A VERSATILE LIGAND FOR PALLADIUM-CATALYZED META-C-H FUNCTIONALIZATIONS

GOVERNMENTAL SUPPORT

This invention was made with governmental support under NIGMS 1R01 GM102265 awarded by the National Institutes of Health. The government has certain rights in the invention.

TECHNICAL FIELD

The present invention contemplates a method for forming a carbon-to-carbon (C-C) bond between a reactive substrate and an aromatic or heteroaromatic iodide, and the reagents that facilitate that

electrophilic bond-formation reaction. More

particularly, the new C-C bond is formed on an aromatic or heteroaromatic substrate molecule that would normally direct electrophilic substitutions to ortho or para positions instead to a position meta to a substituent already present on the substrate through the use of a palladium catalyst, a directing group bonded as part of the substrate, a directing ligand that is dissolved or dispersed in the reaction mixture .

BACKGROUND ART

Cyclopalladation reactions have been extensively studied since 1965. ³ Recently, Pd(II)- catalyzed C-H activation reactions have been shown to be compatible with a wide range of carbon-carbon and carbon-heteroatom bond-forming reactions through Pd(II) /Pd(0) , Pd(II) /Pd(IV) and Pd (II) /Pd (II)

catalytic cycles. ^4-6 However, versatile ligands that can promote both C-H cleavage and the subsequent functionalization steps remain scarce and are largely limited to mono-protected amino acids (MPAAs) and pyridine/quinoline based ligands. ⁷

As effective C-H functionalization often requires a synergistic relationship between ligand and substrate coordinated to the metal center, it is essential to develop ligands that match with a variety of directing groups so that the assembled complexes are reactive in cleaving C-H bonds of a number of substrate classes. ⁷ This fact is

exemplified in recent efforts towards developing broadly useful norbornene-mediated meta-selective C-H functionalizations , where previously developed ligand scaffolds have proven insufficient at promoting reactivity with two important classes of substrates: anilines and phenols. A general pathway for meta- arylation using norbornene as a mediator is shown schematically below, where "DG" is a directing group, L _n is a ligand, and Ar-I is an aryl iodide coupling partner .

The norbornene insertion step from the Catellani reaction ⁸ ' ⁹ has previously been successfully combined with palladium catalyzed C-H activation to achieve selective C-H functionalization of

indoles. ^10,11 Recently, this key step was combined with ortho-directed C-H activation to achieve a net meta-functionalization via a relay process. ^12-14

Further development of this newly emerging meta-C-E functionalization strategy remains a significant, yet important challenge as it is complementary to other approaches for the direct meta-f nctionalization of arenes 15-23

BRIEF SUMMARY OF THE INVENTION

The present invention contemplates method of forming a reaction product containing carbon-to- carbon (C-C) bond to an aryl or heteroaryl

substituent at a position meta to a substituent previously present on the ring of an aromatic reactive substrate compound, and particularly a substituted 3-amino-2-hydroxy-pyridine ligand useful in that reaction. A contemplated method comprises the steps of heating a reaction mixture to a

temperature of about 70° to about 120° C. The reaction mixture contains i) an aromatic reactive substrate compound of Formula I dissolved or

dispersed in a non-aqueous solvent having a boiling point at 1 atmosphere of about 40° to about 200° C, that further contains dissolved or dispersed therein ii) a catalytic amount of a Pd(II) catalyst, iii) a substituted 3-amino-2-hydroxy-pyridine ligand of Formula III is present at about 10 to about 50 mole percent based on the moles of reactive substrate, iv) an ethylenically unsaturated bicyclic compound of Formula II as a transient mediator present in excess over the amount of reactive substrate, v) about 1.5 to about 5 equivalents of an oxidant based on the amount of said reactive substrate, and vi) about 1.1 to about 10 equivalents of a iodo-substituted aryl or heteroaryl coupling agent (Ar-I) . The temperature is maintained for a time period sufficient to carry out the C-C bond formation at a position meta to the substituent and form a reaction product whose

structural formula is shown in Formula IA

that reaction mixture, the iodo

substituted aryl or heteroaryl coupling agent can additionally be unsubstituted. Alternatively, the iodo-substituted aryl coupling agent can be further substituted a) at the meta and para positions with one or two substituents independently selected from the group consisting of halogen (fluoro, chloro, bromo or iodo) , C;i_-C7-hydrocarbyl that is straight, branched or cyclic, C]_-C7-hydrocarbyloxy (C1-C7-O-) , C]_-

C7-hydrocarbylthioxy (C1-C7-S-) , cyano, nitro, perfluoro-C _] _-C3-hydrocarbyl, carboxy C]_-

C7-hydrocarbyl, C _] _-C7-hydrocarboyl (acyl) , protected hydroxyl, protected hydroxyl-substituted C]_-

C7~hydrocarbyl that is straight, branched or cyclic, di- (C _] _-C7-hydrocarbyl) C; _[ -C7-hydrocarbylphosphonate, protected amino wherein the protecting group (s) contains up to 10 carbon atoms and the amine nitrogen has no reactive hydrogen, and a fused ring that includes 3 or 4 added ring atoms, and

b) substituted at the ortho position by a carboxy Cx-C7-hydrocarbyl or NH-Ci-C7-hydrocarboyl group .

An iodo-substituted heteroaryl coupling agent can be further substituted with one or two substituents independently selected from the group consisting of halogen other than iodo, Ο - C7-hydrocarbyl that is straight, branched or cyclic, ^c l ^-c 7 ^~ hydrocarbyloxy (C1-C7-O-) , C]_- C7-hydrocarbylthioxy (C1-C7-S-), perfluoro-Ci~

C3-hydrocarbyl, carboxy C^-C7-hydrocarbyl, C]_- C7-hydrocarboyl (acyl) , a fused ring that includes 3 or 4 added ring atoms and in which any nitrogen atom present is free of reactive hydrogens.

The aromatic reactive substrate compound has a structural formula shown in Formula I, below: U 2017/028116

wherein, Ring A is a heteroaromatic or carbocyclic aromatic ring structure in which the bond shown to X is at the 1-position of the ring and the substituent bonded at the 1-position constitutes the substituent previously present on the ring. The ring position rotated clock-wise from the 1-position is the ort.ho-position at which a hydrogen (H) is bonded, and the next position clock-wise from the ortho- position at which another hydrogen (H) is bonded is the raeta-position and is the position at which the new C-C bond is formed.

The Ring A contains a single ring or two fused rings having a total of 5 to 10 ring atoms and in which the ring bonded to X is aromatic and any other ring fused to that aromatic ring is

independently aromatic or aliphatic. A

heteroaromatic ring structure that is all or a part of Ring A contains one, two or three heteroatoms that can independently be nitrogen, oxygen or sulfur atoms .

The Ring A optionally further contains 1, 2 or 3 substituents other than hydrido (H) bonded to the ring atoms. Those optional substituents when present are selected from the group consisting of halo other than iodo (fluoro, chloro or bromo) , C]_- C7-hydrocarbyl that is straight, branched or includes U 2017/028116 a 4- to 6-membered ring bonded to a straight or

branched chain, C]_-C7-hydrocarbyloxy (C -C7-O-) , C]_-

C7-hydrocarbylthioxy (C1-C7-S-) , C_-

C2-hydrocarbyldioxy, cyano, nitro, perfluoro-Ci_-

C3~hydrocarbyl, carboxy C]_-C7~hydrocarbyl, C]_-

C7~hydrocarboyl (acyl), protected amino wherein the protecting group (s) contains up to 10 carbon atoms, and a fused ring.

In structural Formula I, n is zero (0) or one, such that the methylene group Y within the

brackets is absent when n is zero, and present when n is one.

X is 0 (oxygen) or NPG (a nitrogen bonded to a protecting group) when n is 1, and NPG or CH2

(methylene) when n is zero.

Ring B is a heteroaromatic single 6- membered ring or a fused 6,6- or 5, 6-membered ring system containing the depicted nitrogen atom and 1 or

2 other nitrogen ring atoms. Z is carbon when n is zero or 1. Z is nitrogen (a) when n is zero, and (b) the double bond depicted is absent and replaced by a double bond at the position of the dashed line.

Ring B optionally further contains 1, 2 or

3 substituents other than hydrido (H) bonded to the ring atoms. Those optional substituents when present are selected from the group consisting of C\- C7-hydrocarbyl that is straight, branched or includes a 4- to 6-membered ring bonded to a straight or branched chain C;j_-C3-substituent , C]_-

C7 -hydrocarbyloxy, trifluoromethyl-Ci-C3-hydrocarbyl, trifluoromethyl-C]_-C3-hydrocarbyloxy, and a fused ring . The reaction mixture also contains a transient mediator that is an ethylenically

unsaturated bicyclic compound of Formula II

wherein

A is CH ₂ , C=0 or 0,

each of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ is independently H, C]_-Cg-hydrocarbyl, C]_-Cg- hydrocarbyloxy, C^-Cg-hydrocarbyl carboxylate, C]_-Cg- hydrocarboyl , one or both of R^ plus R^ and R ⁷ plus

R ⁸ together with the carbon atom to which they are bonded form one or two carbonyl groups, or one each of R ⁵ and R^, or R ⁷ and R ⁸ together with the atoms to which they are bonded form a further 4- to 6-membered aliphatic or aromatic ring that itself can be independently substituted with one or two substituent groups selected from the group consisting of a C]_-Cg- hydrocarbyl, a C^-Cg-hydrocarbyloxy, a C]_-Cg- hydrocarbyl carboxylate and a nitro group.

