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)- (lS, 2S)-N (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Nitro-1-naphthylamine was converted to 4-nitro-l-naphthyl isothiocyanate according to Method A2b. (lR, 25)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((lS)-1-tert-butoxyethyl) - 3-isobutyl-1,3-thiazolidine.

Entry 154 (1 R, 2S)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. (lR, 2S)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((lS)-1-tert-butoxyethyl) - 3-cyclopentyl-1,3-thiazolidine.

Entry 155 (lR, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxyvarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-Amino-5,6,7,8- tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (lR, 2R)-l-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitro-5,6,7,8- tetrahydronaphth-1-yl isothiocyanate followed by cyclopentyl bromide according to Method CSb to afford (4R)-2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino)-4-((lR)-1- tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine.

Entry 156

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-Amino-5,6,7,8- tetrahydronaphthalene was converted to 4-nitro-5, 6, 7, 8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (lR, 2R)-l-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitro-5,6,7,8- tetrahydronaphth-1-yl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino)-4-((lR)-1- tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine.

Entry 157 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxyvarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a. (1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2- (2-isopropyl-4- nitrophenylimino)-4- ( (l R)-1-tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine.

Entry 158

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a. (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2- (2-isopropyl-4- nitrophenylimino)-4-((1 R)-1-tert-butoxyethyl)-3-cyclopentyl-1,((1 R)-1-tert-butoxyethyl)-3-cyclopentyl-1, 3-thiazolidine.

Entry 159 ( R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2- (2,3-dimethyl-4- nitrophenylimino)-4-((1 R)-1-tert-butoxyethyl)-3-cyclopentyl-1,((1 R)-1-tert-butoxyethyl)-3-cyclopentyl-1, 3-thiazolidine.

Entry 160 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)- (lS, 2R)-N- (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2- (2,3-dimethyl-4- nitrophenylimino)-4-((1 R)-1-tert-butoxyethyl)-3-isobutyl-1,((1 R)-1-tert-butoxyethyl)-3-isobutyl-1, 3-thiazolidine.

Entry 161

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by 2- ethyl-1-butyl bromide according to Method C5b to afford (4R)-2- (2,3-dimethyl-4- nitrophenylimino)-4-((1 R)-1-tert-butoxyethyl)-3-(2-ethyl-1-butyl)-1,((1 R)-1-tert-butoxyethyl)-3-(2-ethyl-1-butyl)-1, 3-thiazolidine.

Entry 162 (lR, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)- (lS, 2R)-N (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-amino-4-cyano-5,6,7,8- tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (lR, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-cyano-5,6,7,8- tetrahydronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2- (4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((lR)-1- tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine.

Entry 163

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-amino-4-cyano-5,6,7,8- tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (lR, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-cyano-5,6,7,8- tetrahydronaphthyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2- (4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((lR)-1- tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine.

Entry 164

(lR, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)- (IS, 2R)-N- (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (lR, 2R)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-((lR)-1-tert-butoxy)- 3-isobutyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((lR)-1- hydroxyethyl)-3-isobutyl-1,3-thiazolidine.

Entry 165

(1 R, 25)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)- (lS, 2S)-N- (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Nitro-l-naphthylamine was converted to 4-nitro-l-naphthyl isothiocyanate according to Method A2b. (lR, 25)-1-

Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-t4-niko-1-naphthylimino)-4-((lS)-1-tert-butoxyethyl)- 3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((lS)-1-hydroxyethyl)-3- cyclopentyl-1,3-thiazolidine.

Entry 166 (1 R, 25)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)-(15, 25)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R, 2S)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nikophenylimino)-4-((ls)-l- tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (2-methyl-4- nikophenylimino)-4-((l s)-1-hydroxyethyl)-3-cyclopentyl-1,((l s)-1-hydroxyethyl)-3-cyclopentyl-1, 3-thiazolidine.

Entry 167 (lR, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (lR, 2R)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-242-methyl-4-nikophenylimino)-4-((lR)-l- tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (2-methyl-4- nitrophenylimino)-4- ( (lR)-l-hydroxyethyl)-3-cyclopentyl-1,3-thiazolidine.

Entry 168

(1 R, 25)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 25)-N-(benzyloxyzarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R, 25)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((lS)-1- tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (2-methyl-4- nitrophenylimino)-4- ( (lS)-l-hydroxyethyl)-3-cyclopentyl-1,3-thiazolidine.

Entry 169 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-tert-Butyl-4-cyanoaniline was converted to 2-tert-butyl-4-cyanophenyl isothiocyanate according to Method A2b.

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was reacted with 2-tert-butyl-4-cyanophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2- (2-tert-butyl-4- cyanophenylimino)-4- ( (lR)-l-tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (2-tert- butyl-4-cyanophenylimino)-4- ((1 R)-1-hydroxyethyl)-3-cyclopentyl-1,((1 R)-1-hydroxyethyl)-3-cyclopentyl-1, 3-thiazolidine.

Entry 170 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(lS, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-tert-Butyl-4-cyanoaniline was

converted to 2-tert-butyl-4-cyanophenyl isothiocyanate according to Method bA2a.

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-tert-butyl-4-cyanophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2- (2-tert-butyl-4- cyanophenylimino)-4- ( (1R)-1-tert-butoxyethyl)-3- isobutyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (2-tert- butyl-4-cyanophenylimino)-4- ((1 R)-1-hydroxyethyl)-3-isobutyl-1,((1 R)-1-hydroxyethyl)-3-isobutyl-1, 3-thiazolidine.

Entry 171 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxyvarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. (1R, 2R)-1- Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((lR)-1-tert-butoxyethyl) - 3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(4-niko-1-naphthylimino)-4-((lR)-1-hydroxyethyl)-3- cyclopentyl-1,3-thiazolidine.

Entry 172 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)- (IS, 2R)-N- (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-Amino-5,6,7,8- tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (lR, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitro-5,6,7,8- tetrahydronaphth-1-yl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino)-4-((lR)-1- tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (4-nitro-5,6,7,8- tetrahydronaphth-1-ylimino)-4- ( (lR)-l-hydroxyethyl)-3-cyclopentyl-1,3-thiazolidine.

Entry 173

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-Amino-5,6,7,8- tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (lR, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitro-5,6,7,8- tetrahydronaphth-1-yl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino)-4-((lR)-1- tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (4-nitro-5,6,7,8-tetrahydronaphth-1- ylimino)-4- ((1 R)-1-hydroxyethyl)-3-isobutyl-1,((1 R)-1-hydroxyethyl)-3-isobutyl-1, 3-thiazolidine.

Entry 174 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a.

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2- (2-isopropyl-4- nitrophenylimino)-4- ((1 R)-1-tert-butoxyethyl)-3-isobutyl-1,((1 R)-1-tert-butoxyethyl)-3-isobutyl-1, 3-thiazolidine. The tert- butyl ether was deprotected according to Method D3a to afford (4R)-2- (2-isopropyl- 4-nitrophenylimino)-4-((1 R)-1-hydroxyethyl)-3-isobutyl-1,((1 R)-1-hydroxyethyl)-3-isobutyl-1, 3-thiazolidine.

Entry 175

(lR, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxyvarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a.

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2- (2-isopropyl-4- nitrophenylimino)-4- ((1 R)-1-tert-butoxyethyl)-3-cyclopentyl-1,((1 R)-1-tert-butoxyethyl)-3-cyclopentyl-1, 3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (2- isopropyl-4-nitrophenylimino)-4- ((1 R)-1-hydroxyethyl)-3-cyclopentyl-1,((1 R)-1-hydroxyethyl)-3-cyclopentyl-1, 3- thiazolidine.

Entry 176 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)-(15, 2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (lR, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by 2- ethyl-1-butyl bromide according to Method C5b to afford (4R)-2- (2,3-dimethyl-4- nitrophenylimino)-4- ( (lR)-l-tert-butoxyethyl)-3- (2-ethyl-l-butyl)-1,3-thiazolidine.

The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (2,3- dimethyl-4-nitrophenylimino)-4- ((1 R)-1-hydroxyethyl)-3-(2-ethyl-1-butyl)-1,((1 R)-1-hydroxyethyl)-3-(2-ethyl-1-butyl)-1, 3- thiazolidine.

Entry 177

(1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)- (1S, 2R)-N (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was reacted with 2, 3-dimethyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2- (2,3-dimethyl-4- nitrophenylimino)-4-((1 R)-1-tert-butoxyethyl)-3-isobutyl-1,((1 R)-1-tert-butoxyethyl)-3-isobutyl-1, 3-thiazolidine. The tert- butyl ether was deprotected according to Method D3a to afford (4R)-2- (2,3-dimethyl- 4-nitrophenylimino)-4-((1 R)-1-hydroxyethyl)-3-isobutyl-1,((1 R)-1-hydroxyethyl)-3-isobutyl-1, 3-thiazolidine.

Entry 178 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)- (lS, 2R)-N- (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2- (2,3-dimethyl-4- nitrophenylimino)-4- ( (IR)-l-tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (2,3- dimethyl-4-nitrophenylimino)-4- ( (IR)-l-hydroxyethyl)-3-cyclopentyl-1,3- thiazolidine.

Entry 179 (lR, 2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy) propanammonium chloride was made from (L)- (lS, 2R)-N- (benzyloxycarbonyl)-O-tert-butylthreonine

dicyclohexylamine salt as described in Method B8a. 1-amino-4-cyano-5,6,7,8- tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (lR, 2R)-l-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-cyano-5,6,7,8- tetrahydronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2- (4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((lR)-1- tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (4-cyano-5,6,7,8- tetrahydronaphthylimino)-4- ((1 R)-1-hydroxyethyl)-3-cyclopentyl-1,((1 R)-1-hydroxyethyl)-3-cyclopentyl-1, 3-thiazolidine.

Entry 180 (1 R, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was made from (L)- (IS, 2R)-N- (benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-amino-4-cyano-5,6,7,8- tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (lR, 2R)-1-Methanesulfonyloxymethyl)-2- (tert-butoxy) propanammonium chloride was reacted with 4-cyano-5,6,7,8- tetrahydronaphthyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2- (4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((lR)-1- tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2- (4-cyano-5,6,7,8- tetrahydronaphthylimino)-4- ((1 R)-1-hydroxyethyl)-3-isobutyl-1,((1 R)-1-hydroxyethyl)-3-isobutyl-1, 3-thiazolidine.

Entry 181 2-Amino-1,3-propanediol was reacted with excess SOCS2 followed by 2-methyl-4- nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4- nitrophenylimino)-4- (chloromethyl)-1,3-thiazolidine. The thiazolidine was reacted with N-methylamine according to Method D13a to give 2- (2-methyl-4- nitrophenylimino)-4- (N-methylaminomethyl)-1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to afford 2- (2-methyl-4- nitrophenylimino)-3-isobutyl-4- (N-isobutyl-N-methylaminomethyl)-1,3-thiazolidine.

Entry 182

2-Amino-1,3-propanediol was reacted with excess SOC'2 followed by 2-methyl-4- nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4- nitrophenylimino)-4- (chloromethyl)-1,3-thiazolidine. The thiazolidine was reacted with dimethylamine according to Method D13a to give 2- (2-methyl-4- nitrophenylimino)-4- (N-isobutyl-N-methylaminomethyl)-1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to afford 2- (2-methyl-4- nitrophenylimino)-3-isobutyl-4-(N, N-dimethylaminomethyl)-1, 3-thiazolidine.

Entry 183 (L)-Histidinol was reacted with SOC'2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (45)-2-(2-methyl-4- nitrophenylimino)-4- (1- (isobutylimidazoly) methyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2- (2-methyl-4-nitrophenylimino)-3-isobutyl-4- (l- (isobutylimidazolyl) methyl)- 1,3-thiazolidine.

Entry 184 (L)-Histidinol was reacted with SOC12 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (45)-2-(2-methyl-4- nitrophenylimino)-4- (1- (isobutylimidazoly) methyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2- (2-methyl-4-nitrophenylimino)-3-isobutyl-4- (3- (isobutylimidazolyl) methyl)- 1,3-thiazolidine.

Entry 185

2-Hydroxypropylamine was converted to 2-chloropropylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloropropylammonium chloride according to Method Cla to give 2- (2-methyl-4- nitrophenylimino)-5-methyl-1,3-thiazolidine. The thiazolidine was reacted with 2- methylprop-2-en-1-yl bromide according to Method D2g to afford 2- (2-methyl-4- nitrophenylimino)-3- (2-methylprop-2-en-1-yl)-5-methyl-1, 3-thiazolidine HBr salt.

Entry 186

2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2- hydroxyethylamine. The ethanolamine was reacted with SOCS2 followed by 2- chloro-4- (trifluoromethyl) phenyl isothiocyanate according to Method C2f to afford 2- (2-chloro-4- (trifluoromethyl) phenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidine HCl salt.

Entry 187

2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2- hydroxyethylamine. The ethanolamine was reacted with SOCl2 followed by 2,3- dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,3- dichlorophenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidine.

Entry 188

3-Phenyl-2-hydroxypropylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-benzyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-3-phenyl-2- hydroxypropylamine. The propanolamine was reacted with SOCI2 followed by 2,3- dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,3- dichlorophenylimino)-3-isobutyl-5-benzyl-1,3-thiazolidine HCl salt.

Entry 189

2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5, 5-dimethyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl- 2-methyl-2-hydroxypropylamine. The propanolamine was reacted with SOCS2 followed by 2,6-dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,6-dichlorophenylimino)-3-cyclohexyl-5, 5-dimethyl-1,3-thiazolidine.

Entry 190

(lR)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((lR)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl) amine. N-((1 R)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl) amine was reacted with SOC12 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,3-dichlorophenylimino)-3- (R)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.

Entry 191

(lS)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N ( (lS)-1-cyclohexyl-1-ethyl)-N (2,2-dimethyl-2- hydroxyethyl) amine. N-((1 S)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl) amine was reacted with SOC'2 followed by 2,4-dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,4-dichlorophenylimino)-3- ( S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.

Entry 192

(lS)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((lS)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl) amine. N-((1S)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl) amine was reacted with SOCS2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,3-dichlorophenylimino)-3- ((1 S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.

Entry 193

2-Methyl-2-hydroxypropylamine was reacted with SOC'2 followed by 2,3- dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,3- dichlorophenylimino)-5,5-dimethyl-1,3-thiazolidine. 2- (2,3-Dichlorophenylimino)-

was reacted with ethylene oxide according to Method B5b to afford 2- (2, 3-dichlorophenylimino)-5, 5-dimethyl-1,3-thiazolidine HCl salt.

Entry 194 2-Methyl-2-hydroxypropylamine was reacted with SOCS2 followed by 2-methyl-4- nitrophenyl isothiocyanate according to Method Cla to afford 2- (2-methyl-4- nitrophenylimino)-5, 5-dimethyl-1,3-thiazolidine.

Entry 195

2-Methyl-2-hydroxypropylamine was reacted with SOC'2 followed by 2-methyl-4- nitrophenyl isothiocyanate according to Method Cla to afford 2- (2-methyl-4- nitrophenylimino)-5,5-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2- (2-methyl-4- nitrophenylimino)-3- (2-methylprop-2-en-1-yl)-5, 5-dimethyl-1,3-thiazolidine HBr salt.

Entry 196 2-Methyl-2-hydroxypropylamine was reacted with SOC12 followed by 2-methyl-4- nitrophenyl isothiocyanate according to Method Cla to afford 2- (2-methyl-4- nitrophenylimino)-5,5-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2- (2-methyl-4- nitrophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine.

Entry 197

2-Methyl-2-hydroxypropylamine was reacted with SOC12 followed by 2,3- dichlorophenyl isothiocyanate according to Method Cla to afford 2- (2,3- The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2- (2,3- dichlorophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidin e.

Entry 198

2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give The oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl- 2-methyl-2-hydroxypropylamine. The propanolamine was reacted with SOCS2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2- (2-methyl-4-nitrophenylimino)-3-cyclohexyl-5, 5-dimethyl-1,3-thiazolidine.

Entry 199

2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine.

The oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl- 2-methyl-2-hydroxypropylamine. The propanolamine was reacted with SOC'2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2- 3-thiazolidine.

Entry 200

(lR)-l-Cyclohexyl-l-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((lR)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl) amine. N-((1R)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl) amine was reacted with SOC'2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2- (2-methyl-4-nitrophenylimino)- 3- ( (lR)-1-cyclohexyl-1-ethyl)-5, 5-dimethyl-1, 3-thiazolidine HCl salt.

Entry 201

(lS)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((lS)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl) amine. N-( (1S)-1-Cyclohexyl-1-ethyl)-N (2,2-dimethyl-2- hydroxyethyl) amine was reacted with SOC'2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2- (2-methyl-4-nitrophenylimino)- 3-((1 S)-1-cyclohexyl-1-ethyl)-5, 5-dimethyl-1, 3-thiazolidine HCl salt.

Entry 202

Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. N-Isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOC12 followed by 2-methyl- 4-nitrophenyl isothiocyanate according to Method C2f to afford 2- (2-methyl-4- nitrophenylimino)-3-isopropyl-5,5-dimethyl-1,3-thiazolidine.

Entry 203

Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N-(2, 2-dimethyl-2-hydroxyethyl) amine. N-Isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOC12 followed by 2,3- dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,3- dichlorophenylimino)-3-isopropyl-5,5-dimethyl-1,3-thiazolidi ne.

Entry 204

Isobutylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isobutyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. N-Isobutyl-N-(2,2- dimethyl-2-hydroxyethyl) amine was reacted with SOC12 followed by 2,4- dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,4- dichlorophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidin e HCl salt.

Entry 205

1,1-Dimethyl-2-hydroxyamine was converted to 1,1-dimethyl-2- chloroethylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 1,1-dimethyl-2-chloroethylammonium chloride according to Method Cla to give 2- (2-methyl-4-nitrophenylimino)-4,4-dimethyl-1,3- thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2- (2-methyl-4-nitrophenylimino)-4,4-dimethyl-3- (2-methylprop-2-en-1-yl)-1,3-thiazolidine HBr salt.

Entry 206

Methyl aminoisobutyric acid was converted to methyl aminoisobutyrate HCl salt according to method Blc, Step 1. The ester was reduced to 3-hydroxy-2-methyl-2- propylamine according to Method Blc, Step 2. The 2-hydroxyethylamine was treated with SOCL, according to Method B7b, followed by 2-methyl-3-nitrophenyl isothiocyanate according to Method Cla to give 2- (2-methyl-4-nitrophenylimino)- The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 2- (2-methyl-4-nitrophenylimino)-4,4-dimethyl-3- isobutyl-1,3-thiazolidine.

Entry 207 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Blc. 1- (Cyclohexylamino)-1-hydroxymethylcyclopentane(Cyclohexylamin o)-1-hydroxymethylcyclopentane was synthesized as described in Method B4a. The 2-hydroxyethylamine was treated with SOCS2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to afford 3-cyclohexyl-2- (2-methyl-4-nitrophenylimino)-l-thia-3-azaspiro [4.4] nonane.

Entry 208 2-Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1.

The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Bic. The 2- hydroxyethylamine was reacted with with SOC12 according to Method B7a to give 1- amino-1- (chloromethyl) cyclopentane HCl(chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2- (2- ethyl-4-nitrophenylimino)-1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to afford 3-cyclopentyl- 2- (2-ethyl-4-nitrophenylimino)-l-thia-3-azaspiro [4.4] nonane.

Entry 209

2-n-Propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a. The aniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Bic. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-n-propylphenyl isothiocyanate according to Method Cla to give 2- (4-iodo-2-n-propylphenylimino)- 1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2- (4-iodo-2-n- propylphenylimino)-1-thia-3-azaspiro [4.4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2- (4-cyano-2-n- propylphenylimino)-1-thia-3-azaspiro [4.4] nonane.

Entry 210 2-Isopropylaniline was converted to 4-iodo-2-isopropylaniline according to Method A5a. The aniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Bic. The 2-hydroxyethylamine was reacted with SOC12 according to Method B7a to give 1-amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-isopropylphenyl

isothiocyanate according to Method Cla to give 2- (4-iodo-2-isopropylphenylimino)- 1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2- (4-iodo-2- isopropylphenylimino)-1-thia-3-azaspiro [4.4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2- (4-cyano-2- isopropylphenylimino)-1-thia-3-azaspiro [4.4] nonane.

Entry 211 2-tert-Butylaniline was converted to 4-iodo-2-tert-butylaniline according to Method A5a. The aniline was converted to 4-iodo-2-tert-butylphenyl isothiocyanate according to Method A2b. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B l c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-tert-butylphenyl isothiocyanate according to Method Cla to give 2- (4-iodo-2-tert-butylphenylimino)- 1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2- (4-iodo-2-tert- butylphenylimino)-1-thia-3-azaspiro [4.4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2- (4-cyano-2-tert- butylphenylimino)-1-thia-3-azaspiro [4.4] nonane.

Entry 212 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Blc. The amino alcohol was reacted with 2-methylcyclopentanone according to Method B4a, Step 1 to give 13-aza-1-methyl-6-oxodispiro [4.2.4.1] tridecane, which was reduced with NaBH4 according to Method B4a, Step 2 to afford 1- (2- methylcyclopentyl) amino-1- (hydroxymethyl) cyclopentane. The 2- hydroxyethylamine was reacted with SOC'2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to afford 3- (2-methylcyclopentyl)-2- (2- methyl-4-nitrophenylimino)-1-thia-3-azaspiro [4.4] nonane.

Entry 213

1-Amino-1-(hydroxymethyl)(hydroxymethyl) cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOC12 according to Method B7a to give 1-amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro(2-methyl-4-n itrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane.

Entry 214 2-Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Bic. The 2- hydroxyethylamine was reacted with SOC'2 according to Method B7a to give 1- amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2- (2- ethyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2- (2- ethyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane.

Entry 215 2-n-Propylaniline was converted to 2-n-propylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-n-propyl-4-nitroacetanilide according to

Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-n-propyl-4-nitroaniline. The aniline was converted to 2-n-propyl-4- nitrophenyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Blc. The 2- hydroxyethylamine was reacted with SOCS2 according to Method B7a to give 1- amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-n-propyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2- (2- n-propyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2- (2-n- propyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane.

Entry 216 2-Isoropylaniline was converted to 2-isopropylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-isopropyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-isopropyl-4-nitroaniline. The aniline was converted to 2-isopropyl- 4-nitrophenyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Blc. The 2- hydroxyethylamine was reacted with SOC'2 according to Method B7a to give 1- amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate according to Method C 1 a to give 2- (2- isopropyl-4-nitrophenylimino)-3-thia-l-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2- (2- isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane.

Entry 217 2,3-Dimethyl-4-nitroaniline was synthesized as described in Method A4a. The aniline was converted into 2,3-dimethyl-4-nitrophenyl isothiocyanate as described in method A2d. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCS2 according to Method B7e to give 1-amino-1- (chloromethyl) cyclopentane HCl salt. The 2- chloroethylamine was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate

according to Method Clc to give 2- (2, 3-dimethyl-4-nitrophenylimino)-3-thia-l- azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-isopropyl-4-nitrophenylimino)-3-thia-1- azaspiro [4.4] nonane.

Entry 218 3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Bic. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1- (chloromethyl) cyclopentane HC1 salt. The 2-chloroethylamine was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2- (3-methyl-4-nitrophenylimino)-3- thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2- (3-methyl-4-nitrophenylimino)-3- thia-1-azaspiro [4.4] nonane.

Entry 219 1-Amino-5,6,7,8-tetrahydronaphthaline was converted to 1-acetamino-5,6,7,8- tetrahydronaphthaline according to Method A2a, Step 1. The acetanilide was converted to 1-acetamino-4-nitro-5,6,7,8-tetrahydronaphthaline according according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 1-amino-4-nitro-5,6,7,8-tetrahydronaphthaline. The aniline was converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B l c. The 2-hydroxyethylamine was reacted with SOC12 according to Method B7a to give 1-amino-1- (chloromethyl) cyclopentane HCl salt.

The 2-chloroethylamine was reacted with 4-nitro-5, 6, 7, 8-tetrahydro-l-naphthyl isothiocyanate according to Method Cla to give 2- (4-nitro-5, 6, 7, 8-tetrahydro-l- naphthylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2- (4-nitro-5,6,7,8- tetrahydro-1-naphthylimino)-3-thia-1-azaspiro [4.4] nonane.

Entry 220

1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B 1 c. The 2-hydroxyethylamine was reacted with SOCIz according to Method B7e to give 1-amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-cyanophenyl isothiocyanate according to Method Cla to give 2- (4- cyanophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2- (4- cyanophenylimino)-3-thia-1-azaspiro [4.4] nonane.

Entry 221 4-Cyano-2-methylaniline was synthesized as described in Method Ala. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Bic. The 2-hydroxyethylamine was reacted with SOCS2 according to Method B7a to give 1-amino-1- (chloromethyl) cyclopentane HCl salt. The 2- chloroethylamine was reacted with 4-cyano-2-methylphenyl isothiocyanate according to Method Cla to give 2- (4-cyano-2-methylphenylimino)-l-thia-3- azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-iodo-2-methylphenylimino)-l-thia-3- azaspiro [4.4] nonane.

Entry 222 1-Amino-1-(hydroxymethyl) cyclopentane(hydroxymethyl) cyclopentane was synthesized as described in Method Bic. The 2-hydroxyethylamine was reacted with SOCIz according to Method B7a to give 1-amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was

reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cla to give 2- (4-cyano-2-methylphenylimino)-1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4- cyano-2-methylphenylimino)-1-thia-3-azaspiro [4.4] nonane.

Entry 223 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOC12 according to Method B7a to give 1-amino-1- (chloromethyl) cyclopentane HCl salt. 1-Amino-4-cyanonaphthalene was converted into 4-cyano-1-naphthyl isothiocyanate according to Method A2a, Step 3. The 2-chloroethylamine was reacted with 4-cyano-1-naphthyl isothiocyanate to Method Cla to give 2- (4-cyano-l-naphthylimino)-l-thia-3- azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-cyano-l-naphthylimino)-l-thia-3- azaspiro [4.4] nonane.

Entry 224 2,3-Dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Blc. The 2- hydroxyethylamine was reacted with SOCS ; according to Method B7e to give 1- amino-1- (chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method Cle to give 2- (2,3-dimethyl-4-iodophenylimino)-1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2h to give 3-isobutyl-2- (4- iodo-2-n-propylphenylimino)-1-thia-3-azaspiro [4.4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-isobutyl-2- (2,3-dimethyl-4- cyanophenylimino)-1-thia-3-azaspiro [4.4] nonane.

Entry 225

2,3-Dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Blc. The 2- hydroxyethylamine was reacted with SOCl2 folloowed by 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method C2a to give 2- (2,3-dimethyl-4- iodophenylimino)-1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 3-isobutyl-2- (4-iodo-2-n- propylphenylimino)-1-thia-3-azaspiro [4.4] nonane. The phenyl iodide was reacted with trimethylsilylacetylene according to Method D8a, Step 1 to give 3-isobutyl-2- (2,3-dimethyl-4- (2-trimethylsilylethynyl) phenylimino)-l-thia-3-azaspiro [4.4] nonane. The silylacetylene was deprotected according to Method D8a, Step 2 to afford 3- isobutyl-2- (2, 3-dimethyl-4-ethynylphenylimino)-l-thia-3-azaspiro [4.4] nonane.

Entry 226 2,3-Dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method A2a, Step 3.1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method Bic. The 2- hydroxyethylamine was reacted with SOC12 according to Method B7e to give 1- amino-1- (chloromethyl) cyclopentane HCl(chloromethyl) cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method Cle to give 2- (2,3-dimethyl-4-iodophenylimino)-1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2h to give 3-isobutyl-2- (4- iodo-2-n-propylphenylimino)-1-thia-3-azaspiro [4.4] nonane.

Entry 227

2,3-Dimethylaniline was converted to 2,3-dimethyl-6-nitroaniline according to Method A4a. The aniline was converted to 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method A2d. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was converted to 1- chloromethylcyclopentanamine HCl salt according to Method B7e. 1- Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-6- nitrophenyl isothiocyanate according to Method Cle to give 2- (2,3-dimethyl-6- nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to afford 2- (2,3-dimethyl-6- nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

Entry 228 2-Cyano-5-nitrothiophene was reduced to 2-amino-5-cyanothiophene according to Method Ala. The aminothiophene was converted to 5-cyano-1-thiophene isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was converted to 1- chloromethylcyclopentanamine HCl salt according to Method B7e. 1- Chloromethylcyclopentanamine HCl salt was reacted with 5-cyano-1-thiophene isothiocyanate according to Method Cle to give 2- (5-cyanothienylimino)-3-thia-l- azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 2- (5-cyanothienylimino)-l-isobutyl-3-thia-l- azaspiro [4.4] nonane.