The substituted 3-amino-2-hydroxypyridine ligand present in the reaction mixture has the structure of Formula III

III wherein R- ¹ -- ³ is an acyl group containing 2 to about 12 carbon atoms or a pertluorinated acyl group containing 2 to about 6 carbon atoms, RI^ i _s hydrido or C^-Cg-hydrocarbyl , is hydrido, C]_-Cg- hydrocarbyl or trifluoromethyl , j_ _s hydrido or C -

Cg-hydrocarbyl, or R!6 _an d 17 _or ¾17 _a nd R18

together with the carbon atoms to which they are bonded form a 6-membered ring with the depicted pyridine ring, m and p are the same and are zero or 1 such that m and p are zero, the bracketed carbon atoms are absent and the NHR^^ group is bonde

directly to the depicted pyridine ring, and when m and p are both one, -^ and R^O together with the carbons to which they are bonded form a phenyl ring. When R!6 and form a 6-membered ring with the depicted pyridine ring, it is preferred that R^^ be hydrido .

In preferred embodiments, at least one of R!6 and is other than hydrido. In one aspect of a preferred embodiment, R^ is trifluoromethyl . More preferably, R15 j_ _s acetyl, 1-adamantoyl or

trifluoroacetyl and R!6 is hydrido. In another preferred aspect, one of R!6 _anc j R17 _ _s Q^_Qg_ hydrocarbyl and the other is hydrido. In this aspect, _s more preferably acetyl.

In some embodiments, m and p are both zero.

In some preferred aspects of this embodiment,

, and R18 are independently hydrido, C]_-Cg- hydrocarbyl or trifluoromethyl as defined above so that the ligand is a 2-hydroxypyridine derivative as is shown in Formula Ilia, below. In other preferred

aspects of this embodiment, R ¹ " and R ¹ ', or R ¹ ' and R!8 together with their bonded carbons form a

6-membered aromatic ring so that the ligand is a derivative of a quinoline or isoquinoline, as are shown in Formulas Illb and IIIc, respectively, below.

In a still further embodiment, m and p are both one and R ¹⁹ and R ²⁰ together with the carbons to which they are bonded form a phenyl ring. In this case, the ligand is a 3- (ortho-aminophenyl) -2- hydroxypyridine derivative as is shown in Formula

Hid, below.

Hid

The present invention has several benefits and advantages.

One benefit is that it provides a new route to the preparation of meta-substituted aromatics that are either not possible to readily synthesize by other means or can be synthesized but _. require the presence of a chemically bonded directing ligand.

An advantage of the invention is that one can prepare meta-substituted aromatic compounds using aromatic reactive substrates whose substituent group (s) would usually direct a new C-C bond to an ortho position.

Another benefit of the invention is that the meta-directing ligand not being bonded to the aromatic substrate need not be removed by a separate reaction as compared to removal by physical

separation .

Another advantage of the invention is that the desired products can often be prepared in yields that are greater than about 50%.

Still further benefits and advantages of the invention will be apparent to the skilled worker from the discussion that follows. P T/US2017/028116

DEFINITIONS

In the context of the present invention and the associated claims, the following terms have the following meanings:

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

The words "ortho" , "meta" and "para" are used in their usual manner to describe benzenoid compounds that are substituted "1-2", "1-3" and "1- 4", respectively. Those same words are also used herein as a convenience to describe those same

substitution patterns in aliphatic compounds.

The word "hydrocarbyl" is used herein as a short hand term for a non-aromatic group that

includes straight and branched chain aliphatic as well as alicyclic groups or radicals that contain only carbon and hydrogen. Thus, alkyl, alkenyl and alkynyl groups are contemplated, whereas aromatic hydrocarbons such as phenyl and naphthyl groups, which strictly speaking are also hydrocarbyl groups, are referred to herein as aryl groups or radicals, as discussed hereinafter.

Where a specific aliphatic hydrocarbyl substituent group is intended, that group is recited; i.e., C _] _-C alkyl, methyl or hexenyl . Exemplary hydrocarbyl groups contain a chain of 1 to about 7 carbon atoms, and preferably 1 to about 4 carbon atoms .

A particularly preferred hydrocarbyl group is an alkyl group. As a consequence, a generalized, 7 028116 but more preferred substituent can be recited by replacing the descriptor "hydrocarbyl" with "alkyl" in any of the substituent groups enumerated herein.

Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,

sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4- pentadienyl, 1 , 4-butadienyl , 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

Usual chemical suffix nomenclature is followed when using the word "hydrocarbyl" except that the usual practice of removing the terminal "yl" and adding an appropriate suffix is not always

followed because of the possible similarity of a resulting name to one or more substituents . Thus, a hydrocarbyl ether is referred to as a

"hydrocarbyloxy" group rather than a "hydrocarboxy" group as may possibly be more proper when following the usual rules of chemical nomenclature.

Illustrative hydrocarbyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclohexenyloxy groups and the like. On the other hand, a

hydrocarbyl group containing a -C(0)0- f nctionality is referred to as a hydrocarboyl (acyl) group

inasmuch as there is no ambiguity in using that suffix. Exemplary hydrocarboyl and hydrocarboyloxy groups include acyl and acyloxy groups, respectively, such as acetyl and acetoxy, acryloyl and acryloyloxy. T/US2017/028116

As a skilled worker will understand, a substituent that cannot exist such as a C alkenyl group is not intended to be encompassed by the word "hydrocarbyl" , although such substituents with two or more carbon atoms are intended.

A "carboxyl" substituent is a -C(0)OH group. A C^-Cg hydrocarbyl carboxylate is a C^-Cg hydrocarbyl ester of a carboxyl group [-C (=0) -0-C]_-Cg hydrocarbyl] .

The term "aryl", alone or in combination, means a phenyl or naphthyl or other aromatic radical. An aryl group can be carbocyclic, containing only carbon atoms in the ring(s) or heterocyclic as a heteroaryl group discussed hereinafter. A

"heteroaryl" group is an aromatic heterocyclic ring substituent that preferably contains one, or two, up to three or four, atoms in the ring other than

carbon. Those heteroatoms can be nitrogen, sulfur or oxygen. A heteroaryl group can contain a single 5- or 6-membered ring or a fused ring system having two 6-membered rings or a 5- and a 6-membered ring.

Exemplary heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl ; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1, 2, 3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl,

thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4- oxadiazolyl and isothiazolyl groups; 6-/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl , benzisoxazolyl , benzoxazolyl, purinyl and anthranilyl groups; and 6- /6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1- 17 028116 benzopyronyl , quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1, 4-benzoxazinyl groups.

The term "halogen" means fluorine, chlorine or bromine. The term perfluorohydrocarbyl means a hydrocarbyl group wherein each hydrogen is replaced by a fluorine atom. Examples of such

perfluorohydrocarbyl groups, in addition to

trifluoromethyl , which is preferred, are

perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl .

The terms "amino-protecting group" and

"amine-protecting group" as used herein refer to one or more selectively removable substituents on the amino group commonly employed to block or protect the amino functionality. Examples of such amine- protecting groups include the formyl ("For") group, the trityl group ("Trt") , the phthalimido group

("Phth") , the trichloroacetyl group, the

chloroacetyl, bromoacetyl, and iodoacetyl groups.

Urethane blocking groups, such as t-butoxy-carbonyl ("Boc") , 2- (4-biphenylyl) propyl- (2) oxycarbonyl

("Bpoc"), 2-phenylpropyl (2 ) oxycarbonyl ("Poc"),

2- (4xenyl) -isopropoxycarbonyl , 1, 1-diphenyl- ethyl (1) oxycarbonyl, 1, 1-diphenylpropyl (1) - oxycarbonyl, 2- (3, 5-dimethoxyphenyl )

propyl (2) oxycarbonyl ("Ddz"), 2- (p-5-toluyl) - propyl (2) oxycarbonyl, cyclopentanyl-oxycarbonyl ,

1-methylcyclopentanyloxycarbonyl ,

cyclohexanyloxycarbonyl, l-methylcyclohexanyl- oxycarbonyl, 2-methylcyclohexanyloxycarbonyl,

2- ( 4-toluylsulfonyl) ethoxycarbonyl, 2- (methyl- sulfonyl) -ethoxycarbonyl, 2- (triphenylphosphino) - ethoxy-carbonyl , 9-fluoroenylmethoxycarbonyl ("Fmoc") , 2- (trimethyl-silyl) ethoxycarbonyl ,

allyloxycarbonyl , 1- (trimethyl-silylmethyl ) prop-1- enyloxycarbonyl , 5-benzisoxalyl-methoxycarbonyl, 4-acetoxybenzyloxycarbonyl , 2 , 2 , 2-trichloro- ethoxycarbonyl, 2-ethynyl(2) propoxy-carbonyl , cyclopropylmethoxycarbonyl , isobornyloxycarbonyl , 1-piperidyloxycarbonyl, benzyloxycarbonyl ("Z"), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxy- carbonyl, -2 ,4,5, -tetramethylbenzyloxycarbonyl

("Tmz"), 4-methoxybenzyloxycarbonyl, 4-fluorobenzyl- oxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chloro- benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,

dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,

3-bromobenzyloxycarbonyl , 4-nitrobenzyloxycarbonyl,

4-cyanobenzyIoxycarbonyl, 4- (decyloxy) benzyloxycarbonyl, and the like, the benzoylmethylsulfonyl group, dithiasuccinoyl ("Dts ¹ ) group, the 2-(nitro)- phenylsulfenyl group ("Nps' ) , the 2- or 4-nitro- phenylsulfonyl ("Nos") group, 4-toluenesulfonyl

("Ts") , the diphenylphosphine oxide group, and like amino-protecting groups.

The species of amine-protecting group employed is usually not critical so long as the derivatized amino group is stable to the conditions of the subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the compound. A preferred amine-protecting group is a phthalimido group.

Further examples of amino-protecting groups embraced to by the above term are well known in organic synthesis and the peptide art and are

described by, for example: T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons, New York. N.Y., Chapter 7, 1991; M. Bodanzsky, Principles of Peptide Synthesis, 1st and 2nd revised ed., Springer-Verlag, New York, N.Y., 1984 and 1993; and Stewart and Young, Solid Phase Peptide Synthesis, 2nd ed. , Pierce Chemical Co Rockford, IL 1984.

The related term "protected amino" or "protected amine" defines an amino group substituted with an amino-protecting group discussed above.