Entry 229 6-Amino-3-cyano-2,3-dimethylpyridine was converted to 3-cyano-2,3-dimethyl-6- pyridyl isothiocyanate according to Method A2c. 1- Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted

with 3-cyan-2,3-dimethyl-6-pyridyl isothiocyanate according to Method Cle to give 2- (3-cyano-2, 3-dimethyl-6-pyridylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2h to give 2- (5-bromothienylimino)-1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

Entry 230

1- (Hydroxymethyl) cyclopentanamine was prepared according to Method Bic. The 2-hydroxyethylamine was sequentially reacted with SOCS2 and 2-methyl-4- nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4- nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with 1-bromo-2-ethylbutane according to Method D2a to afford 2- (2-methyl-4- nitrophenylimino)-1-(2-ethyl-1-butyl)-3-thia-1-azaspiro(2-et hyl-1-butyl)-3-thia-1-azaspiro [4.4] nonane.

Entry 231

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with 3-bromopentane according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1- (3-pentyl)-3-thia-1-azaspiro [4.4] nonane.

Entry 232 1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted

with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isopropyl bromide according to Method D2e to give 2- (2-methyl-4- nitrophenylimino)-1-(2-propyl)-3-thia-1-azaspiro(2-propyl)-3 -thia-1-azaspiro [4.4] nonane.

Entry 233

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with 3-bromo-2-methylpropene according to Method D2e to give 2- (2- methyl-4-nitrophenylimino)-1- (2-methylprop-1-en-3-yl)-3-thia-1- azaspiro [4.4] nonane.

Entry 234 1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2- methyl-4-nitrophenylimino)-3-thia-l-azaspiro [4.4] nonane. The thiazolidine was reacted with allyl bromide according to Method D2e to give 2- (2-methyl-4- nitrophenylimino)-1- (prop-1-en-3-yl)-3-thia-1-azaspiro [4.4] nonane.

Entry 235

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2- methyl-4-nitrophenylimino)-3-thia-l-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2e to give 2- (2- methyl-4-nitrophenylimino)-1- (cyclopropylmethyl)-3-thia-1-azaspiro [4.4] nonane.

Entry 236

1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclohexylmethyl bromide according to Method D2e to give 2- (2- methyl-4-nitrophenylimino)-1- (cyclohexylmethyl)-3-thia-1-azaspiro [4.4] nonane.

Entry 237

1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with 2- (bromomethyl) tetrahydro-2H-pyran according to Method D2e to give

2-(2-methyl-4-nitrophenylimino)-1-(tetrahydro-2H-pyran-2-ylm ethyl)-3-thia-1- azaspiro [4.4] nonane.

Entry238

1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2- methyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with 2- (2-bromoethyl)-1,3-dioxane according to Method D2e to give 2- (2- methyl-4-nitrophenylimino)-1- (2- ( 1,3-dioxan-2-yl)ethyl)-3-thia-1- azaspiro[4.4] nonane.

Entry 239

1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2- methyl-4-nitrophenylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclobutyl bromide according to Method D2e to give 2- (2-methyl- 4-nitrophenylimino)-1-cyclobutyl-3-thia-1-azaspiro [4.4] nonane.

Entry 240

1- (Hydroxymethyl) cyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was treated with SOCS2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4- nitrophenylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4- nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 241

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was reacted with SOC12 followed by with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4- nitrophenylphenylimino)-3-thia-l-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4- nitrophenylimino)-l-2-cyclopentyl-3-thia-l-azaspiro [4.4] nonane. The thiazolidine was oxidized with m-CPBA according to Method D4a to afford 2- (2-methyl-4- nitrophenylimino)-l-cyclopentyl-3-thia-l-azaspiro [4.4] nonane 3-oxide.

Entry 242

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was reacted with SOC12 followed by with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4- nitrophenylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4- nitrophenylimino)-1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was oxidized with m-CPBA according to Method D4a to afford 2- (2-methyl-4- nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane 3,3-dioxide.

Entry 243

2-Ethylaniline was protected as 2-ethylacetanilide according to Method A2a, Step 1.

The acetamide was converted to 2-ethyl-4-nitroaniline, then deprotected according to Method A2a, Step 2. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3.1- Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2- ethyl-4-nitrophenylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-ethyl-4- nitrophenylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 244 3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3.1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was converted to 1- chloromethylcyclopentanamine HCl salt according to Method B7e. 1- Chloromethylcyclopentanamine HCl salt was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (3-methyl-4-nitrophenylimino)-3- thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (3-methyl-4-nitrophenylimino)-l-cyclopentyl-3- thia-1-azaspiro [4.4] nonane.

Entry 245

2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, Step 1. The acetamide was converted to 2,3-dimethyl-4-nitroaniline, then deprotected according to Method A2a, Step 2. The aniline was converted to 2,- dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3.1- Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2- (2,3-dimethyl-4-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2,3- dimethyl-4-nitrophenylimino)-l-cyclopentyl-3-thia-l-azaspiro [4.4] nonane.

Entry 246 2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, step 1. The acetamide was converted to 2,3-dimethyl-6-nitroaniline, then deprotected according to Method A2a, step 2. The aniline was converted to 2,- dimethyl-6-nitrophenyl isothiocyanate according to Method A2a, step 3.1- Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method Cle to give 2- (2,3-dimethyl-6-nitrophenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2,3- dimethyl-6-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 247

1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-iodophenyl isothiocyanate according to Method Cle to give 2- (4- iodophenylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodophenylimino)- 1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide was reacted with CuCN according to Method D2h to afford 2- (4-cyanophenylimino)-l-cyclopentyl-3- thia-1-azaspiro [4.4] nonane.

Entry 248

4-Cyano-2-methylaniline was prepared according to Method Ala. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate according to Method A2b. 1- Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-methylphenyl isothiocyanate according to Method Cle to give 2- (4- cyanophenylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 249

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted

with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 250 4-Iodo-2-n-propylaniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was sequentially reacted with SOCS2 and 4-iodo-2-n-propylphenyl isothiocyanate according to Method C2a to give 2- (4-iodo-2-n-propylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-2- n-propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2- (4-cyano-2-n- propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 251 4-Iodo-2-isopropylaniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was sequentially reacted with SOCS2 and 4-iodo-2-isopropylphenyl isothiocyanate according to Method C2a to give 2- (4-iodo-2-isopropylphenylimino)-3-thia-l-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-2- isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2- (4-cyano-2- isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 252

4-Iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was sequentially reacted with SOC'2 and 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method C2a to give 2- (4-iodo-2, 3-dimethylphenylimino)-3-thia-l- azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-2, 3-dimethylphenylimino)-l- cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2- (4-cyano-2, 3-dimethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro [4.4] nonane.

Entry 253 1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to afford 2- (4-carboxy-2-ethylphenylimino)-l- cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 254 4-Cyano-2-methylaniline was prepared according to Method Ala. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate according to Method A2b. 1-

Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-methylphenyl isothiocyanate according to Method Cle to give 2- (4- cyanophenylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to afford 2- (4-carboxy-2-methylphenylimino)- 1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 255 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino)-1-2- cyclopentyl-3-thia-l-azaspiro [4.4] nonane. The benzoic acid was converted to 2- (4- acetyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane according to Method D 1 Oa.

Entry 256 Methyl 4-amino-3-methylbenzoate was converted to 4-methoxycarbonyl-2- methylphenyl isothiocyanate according to Method A2b. 1- Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was sequentially reacted with SOC12 and 4-methoxycarbonyl-2-

methylphenyl isothiocyanate according to Method C2a to give 2- (4- methoxycarbonyl-2-methylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2h to give 2- (4-methoxycarbonyl-2-methylphenylimino)-1-cyclopentyl-3-thia -1- azaspiro [4.4] nonane.

Entry 257 1-Hydroxymethylcyclopentanamine was prepared according to Method B I c. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino)-1-2- cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The benzoic acid was reacted with methylamine according to Method D6b to afford 2- (4- (N-methylcarbamoly)-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 258 1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino)-1-2- cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The benzoic acid was reacted with dimethylamine according to Method D6b to afford 2-(4-(N, N-dimethylcarbamoly)-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 259

2,3-Dichloroaniline was converted to the 2,3-dichloroformanilide according to Method A3a, Step 1. The formanilide was converted to 2,3-dichlorophenyl isocyanide dichloride according to Method A3a, Step 2.1- Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method Blc. The 2-hydroxyethylamine was converted to 13-aza-6- oxadispiro [4.2.4.1] tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1- (cyclopentylamino)-1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino)-1- (acetylthiomethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-1-(thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 2,3-dichlorophenyl isocyanide dichloride according to Method C6c to afford 2- (2,3-dichlorophenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 260 2- (Trifluoromethyl) aniline was converted to the 2- (trifluoromethyl) formanilide according to Method A3a, Step 1. The formanilide was converted to 2- (trifluoromethyl) phenyl isocyanide dichloride according to Method A3a, Step 2.1- Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B l c. The 2-hydroxyethylamine was converted to 13-aza-6- oxadispiro [4.2.4.1] tridecane according to Method B4d, Step 1. The oxazolidine was

reductively opened according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino)-1- (thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-1-(thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 2- (trifluoromethyl) phenyl isocyanide dichloride according to Method C6c to afford 2-(2-(trifluoromethyl) phenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane.

Entry 261 4- (Trifluoromethyl) aniline was converted to the 4- (trifluoromethyl) formanilide according to Method A3a, Step 1. The formanilide was converted to 4- (trifluoromethyl) phenyl isocyanide dichloride according to Method A3a, Step 2.1- Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B l c. The 2-hydroxyethylamine was converted to 13-aza-6- oxadispiro [4.2.4.1] tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1- (cyclopentylamino)-1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino)-1- (thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-1-(thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 4- (trifluoromethyl) phenyl isocyanide dichloride according to Method C6c to afford 2- (4- (trifluoromethyl) phenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane.

Entry 262 2-Chloro-3-methylaniline was converted to the 2-chloro-3-methylformanilide according to Method A3a, Step 1. The formanilide was converted to 2-chloro-3- methylphenyl isocyanide dichloride according to Method A3a, Step 2.1-

Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method Blc. The 2-hydroxyethylamine was converted to 13-aza-6- oxadispiro [4.2.4.1] tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino)-1-(thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-1-(thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 2-chloro-3-methylphenyl isocyanide dichloride according to Method C6c to afford 2- (2-chloro-3-methylphenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane.

Entry 263 3- (Trifluoromethyl) aniline was converted to the 3- (trifluoromethyl) formanilide according to Method A3a, Step 1. The formanilide was converted to 3- (trifluoromethyl) phenyl isocyanide dichloride according to Method A3a, Step 2.1- Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B l c. The 2-hydroxyethylamine was converted to 13-aza-6- oxadispiro [4.2.4.1] tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1- (cyclopentylamino)-1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino)-1-(thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-1-(thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 3- (trifluoromethyl) phenyl isocyanide dichloride according to Method C6c to afford 2- (3- (trifluoromethyl) phenylimino)-l-cyclopentyl-3-thia-l- azaspiro [4.4] nonane.

Entry 265

3-Chloro-2-methylaniline was converted to the 3-chloro-2-methylformanilide according to Method A3a, Step 1. The formanilide was converted to 3-chloro-2- methylphenyl isocyanide dichloride according to Method A3a, Step 2.1- Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B l c. The 2-hydroxyethylamine was converted to 13-aza-6- oxadispiro [4.2.4.1] tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino)-1-(thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-1-(thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 3-chloro-2-methylphenyl isocyanide dichloride according to Method C6c to afford 2- (3-chloro-2-methylphenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane.

Entry 265 2,3-Dichloro-4-methylaniline was converted to the 2,3-dichloro-4-methylformanilide according to Method A3a, Step 1. The formanilide was converted to 2,3-dichloro-4- methylphenyl isocyanide dichloride according to Method A3a, Step 2.1- Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B l c. The 2-hydroxyethylamine was converted to 13-aza-6- oxadispiro [4.2.4.1] tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino)-1-(thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-1-(thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 2,3-dichloro-4-methylphenyl isocyanide dichloride according to Method C6c to afford 2- (2, 3-dichloro-4-methylphenylimino)-1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane.

Entry 266

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was sequentially reacted with SOC12 and 4-bromo-2- methylphenyl isothiocyanate according to Method C2a to give 2- (4-bromo-2- methylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-bromo-2- methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 267

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced according to Method Dlla to give 2- (4-formyl-2-ethylphenylimino)-1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 268

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was

reduced according to Method Dlla to give 2- (4-formyl-2-ethylphenylimino)-1- cyclopentyl-3-thia-l-azaspiro [4.4] nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a according to afford 2-(2-ethyl-4-((lE)- 2-ethoxycarbonylvinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 269 1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced according to Method Dlla to give 2- (4-formyl-2-ethylphenylimino)-1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde was reacted with nitromethane according to Method D12b according to afford 2-(2-ethyl-4-((1E)-2- nitrovinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 270 1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro [4.4] nonane. The nitrile was reduced according to Method Dlla to give 2- (4-formyl-2-ethylphenylimino)-1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a according to afford 2- (2-ethyl-4- ( (lE)- 2-ethoxycarbonylvinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4. 4] nonane. The ester was saponified according to Method D6a to afford 2-(2-ethyl-4-((1E)-2- carboxyvinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 271

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced according to Method Dlla to give 2- (4-formyl-2-ethylphenylimino)-1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde was reacted with malononitrile according to Method D12c according to afford 2- (2-ethyl-4- (2,2- dicyanovinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 272 1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced according to Method Dlla to give 2- (4-formyl-2-ethylphenylimino)-1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde was reacted with diethyl (2- oxopropyl) phosphonate according to Method D12a according to afford 2- (2-ethyl-4- ((1E)-2-acetylvinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 273

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2- (4- cyano-2-ethylphenylimino)-3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2- ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced according to Method Dlla to give 2- (4-formyl-2-ethylphenylimino)-1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde was reacted with acetonitrile according to Method D12d according to afford 2-(2-ethyl-4-((1E)-2- cyanovinyl) phenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 274

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was sequentially reacted with SOC12 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino)-3- thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclohexyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino)-1-cyclohexyl-3- thia-1-azaspiro [4.4] nonane.