The terms "hydroxy-protecting group" and "hydroxyl-protecting group" refer to readily

cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxyprop-2-yl,

1-ethoxyeth-l-yl, methoxymethyl , methylthiomethyl, β-methoxyethoxymethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4 , 4 ' -dimethoxytrityl , 4, 4', 4"- trimethoxytrityl, benzyl, allyl, trimethylsilyl ("TMS") , t-butyldiphenylsilyl ("TBDPS") ,

(t-butyl) dimethylsilyl ("TBS" or "TBDMS") ,

triisopropylsilyl ("TIPS"), and 2 , 2 , 2-trichloro- ethoxycarbonyl groups, and the like. Ester groups such as C _] _-Cg-hydrocarboyl esters such as acetate

("OAc") , propionate and hexanoate are also useful, a is a benzyl ether ("Bn") group. The species of hydroxyl-protecting groups is also usually not critical so long as the derivatized (protected) hydroxyl group is stable to the conditions of subsequent reaction (s) and the protecting group can be removed at the appropriate point without

disrupting the remainder of the compound.

Further examples of hydroxy-protecting groups are described by C. B. Reese and E Haslam, Protective Groups in Organic Chemistry, J. G. W. 2017/028116

McOmie Ed., Plenum Press, New York, N.Y., Chapters 3 and 4, 1973, and T. . Greene and P. G. M. uts,

Protective Groups in Organic Synthesis, 2nd ed. , John Wiley and Sons, New York, N.Y., Chapters 2 and 3,

1991.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In an attempt to expand the scope of norbornene-mediated meta-C-H arylation reactions, aniline was selected as a model substrate. Meta- functionalization of this class of substrates 20-22 i's highly valuable as electrophilic substitution

reactions predominantly afford ortho- and/or para- substituted products due to the electronic directing effects of the aniline nitrogen atom.

Because of the multiple possible reaction pathways at several steps of the catalytic cycle, development of a ligand to orchestrate each step is a tremendous challenge. The discovery of mono- protected 3-amino-2-hydroxypyridine ligands (MPAHPs) that promote a highly efficient meta-C-H arylation of anilines, phenols, phenylacetic acids and

heterocycles is disclosed hereinafter. This class of ligands has also enabled a meta-C-H amination

reaction and a meta-C-H alkynylation reaction both of which, have not previously been achieved so far as is known .

Thus, a method of forming a reaction product containing carbon-to-carbon (C-C) bond to an aryl or heteroaryl substituent at a position meta to a substituent previously present on the ring of an aromatic reactive substrate compound is contemplated. Particularly contemplated in conjunction with that reaction is a substituted 3-amino-2-hydroxy-pyridine ligand useful in that reaction.

A contemplated method comprises the steps of heating a reaction mixture to a temperature of about 70° to about 120° C. The reaction mixture contains i) an aromatic reactive substrate compound of Formula I dissolved or dispersed in a non-aqueous solvent having a boiling point at 1 atmosphere of about 40° to about 200° C. That reaction mixture further contains dissolved or dispersed therein ii) catalytic amount of a Pd(II) catalyst, iii) a substituted 3-amino-2-hydroxy-pyridine ligand of Formula III is present at about 10 to about 50 mole percent based on the moles of reactive substrate, iv an ethylenically unsaturated bicyclic compound of Formula II as a transient mediator present in excess over the amount of reactive substrate, v) about 1.5 to about 5 equivalents of an oxidant based on the amount of said reactive substrate, and vi) about 1.1 to about 10 equivalents of a iodo-substituted aryl o heteroaryl coupling agent (Ar-I). The temperature i maintained for a time period sufficient to carry out the C-C bond formation at a position meta to the substituent and form a reaction product whose structural formula is shown in Formula ΙΆ

In some aspects, the reaction product is recovered from the reaction mixture. Where Y is methylene, the reacted A Ring can be separated from the B Ring by treatment with hydrogen in the presence of a catalyst such as palladium on charcoal, or by reaction with an acid such as trifluoroacetic acid. In other aspects, either treatment can be used without isolating the product from the reaction mixture .

In that reaction mixture, the iodo- substituted aryl or heteroaryl coupling agent can no further substituent that the iodo group; i.e., additionally be unsubstituted. Alternatively, the iodo-substituted aryl coupling agent can be further substituted a) at the meta and para positions with one or two substituents independently selected from the group consisting of halogen (fluoro, chloro, bromo or iodo) , C _] _-C7-hydrocarbyl that is straight, branched or cyclic, C _] _-C7-hydrocarbyloxy (C1-C7-O-) ,

C2~C7-hydrocarbylthioxy (C1-C7-S-) , cyano, nitro, perfluoro-C _] _-C3-hydrocarbyl , carboxy C^-

C7~hydrocarbyl, C; _] _-C7-hydrocarboyl (acyl) , protected hydroxyl, protected hydroxyl-substituted C]_-

C7-hydrocarbyl that is straight, branched or cyclic, di- (C _] _-C7-hydrocarbyl) C _] _-C7-hydrocarbylphosphonate, protected amino wherein the protecting group (s) contains up to 10 carbon atoms and the amine nitrogen has no reactive hydrogen, and a fused ring that includes 3 or 4 added ring atoms. That iodo- substituted aryl coupling agent can also be

substituted b) at the ortho position by a carboxy C -

C7~hydrocarbyl or NH-C]_-C7-hydrocarboyl group. substituted heteroaryl coupling agent can also be further substituted with one or two substxtuents independently selected from the group consisting of halogen other than iodo, C^-

C7-hydrocarbyl that is straight, branched or cyclic, Ci-C7-hydrocarbyloxy (C1-C7-O-) , C _] _-C7~hydrocarbyl- thioxy (C1-C7-S-) , perfluoro-Ci-C3-hydrocarbyl, carboxy C _] _-C7~hydrocarbyl , C _] _-C7-hydrocarboyl (acyl) , a fused ring that includes 3 or 4 added ring atoms and in which any nitrogen atom present is free of reactive hydrogens.

The phrase "any nitrogen atom present is free of reactive hydrogens" and similar phrases are used herein to mean that a primary or secondary amine that normally contains one or two hydrogens bonded to the amine nitrogen atom are replaced by amine

protecting groups (PG) that can be the same or different. Thus, a hydrogen that could otherwise react with a reactive group such as a isocyanate is absent. Illustrative protecting groups for a primary amine are benzyl (Bn) and t-butoxycarbonyl (Boc) , and one or the other for a secondary amine.

The aromatic reactive substrate compound has a structural formula shown in Formula I, below:

In Formula I, Ring A is a heteroaromatic or

carbocyclic aromatic ring structure in which the bond 6 shown to X is at the l-position of the ring and the substituent bonded at the l-position constitutes the substituent previously present on the ring that was noted above. The ring position rotated clock-wise from the l-position is the ortho-position at which a hydrogen (H) is bonded, and the next position clockwise from the ortho-position at which another

hydrogen (H) is bonded is the meta-position and is the position at which the new C-C bond is formed.

The Ring A contains a single ring or two fused rings having a total of 5 to 10 ring atoms and in which the ring bonded to X is aromatic and any other ring fused to that aromatic ring is

independently aromatic or aliphatic. A

heteroaromatic ring structure that is all or a part of Ring A contains one, two or three heteroatoms that can independently be nitrogen, oxygen or sulfur atoms .

The Ring A optionally further contains 1, 2 or 3 substituents other than hydrido (H) bonded to the ring atoms. Those optional substituents when present are selected from the group consisting of halo other than iodo (fluoro, chloro or bromo) , C]_-

C7~hydrocarbyl that is straight, branched or cyclic,

C _] _-C7-hydrocarbyloxy (C1-C7-O-) , C _] _-C7-hydrocarbyl- thioxy (C1-C7-S-) , cyano, nitro, perfluoro-C^-

C3~hydrocarbyl, carboxy C^-C7-hydrocarbyl , C]_-

C7-hydrocarboyl (acyl) , protected amino wherein the protecting group (s) contains up to 10 carbon atoms, and a fused ring. Preferably, zero or 1 additional substituent is present bonded to a ring atom of Ring A. Illustrative ring structures of Ring A include benzene and naphthalene rings, thiophene and furan rings, as well as pyridine, pyrazine,

quinoline, quinoxaline, indole, indoline, indazole, dihydrobenzodioxine, and chromen-4-one rings. It is noted that in any of the Ring A heterocyclic rings that include a nitrogen ring atom, that nitrogen atom is bonded to a C; _j _-C7-hydrocarbyl group as discussed above, or to a removable nitrogen protecting group so that no reactive hydrogen is present bonded to a Ring A nitrogen.

In structural Formula I, n is zero (0) or one. Thus, the methylene group (CH2) , Y, within the depicted brackets is absent when n is zero, and present when n is one. Z is carbon when n is zero or 1. Z is nitrogen (a) when n is zero, and (b) the double bond depicted is absent and replaced by a double bond at the position of the dashed line. In preferred aspects of the invention, n is 1.

X is 0 (oxygen) or NPG (a nitrogen bonded to a protecting group) when n is 1, and NPG or CH2 (methylene) when n is zero. Additionally, when n is zero, the double bond depicted is absent and is replaced by a double bond at the position of the dashed line.

Ring B is a heteroaromatic single 5- or 6-membered ring or a fused 6,6- or 5,6-membered fused ring system containing the depicted nitrogen atom and 1 or 2 other nitrogen ring atoms. Ring B is often referred to herein as a directing group (DG or DG' ) .

Preferably, when n is one, Ring B contains a single 6-membered ring and one nitrogen atom and up to three substituents other than hydrido (H) bonded to the ring atoms at ring positions other than that shown by the hydrido (hydrogen) bonded to the carbon atom adjacent to the depicted Ring B nitrogen in Formula I. Those optional substituents , R^, R^ and

R3, when present are selected from the group

consisting of C;i_-C7-hydrocarbyl that is straight, branched or cyclic, C _] _-C7-hydrocarbyloxy,

trifluoromethyl-C _] _-C3-hydrocarbyl, trifluoromethyl-

C _] _-C3-hydrocarbyloxy.