Entry 275

1-Hydroxymethylcyclopentanamine was prepared according to Method Bic. The 2- hydroxyethylamine was sequentially reacted with SOC12 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino)-3- thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cycloheptyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-cycloheptyl-3- thia-l-azaspiro [4.4] nonane.

Entry 276

1-Aminocyclohexane-1-carboxylic acid was protected as the benzyloxycarbonylamine according to Method Bla, Step 1.1- (Benzyloxycarbonylamino) cyclohexane-1-carboxylic acid was reduced to 1- (benzyloxycarbonylamino)-l- (hydroxymethyl) cyclohexane according to Method Bla, Step 2. The carbamate was deprotected according to Method Bla, Step 3 to give 1-amino-1- (hydroxymethyl) cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOC12 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1- azaspiro [4.5] decane. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3- thia-1-azaspiro [4.5] decane.

Entry 277 2-Methyl-4-nitroaniline was converted to the 2-methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was converted to 2-methyl-4-nitrophenyl isocyanide dichloride according to Method A3a, Step 2.3-Aminotetrahydro-2H pyran-3-carboxylic acid was converted to the methyl ester according to Method Blb, Step 1. Methyl 3-aminotetrahydro-2H-pyran-3-carboxylate was reduced to 3-amino- 3- (hydroxymethyl) tetrahydro-2H-pyran according to Method Blb, Step 2. The 2- hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford 2-isopropyl-l-aza-3,7-dioxaspiro [4.5] decane. The oxazolidine was reduced to 3-isobutylamino-3- (hydroxymethyl) tetrahydro-2H-pyran. The substituted 2-hydroxyethylamine was converted to 3-isobutylamino-3- (acetylthiomethyl) tetrahydro-2H-pyran according to Method C6c, Step 1. The thioacetate was saponified according to Method C6c, Step 2 to give 3-isobutylamino- 3- (thiomethyl) tetrahydro-2H-pyran. The 2-thioethylamine was reacted with 2- methyl-4-nitrophenyl isocyanide dichloride to afford 2- (2-methyl-4- nitrophenylimino-1-isobutyl-1-aza-7-oxa-3-thiaspiro [4.5] decane.

Entry 278

2-Methyl-4-nitroaniline was converted to the 2-methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was converted to 2-methyl-4-nitrophenyl isocyanide dichloride according to Method A3a, Step 2.4-Aminotetrahydro-2H- pyran-4-carboxylic acid was converted to the methyl ester according to Method B 1 b, Step 1. Methyl 4-aminotetrahydro-2H-pyran-4-carboxylate was reduced to 4-amino- 4- (hydroxymethyl) tetrahydro-2H-pyran according to Method Blb, Step 2. The 2- hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford 2-isopropyl-1-aza-3,8-dioxaspiro [4.5] decane. The oxazolidine was reduced to 4-isobutylamino-4- (hydroxymethyl) tetrahydro-2H-pyran. The substituted 2-hydroxyethylamine was converted to 4-isobutylamino-4- (acetylthiomethyl) tetrahydro-2H-pyran according to Method C6c, Step 1. The thioacetate was saponified according to Method C6c, Step 2 to give 4-isobutylamino- 4- (thiomethyl) tetrahydro-2H-pyran.(thiomethyl) tetrahydro-2H-pyran. The 2-thioethylamine was reacted with 2- methyl-4-nitrophenyl isocyanide dichloride to afford 2- (2-methyl-4- nitrophenylimino-1-isobutyl-1-aza-8-oxa-3-thiaspiro [4.5] decane.

Entry 279 2-Amino-2-norbornane-1-carboxylic acid as a mixture of isomers was converted to the N-benzyloxycarbonyl analogue according to Method Bla, Step 1.1- (Benzyloxycarbonylamino)-2-norbornane-1-carboxylic acid was reduced to 1- (benzyloxycarbonylamino)-1-(hydroxymethyl)-2-norbornane according to Method Bla, Step 2. The carbamate was deprotected according to Method Bla, Step 3 to give 1-amino-1- (hydroxymethyl)-2-norbornane. The 2-hydroxyethylamine was alkylated with isobutyl bromide according to Method B2a to give N-isobutyl-1- amino-1- (hydroxymethyl)-2-norbomane. The alkylated 2-hydroxyethylamine was treated with SOC12 according to Method B7a to give N-isobutyl-2-chloroethylamine HCl salt. The chloroethylamine was treated with 2-methyl-4-nitrophenyl isothyiocyanate according to Method C 1 a to afford 2- (2-methyl-4-nitrophenylimino)- 3-isobutylspiro [1,3-thiazolidine-4,3'-bicyclo [3.2.1] octane].

Entry 280

N-(tert-Butoxycarbonyl)- (L)-valine(tert-Butoxycarbonyl)- (L)-valine was converted to (S)-3- (tert- butoxycarbonylamino)-1-diazo-4-methylpentan-2-one according to Method B6a, Step 1. The diazo compound was converted to methyl (R)-3- (tert- butoxycarbonylamino)-4-methylpentanoate according to Method B6a, Step 2. The ester was reduced according to Method B6a, Step 3 to give (R)-3- (tert- butoxycarbonylamino)-4-methylpentan-1-ol. The carbamate was deprotected and converted to (R)-3-amino-1-chloro4-methylpentane according to Method B7e. The 3-chloropropylamine was treated with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2- (2-methyl-4-nitrophenylimino)-4-isopropyl- 1,3-thiazine. The thiazine was alkylated with isobutyl bromide according to Method D2a to afford (4R)-2- (2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3- thiazine HCl salt.

Entry 281 3-Aminopropanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydrol, 3-oxazine. The oxazine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxypropylamine. The 3- hydroxypropylamine was reacted with SOCl2 according to Method B9a, Step 3 to give N-isobutyl-3-chloropropylamine HCl salt. The 3-chloropropylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to afford 2- (2-methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiaz ine.

Entry 282

4-Aminobutanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydrol, 3-oxazepine. The 1,3-oxazepine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxybutylamine. The 3- hydroxybutylamine was reacted with SOC12 according to Method B9a, Step 3 to give N-isobutyl-3-chlorobutylamine HCl salt. The 3-chlorobutylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to afford 2- (2- methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiazepi ne.

Entry 283 3-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by chloroacetic acid according to Method C8a to afford 2- (3-methyl-4- nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one.

Entry 284 3-Methyl-4-nitrophenyl isothiocyanate was reacted with benzylamine followed by chloroacetic acid according to Method C8a to afford 2- (3-methyl-4- nitrophenylimino)-3- (phenylmethyl)-1,3-thiazolidin-4-one.

Entry 285 3-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to afford 2- (3-methyl-4- nitrophenylimino)-3- (2-methylbutyl)-1,3-thiazolidin-4-one.

Entry 286

3-Methyl-4-nitrophenyl isothiocyanate was reacted with 1-amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2- (3-methyl-4- nitrophenylimino)-3- (1-cyclohexylethyl)-1,3-thiazolidin-4-one.

Entry 287 2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by chloroacetic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one.

Entry 288 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3- (2-methylbutyl)-1,3-thiazolidin-4-one.

Entry 289 2-Methyl-4-nitrophenyl isothiocyanate was reacted with benzylamine followed by chloroacetic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3- (phenylmethyl)-1,3-thiazolidin-4-one.

Entry 290 2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by a-chloropropionic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3-isobutyl-5-methyl-1,3-thiazolidin-4-one.

Entry 291

2-Methyl-4-nitrophenyl isothiocyanate was reacted with 1-amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3- (1-cyclohexylethyl)-1,3-thiazolidin-4-one.

Entry 292 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (75)-7-amino-l- cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2- (2-methyl-4-nikophenylimino)-3-((1S)-1-cyclohexylethyl)-1,(2 -methyl-4-nikophenylimino)-3-((1S)-1-cyclohexylethyl)-1, 3-thiazolidin-4-one.

Entry 293 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (IR)-I-amino-1- cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2- (2-methyl-4-nitrophenylimino)-3-((lR)-1-cyclohexylethyl)-1,( 2-methyl-4-nitrophenylimino)-3-((lR)-1-cyclohexylethyl)-1, 3-thiazolidin-4-one.

Entry 294

2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by a-chloro-a-phenylacetic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidin-4-one.

Entry 295 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (lR)-I-amino-l- cyclohexylethane followed by a-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((lR)-1-cyclohexylethyl)-5 -methyl-1,3- thiazolidin-4-one.

Entry 296 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (IR)-1-amino-1- cyclohexylethane followed by a-chloro-a-phenylacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((lR)-1-cycloheXylethyl)-5 -phenyl- 1,3-thiazolidin-4-one.

Entry 297

2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-amino-1- cyclohexylethane followed by a-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1S)-1-cyclohexylethyl)-5 -methyl-1,3- thiazolidin-4-one.

Entry 298

2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-amino-1- cyclohexylethane followed by a-chloro-a-phenylacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1S)-1-cyclohexylethyl)-5 -phenyl- 1,3-thiazolidin-4-one.

Entry 299

2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by a-chloropropionic acid according to Method C8a to afford 2- (2-methyl- 4-nitrophenylimino)-3-(2-ethyl-1-butyl)-5-methyl-1,(2-ethyl- 1-butyl)-5-methyl-1, 3-thiazolidin-4-one.

Entry 300

2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3-isobutyl-5-isobutyl-1,3-thiazolidin-4-on e.

Entry 301

2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to afford 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-5- (2-ethyl-1-butyl)-1,3-thiazolidin-4-one.

Entry 302 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methylbutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to afford 2- (2-methyl-4-nitrophenylimino)-3- (2-butyl)-5-isobutyl-1,3-thiazolidin-4-one.

Entry 303 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methylbutylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to afford 2- (2- methyl-4-nitrophenylimino)-3- (2-butyl)-5-isopropyl-1,3-thiazolidin-4-one.

Entry 304 2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3-isobutyl-5-isopropyl-1,3-thiazolidin-4-o ne.

Entry 305

2-Methyl-4-nitrophenyl isothiocyanate was reacted with (2S)-2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3-((2S)-2-methyl-1-butyl)-1,((2S)-2-methyl -1-butyl)-1, 3-thiazolidin-4-one.

Entry 306

2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to afford 2- (2- methyl-4-nitrophenylimino)-3- (2-ethyl-1-butyl)-5-isopropyl-1,3-thiazolidin-4-one.

Entry 307

(R)-N-isobutylserine methyl ester HCl salt was prepared from (D)-serine methyl ester as described in Method B3a. The alcohol was reacted with SOC12 according to Method B7b, followed reaction with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to afford 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-4- methylene-1,3-thiazolidin-5-one.

Entry 308 2,4,6-Trichlorophenyl isothiocyanate was reacted with 2-butylamine followed by chloroacetic acid according to Method C8a to afford 2- (2,4,6-trichlorophenylimino)- 3- (2-butyl)-1, 3-thiazolidin-4-one.

Entry 309 3,4-Dichlorophenyl isothiocyanate was reacted with 2-methylbutylamine followed by chloroacetic acid according to Method C8a to afford 2- (3,4-dichlorophenylimino)-3- (2-butyl)-1,3-thiazolidin-4-one.

Entry 310 N-Isobutylglycine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cl la to afford 2- (2-methyl-4-nitrophenylimino)-3-isobutyl-1,3- thiazolidin-5-one.

Entry 311 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by chloroacetic acid according to Method C8a to afford 2- (2-methyl-4- nitrophenylimino)-3- (2-ethyl-1-butyl)-1,3-thiazolidin-4-one.

Entry 312 N-Isobutylleucine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Clla to afford (4S)-2- (2-methyl-4-nitrophenylimino)-3,4- diisobutyl-1,3-thiazolidin-5-one.

Entry 313

N-Isobutylproline ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Clla to afford 4- (2-methyl-4-nitrophenylimino)-l- oxoperhydro-2-thiapyrrolizine.

Entry 314

N- (tert-Butoxycarbonyl) glycine tert-butyl ester was reacted with 3-bromo-2- methylpropene according to Method B8b, Step 1 to give N-(tert-butoxycarbonyl)-N- (2-methylprop-2-enyl) glycine tert-butyl ester. The ester was reduced according to Method B8b, Step 2 to give N-(tert-butoxycarbonyl)-N (2-hydroxyethyl)-1-amino-2- methylprop-2-ene. The alcohol was treated with p-toluenesulfonyl chloride according to Method B8b, Step 3 to give N-(tert-butoxycarbonyl)-N (2- tosyloxyethyl)-l-amino-2-methylprop-2-ene. The carbamate was deprotected according to Method B8b, Step 4 to give N-(2-tosyloxyethyl)-2-methylprop-2-en-1- ammonium trifluoroacetate. The tosylate was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C5a to afford 2- (2-methyl-4-nitrophenylimino)-3- (2- methylprop-2-enyl)-1,3-oxazolidine.

Entry 315

(L)-Valine methyl ester was reduced to (1S)-1- (hydroxymethyl)-2- methylpropylamine according to Method B 1 b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2,4- diisopropyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (lS)-1-(hydroxymethyl)-N-isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine was reacted with SOC12 according to Method B7b to give (lS)-1-(chloromethyl)-N-isobutyl-2-methylpropylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2- (2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl- 1,3-oxazolidine.

Entry 316

(L)-Leucine methyl ester was reduced to (lS)-1-(hydroxymethyl)-3- methylbutylamine according to Method Blb, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2- isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (lS)-1-(hydroxymethyl)-N-isobutyl-3-methylbutylamine. The substituted 2-hydroxyethylamine was reacted with SOC12 according to Method B7b to give (lS)-1-(chloromethyl)-N-isobutyl-3-methylbutylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3, 4-diisobutyl-1,3- oxazolidine.

Entry 317 (L)-Leucine methyl ester was reduced to (lS)-1-(hydroxymethyl)-3- methylbutylamine according to Method Bulb, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (45)-2- isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (lS)-1-(hydroxymethyl)-N-isobutyl-3-methylbutylamine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, Step 1. The formanilide was reacted with SOC12 and SO2C12 according to Method A3a, Step 2 to give 4-cyano-2-ethylphenyl isocyanide dichloride. The substituted 2-hydroxyethylamine was reacted with 4-cyano-2- ethylphenyl isocyanide dichloride according to Method C7b to afford (4S)-2- (4- cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-oxazolidine.

Entry 318

2-Amino-2-methyl-1-propanol was reacted with cyclopentanone according to Method B4b, Step 1 to afford 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane. The oxazolidine was reduced according to Method B4b, Step 2 to give N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine. 2-Methyl-4-nitroaniline was converted to 2- methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was reacted with SOC12 and SO2Cl2 according to Method A3a, Step 2 to give 2-methyl-4- nitrophenyl isocyanide dichloride. The substituted 2-hydroxyethylamine was reacted with 2-methyl-4-nitrophenyl isocyanide dichloride according to Method C7a to afford 2- (2-methyl-4-nitrophenylimino)-3-cyclopentyl-4,4-dimethyl-1,3 -oxazolidine.

Entry 319 2-Amino-2-methyl-1-propano l was reacted with cyclopentanone according to Method B4b, Step 1 to afford 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane. The oxazolidine was reduced according to Method B4b, Step 2 to give N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, Step 1. The formanilide was reacted with SOCl2 and SO2Cl2 according to Method A3a, Step 2 to give 4-cyan-2- ethylphenyl isocyanide dichloride. The substituted 2-hydroxyethylamine was reacted with 4-cyano-2-ethylphenyl isocyanide dichloride according to Method C7a to afford 2- (4-cyano-2-ethylphenylimino)-3-cyclopentyl-4, 4-dimethyl-1,3-oxazolidine.

Entry 320

1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B 1 c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method Bic, Step 2. The hydroxyethylamine was reacted with cyclopentanone according to Method B4d, Step 1 to give 6-aza-12- oxadispiro [4.1.4.2] tridecane. The oxazolidine was reduced according to Method B4d, Step 2 to give 1- (cyclopentylamino)-1-(hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOC12 according to Method B7b to 1- (cyclopentylamino)-1-(chloromethyl) cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro [4.4] nonane.

Entry 321 1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B 1 c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method Blc, Step 2. The 2-hydroxyethylamine was reacted with cyclobutanone according to Method B4a, Step 1 to give 5-aza-12- oxadispiro [3.1.4.2] dodecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1- (cyclobutylamino)-1-(hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOC12 according to Method B7b to 1- (cyclobutylamino)-1-(chloromethyl) cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1- cyclobutyl-2- (2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro(2-methyl-4-ni trophenylimino)-3-oxa-1-azaspiro [4.4] nonane.

Entry 322

1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method Bic, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method Blc, Step 2. The hydroxyethylamine was reacted with cyclohexanone according to Method B4a, Step 1 to give 6-aza-13- oxadispiro [4.1.5.2] tetradecane. The oxazolidine was reduced according to Method B4a, Step 2 to give l- (cyclohexylamino)-1-(hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOC12 according to Method B7b to 1- (cyclohexylamino)-1-(chloromethyl) cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1- cyclohexyl-2- (2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro(2-methyl-4-ni trophenylimino)-3-oxa-1-azaspiro [4.4] nonane.

Entry 323 1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method Bic, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method Bic, Step 2. The hydroxyethylamine was reacted with cyclopentanone according to Method B4d, Step 1 to give 6-aza-12- oxadispiro [4.1.4.2] tridecane. The oxazolidine was reduced according to Method B4d, Step 2 to give 1- (cyclopentylamino)-1-(hydroxymethyl) cyclopentane. 4- Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, Step 1. The formanilide was reacted with SOC12 and SO2C12 according to Method A3a, Step 2 to give 4-cyano-2-ethylphenyl isocyanide dichloride. The substituted 2-hydroxyethylamine was reacted with 2-methyl-4-nitrophenyl isocyanide dichloride according to Method C7a to afford 1-cyclopentyl-2- (2-methyl- 4-nitrophenylimino)-3-oxa-l-azaspiro [4.4] nonane.

Entry 324

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bulb. The 2-hydroxyethylamine was converted to (2S)- 4-methyl-2- (isobutylamino) pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride as described in Method B7c. 4-Nitrophenyl isothiocyanate was reacted with N-(lS)-1-(chloromethyl)-3-methylbutyl)-N- (isobutyl) ammonium chloride according to Method Clf to give 2- (4- nitrophenylthio)-1,5-diisobutylimidazoline.

Entry 325

(lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4s)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give (4S)-2-(N-(4-heptyl)-N-(2-methyl-5- nitrophenyl)amino)-4-isobutyl-1,3-thiazoline.

Entry 326

(lR)-1-(Hydroxymethyl)-3-methylbutylamine was made from (D)-leucine methyl ester according to Blb. The 2-hydroxyethylamine was converted to (lR)-l- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-5-nitrophenyl isothiocyanate was reacted with (1 R)-1- (chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4R)-2- (2-methyl- 5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2- (N-isobutyl-N (2- methyl-5-nitrophenyl) amino)-4-isobutyl-1,3-thiazoline HC1 salt.

Entry 327

(lS)-1- (Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2- (2-methyl- 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with neopentyl bromide according to Method D2a to afford (4S)-2- (N (2,2- dimethylpropyl)-2-methyl-4-nitrophenylamino)-4-isobutyl-1,3- thiazoline.

Entry 328 (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S)- 1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a.

2,3-Dichlorophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2- (2,3- dichlorophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 3-bromopentane according to Method D2a to afford (4S)-2-(N-(3-pentyl)-2-methyl-4- nitrophenylamino)-4-isobutyl-1,3-thiazoline.

TABLES The compounds listed in Tables 1-4 below were synthesized according to the methods described above.