In preferred aspects of this embodiment, a Ring B is a pyridine derivative whose structural formula is shown below, where the dotted line denotes

a bond to the methylene group Y of Formula I, ΐ-, R^ and R3 are independently hydrido, C _] _-Cg-hydrocarbyl, C^-Cg-hydrocarbyloxy or trifluoromethyl-C]_- C3~hydrocarbyloxy . More preferably, at least one of

R1, R2 and R ³ is other than hydrido. Preferred and particularly preferred Ring B groups are shown below with numerals identifying the compound of Formula I in which they are exemplified.

When n is zero, exemplary Ring B ring systems include pyridine, pyrimidine, pyrazine, pyrazole, indazole and quinolone. These B ring systems can contain one or two substituent groups such as a C _] _-C7-hydrocarbyl and a C _] _-C7-hydro- carbyloxy group.

The reaction mixture also contains a transient mediator that is an ethylenically

unsaturated bicyclic compound of Formula II

wherein

A is CH2, C=0 or 0,

each of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ is independently H, C _] _-Cg-hydrocarbyl, C^-Cg- hydrocarbyloxy, C _] _-Cg-hydrocarbyl carboxylate, C]_-Cg- hydrocarboyl, one or both of R ⁵ plus R ⁶ and R ⁷ plus

R ⁸ together with the carbon atom to which they are bonded form one or two carbonyl groups, or one each of R ⁵ and R ⁶ , or R ⁷ and R ⁸ together with the atoms to which they are bonded form a further 4- to 6-membered aliphatic or aromatic ring that itself can be independently substituted with one or two substituent groups selected from the group consisting of a C^-Cg- hydrocarbyl, a C_-Cg-hydrocarbyloxy, a C^-Cg- hydrocarbyl carboxylate and a nitro group.

ethylenically unsaturated bicycli

transient mediator compound of Formula II is present in excess over the amount of reactive substrate used. Preferably, that compound is present in an amount of about 1.2 to about 3 equivalents relative to the reactive substrate. More preferably, that amount is about 1.5 to about 2 times the moles of reactive substrate. Structural formulas of illustrative transient mediator ethylenically unsaturated bicyclic compounds are shown below.

An improved transient mediator, methyl bicyclo [2.2.1] hept-2-ene-2-carboxylate (NBE-C0 ₂ Me) , whose structural formula is shown below is preferred in place of 2-norbornene that had been used in prior publications . ¹⁴

NBE-C0 ₂ Me

A ligand that can be viewed as a substituted 3-amino-2-hydroxypyridine is also present in the reaction mixture has the structure of Formula III , below,

III wherein R- ¹ -- ³ is an acyl group containing 2 to about 12 carbon atoms or a perfluorinated acyl group containing 2 to about 6 carbon atoms, ± _s hydrido or C _x -Cg-hydrocarbyl, R^ ⁷ is hydrido, C^-Cg- hydrocarbyl or trifluoromethyl, is hydrido or C]_-

Cg-hydrocarbyl, or R ¹⁶ and R ¹⁷ or R ¹⁷ and R ¹⁸ together with the carbon atoms to which they are bonded form a 6-membered ring with the depicted pyridine ring, m and p are the same and are zero or 1. When m and p are zero, the bracketed carbon atoms are absent and the NHR^-S group is bonded directly to the depicted pyridine ring. When R^-6 _an d R17 form a 6-membered ring with the depicted pyridine ring, it is preferred that be hydrido. When m and p are both one, R^ ⁹ and R ² ^ together with the carbons to which they are bonded form a phenyl ring.

In some embodiments, when m and p are both zero, ΐ-&, R^ ⁷ , R^ ⁷ and R18 _are independently

hydrido, C^-Cg-hydrocarbyl or trifluoromethyl as defined above so that the ligand is a 2- hydroxypyridine derivative as is shown in Formula

Ilia, below. Here, preferably at least one of R^,

R^ ⁷ and R ¹⁸ i _s other than hydrido. In one aspect of a preferred embodiment, R^- ⁷ is trifluoromethyl . More preferably, R^5 _1S acetyl, 1-adamantoyl or

trifluoroacetyl and R^-6 is hydrido. In another preferred aspect, one of R16 and R^- ⁷ is C]_-Cg- hydrocarbyl and the other is hydrido. In this aspect, i _s more preferably acetyl.

In other preferred aspects of this embodiment, R1 ⁶ and R ¹⁷ , or R ¹⁷ and R ¹⁸ together with their bonded carbons form a 6-membered aromatic ring so that the ligand is a derivative of a guinoline or isoquinoline, as are shown in Formulas Illb and Illc, respectively, below.

In a still further embodiment, m and p are both one and and R20 together with the carbons to which they are bonded form a phenyl ring. In this case, the ligand is a 3- ( ortiio-aminophenyl ) -2- hydroxypyridine derivative as is shown in Formula

Hid, below, where R^ ⁶ , R^ ⁷ and R^ ⁸ are as defined above .

11Id

In preferred embodiments of a compound of Formula Ilia, at least one of R ¹⁶ and R ¹⁷ is other than hydrido. In one aspect of a preferred

embodiment, R^- ⁷ is trifluoromethyl . More preferably, is acetyl, 1-adamantoyl or trifluoroacetyl and R!6 _s hydrido. In another preferred aspect, one of R!6 and R^ ⁷ is C _] _-Cg-hydrocarbyl and the other is hydrido. In this aspect, R15 ± _s more preferably acetyl. R^ ⁸ is preferably hydrido when not part of a ring system. Structural formulas of six of these more preferred ligand compounds are shown below along with their numerical identifiers used herein.

A ligand of Formula II I is present in the reactin mixture in an amount of about 10 to about 50 mole percent based on the moles of reactive

substrate. Preferably, that amount is about 20 to about 40 mole percent.

A contemplated method utilizes an excess, about 1.5 to about 5 equivalents (moles) of an oxidant per mole of reactive substrate, and

preferably about 2 to about 4 equivalents of oxidant.

A silver oxidant is typically used, although oxygen and other mild oxidants can also be used.

Illustrative catalysts include Ag(Piv), Ag(OAc), Ag ₂ 0,

Me Me Me

AgTFA, AgOTf, Ag ₂ C0 ₃ , Et^—C0 ₂ Ag, Et-—C0 ₂ Ag, Et^—C0 ₂ Ag, and

Me Me Me

Cu(OAc)2- Ag(OAc) is a preferred oxidant.

A contemplated reaction is carried out with the ingredients dissolved or dispersed in a solvent and with agitation as can be provided by the use of a magnetic stir bar. Additional means of agitation such as shaking can also be utilized.

The reaction is carried out at a temperature of about 70° to about 120° C. More preferably, the reaction temperature is about 90° to about 110° C. Because many useful solvents boil at a temperature less than 70° C, the reactions are typically carried out in sealed containers under pressure greater than 1 atmosphere. Thus, the pressure under which the ingredients are maintained is mostly that created by the solvent used at the reaction temperature, with some contribution from the reactants .

The reaction is carried out at an above elevated temperature for a time period sufficient to carry out the electrophilic insertion and form a reaction product having the new carbon-carbon (C-C) bond. Reaction times are typically about 15 to about 50 hours, with times -of about 18-30 hours being usual.

A contemplated solvent is a non-aqueous solvent having a boiling point at 1 atmosphere of about 40° to about 200° C. Exemplary solvents include BuC0 ₂ Me, hexafluoro-isopropanol (HFIP) , ethyl acetate (EtOAc or EA) , acetonitrile, acetone, 'BuCN, ¾uOMe (TBME) , dioxane, toluene, t-amylOH, 'Bu^OJMe, n-hexane, (trifluoromethyl) benzene, C ₆ F _S , chloroform (CC1H ₃ ), dichloromethane (DCM) , and 1,2- dichloroethane (DCE) . DCE, t-amylOH and HFIP are preferred among these materials.

Upon completion of the reaction, the desired product can be recovered by usual work-up procedures, or can be left in situ and reacted further as desired. In preferred situations in whic Y is methylene and Z is carbon, the Ring B portion o the molecule is a pyridine derivative as discussed previously, a reaction product of Formula IA is chemically similar to a benzyl ether or benzyl amine

As such, the two portions of the reaction product can be severed at the bond between X and Y in the structural formula to provide Ring A-Prod and Ring B-Prod whose structural formulas are shown below. This cleavage can be carried out using

Ring A-Prod Ring B-Prod

chemistry utilized for benzyl protecting group cleavage as is discussed in Greene and Wuts,

Protective Groups in Organic Synthesis, 3 ^rd ed. John Wiley & Sons, Inc., New York (1999). Further

illustrative cleavage reactions are illustrated hereinafter .

Results and discussion

The initial evaluation of aniline substrates focused on finding a reactive and readily removable directing group that would be compatible with the desired catalytic cycle. The screening reaction used to identify a useful directing group (DG) is illustrated below in Table 1 along with eight aniline derivatives examined. 2017/028116

After a survey of the several directing groups, a benzylic-pyridine based directing group bonded to the aniline amine nitrogen along with a t-Boc protecting group (PG) was found to provide the meta-arylated product in 13% yield. Other directing groups were not reactive, as is shown.

Table 1

13%, 75% SM

NR = no reaction; SM = starting material; The yield was determined by ¹ H NMR.

Ligands that could match with this directing group and promote the reaction were sought, starting with both amino acid- and heterocyclic base-derived ligands that have been shown to promote C-H activation reactions ⁷ ' ¹² . Unexpectedly, there was no significant improvement of the yield when utilizing either of these previously established

ligand classes. These results are surprising given the enabling role of the pyridine-derived ligand Ll in the norbornene-mediated meta-C-R arylation of phenylacetic acid derived substrates previously reported by the inventor and co-workers. ¹² Phosphine (L4 and L5) and N-heterocyclic carbene (L6) ligands were also evaluated, but neither class provided a significant improvement of the yield. This indicated that design of a new ligand would be crucial for developing broadly useful meta-C-R functionalizations of anilines utilizing this approach. See Table 2 below for results with ligands Ll-Lll .

*The yields were determined by Ή NMR; SM = starting material.

Considering that the MPAAs have been shown to be highly versatile ligands that promote

palladium (II) catalyzed C-H functionalization

reactions of C{sp ² )-R and in some cases C (sp ³ ) -H bonds, ²⁴ ' ²⁵ the vital structural features of this ligand were sought to be incorporated into other backbones that would enable new reactivity. Although varying the side chain of MPAA ligands permits tuning of their steric properties, modulation of the electronic properties of the C- and JV-termini (COOH and NHPG, respectively, PG = protecting group such as Ac, Boc) remains limited. Notably, both

computational studies and experimental investigations indicated the NHAc and COOH moieties are essential for forming a bis-dentate complex with Pd(II), generating the active catalytic species. ²⁶ ' ²⁷

Computational work has also identified a transition state in which the Pd-NAc or Pd-NBoc moiety can assist C-H deprotonation in the C-H cleavage step. ²⁶ ' ²⁷ Recognizing the similarity of 2-hydroxypyridine and 2-pyridone tautomers with the various coordination modes of a carboxylate in MPAA ligands (below) , MPAHP ligands were designed and prepared based on a hydroxypyridine scaffold that also incorporates the NHAc group from the MPAAs. A schematic that illustrates these ligands and their structural differences is shown below, where PG is a protecting group.

MPAA ligand:

MPAHP ligand:

It is important to emphasize that MPAHP ligands were not only designed to act as structural mimics of the MPAAs but also to address the limited opportunities for electronic tuning of the latter ligand class. Specifically, as indicated above, substitution of the aromatic ring of MPAHP ligands permits significant modulation of electronic

properties and hence, binding of the OH and NHAc groups (owing to their conjugation to the aromatic ring) to the Pd(II) catalyst. Illustrative ligands examined are shown in Table 3 below along with yield data for the use of each in the model ligand

screening reaction shown in the previous table.

With these newly prepared ligands in hand, their use in a model system was investigated, and it was found that the yield approximately tripled with the introduction of L12. *

L20 L21 L22 L23

N 17%, 69% SM 11%,81% SM 18%,78% SM

*The yields were determined by ¹ H NMR; SM = starting

material.

The use of a MPAHP ligand permits the use of a wide range of coupling partners such as a heteroaryl iodide, an alkynyl bromide and an N-OBz amine as are exemplarily illustrated below.

Coupling Partners Enabled by use of a MPAHP Ligand

Similarly, use of a MPAHP ligand permits the use a wide range of substrates as are exemplarily shown below .

Given the importance of synergy between directing group and ligand for efficient C-H

functionalization, the directing groups were re ^¬ examined. The effects of several directing groups were examined under standardized conditions as is sown in Table A, below. As shown by the data, it was

The yield was determined by ¹ H NMR; SM = starting material; The yields in parentheses are isolated yields. found that electron rich benzylic pyridine-based directing groups matched well with this ligand

scaffold, with a commercially available directing group (DG, shown below) cooperating with the ligand to provide the desired product in 98% isolated yield. With the optimized reaction conditions in hand, the scope of substrate reaction was examined.

As can be seen in Tables 4-7 below, the substrate scope of this transformation is very broad. Electron-donating and electron-withdrawing groups

(5a-o) are well tolerated at both the ortho- and meta-positions of the aniline. It is noteworthy that the commonly troublesome cyano and nitro

functionalities (5j, 5k) are well tolerated in this reaction when utilizing an improved transient

mediator, methyl bicyclo [2.2.1] hept-2-ene-2- carboxylate (NBE-C0 ₂ Me) , in place of 2-norbornene . ¹⁴

Interestingly, unsubstituted aniline lj and para-substituted substrate lp showed high selectivity for the di-substituted product, whereas 4-methoxy substituted aniline lq showed high mono-selectivity. It is hypothesized that after the initial arylation of substrate lq, a conformational change is induced wherein the methyl group on the methoxy is primarily positioned away from the newly installed aryl ring, blocking the alternative meta-position which prevents di-arylatio . Table 4*

5i, 93% 5j, 93% 5k, 89% 5I, 92%

mono.di <1 ;20

mono:di > 20:1

5u, 87% 5v, 87% 5w, 68% *In the above and following three tables: DG = directing group;

Ar-I = methyl 2-iodobenzoate ; Ar = 2- { carboxymethyl ) henyl; NBE- C0 ₂ Me = methyl bicyclo [2.2.1] hept-2-ene-2-carboxylate; Boc = terfc-butyloxycarbonyl ; Ac = acetyl; Bn = benzyl. The values under each structure indicate isolated yields. Substrates la- and 2a-l were arylated using L12 in 1 , 2-dichloroethane . For substrates lg, lj, lk, 2a, 2d and phenol substrates 3a-l, NBE- C0 ₂ e was used; other substrates were arylated using 2- norbornene as mediator. The selectivity of the mono- and di- arylated products was determined by ¹ H NMR analysis using CH ₂ Br ₂ as an internal standard.

A deeper investigation into the scope of this ^■ reaction revealed that heterocyclic substrates (2a-l) , which are commonly incompatible with C-H cross-coupling methodology, were well tolerated in this reaction providing good to excellent yields of products 6a-l , as shown in Table 5 below.

Importantly, the yield of product 6b was reduced to 4% in the absence of L12 , thus indicating the

importance of the ligand to achieve a broad substrate scope for this transformation.

Table 5 *

* Het = heteroaromatic.

Being interested in further examining the breadth of this reaction, was next evaluated meta-C-E arylation of phenol ^28,29 -derived substrates bearing benzylic pyridine based directing groups was next evaluated. ³⁰ Although good yields were obtained with the same directing group that was utilized for the aniline derived substrates, deprotection proved problematic. To circumvent this problem, a

2,3-lutidine derived directing group (DC, whose structure is shown adjacent to the reaction scheme in Table 6 ) was used that is removed by hydrogenolysis with catalytic palladium on carbon under 30 bar hydrogen .

As shown in Table 6, a variety of phenols could be successfully arylated at the meta-position utilizing methyl bicyclo [2.2.1 ] hept-2-ene-2- carboxylate (NBE-CC>2Me) and a modified ligand (L14)

Successful use of both ligand attests to the importance of being able to tune the electronics of this newly disclosed ligand scaffold.

Intriguingly, although substrate 1j shows high selectivity for di-arylated product, phenolic substrate 3d provides a mono : di ratio of 1:1. This result is attributed to the phenolic substrates bei slightly less reactive than their aniline

counterparts .

Table 6*

mono:di = 1 :1

*Substrates 3a-l and 4a-l were arylated using L14 in chloroform; substrate 3h was arylated using L12 in chloroform for 36 hours.

To more fully explore the scope of this methodology, the activity of this ligand was examined with substrates containing native heterocycles as directing groups. Gratifyingly, heterocyclic

substrates that form 6-membered palladacycles upon cyclopalladation worked exceedingly well. Substrates directed by native pyridine, pyrimidine, pyrazine, pyrazole, indazole, isoindazole and isoquinoline were all successfully arylated at the previously

inaccessible roeta-positions as is seen in Table 7 , below .

As all of these substrates are

unsubstituted, the mono:di ratio appears to be loosely correlated to the coordination strength of the various heterocyclic directing groups with weaker coordinating directing groups tending away from highly di-selective arylations . Dotted bond lines in that table indicate the presence of diarylation products with the ratio of mono:di products being shown. Importantly, the ligand should be present for this reaction to proceed in synthetically useful yields with all of the substrate classes shown in

Table 7.

Table 7*

Pd(OAc) ₂

8d', 60% 8e/8e", 64% 8f/8f',84%

monodi = 4:1 monodi = 2:1

8j/8j', 74% 8k8k', 50% 81', 78%

monodi = 3: 1 monodi = 3: 1 mono:di < 1 :20

Het = eteroaromatic.

The effects of solvent and oxidation on the arylation in the standard reaction were also 17 028116 examined. Those results are illustrated by the reaction scheme and results shown below in Tables 8a and 8b .

Table 8a

Entry Solvent BP (° C) 2 (%) 1 (%) Entry Solvent BP (° C) 2 (%) 1 (%)

1 PhCH ₃ 110 24 65 7 f-Amyl-OH 102 35 53

2 PhCF ₃ 31

101 64 8 DCM 40 34 64

3 TBME 20

131 78 9 DCE 84 42 58

4 Dioxane 101 37 51 10 CHCI ₃ 61 42 57

5 EA 77 30 67 11 Acetone 56 38 60

6 CH ₃ CN 82 36 47 12 D F 153 14 85

The yields were determined by ¹ H NIVIR.

Thus, use of each of the above-listed solvents provided product. However, DCE and

chloroform (CHCI3) provided the highest yield of product (2 ) and the lowest amount of residual

starting material ( 1 ) .

P T/US2017/028116

1

Entry Oxidant 2 (%) 1 (%) Entry Oxidant 2 (%) 1 (%)

1 .... 2 84 8 AgOPiv 10 87

2 AgOAc 42 58 9 AgOTs <1 <1

3 Ag ₂ C0 ₃ 12 82 10 K ₂ S ₂ 0s <1 <1

4 Ag ₂ 0 6 90 11 Na ₂ S ₂ 0 ₈ <1 <1

5 AgF <1 <1 12 BQ <1 44

6 AgN0 ₃ 4 88 13 Phl(OAc) ₂ 2 64

7 AgOBz 17 76 14 Cu(OAo) ₂ <1 <1

The yields were determined by Ή NMR.

As is seen from the data above, silver acetate (AgAOc) provided the best yields of the

several oxidants examined.