Table and Ring Expanded Homologues TLC Mass Spec. mp HPLC TLC Solvent [Source] Synth. Entry Compound (°C) (min.) Rf System Method 1 nô 90-0.36 30% 238 Cla L/\\ yOz 92 EtOAc/ (M+H) + H Me hex [FAB] CSN NO 0.49 20% 280 Cla, N EtOAc/ (M+H) + D2a i-Bu pentane [CI] CSN NO 0. 52 20% 294 Cla, N EtOAc/ (M+H) + D2a i-Bu Me pentane [CI] 4 rus/=\ 0. 78 20% 303 Cla, N EtOAc/ (M+H) + D2a i-Bu Cl Cl pentane [CI] 5 S < 11 9 310 Cld N (h) (M+H) + i-Bu MeO [HPLC ES-MS] 6 CN 9. 9 260 Cld N (h) (M+H) + i-Bu í-Bu [HPLC ES-MS] HCI N02 0.50 20% Cla, CS) =Nt) EtOAc/D2a hex i-Bu Me i-Bu Me CSN CN 25.0 288 Cld N (h) (M+H) + i-Bu Et [HPLC ES-MS] CSN CI 32. 0 337 Cld N (h) (M+H) + i-Bu F3C [HPLC ES-MS] 10 0) =N<NO2 0.23 20% 278 Cla, N EtOAc/ (M+H) + D2a, pentane [CI] D 14a 11 0) =N4NO2 0. 49 292 292 Cla, N EtOAc/ (M+H) + D2a Me pentane [CI] 12 CS N NO 0.33 20% 278 Cla, N EtOAc/ (M+H) + D2a pentane [CI] 13 CSN CI 0. 43 11% 301 Cla, N EtOAc/ (M+H) + D2a _ H pentane [Cl] 14 CSN NO 77 30% 308 B2b L//N02 N EtOAc/ (M+H) + steps mye hex [FAB] 1-3, B7a, Cla 15 CSN N02 69-0.78 30% 292 Cla, N 70 EtOAc/ (M+H) + D2a Me Me hex [FAB] 16 C NO 108-0.78 30% 290 Cla, N/109 EtOAc/ (M+H) + D2a hex [FAB] 17 0 FN4NO2 0. 77 30% 322 Cla, N EtOAc/ (M+H) + D2a --J Me hex [FAB] 18 0 » hT 2 0. 77 30% 308 Cla, L/\/N02 N EtOAc/ (M+H) + D2a hex [FAB] 19 0. 72 40% 364 364 Cla, N/N02 EtOAc/ EtOAc/ (M+H) D2a hex [FAB] mye 20 0 FNnNO2 0.67 30% 308 Cla, N EtOAc/ (M+H) + D2a mye hex [FAB] 21 CS=N NO 0.71 40% 294 B5a, N EtOAc/ (M+H) + B7a, hex [FAB] [FAB] 22 0 » hT °2 0.71 40% 308 B5a, L/\/y02 N EtOAc/ (M+H) + B7a, Me hex [FAB] Cla 23 \ S = 0.72 40% 336 Cla, EtOAc/ (M+H) + D2a Me hex [FAB] 24 (S 0. 71 40% 348 Cla, C NOz EtOAc/ (M+H) + D2a hex [FAB] mye 25 CSN NO. 71 40% 350 B2b, N EtOAc/ (M+H) + step 2, mye hex [FAB] Cla, D2a 26 <| C FN4NO2 0. 68 30% 372 Cla, EtOAc/ (M+H) + D2a Me hex [FAB] CSN NO 0. 74 40% 356 Cla, Br N EtOAc/ (M+H) + D2a Me hex [FAB] 29 CSN NOz 0. 74 40% 312 Cla, N EtOAc/ (M+H) + D2a Cl hex [FAB] 30 rS < 129-276 Cla, N H 131 (M+H) + D2a Me [FAB] 31 0 FN4NO2 112-356 Cla, N 113 (M+H) + D2a Me [FAB] 32 0) =N 4No2 394 C 1 a, J Met' (M+H) + D2a EtO Me [FAB] p OEt 33 o 0) CN4No2 0.40 40% 238 Cla, M e EtOAc/ (M+H) + D2a Me0 e Me hex [FAB] 34 C) = 4 °2 0.63 40% 309 (M+) Cla, 2 MeO N EtOAc/ [EI] D2a hex 0 35 CSN NO 358 Cla, Ph N p (M+H) + D2a, Me [FAB] D5a HO 36 0.65 40% 336 Cla, o N H EtOAc/ (M+H) + D2a eI Me hex 37 0) c 4 2 0.63 40% 308 Cla, z o N)-'EtOAc/ (M+H) + D2a hex [FAB] 38 0 sN4NO2 310 Cla, HO N (M+H) + D2a, [FAB] D5a 39 0) c 4 °2 338 Cla, HO N (M+H) + D2a, [FAB] D5a 40 CS--. N NO 0.65 40% 321 Cla, > EtOAc/ (M+H) + D2a Me 0 hex [FAB] 41 CSN NO. 74 40% 346 Cla, ci N EtOAc/ (M+H) + D2a hex M hex [FAB] 42 CSN N02 0. 63 40% 394 Cla, N EtOAc/ (M+H) + D2d gA Me hex [FAB] 43 0) =N4NO2 0. 40 40% 335 Cla, N EtOAc/ (M+H) + D2a hex [FAB] zone 44 0) =N4NO2 14.9 306 B4b, (M+H) + B7c, Me Me [HPLC C 1 d k s pC dd ES-MS] 45 CSN NO 14.4 322 B4b, 2 N (h) (M+H) + B7c, Me0 [HPLC Cld ES-MS] 46 0) =Nm 15. 6 315 B4b, Cl Cl (f) (M+H) + B7c, [HPLC Cld ES-MS] -0. 77 30% 318 B2b N N02 EtOAc/ (M+H) + steps hex [FAB] [FAB] B7a, Cla 48 ces 320 B4a, N N02 N 2 (M+H) + B7c, [HPLC Cld ES-MS] 49 0) =N4NO2 119-0.37 20% 314 B7a, N/121 EtOAc/ (M+H) + Cla fA Me hex [HPLC ES-MS] 50 CS-15. 4 334 B2a, !/=N-/r-N02 (M+H) + B7c, [HPLC Cld ES-MS] 51 CS-19. 1 348 B2a, N (h) (M+H) + B7c, (M+H) + B7c, Me [HPLC Cld ES-MS] 52 CS-16.9 364 B2a, N (h) (M+H) + B7c, (M+H) + B7c, mye0 [HPLC C 1 d ES-MS] 53 CS'22. 1 357 B2a, N (M+H) + B 7c, CI [HPLC Cld ES-MS] 54 CS-2.2. 63 301 B2a, N Cl CI (i) (M+H) + B7c, Ci cl [HPLC Cld ES-MS] 55 0) c NN°2 2. 31 292 B2a, N N02 (M+H) + B7c, Me [HPLC Cld ES-MS] 56 CS-2. 78 301 B2a, N (M+H) + B7c, (M+H) + B c, ES-MS] ES-MS, -2.95 301 B2a, N (M+H) + B7c, CI [HPLC Cld ES-MS] 58 Cg-'_'3. 18 315 B2a, N N (M+H) + B7c, [HPLC Cld ES-MS] 59 CS=N CI 3. 29 315 B2a, N (i) (M+H) + B7c, CI E [HPLC Cld ES-MS] 60 CS-3. 48 315 B2a, ci N (M+H) + B7c, E ci [HPLC Cld ES-MS] 61 CS-3. 18 275 B2a, \/ N H (i) (M+H) + B7c, Me [HPLC Cld ES-MS] 62 CS-3. 23 295 B2a, N (i) (M+H) + B7c, HPLC Cld ES-MS] 63 CS-3. 99 329 B2a, N (M+H) + B7c, CI CI [HPLC Cld ES-MS] 64 CS-"4. 13 329 B2a, N CI (M+H) + B7c, [HPLC Cld ES-MS] 65 CS-3. 60 320 B2a, N NOZ N (M+H) + B7c, Me [HPLC Cld ES-MS] 66 CS- 4. 08 329 B2a, ci (i) (M+H) + B7c, [HPLC Cld ES-MS] 67 CSN-3. 99 289 B2a, N H (i) (M+H) + B7c, Me Cld ES-MS] 68 CS » Nn 4. 05 309 B2a, ZON (i) (M+H) + B7c, Me CI [HPLC Cld ES-MS] 69 CSN-17. 0 343 B2a, Cl Cl (f) (M+H) + B7c, [HPLC Cld ES-MS] 70 CNF 4 2 16.7 334 B2a, N (f) (M+H) + B7c, [HPLC Cld ES-MS] 71 0 FNnNo2 16.3 350 B2a, N (f) (M+H) + B7c, Me0 [HPLC Cld ES-MS] 72 0 FN4NO2 125-0.77 30% 348 B5a, N 2 126 EtOAc/ (M+H) + B7a, M hex [FAB] Cla -3. 40 317 B2a, N (M+H) + B7c, Bn Me CI [HPLC Cld ES-MS] 74 CI 3.63 337 B2a, N (M+H) + B7c, Bn Ci [HPLC Cld ES-MS] 75 cs CI 3.3.337 B2a, N (M+H) + B7c, Bn [HPLC Cld ES-MS] CSN N02 3.45 328 B2a, N (i) (M+H) + B7c, Bn Me [HPLC Cld ES-MS] 77 CS>=N 3. 66 337 B2a, N H (i) (M+H) + B7c, Bn CI CI Bn Cl Cl [HPLC C 1 d ES-MS] 78 0 FN 4CN 13. 9 356 B2a, N (g) (M+H) + B7c, [HPLC Cld ES-MS] Cl 79 CN 15. 3 362 B2a, N (g) (M+H) + B7c, Y Cld ES-MS] 0 80 C FN4NO2 19. 6 348 B2a, N (h) (M+H) + B7c, Me [HPLC Cld ES-MS] 81 C » nNO2 18. 1 364 B2a, \/ N (h) (M+H) + B7c, Me0 [HPLC Cld ES-MS] 82 0 sNn 18. 7 357 B2a, N (h) (M+H) + B7c, [HPLC Cld ES-MS] g3 CS 15. 4 314 B2a, NN CN + N H) (M+H) + B7c, [HPLC Cld ES-MS] 84 r-\-NO, 0.68 30% 404 B2b 2 EtOAc/ (M+H) + steps Me hex [FAB] 1-3, B7a, Cla 85 0 FN 4NO2 0.68 30% 372 Cla, EtOAc/ (M+H) + D2a Me hex [FAB] 86 0 sN4No2 0. 71 40% 344 Cla, N EtOAc/ (M+H) + D2a LJ Me hex [FAB] 87S-N 0. 38 30% 342 A2c, N EtOAc/ (M+H) + Blb, i-Bu hex [HPLC B4c, ES-MS] B7c, Clf 88S-0. 78 30% 336 Blb, EtOAc/ (M+H) + B4c, i-Bu hex [HPLC B7c, ES-MS] Clf 89 0. 79 30% 316 Blb, N EtOAc/ (M+H) + B4c, i-Bu hex [HPLC B7c, _ ES-MS] C1f 90 g sN4NO2 0.74 20% B7a, N EtOAc/Cla, i-Bu Me HCI hex D2a 91 \ 0) =N4No2 7.85 0.74 20% 350 B7a, N (b) EtOAc/ (M+H) + Cla, i-Bu [FAB] D2a 92 ANO2 0.77 20% B7a, S ) EtOAc/Cla, .... C i-Bu Me HCI hex D2a i-Bu Me" 93 NO2 0.76 20% B7a, N EtOAc/Cla, Jw/ N i-Bu Me HC hex D2a 94. s>=N N02 0. 50 20% B7a, N EtOAc/Cla, Me Me HCI hex D2a 95 SN NO 0.50 20% B7a, EtOAc/Cla, Me Me HCI hex D2a 96 ans2 52 20% B7a, S EtOAc/Cla, hex D2a Me Me HCI 97 s Me 0.79 20% B7a, t EtOAc/Cla, hex hex D2a _ 98 mesa 0.70 30% 391 Blb, ) =N<No2 EtOAc/ (M+) B7a, hex [EI] Cla, °YD2a O D2a SN CN 46-0. 65 10% 344 Blb, N N H 49 EtOAc/ (M+H) + B7a, i-Bu Et hex [HPLC Cla, ES-MS] D2f 100 S-347 B l b, N NOZ (M+) B7a, [EI] Cla, D2a 101 S-0. 63 30% 361 Blb, I N N02 EtOAc/ (M+) B7a, heuMe hex [FAB} Cla, D2a 102 s N N02 0. 63 30% 394 Blb, P N,} EtOAc/ (M+H) + B7a, mp-hex [FAB] Cla, OH D2a, D5a 103 Me _ 7.67 363 A2b, >=N N02 (b) (M+) B7a, N [EI] Cla, i-Bu Me HCI D2a D2a 104 S CI CI 0.74 30% 387 Blb, \ C) =N t EtOAc/ (M+H) + B7a, hex [FAB] Cla, D2a 105 Me 0.81 30% 392 bulb, s>=N-b-N02 EtOAc/ (M+H) + B7a, hex [FAB] Cla, Da 106 CIWCI 53-360 Blb, 55 (M+H) + B7a, )-,. C 1 a, i-bu D2a 107 FN4NO2 17.5 348 Blb, N (d) (M+H) + B7a, FsC CF3CO2H [HPLC C 1 c ES-MS] 108 SN/No2 28. 9 404 Blb, / _N (d) (M+H) + B7a, i-Bu FsC CF3COZH [HPLC C 1 c, ES-MS] D2f 109 NN cN 23.7 383 Blb, N, > (e) (M+H) + B7a, i-Bu F3C CF3CO2H [HPLC Clc, ES-MS] D2f 110 Cula 23.8 364 Blb, t, C) =N9CN (d) (M+H) + B7a, . _o [HPLC Clc, CF3COZH ES-MS] D2f 111 SN- 0. 36 30% 363 Blb, N Me EtOAc/ (M+H) + B7a, i-BU Me, rr'Artl/1 hex hex [FAB] Cla, D2a 112 Me 0. 79 30% 364 A2a, >==N N02 EtOAc/ (M+H) + step 3, hex hex [CI] Blb, i-Bu Me B7a, Cla, D2a 113 SN- 130-348 Blb, NH2 131 (M+H) + B7a, i-Bu Me [CI] Cula, D2a, D6a 114 0. 74 30% 323 Blb, N EtOAc/ (M+H) + B7a, i-Bu Me hex [FAB] Cla, D2a 115 SN CI 4. 74 30% 338 Blb, EtOAc/ (M+) B7a, i-Bu Me hex [EI] C 1 a, D2a 116 S-0. 74 30% 383 Blb, N Br N EtOAc/ (M+H) + B7a, i-Bu Me hex [FAB] Cla, D2a 117 I S) =N<CN 0. 54 50% C2a, N CN EtOAc/D2a i-Bu Et hex 118 S-0. 44 5% 350 Blb, N N02 EtOAc/ (M+H) + B4c, i-Bu Me hex [CI] B7c, Clb v 119 | g FN\N 0. 50 80% 306 A2b, N EtOAc/ (M+H) + Bulb, i-Bu Me hex [CI] B4c, B7c, Clb 120 \ S) =N4No2 124-0.43 10% A2b, N 126 EtOAc/Blb, i-Bu hex C2a, D2a 121 C) = 4 0.80 30% 336 Blb, N EtOAc/ (M+H) + B4c, i-Bu hex [HPLC B7c, ES-MS] Clf 122 SN CN 0. g5 30% 316 Blb, N EtOAc/ (M+H) + B4c, i-Bu hex [HPLC B7c, ES-MS] Clf 123 0.26 100% 322 A2b, ) EtOAc (M+H) + Blb, [HPLC B4c, i-Bu Me ES-MS] B7c, Clb, D4a 124 g) CN4No2 0. 51 10% B7a, 2 N EtOAc/Cla, i-Bu Me HCI hex D2a 125 | C FN4NO2 8. 83 350 Bla 'N, (b) (M+H) + step 2, Cl - [CI] B7b, Cle, D2a 126 ß sN4No2 0. 50 10% Bla EtOAc/step 2 i-Bu Me HCI' hex B 1 b, Cla, D2a 127 0.36 30% 362 Blb, OMe EtOAc/ (M+H) + B7a, i-Bu Me HCI hex [EI] Cla, D2a 128 s>==N-N02 0.80 25% B7a, N EtOAc/Cla, N)-'EtOAc/Cla, i-Bu Me hex D2a 129 SN \, O 62-345 A2a, N 64 (M+H) + B7a, 'N - (J 64 (M+H) + B7a, i-Bu [FAB] Cla, D2a D2a 130 SN C 0.91 30% 393 A2a, N EtOAc/ (M+H) + step 3, ''-Bu i-Bu CF3 hex [FAB] Blb, B7a, Cla, D2a 131 >==N CN 0. 70 30% 384 A2a uN EtOAc/ (M+H) + step 3, i-Bu CF3 hex [FAB] Blb, B7a, Cla, D2a 132 go/=\ 386 A2b, L/\/r-N02 N (M+H) + Blb, ;-BU w [FAB] Bcl7a, Cla, D2a 133 C SN4CN 0. 72 20% 343 Blb, N EtOAc/ B7a, i-Bu Et hex [EI] Cla, D2a 134 4S N-M-0. 70 30% 330 Ala, N EtOAc/ (M+H) + A2a u hex [FAB] step 3, Bla, B7a, D2a 135 Me 0.70 30% 344 Ala, I EtOAc/ (M+H) + A2a hex [FAB] step 3, i-bu Me'' Bla, B7a, D2a 136 Me 0.74 30% 364 A2a, t (M+H) + Blb, N hex [FAB] B7a, i-Bu Me Cla, D2a 137 0 FN4NO2 8. 18 336 C2a, N (b) (M+H) + D2a i-Bu Me [FAB] 138 S) =N4NO2 7. 91 0.73 25% C2a, N Mep (b) EtOAc/D2a k s hex Me hex 139 SN NO. 82 33% B7b, N EtOAc/Cla, i-Bu Me hex D2a U HCI HCI 140 S) =N4No2 0.80 33% B7b, 2 N EtOAc/Cla, i-Bu Me HCI hex D2a 141 g sN4NO2 0.59 50% 292 Blb, zon 9 EtOAc/ (M+H) + B7a, hex [CI] Cla 142 g) =NnNO2 0. 