Several removable aniline-nitrogen protecting groups (PG) were studied for their effect if any on product yield. As is seen from the data in Table 8c, below, most were useful, with t-boc

providing the greatest yield in the conditions

examined. The protecting groups (PG) used are *

27%, 73% SM 17%, 82% S 42%, 58% S

<5%, 89% SM <1 %, 12% SM <1 %, decomposed

*The yields were determined by ¹ H NMR; SM = starting material.

Ac = acetyl, Piv = pivaloyl, Boc = t-butoxycarbonyl, Cbz = benzyloxycarbonyl , Troc = 2 , 2 , 2-trichloro- ethoxycarbonyl, Fmoc = 9-fluorenylmethoxycarbonyl , Ms = methanedulfonyl, Tf = trifluoromethanesulfonyl, and Nos = nitrobenzenesulfonyl .

Having thoroughly examined the substrate scope of this reaction, focus was turned to

evaluating the coupling partner scope using aniline la as the model substrate. Although 3-aryl-5-methyl anilines are alternatively accessible via Suzuki- coupling of the commercially available 3-bromo-5~ methylaniline, Compound la was chosen as the model substrate to investigate the reactivity of a wide range of aryl iodides as it is relatively electron neutral when compared to alternatively substituted anilines .

Experimental results shown in Table 9, below, indicate that this reaction exhibited an exceptionally broad coupling partner scope when utilizing a modified norbornene . ¹⁴ Electron donating and electron withdrawing groups at the para- and meta-positions of the aryl iodide coupling partner were- well tolerated, providing the desired products in good yields (9a-y) .

Table 9*

* In Tables 9-11: TBS = tert-butyldimethylsilyl; Ts = 4- toluenesulfonyl; NBE-C0 ₂ Me = methyl bicyclo [2.2.1] hept-2-ene-2- carboxylate. The values under each structure indicate isolated yields. Reaction conditions: Substrate (0.1 mmol) , Ar-I (0.2 mmol), Pd(OAc) ₂ (10 mol%) , L12 (20 mol%) , NBE-C0 ₂ Me (1.5 equiv.) AgOAc (3.0 equiv.), 1 , 2-dichloroethane (0.5 mL) , 100 °C, 24 hours .

Interestingly, this reaction was not limited to simple aryl iodides and an array of heterocyclic aryl iodides worked well in this reaction (9ae-ba). Indoles, thiophenes , furan, indazole, quinoline, quinazoline, and a range of pyridines were suitable coupling partners, showcasing the utility of this reaction for medicinal chemistry efforts where heterocyclic motifs are prevalent.

These results are shown in Table 10, below.

Table 10

9am, 63% 9an, 61 % 9ao, 54% 9ap, 41 %

*For 9ap, 9av, 9ba, 9bb and 9bc, Pd(OAc) ₂ (20 mol%) and L12 mol%) were used.

To determine whether the broad coupling partner scope observed in this reaction was enabled by the ligand, the reaction was carried out under the optimized conditions with 2-chloro-4-iodopyridine in the absence of L12 and found the yield to be 9% by ¹ H NMR. This result highlights the importance of the MPAHP ligands for this transformation.

In order to fully investigate the compatibility of this reaction with heterocycles, the efficiency of coupling heterocyclic substrates with heterocyclic aryl iodides was examined. As can be 2017/028116 seen in Table 11, (compounds 9bb-9bh) , this ligand enables the coupling of heterocyclic coupling

partners with heterocyclic substrates in good to excellent yields. Furthermore, the scalability of this reaction was demonstrated by performing the meta-C-H coupling of aniline substrate la on gram- scale with 5 mol% Pd(OAc) ₂ and 5 mol% L12, providing the desired product cleanly in 93% yield.

Table 11*

^ NHAc

^ ^OH (20 mol%)

Given the efficiency of the meta-C-H coupling of aniline substrates on a preparative scale, the applicability of this methodology was sought to be demonstrated using medicinally relevant compounds. Recently, the drug thalidomide and its 7028116 derivatives pomalidomide and lenalidomide (IMiDs) have been repurposed for several clinical indications including multiple myeloma (MM) and myelodysplasia. Crystallographic evidence for IMiD binding to a key target, cereblon (CRBN), ³¹ suggests that chemical modification of the solvent-exposed phthalimide part of the IMiDs could lead to molecules with altered specificity.

Efforts were therefore initiated to evaluate the feasibility of applying the ligand enabled, meta-C-H arylation of aniline derivatives to functionalize the solvent-exposed, meta-position of lenalidomide. This exemplifies a scenario where utilizing norbornene-mediated meta-C- .

functionalization is advantageous as it allows

elaboration of the parent drug molecule in relatively few steps. Gratifyingly, the meta-arylation of a lenalidomide derivative proceeded smoothly to provide the desired product (Compound 11) in 61% isolated yield (below) . The successful utilization of the

lenalidomide derivative 11, 61% yield

Boc = tert-butyloxycarbonyl; NBE-C02Me = methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate;

Ac = Acetyl; DCE = 1 ,2-dichloroethane norbornene mediated meta-C-H functionalization in this setting showcases the potential utility of this reaction in drug discovery.

Recognizing the robust nature of the MPAHP ligands, an improvement of the practicality of the 6 reaction conditions in collaboration with Bristol- Myers Squibb. A high throughput screen was

undertaken to establish Ag-free conditions with process friendly solvents. Through this screen, it was found that the use of CsOAc in place of AgOAc in t-Amyl-OH could provide excellent yields on gram- scale reactions with ortho-substituted aryl iodides, and synthetically useful yields with simple aryl iodides when utilizing L12 or L17 respectively as are illustrated in the reaction schemes below. The

1a then Pd(OAc) ₂ (5 mol%)

CsOAc (3.0 equiv.) 9a, 73% yield f-Amyl-OH, 16 hours

DCM = dichloromethane . removal of silver from the Pd(II) catalyzed,

norbornene mediated meta-C-H arylation reaction for the first time is crucial for adopting this method in synthesis, especially when reactions need to be performed beyond gram-scale.

The applicability of this ligand scaffold in promoting other transformations was attempted in othere challenging meta-C-H amination reactions.

After systematic optimization, the MPAHP ligand L24 7028116 was found to promote the norbornene mediated meta- amination of a variety of anilines with N-0 benzoyl morpholine to provide Compounds lOa-j in

synthetically useful yields. These reactions are illustrated below in Table 12.

Table

10k, 81% 101, 84% 10m, 70% 10n, 62% 10o, 53%

*Bz = benzoyl; DCM = dichloromethane; Boc = tert- butyloxycarbonyl; Bn = benzyl; NBE-C0 ₂ e = methyl

bicyclo [2.2.1] hept-2-ene-2-carboxylate . Reaction conditions: Compound 1 or 2 (0.1 mmol) , aminating reagent (0.15 initio1) ,

Pd(OAc) ₂ (10 mol%), L24 (10 mol%), NBE-C0 ₂ Me (1.5 equiv.), AgOAc (2.0 equiv.), dichloromethane (1.0 mL) , 100 °C, 24 hours. For Compounds lOf, 10η and 10ο, Pd(OAc) ₂ (15 mol%), L24 (15 mol%), AgOAc (3.0 equiv.) and NBE-C0 ₂ Me (3.0 equiv.) were used. Although linear amines do not work well in this transformation under the current conditions, a variety of 6-membered amines can be smoothly coupled to provide lOk-o. These results are also shown in Table 12, above. This is believed to be the first report of a meta-C-R amination reaction in the literature . ³²

Furthermore, due to the robust catalysis enabled by the MPAHP ligands, the possibility of utilizing alkynyl bromides as coupling partners to provide meta-alkynylated products was considered. It is important to note that this reaction has no precedent in the Catellani reaction, and it is believed that no meta-C-R alkynylation reactions have been reported. To our great delight, after a brief evaluation of MPAHP ligands and reaction conditions, meta-C-R alkynylation of a variety of aniline-derived substrates could be achieved, providing Compounds 14a-j in good yields. This reaction scheme and results are shown in Table 13, below.

Table 13*

OMe

Me. ^k. .Me

Boc

Boc L25 (30 mol%;

N .

N . Pd(OAc) ₂ (10 mol%) DG

DG Br

Ag ₂ C0 ₃ (1.5 equiv.)

LiF (2.0 equiv.)

H TIPS NBE-C0 ₂ Me (2.5 equiv.)

1 or 2 DCM, 100 °C, 24 hours TIPS

14a, 72% 14b, 62% 14 14d, 50%

c,

70

14h, 56% 14i, 53% 14j, 46%

*TIPS = triisopropylsilyl; TBS = tert-butyldimethylsilyl ;

Reaction conditions: Compounds 1 or 2 (0.1 iranol) , alkynylating reagent (0.2 mmol), Pd(OAc) ₂ (10 mol%) , L25 (30 mol%), NBE-CO _z e (2.5 equiv.), Ag ₂ C0 ₃ (1.5 equiv.), LiF (2.0 equiv.),

dichloromethane (1.0 mL) , 100 °C, 24 hours.

Given that the original report ¹² ' ¹⁴ of this norbornene-mediated meta-C-H arylation strategy required installation of a directing group with phenylacetic acid substrates, wheteher the MPAHP ligands could enable a meta-C-H arylation of

phenylacetic acids using the free acid as the directing group was examined. Indeed, as can be seen P T/US2017/028116 from the reaction scheme and results shown in the reaction scheme shown below, 2-methylphenylacetic acid could be arylated at the meta-position in the presence of MPAHP L2 to provide Compound 15 in 85% isolated yield. Importantly, all three of the

palladium-catalyzed transformations shown in the reaction schemes of Tables 12 and 13 , and that below that was carried out in hexafluoroisopropanol (HFIP) are ligand-enabled and provide only trace product amounts in the absence of an MPAHP ligand.

A versatile ligand scaffold for Pd(II) catalyzed meta-C-H arylation of a wide range of arenes using norbornene as a transient mediator is disclosed. Heterocyclic substrates and coupling partners are well tolerated under the developed reaction conditions, which should enable rapid uptake of this ligand enabled methodology in drug discovery. The utility of this ligand is further demonstrated by enabling the development of both a challenging meta- C-H amination reaction and an unprecedented meta-C-H alkynylation reaction. In addition, in the case of phenylacetic acid substrates, installation of a directing group is omitted as the MPAHP ligand

promotes the meta-C-H functionalization of this class of substrates using the native acid as the directing group . Methods Summary- General procedure for the MPAHP-promoted norbornene- mediated mefca-C-H activation of anilines . Substrate

(0.1 mmol), Ar-I (0.2 mmol) , Pd(0Ac) ₂ (2.2 mg, 10 mol%), L12 (3.0 mg, 20 mol%) , AgOAc (50.1 mg, 0.3 mmol), 2-norbornene (14.1 mg, 0.15 mmol) or NBE-C0 ₂ Me

(21.6 mg, 0.15 mmol) and 1, 2-dichloroethane (0.5 mL) were added to a 2-dram vial. The vial was capped and closed tightly, then the reaction mixture was stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was passed through a pad of

Celite® with dichloromethane as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC to afford the desired arylated product.

General Information

2-Norbornene and AgOAc were purchased from Sigma-Aldrich. NBE-C0 ₂ Me (methyl bicyclo [2.2.1] hept-2- ene-2-carboxylate) was synthesized following

literature procedures. [Shen et al., J. Am. Chem. Soc. 137 : 11574-11577 (2015).] Solvents were obtained from Sigma-Aldrich, Alfa-Aesar and Acros and used directly without further purification. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254. Visualization was carried out with UV light and Vogel's permanganate. ¹ H NMR was recorded on Bruker AMX-400 instrument (400 MHz) or Bruker DRX-600 instrument (600 MHz) . Chemical shifts were quoted in parts per million (ppm) referenced to 0.0 ppm for tetramethylsilane . The following

abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = T/US2017/028116 triplet, q = quartet, p = pentet, sext = sextet, sep

= septet m = multiplet, br = broad. Coupling

constants, J, were reported in Hertz unit (Hz) . ¹³ C NMR spectra were recorded on Bruker AMX-400

instrument (100 MHz) or Bruker DRX-600 instrument

(150 MHz) , and were fully decoupled by broad band proton decoupling. ¹⁹ F NMR spectra were recorded on Bruker AMX-400 instrument (376 MHz), and were fully decoupled by broad band proton decoupling. Chemical shifts were reported in ppm referenced to either the center line of a triplet at 77.0 ppm of chloroform-d or referenced to the center line of a septet at 39.52 ppm of DMSO-d6. High-resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using ESI-TOF (electrospray ionization-time of flight) .

Slabstrate Molecules

3k 31

17028116

S5d S5e

Preparation of Aniline Substrates

Boc-protected anilines (Si) were synthesized following literature procedures starting from the free anilines.

Substrates la- were synthesized following the general procedure .

General procedure for synthesis of Boc-protected amines

Si: To a solution of anilines in ethanol was added (Boc) ₂ 0 (1.1 equiv.) at room temperature. After the reaction was completed, the solution was concentrated under vacuum to afford the Boc-protected amines in high yield. The Boc- protected amines were used for next step without further purification. [Vilaivan, Tetrahedron Lett 47, 6739- 6742 (2006) .]

General procedure for synthesis of substrates la-w: To a solution of Boc-protected anilines SI (1.2 equiv.) in DMF was added NaH (3.0 equiv.) at 0 °C, and the resulting mixture was allowed to warm up to room temperature for 30 min. The mixture was cooled to 0 °C again, then

2-chloromethyl-4-methoxy-3 , 5-dimethylpyridine

hydrochloride (1.0 equiv.) was added into the mixture slowly. The resulting mixture was allowed to warm up to room temperature for another 12 hours. After the reaction completed, EtOAc was added to dilute the reaction mixture, then the organic phase was washed with water, brine and dried over Na ₂ S0 ₄ . After concentrated by rotatory

evaporation, the residue was purified by silica gel chromatography to afford the desired substrates la- .

tert-Butyl ( (4-methoxy-3 , 5-dimethylpy idin-2-yl) methyl) - (m-tolyl) carbamate (la)

Colorless solid, mp = 73 °C, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 7.10 (t, J = 7.7 Hz, 1H) , 7.06 (s, 1H) , 7.02 (d, J = 8.1 Hz, 1H) , 6.91 (d, J = 7.5 Hz, 1H) , 4.90 (s, 2H) , 3.72 (s, 3H) , 2.27 (s, 3H) , 2.21 (s, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.62, 155.18, 154.78, 148.91, 142.70, 138.03, 128.05, 126.95, 126.29, 124.57, 123.68, 123.50, 80.14, 59.83, 53.54, 28.25, 21.34, 13.19, 10.40; HRMS (ESI-TOF) m/z Calcd for C ₂₁ H ₂₉ N ₂ 0 ₃ [M+H] ⁺ : 357.2173, found: 357.2172.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-y1) methyl) - (3-methoxyphenyl) carbamate (lb)

Colorless solid, mp = 65 °C, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 7.13 (t, J = 8.2 Hz, 1H) , 6.84 (d, J = 7.4 Hz, 2H) , 6.70-6.63 (m, 1H) , 4.90 (s, 2H) , 3.73 (s, 3H) , 3.72 (s, 3H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.62, 159.49, 155.04, 154.68, 148.97, 144.04, 128.84, 124.62, 123.67, 118.87, 112.47, 111.17, 80.29, 59.84, 55.23, 53.51, 28.27, 13.20, 10.39; HRMS (ESI-TOF) m/z Calcd for C ₂₁ H ₂₉ N ₂ 0 ₄ [M+H] ⁺ : 373.2122, found: 373.2121. U 2017/028116

terfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - (3- (methylthio) henyl) carbamate (lc)

Colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 7.18-7.11 (m, 2H) , 7.07-6.97 (m, 2H) , 4.89 (s, 2H) , 3.72 (s, 3H) , 2.40 (s, 3H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.62, 154.88, 154.56, 148.92, 143.30, 138.20, 128.52, 124.82, 124.65, 123.89, 123.65, 123.30, 80.37, 59.81, 53.31, 28.21, 15.89, 13.16, 10.36; HRMS (ESI-TOF) m/z Calcd for C ₂ iH ₂₉ N ₂ 0 ₃ S [M+H] ⁺ :

389.1893, found: 389.1893.

terfc-Butyl (3- (benzyl ( terfc-butoxycarbonyl) -amino) phenyl) - ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (Id)

Colorless liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.10 (s, 1H) , 7.31-7.02 (m, 8H) , 6.88 (d, J= 7.4 Hz, 1H) , 4.84 (s, 2H) , 4.73 (s, 2H) , 3.71 (s, 3H) , 2.19 (s, 3H) , 2.16 (s, 3H) , 1.44-1.30 (m, 18H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.55,

154.78, 154.50, 154.46, 148.85, 143.15, 142.72, 138.49, 128.17, 128.02, 127.20, 126.84, 124.51, 124.17, 123.87, 123.73, 123.50, 80.29, 80.19, 59.73, 53.82, 53.27, 28.13, 28.11, 13.09, 10.25; HRMS (ESI-TOF) m/z Calcd for Cs^ sC^ [M+H] ⁺ : 548.3119, found: 548.3120.

terfc-Butyl (3-fluoropheny1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (le)

Colorless solid, ^X H NMR (400 MHz , CDC1 ₃ ) δ 8.16 (s, 1H) , 7.18 (q, J= 7.4 Hz, 1H) , 7.10-6.97 (m, 2H) , 6.86-6.76 (m, 1H) , 4.89 (s, 2H) , 3.73 (s, 3H) , 2.22 (s, 3H) , 2.21 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.68, 162.38 (d, J= 245.3 Hz), 154.63, 154.37, 149.03, 144.52

(d, J = 10.3 Hz), 129.15 (d, J= 9.6 Hz), 124.76, 123.52, 121.78, 113.69 (d, J= 23.4 Hz), 112.25 (d, J= 21.0 Hz), 80.68, 59.86, 53.27, 28.17, 13.20, 10.33; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -113.42; HRMS (ESI-TOF) m/z Calcd for C ₂₀ H ₂₆ F ₂ O ₃

[M+H] ⁺ : 361.1922, found: 361.1920.

tert-Butyl (3-chloropheny1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (If)

Colorless solid, mp = 68 °C, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8. (s, 1H), 7.29 (s, 1H) , 7.21-7.12 (m, 2H) , 7.12-7.04 (m, 1H) , 4.88 (s, 2H) , 3.73 (s, 3H) , 2.22 (s, 3H) , 2.20 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.68, 154.60, 154.35, 149.06, 144.17, 133.61, 129.15, 126.59, 125.52, 124.78, 124.51, 123.52, 80.72, 59.88, 53.23, 28.19, 13.22, 10.36; HRMS (ESI-TOF) m/z Calcd for

C ₂₀ H ₂₆ C1N ₂ 03 [M+H] ⁺ : 377.1626, found: 377.1628.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - (3- (trifluorometh 1) phenyl) carbamate (lg)

Colorless solid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 7.54 (s, 1H) , 7.47 (s, 1H) , 7.39-7.31 (m, 2H) , 4.92 (s, 2H) , 3.73 (s, 3H) , 2.21 (s, 6H) , 1.40 (s, 9H) ; C NMR (150 MHz , CDC1 ₃ ) δ 163.75, 154.49, 154.30, 149.08, 143.44, 130.58 (q, J= 32.2 Hz), 129.39, 128.76, 124.89, 123.88 (d, J= 272.3 Hz); 123.59, 123.54, 121.95, 80.92, 59.86, 53.10, 28.16, 13.20, 10.38; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ - 62.90; HRMS (ESI-TOF) m/z Calcd for C ₂ iH ₂₆ F ₃ N ₂ 0 ₃ [M+H] ⁺ :

411.1890, found: 411.1890.