49 50% 278 Blb, N EtOAc/ (M+H) + B7a, Me hex [FAB] Cla 143 g sN4CN 0.24 20% 394 Blb, eN, EtOAc/ (M+H) + B4c, i-Bu Et hex [HPLC B7c, i HCI ES-MS] Clb OH 144 SN CN 0. 43 10% 412 Blb, N EtOAc/ (M+H) + B4c, i-Bu Et hex [HPLC B7c, HCI ES-MS] Clb ci 145 s>=N CN 88-0.20 10% 424 Blb, N 90 EtOAc/ (M+H) + B4c, i-Bu Et hex [HPLC B7c, HCI ES-MS] Clb 146 S FNnNO2 0. 40 25% B3a, MeO N EtOAc/C2a i-Bu Me HC hex 147 (CSN 40 25% B3a, MeO. N EtOAc/C2a i-Bu Me HCI hex 148 g sN4NO2 8. 79 B8a, Me (b) CSb i-Bu Mep 149 g sN4No2 9.11 406 B8a, Me (b) (M+H) + C5b Me z 'I 150 g sN4NO2 8. 84 406 B8a, Me N (b) (M+H) + CSb 0 k [CI] _ 151 S>=N N02 8.63 394 B8a, Me N 2 fi-Bu (b) (M+H) + C5b i-Bu Mez [CI] 152 >=N CN 4. 05 385 B8a, Me N (a) (M+H) + C5b Me [HPLC ES-MS] 153 S 5.26 430 A2b, !/=N-\\/r-N02 Me N (a) (M+H) + B8a, o'-B"\/ [HPLC C5b ES-MS] 154 S-5. 44 442 A2b, N N02 Me N (a) (M+H) + B8a, [HPLC CSb ES-MS] 155 S-4. 19 446 A2a, !/=N-//-N02 Me N a (a) (M+H) + B8a, 0 [HPLC C5b z 156 S-4.80 434 A2a, N N02 MeN a M+ + 0 [HPLC C5b [ES-MS] ES-MS] 157 g N4No2 3.98 422 A2a, N N02 MeN a 1Vj+ + (H) B8a, i-Bu i-Pr [HPLC CSb ES-MS] 158 S-"6. 12 434 A2a, N NOZ MeN a + + Me N H (a) (M+H) + B8a, [HPLC CSb ES-MS s 1 Me-N- ( (a) (M+H) + B8a, MeN a + + 0 [HPLC C5b ES-MS 160 S>=N N02 5. 40 408 A2b, MeN- ( (a) (M+H) + B8a, MeN a + + (M H) B8a, Õ i-Bu Me Me 0 [HPLC C5b ES-MS] 161 S-3. 65 436 A2b, N N02 MeN a + + me,.. Me Me (a) (M+H) + B8a, Me Me [HPLC CSb ES-MS J 162 S-5. 07 426 A2b, N CN Me N H (a) (M+H) + B8a, 0 [HPLC C5b ES-MS] 163 >=N CN 5. 00 414 A2b, ont Me N H (a) (M+H) + B8a, i-Bu 0 [HPLC C5b ES-MS] 164 0) =N4No2 0. 13 25% B8a, N N02 Me, N H/EtOAc/CSb, OHi-Bu Me hex D3a 165 S- 4. 75 386 A2b, N N02 Me N < (a) (M+H) + B8a, OH [HPLC C5b, ES-MS] D3a 166 C) =N4NO2 7. 29 338 B8a, N N02 Me N (b) (M+H) + CSb, OHi-Bu Me [CI] D3a 167 S-0. 16 25% B8a, N NOZ Me N H EtOAc/CSb, OH Me hex D3a 168 S-7. 18 350 B8a, N N02 Me N (b) (M+H) + CSb, OH Me [CI] D3a 169 S-5. 07 372 A2b, N N02 Me N H (a) (M+H) + B8a, ) OH [HPLC C5b, ES-MS] D3b 170 S) =N4CN 4. 75 360 A2b, /CN Me, N H (a) (M+H) + B8a, () 8a, ÕH i-Bu t-Bu [HPLC CSb, ES-MS] D3b 171 s =N N02 4. 68 374 A2b, Me N \//-N02 MeN a M+ + (H) B8a, OH'-B"\/ [HPLC CSb, ES-MS] D3b 172 02 390 A2a, N N02 Me N (a) (M+H) + B8a, OH [HPLC C5b, ES-MS] D3b 173 55 378 A2a, N N02 Me a M+H + Me". \C/ (a) (M+H) + B8a, OH [HPLC C5b, ES-MS] D3b 174 S-5. 86 366 A2a, N/N02 Me N, H (a) (M+H) + B8a, () B8a, OH [HPLC C5b, ES-MS] D3b 175MeuN»N9No216. 00 _ (M+H) + A2a,O[HPLCCSb,176MeuN»N9No2 _ (a)_ ES-MS] A2b,175S-6. 00 378 A2a, N N02 Me,, - (a) (M+H) + B8a, pu r ES-MS] D3b, 176 S-0. 89 380 A2b, N N02 "cl (H) B8a, OH Me Me OH [HPLC C5b, ES-MS] D3b -5. 42 352 A2b, N N02 MeN a M+ + i-6u MRM e [HPLC CSb, ES-MS] D3b 178 s>==N N02 5. 64 364 A2b, N NOZ MeN a + + Me H + B8a, OH Me Me [HPLC CSb, ES-MS] D3b 179 S-4. 26 370 A2b, rv ctv O a +b, (M H) B8a, OH [HPLC CSb, ES-MS] D3b 180 S-3. 94 358 A2b, N C, MeN a + (M H) + B8a, OH[HPLC C5b, ES-MS] D3b 181 8.46 C2a, z N02 (b) D13a, Dia i-Bu Me D2a 182 N02 0.82 5% C2a, iN N » S'MeOH/D13a, i-Bu Me CH2C12 D2a 183 0.15 25% C2a, s EtOAc/D2a , M 9 _ CH2C12 D2a N I i-Bu Me 0. 04 25% C2a, N >=N--N02 9 i-Bu Me CH2C12 185 \-S\/=\ 211 0.78 10% B7a, /=N--N02 N MeOH/Cla, Mye 90% D2g HBr CH2C12 186 159 0.28 10% B4c, -EtOAc/C2f N 90% pet. i-Bu Cl HCI ether 187 0. 26 10% B4c, -EtOAc/C2f N 90% pet. i-Bu CI Cl ether 188 X S/=\ 177 0.24 10% B4c, r N N EtOAc/C2f i-Bu Cl Cl 90% pet. HCI ether 189 s » N 134 C2f S- 6 cri 6° CI 190 209 B5b, _N » N C2f N C2f U CIPCI HCI 191 S 162 BSb, -N C2f CRI CI Me HCI 192 \S 209 BSb, C2f Me CI CI 'Me HCI 193 \ S R 164 C2f, \/B5b N HO J CI CI HO 194 N02 178 0.80 10% C2f N N » N9NO2 MeOH/ Me 90% CH2Cl2 195 S 181 Cla, N N9NO2 D2g Me HBr 196 \S R 97 Cla, D2g i-Bu Me 197 _S R 154 Cla, N D2g N D2g -Bu CI CI HCI 198 XS 156 B4c, tN) =N9NO2 C2f N C2f Me 199 s N : Rl 154 B4c, \/Clf N CI CI 200 \_S/=\ 196 B5b, N C2f ", mye HCI LJ HC! 201 g 1 188 0.28 10% B5b, LN » N<NO2 EtOAc/C2f Me Me 190 90% pet. rTMe. H C I ether 202 g 1os 0.16 10% B5b, N >= EtOAc/C2f i-Pr Me 90% pet. ether 203 vs 63 0.26 10% B5b, /EtOAc/C2f N i-Pr pet. ether 204 s 95-0.34 10% B5b, /C 97 EtOAc/C2f i-Bu Cl 0% pet. HCI ether 205 XC FN9NO2 229 ~ B7a, N Cla, Cla, Me HBr D2g 206 7. 83 321 Blc, N N02 /~, N' (b) (M+H) + B7b, i-Bu Cla, D2a 207 8.59 374 Blc, ") » N4NO2 (b) (M+H) + B4a [CI] C2a Me 208 S 0.64 30% 374 A2a, ton EtOAc/ (M+H) + Blc, hex hex [CI] B7a, ex Cla, D2b 209 S 0. 74 20% 368 ASa, N 5 :-CN EtOAc/ (M+H) + A2b, b n-Pr hex [CI] B7a' B7a, Cla, D2b, D7a 210 0.74 20% 368 A5a, N » CN EtOAc/ (M+H) + A2b, hex [CI] Bic, i-pur B7a, Cla, D2b, D7a 211 S 200 0.74 20% 382 382 ASa, NN/CN-EtOAc/ (M+H) + A2b, 201 hex [CI] Bic, B7a, Cla, D2b, D7a 212 AS 8.65 374 Blc, cc NFNvNo2 (b) (M+H) + B4a, Me [CI] C2a 213 SN NO. 82 25% Blc, N EtOAc/B7a, i-Bu Me hex Cle, D2a 214 g 9N4NO2 0. 86 30% 362 A2a, N EtOAc/ (M+H) + Blc, i-Bu Et hex [FAB] B7a, Cla, D2a 215 SN NO. g0 30% 376 A2a, N EtOAc/ (M+H) + B l c, i-Bu n-Pr hex [FAB] B7a, Cla, _ D2a 216 g FN4NO2 0. 86 30% 376 A2a, N EtOAc/ (M+H) + Bic, i-Bu i-Pr hex [FAB] B7a, Cla, D2a 217 C FN4NO2 0.83 30% 362 A4a, N EtOAc/ (M+H) + A2d, i-Bu Me Me hex [CI] Blc, B7e, Cle, D2a 218 >==N N02 68-348 A2a N 70 (M+H) + Blc, i-Bu Me [CI] B7a, Cla, D2a 219 SN NO 0. 64 30% 383 (M+) A2a, N EtOAc/ [EI] Blc, hex hex B7a, Cla, D2a 220 SN CN1 Blc, N 72 B7e, /--N - 72 B7e, i-Bu D2a 221 xr >=N 4 CN 98-327 (M+) Ala, N 100 [EI] A2a, i-Bu Me step 3, B7a, B7a, Cla, D2b 222 SN CN 26. 5 342 Blc, N (j) (M+H) + B7a, i-Bu Et [HPLC C 1 a, ES-MS] D2b 223 r) =N 4 CN 0. 73 20% 364 A2a N EtOAc/ (M+H) + step 3, i_ 6u hex [FAB] Blc, B7a, Cla, D2b 224 r s N 4 CN 0. 16 50% 342 A5a, N CH2CI2/ (M+H) + A2a i-Bu Me Me hex [CI] step 3, Blc, B7e, Cle, D2h, D7a 225, S-0. 70 20% A5a, N EtOAc/A2a hex Me hex step 3, Blc, Bic, C2a, D2a, D8a 226 S-0. 39 50% 443 A5a, N N H CH2Cl2/ (M+H) + A2a i-Bu Me Me hex [CI] step 3, Blc, B7e, Cle, D2h 227 02N 362 A4a, (M+H) + A2d, i-Bu Me Me B7e, B7e, Cle, D2b 228 S S>CN 58-320 Ala, 60 (M+H) + A2b, \ J i-Bu [CI] B l c, B7e, Cle, D2a 229 N-Me 140 0.68 30% 343 A2c, >=N--\/CN-EtOAc/ (M+H) + Blc, 9) mye 143 hex [CI-MS] B7e, i-Bu Me Cle, D2h 230 SN NO. g3 25% Blc, X _ EtheAxC/C2a, Me hex D2a CI 231 g F N n CN 86-0. 74 20% 356 Blc, N N 88 EtOAc/ (M+H) + B7e, hex [CI] Cle, D2b 232 SN NO 135 Blc, N-B7e, Me 13 Cle, D2e 233 S- N02 95-blé, N 97 B7e, Me, due D2e 234 SN NO 0.28 40% Blc, EtOAc/B7e, /"-N)- EtOAc/B7e, Me he, D2h D2h 235 N \2 100 Blc, N-B7e, B7e, V D2e 102 Cle, D2e 236- /NOZ 85 Blc, 0 Mu Clé, Due 237 S- /N02 96-Blc, N 98 B7e, Me Cle, De 23 8 S-4. 8 I 406 B 1 c, / (M+H) + B7e, Me [HPLC Cle, ES-MS] D2e 239 S-5. 29 346 Blc, (M+H) + B7e, Me [HPLC-Cle, ES-MS] D2e 240 S-120 0.45 10% bloc, -EtOAc/C2a, mye 121 hex hex D2b 241 If 126-0.10 25% Blc, G 128 EtOAc/C2a, b hex D2b, mye dia 242 0 181 0.27 25% Blc, o \=N--N09 DEC EtOAc/C2a, hex D2b, Da da 243 SN NO. 86 30% 374 A2a, EtOAc/ (M+H) + Blc, hex [CI] B7e, Cle, D2b 244 J » nNO2 136-360 A2a N (M+H) + step 3, Me [FAB] Blc, B7e, Cle, D2b 245 g) =N 4NO2 83-374 A2a, --N 84 (M+H) + B l c, Me Me [CI] B7e, Cle, D2b 246 02N 374 A2a, S S>==N (M+H) + Bic, N Me Me [CI] B7e, mye Me Me Cle, D2b 247 158-Blc, / N 159 B7e, Cle, D2b D2h 248 C) =N 4 CN 106-0.30% 340 Ala, N 107 EtOAc/ (M+H) + A2b, Me hex [CI] Blc, B7e, Cle, D2b 249 SN CN lg. l 0.66 20% 354 Ala, c--N Etp EtOAc/ (M+H) + A2b, Et hex [HPLC [HPLC \ ES-MS] D2f 250 r VcN 4 CN 0.20% 368 Bic, /N9 EtOAc/ (M+H) + B7e, n hex [CI] Cle, D2b 251 -S N 0.74 20% 368 A2b, /ton Prp-CN EtOAc/ (M+H) + Blc, hex [CI] C2a, D2b, D7a 252 g » N 4 CN 0.18 50% 354 A2b, zon MPME CH2C12/ (M+H) + Blc, hex [CI] C2a, D2b, D7a 253 S 208-Blc, N OH 209 B7e, Et C2e, D2b, D9a 254 __s 0 228-Ala, -N H 229 A2b, Me Blc, B7e, Cle, D2b, D9a 255 SN- 114-Blc, N \ Me 115 B7e, Et C2e, \/D2b, D9a D l0a 256 -S 0 0.0.30% A2b, N me heu C2a, D2h 257 SN- 0. 44 30% Blc, N EtOAc/B7e, Et hex Cle, D2b, D9a, D6b 258 -S) =N 0 0.44 30% Blc, ¢!'NMe2 EtOAc/B7e, Et hex Cle, D2b, D9a, D6b 259 S-0. 71 10% 369 A3a, N N EtOAc/ (M+H) + Bic, hex [CI] B4d, CF3CO2H C6c 260 SN-0. 62 10% 369 A3a, zon EtOAc/ (M+H) + Bic, A F3C hex [CI] B4d, \/C6c 261 >==N CF3 0.78 10% 369 A3a, as EtOAc/ (M+H) + Bic, hex [CI] B4d, _ \J C6c 262 SN-0.0. 84 10% 349 A3a, gon EtOAc/ (M+H) + Blc, CI Me hex [CI] B4d, CF3CO2H C6c 263 SN-0. 80 10% 369 A3a, N EtOAc/ (M+H) + Bic, CF3 hex [CI] B4d, \/C6c 264 SN C 0. 44 2% 383 A3a, C sN H EtOAc/ (M+H) + Blc, Me CI hex [CI] B4d, \ CF3CO2H C6c 265 -S >=N 0. 65 2% 349 A3a, N EtOAc/ (M+H) + Bic, hex [CI] B4d, \/CF3CO2H C6c 266 SN g 0. 71 20% C2a, -N EtOAc/D2a me heu 267 S N- 104-0.16 10% Blc, N>= E 5H 105 EtOAc/B7e, Et hex Cle, D2b, Dlla 268,-CSSNA"° 0.68 30% Blc, EtOAc/B7e, Et OEt hex Cle, D2b, Dlla D12a 269 XS) =N X 141-0.61 20% Blc, N 142 EtOAc/B7e, Et hex Cle, VJ D2b, Dlla D12b 270 IsN 182-Blc, N 183 B7e, Etc oh Cle, D2b, Dlla D12a D6a 271 NN \/135-0.52 20% Blc, N CN 136 EtOAc/B7e, Et NC hex Cle, D2b, Dlla D 12c 272 s 0, 0. 68 30% BIC, EtOAc/B7e, M hex Cle, D2b, Dlla D12a 273 _s) =N 0. 56 30% Blc, 'N-CN EtOAc/B7e, Et hex Cle, D2b, Dlla D12d 274 SN NO 155-Blc, N 157 C2a, mye D2e 275 SN-N 159-_ glc, c : N mp 162 C2a, Me D2e 276 SN NO 0.69 20% Bla, N EtOAc/C2a, \/i-Bu Me hex D2b 277 su 101-0.15 10% 364 A3a, dN-p-104 EtOAc/ (M+H) + Blb, i-Bu Me hex [HPLC B4c, ES-MS] C6c 278 NOZ 102-0.102-0.10% 10% 364 A3a, OJN OS EtOAc/ (M+H) + B 1 b, i-Bu Me hex [HPLC B4c, ES-MS] C6c 279 S NO 0.72 25% Bla, EtOAc/B2a, i-Bu Me hex B7a, Cla 280 4) =N9No2 0.76 33% B6a, N y-N)- EtOAc/B7e, i-Bu Me HCI hex C2a, D2a 281 0.53 20% 308 B9a, EtOAc/ (M+H) + Cla N i-Bu Me hex [HPLC ES-MS] 282 nu = 0.51 20% 322 B9a, EtOAc/ (M+H) + Cla hex Me hex [HPLC ES-MS]

(a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2x300 mm Phenomenex 3 uM C-18 column; flow rate 1.0 mL/min.; Buffer A: 0.02% TFA/2% CH3CN/water, Buffer B: 0.018% TFA/98% CH3CN/water; hold at 100% Buffer A for 1 min., gradient from 100% Buffer A to 100% Buffer B over 3 min., hold at 100% Buffer B 1 min., gradient from 100% Buffer B to 100% Buffer A over 0.5 min., hold at 100% Buffer A 1.5 min.

(b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4x100 mm Dynamax 3 uM C-18 column; flow rate 1.5 mL/min.; Buffer A: 0.5% TFA/water, Buffer B:

0.5% TFA/CH3CN; gradient from 100% Buffer A to 100% Buffer B over 10 min, hold at 100% Buffer B 5 min.

(c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H3PO4/water, Buffer B: 0.01 mol% H3PO4/CH3CN; 10% Buffer B for 1 min., gradient from 10 Buffer B to 90% Buffer B over 8 min., gradient from 90% Buffer B to 10% Buffer B over 4 min.

(d) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% Buffer B 30 min.

(e) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 50% Buffer B to 60% Buffer B over 25 min., gradient from 60% to 100% over 32 min.

(f) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 30 min.

(g) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 50% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 7 min.

(h) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water,

Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 10% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.

(i) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4.6x100 mm Microsorb 5 uM C-8 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min.

(j) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.

Table and 2-Imino-1,3-thiazolidin-5-ones TLC Mass Spec. mp HPL TLC Solvent [Source] Synth. Entry Compound (°C) (min.) Rf System Method 283 >=N N02 8. 03 0.44 100% 307 (M+) C8a N (C) CH2CI2 [Ell i-Bu Me _ _ 284 s>=N N02 7.98 0.20 100% 341 (M+) C8a l Me (c) CH2C12 [El] Me 285 C FN4NO2 8.46 0.26 100% 321 (M+) C8a o+N v (c) CH2Cl2 [EI] Me 286 s>=N N02 9.46 0.30 100% 361 (M+) C8a OFN v (C) CH2Cl2 [EI] Me 287 N N02 8.03 0.58 100% 307 (M+) C8a N H (C) CH2Cl2 [EI] i-Bu Me 288 NO g. 45 0.62 100% 321 (M+) C8a \/ (c) CH2C12 [EI] mye 289 g FN4NO2 8. 02 0.61 100% 341 (M+) C8a (c) CH2C12 [EI] O Me I \ i 290 SN N02 g. 53 0.67 100% 321 (M+) C8a (c) CH2Cl2 [EI] i-Bu Me 291 g >=N4No2 9.37 0.62 100% 361 (M+) C8a fN-- (c) CH2CI2 [EI] Me 292 g >=N 4NO2 9.35 0.76 100% 361 (M+) C8a ZON Me H (c) CH2Cl2 [EI] Me 293 s>=N N02 98 9.36 0.76 100% 361 (M+) C8a 0 J""Me () CH2C12 [El] Mu (j" 294 9.01 0.78 100% 383 (M+) C8a S- (c) CH2C12 [EI] N N02 A sN9NO2 i-Bu Me 295 Me 63-9.78 0.73 100% 375 (M+) C8a o N 67 (c) CH2C12 [EI] 0 !/ Me 296 62-10.1 0.86 100% 437 (M+) C8a WS R 63 1 (c) CH2C12 [EI] N I N02 X N Me 297 Me S-68-9.77 0.74 100% 375 (M+) C8a o 71 (c) CH2Cl2 [EI] O Me 298 n 69-10.0 0.91 100% 437 (M+) C8a WS 0 (c) CH2C12 [EI] X N <No2 O N Me 299 Me S 9. 23 0.70 100% 349 (M+) C8a _ FN<NO2 (c) CH2Cl2 [EI] 0 !/ Me 300 S-9. 47 0.79 100% 363 (M+) C8a o z (c) CH2C12 [EI] i-Bu Me !-Bu Me 301 s>==N--5N02 10.2 0.86 100% 391 (M+) C8a J i/="4 02 0 (c) CH2Cl2 [EI] i-Bu Me 302 S-9. 83 0.82 100% 377 (M+) C8a OWNS (e) CH2C12 [EI] X Me Me 303 9.61 0. 34 50% 363 (M+) C8a ~ CH2C12/ [EI] N N02 o N Mep cyclohex Me 304 9.23 0.32 50% 349 (M+) C8a (c) CH2C12/ [EI] N NOZ o cyclohex i-Bu Me 305 SN NO g37 0.55 100% 321 (M+) C8a (c) CH2C12 [EI] ..,, mye 306 9.90 0.78 100% 377 (M+) C8a u CH2C12 [EI) X e X L mye mye 307 °9S S 0.50 25% B3a, NN N02 EtOAc/B7b, i-Bu Me hex C2a 27 Cl 8.97 0.40 30% 362 C8a =N <No2 (c) EtOAc/ (M+H) + hex [FAB] 308 ci 7.95 0.35 10% 365 C8a g ci (c) EtOAc/ (M+H) + o + N P'hex [FAB] 309 SN C 7.95 0.35 10% 635 C8a 0 i (c) EtOAc/ (M+H) + CI hex [FAB] 310 °9S S 152 7.28 307 (M+) Clla tN) (.) [EI) N i-Bu Me 311 S) =N 4 NO2 8. 79 0.66 100% 335 (M+) C8a 0 (c) CH2C12 [El] Mye 312 ArS/=\ 8.66 0.17 100% 363 (M+) Clla i-Bu (c) CH2C12 [El] i-Bu Me 313 S-138 5. 88 0.57 2% 291 (M+) Clla Me (c) MeOH/ [EI] Me CH2C12

(a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2x300 mm Phenomenex 3 uM C-18 column; flow rate 1.0 mL/min.; Buffer A: 0.02% TFA/2% CH3CN/water, Buffer B: 0.018% TFA/98% CH3CN/water; hold at 100% Buffer A for 1 min., gradient from 100% Buffer A to 100% Buffer B over 3 min., hold at 100% Buffer B 1 min., gradient from 100% Buffer B to 100% Buffer A over 0.5 min., hold at 100% Buffer A 1.5 min.

(b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4x100 mm Dynamax 3 uM C-18 column; flow rate 1.5 mL/min.; Buffer A: 0.5% TFA/water, Buffer B: 0.5% TFA/CH3CN; gradient from 100% Buffer A to 100% Buffer B over 10 min, hold at 100% Buffer B 5 min.

(c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H3PO4/water, Buffer B: 0.01 mol% H3PO4/CH3CN; 10% Buffer B for 1 min., gradient from 10 Buffer B to 90% Buffer B over 8 min., gradient from 90% Buffer B to 10% Buffer B over 4 min.

(d) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% Buffer B 30 min.

(e) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 50% Buffer B to 60% Buffer B over 25 min., gradient from 60% to 100% over 32 min.

(f) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 30 min.

(g) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 50% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 7 min.

(h) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 10% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.

(i) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4.6x100 mm Microsorb 5 uM C-8 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min.

(j) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.

Table 3.2-Imino-1, 3-oxazolidines TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry Compound (°C) (min.) R System [Source] ethod 314 0) =N SNO2 0. 30 30% 276 B8a N EtOAc/ (M+H) + C5a Me hex [CI] 315 g F N < NO2 6. 77 0.30 20% 319 B 1 b N (c) EtOAc/ (M+) B4c i-Bu Me hex [EI] B7b C4a 316 N No 7.42 0.25 30% 334 U l n (c) EtOAc/ (M+H) + B4c i-Bu Me hex [CI] B7b C4a 317 -0. 35 10% 328 A3a N EtOAc/ (M+H) + i-Bu Et hex [HPLC B4c ES-MS] C7b 318 N N02 134-0.134-0.15% 318 A3a N 136 EtOAc/ (M+H) + B4c Me hex [CI] C7a 319 r s N 4 CN 112-0.60 15% 312 A3a, N -/114 EtOAc/ (M+H) + B4c, et heu [CI] C7a 320 N NO 8.25 344 B l c, \/ N (b) (M+H) + B4d, [CI] B7b, C4a 321 X 7 83 X N (b) B4a, Me B7b, C4a V C4a 322 0 N-N02 8.30 358 Blc, xL/ y2 N (b) (M+H) + B4a, B7b, Mu C4a 323 4 F N 4 CN 0.10% 338 A3a, N EtOAc/ (M+H) + B l c, Et hex [FAB] B4d, C7a

(a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2x300 mm Phenomenex 3 uM C-18 column; flow rate 1.0 mL/min.; Buffer A: 0.02% TFA/2% CH3CN/water, Buffer B: 0.018% TFA/98% CH3CN/water; hold at 100% Buffer A for 1 min., gradient from 100% Buffer A to 100% Buffer B over 3 min., hold at 100% Buffer B 1 min., gradient from 100% Buffer B to 100% Buffer A over 0.5 min., hold at 100% Buffer A 1.5 min.

(b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4x100 mm Dynamax 3 uM C-18 column; flow rate 1.5 mL/min.; Buffer A: 0.5% TFA/water, Buffer B: 0.5% TFA/CH3CN; gradient from 100% Buffer A to 100% Buffer B over 10 min, hold at 100% Buffer B 5 min.

(c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H3PO4/water, Buffer B: 0.01 mol% H3PO4/CH3CN; 10% Buffer B for 1 min., gradient from 10 Buffer B to 90% Buffer B over 8 min., gradient from 90% Buffer B to 10% Buffer B over 4 min.

(d) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% Buffer B 30 min.

(e) Ranin Dynamax HPLC equipped with IJV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 50% Buffer B to 60% Buffer B over 25 min., gradient from 60% to 100% over 32 min.

(f) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 30 min.

(g) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 50% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 7 min.

(h) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 10% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.

(i) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4.6x100 mm Microsorb 5 uM C-8 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min.

(j) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.

Table 4. Additional Examples TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry Compound (°C) (min.) R System [Source] Meth. 324 N 0. 67 30% 336 Blb, N EtOAc/ (M+H) + B4c, i-Bu hex [HPLC B7c, ES-MS] C 1 f 325 S Me 0.81 30% 392 B7a, i-N N02 EtOAc/ (M+H) + Cla, N hex [FAB] D2a w 326 0/N4No2 7.99 0.59 20% 350 Blb 2 N (b) EtOAc/ (M+H) + B7a, HCI Me hex [FAB] Cla, D2a 327 rS < 0 81 30% 364 B7a, N EtOAc/ (M+H) + Cla, Me hex [FAB] D2a 328 ci ci. 74 30% 387 B7a, EtOAc/ (M+H) + Cla, hex [FAB] D2a

(a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2x300 mm Phenomenex 3 uM C-18 column; flow rate 1.0 mL/min.; Buffer A: 0.02% TFA/2% CH3CN/water, Buffer B: 0.018% TFA/98% CH3CN/water; hold at 100% Buffer A for 1 min., gradient from 100% Buffer A to 100% Buffer B over 3 min., hold at 100% Buffer B 1 min., gradient from 100% Buffer B to 100% Buffer A over 0.5 min., hold at 100% Buffer A 1.5 min.

(b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4x100 mm Dynamax 3 uM C-18 column; flow rate 1.5 mL/min.; Buffer A: 0.5% TFA/water, Buffer B:

0.5% TFA/CH3CN; gradient from 100% Buffer A to 100% Buffer B over 10 min, hold at 100% Buffer B 5 min.

(c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H3PO4/water, Buffer B: 0.01 mol% H3PO4/CH3CN; 10% Buffer B for 1 min., gradient from 10 Buffer B to 90% Buffer B over 8 min., gradient from 90% Buffer B to 10% Buffer B over 4 min.

(d) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% Buffer B 30 min.

(e) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 50% Buffer B to 60% Buffer B over 25 min., gradient from 60% to 100% over 32 min.

(f) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 30 min.

(g) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 50% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 7 min.

(h) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water,

Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 10% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.

(i) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4.6x100 mm Microsorb 5 uM C-8 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min.

(j) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.

Biological Protocol The activity of a given compound to bind to the progesterone receptor can be assayed routinely according to procedure disclosed below. This procedure was used to determine the progesterone binding activities of the compounds of the invention.

Progesterone Receptor Binding Assay To siliconized glass test tubes cooled over an ice water bath was added binding buffer (100 mL; 50 mM Tris, pH 7.4,10 mM molybdic acid, 2 mM EDTA, 150 mM NaCl, 5% Glycerol, 1% DMSO) containing various concentrations of a compound to be assayed, T47D cell cytosol (100 pL of a solution which will give at least 4000 cpm of binding) and 3H-progesterone (50 pL, 10 nM, NET-381). The mixture was incubated for 16 h at 4 °C, and treated with charcoal (250 gel of a 0.5% mixture of 0.05% dextran-coated charcoal which had been washed twice with binding buffer). The resulting mixture was incubated for 10 min. at 4 °C. The tubes were centrifuged (20 min at 2800 x g) at 4 °C. The supernatant was transferred into scintillation vials containing scintillation fluid (4 mL). Remaining 3H-progesterone was determined with a Packard 1900TR beta counter. Each assay included the following control groups: 1) total binding group (without compound), 2) non-specific binding group (with 400 nM progesterone), and 3) positive control group (with 2 nM progesterone or a known inhibitor).

The compounds of the present invention were found to cause greater than or equal to 30% inhibition of binding of 3H-progesterone to the progesterone receptor at

a compound concentration of 200 nM. Activity ranges of the compounds of the present invention in the Progesterone Receptor Binding Assay at a compound concentration of 200 nM are listed in Table 5.

Table 5. Inhibitory Activity of Exemplified Compounds Compounds Which Cause 30-Compounds Which Cause 60-Compounds Which Cause 59% Inhibition at 200 nM 79% Inhibition at 200 nM (Entry 80-100% Inhibition at (Entry Number) Number) 200 nM (Entry Number) 1 2 3 5 4 8 6 9 11 7 15 14 10 16 17 12 19 18 13 26 20 27 29 21 34 30 22 43 31 23 45 32 24 48 35 25 49 36 28 56 37 33 57 38 40 59 39 41 61 42 44 64 46 47 66 54 50 67 60 51 74 63 52 75 71 53 79 73 55 83 77 58 84 78 62 87 81 65 89 82 68 92 86 69 94 88 70 96 95 72 108 103 76 113 106 80 120 110 85 123 112 90 129 114 91 130 119 93 131 134 9 135 144 99 136 149 102 141 150 104 143 153 105 146 154 107 147 155 109 148 160 111 148 160 111 151 162 115 152 164 116 156 166 117 157 170 118 158 174 121 159 180 122 161 188 125 163 193 126 169 198 127 175 200 128 181 201 132 182 210 133 183 211 137 184 212 138 185 225 139 186 236 140 187 241 145 189 242 165 190 246 167 191 258 168 192 260 171 194 261 172 195 269 173 199 277 176 202 279 177 203 290 178 204 294 179 205 296 196 207 297 197 226 300 206 227 301 208 228 317 209 229 213 238 215 254 218 257 219 262 220 263 221 264 223 265 224 266 230 270 231 272 232 273 233 308 234 309 235 310 237 312 240 313 243 314 244 321 245 324 247 326 248 327 249 328 250 251 252 253 255 256 259 267 268 271 274 275 276 278 280 281 282 283 284 285 286 287 288 289 291 292 293 295 298 299 302 303 304 305 306 307 311 315 316 318 319 320 322 323 325

The preceeding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceeding examples.

Other embodiments of the invention will be apparent to the skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.