Methyl 3- ( ( tert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) benzoate (lh)

Colorless solid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 7.92 (s, 1H) , 7.78 (d, J= 7.7 Hz, 1H) , 7.48 (d, J= 8.0 Hz, 1H) , 7.30 (t, J= 7.9 Hz, 1H) , 4.93 (s, 2H) , 3.87 (s, 3H) , 3.73 (s, 3H) , 2.22 (s, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 166.64, 163.67, 154.63, 154.42, 148.94, 142.99, 131.04, 130.33, 128.26, 127.55, 126.54, 124.72, 123.66, 80.59, 59.79, 53.10, 52.01, 28.13, 13.13, 10.36; HRMS (ESI-TOF) m/z Calcd for C ₂ 2H _{29 2} 05 [M+H] ⁺ : 401.2071, found: 401.2072.

tert-Butyl (3-benzoylpheny1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (li)

Light yellow liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.13 (s, 1H) , 7.75 (d, J= 7.4 Hz, 2H) , 7.67 (s, 1H) , 7.61-7.50 (m, 3H) , 7.45 (t, J= 7.6 Hz, 2H) , 7.36 (t, J= 7.8 Hz, 1H) , 4.93 (s, 2H) , 3.72 (s, 3H) , 2.26-2.16 (m, 6H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 196.04, 163.69, 154.63, 154.51, 148.97, 142.97, 137.71, 137.35, 132.32, 130.55, 130.00, 128.21, 128.15, 127.87, 127.10, 124.75, 123.63, 80.66, 59.83, 53.16, 28.18, 13.18, 10.36; HRMS (ESI-TOF) m/z Calcd for C ₂₇ H ₃ iN ₂ 0 ₄ [M+H] ⁺ : 447.2278, found: 447.2278.

terfc-Butyl (3-cyanopheny1) ( (4-methoxy-3 , 5-dimethylpyridin- 2-yl) methyl) carbamate (1j )

Colorless solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 7.66-7.54 (m, 2H) , 7.43-7.31 (m, 2H) , 4.87 (s, 2H) , 3.75 (s, 3H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 1.38 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.76, 154.14, 149.14, 144.04, 130.83, 129.57, 129.11, 128.74, 124.98, 123.37, 118.61, 112.31, 81.20, 59.92, 52.98, 28.12, 13.23, 10.32; HRMS (ESI-TOF) m/z Calcd for C ₂ iH2 _.6 N ₃ 0 ₃ [M+H] ⁺ : 368.1969, found: 368.1969.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- nitrophenyl) carbamate (lk)

Light yellow solid, ^Χ Η NMR (400 MHz, CDC1 ₃ ) δ 8.18 (t, J = 2.2 Hz, 1H) , 8.16 (s, 1H) , 8.00-7.93 (m, 1H) , 7.68 (d, J = 8.0 Hz, 1H) , 7.41 (t, J = 8.1 Hz, 1H) , 4.93 (s, 2H) , 3.75 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.81, 154.13, 154.07, 149.15, 148.12, 144.24, 132.19, 128.82, 125.02, 123.49, 121.22, 119.98, 81.36, 59.92, 52.91, 28.12, 13.22, 10.36; HRMS (ESI-TOF) m/z Calcd for C ₂₀ H _{26 3} O ₅ [M+H] ⁺ : 388.1867, found: 388.1865.

terfc-Butyl ( (4-methoxy-3 , 5-dime hylpyridin-2-yl) - methyl) (phenyl) carbamate (11)

Light yellow solid, mp = 60 °C, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 7.26-7.18 (m, 4H) , 7.14-7.15 (m, 1H) , 4.92 (s, 2H) , 3.72 (s, 3H) , 2.25-2.17 (m, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.63, 155.06, 154.74, 148.93, 142.74, 128.29, 126.46, 125.49, 124.63, 123.76, 80.23, 59.82, 53.45, 28.23, 13.19, 10.39; HRMS (ESI-TOF) m/z Calcd for C ₂ oH2 ₇ N ₂ 0 ₃ [M+H] ⁺ : 343.2016, found: 343.2015.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - (o-tolyl) carbamate (lm)

Light yellow liquid, rotameric mixture; ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.09 (s, 1H) , 7.25-6.87 (m, 4H) , 5.13 (d, J = 14.8 Hz, 1H) , 4.70-4.39 (m, 1H) , 3.71 (s, 3H) , 2.20 (s, 6H) , 2.13 (s, 3H) , 1.54-1.28 (m, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) rotameric mixture, resonances for the minor rotamer are enclosed in parenthesis (): δ 163.68, 154.95 (155.19), 154.85 (154.37), 148.85, 140.63 (141.16) , 135.87

(136.15) , 130.22 (130.55) , 128.28 , 126.87 , 126.06 (126.40), 124.97 (124.72), 124.87 (124.00), 79.71 (80.05), 59.71, 52.50 (53.38), 28.22, 17.49 (17.63), 13.18, 10.60; HRMS (ESI-TOF) m/z Calcd for C ₂ iH ₂₉ N ₂ 0 ₃ [M+H] ⁺ : 357.2173, found: 357.2172.

text-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - (2-me hoxyphenyl) carbamate (In)

Colorless liquid, ½ N R (400 MHz , CDC1 ₃ ) δ 8.05 (s, 1H) , 7.12 (t, J= 7.6 Hz, 1H) , 6.93-6.65 (m, 3H) , 5.46-4.37 (m, 2H) , 3.77 (brs, 3H) , 3.72 (s, 3H) , 2.25 (s, 3H) , 2.18 (brs, 3H) , 1.55-1.26 (m, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture, resonances for the minor rotamerthe the minor rotamer are enclosed in parenthesis () : δ 163.68 (163.60), 155.45 (155.59), 155.32, 155.10 (154.83),

148.58, 130.61 (130.28), 129.42, 127.79 (128.02), 125.35 (124.59), 124.76 (124.49), 119.95 (120.39), 110.89

(111.68), 79.47 (80.09), 59.72, 55.14 (55.59), 52.42 (53.29), 28.17 (28.26), 13.16, 10.57; HRMS (ESI-TOF) m/z Calcd for C ₂ iH _{29 2} 04 [M+H] ⁺ : 373.2122, found: 373.2121.

tert-Butyl (2-fluorophenyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (lo)

Colorless solid, mp = 59 °C, rotameric mixture, ratio of the rotamers = 75/25; ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.07 (s, 1H) , 7.40-7.06 (m, 2H) , 7.05-6.89 (m, 2H) , 4.93 (s, 2H) , 3.72 (s, 3H) , 2.25 (s, 3H) , 2.18 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture, resonances for the minor rotamerthe the minor rotamer are enclosed in parenthesis (): δ 163.79, 158.15 (d, J= 248.9 Hz),

154.68, 154.30, 148.72, 129.69 (d, J= 12.0 Hz), 129.28, 127.90 (d, J= 7.8 Hz), 125.12, 124.97, 123.79, 115.56 (d, J = 21.3 Hz) , 80.48, 59.75, 52.69 (53.39), 28.07, 13.16, 10.49; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) for major isomer: δ - 121.13; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) for minor isomer: δ - 120.82; HRMS (ESI-TOF) m/z Calcd for C ₂₀ H ₂₆ FN ₂ O ₃ [M+H] ⁺ :

361.1922, found: 361.1922.

tert-Butyl (4-fluoropheny1) ( (4-methoxy-3 , 5- dime hylpyridin-2-y1) methyl) carbamate (lp)

Light yellow solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.13 (s, 1H) , 7.19 (s, 2H) , 6.91 (t, J= 8.6 Hz, 2H) , 4.88 (s, 2H) , 3.72 (s, 3H) , 2.21 (s, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.72 , 160.46 (d, J= 244.4 Hz), 154.82 , 154.78 , 148.96 , 138.65 , 128.43 (d, J= 8.0 Hz),

124.81 , 123.93 , 115.06 (d, J= 22.8 Hz), 80.39, 59.85, 53.50, 28.22, 13.20, 10.40; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ - 117.08; HRMS (ESI-TOF) m/z Calcd for C ₂₀ H ₂₆ FN ₂ O ₃ [M+H] ⁺ :

361.1922, found: 361.1923.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - (4-methoxyphenyl) carbamate (lq)

Red solid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.12 (s, 1H) , 7.10 (brs, 2H) , 6.74 (d, J= 8.4 Hz, 2H) , 4.89 (s, 2H) , 3.74 (s, 3H) , 3.72 (s, 3H) , 2.25-2.16 (m, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.67, 157.34, 155.15, 155.08, 148.88, 135.52, 127.99, 124.68, 124.09, 113.56, 80.04, 59.81, 55.31, 53.67, 28.28, 13.19, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂ iH ₂ g ₂ 0 ₄ [M+H] ⁺ : 373.2122, found: 373.2123.

tert-Butyl benzo [d] [1 , 3] dioxol-5-yl ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (lr)

Colorless solid, mp = 87 °C, ¾ NMR (400 MHz , CDC1 ₃ ) δ 8.14 (s, 1H), 6.77 (s, 1H) , 6.65 (s, 2H) , 5.90 (s, 2H) , 4.84 (s, 2H) , 3.73 (s, 3H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz , CDC1 ₃ ) δ 163.24, 154.58, 154.53, 148.48, 146.76, 145.02, 136.32, 124.28, 123.48, 119.75, 108.27, 107.11, 100.71, 79.75, 59.40, 53.38, 27.82, 12.76, 9.98; HRMS (ESI-TOF) m/z Calcd for C ₂₁ H ₂ 7 ₂ 05 [M+H] ⁺ :

387.1914, found: 387.1914.

tert-Butyl (4-fluoro-3-methylpheny1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (Is)

Colorless solid, mp = 78 °C, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 7.07 (s, 1H) , 6.98 (s, 1H) , 6.83 (t, J= 9.0 Hz, 1H) , 4.86 (s, 2H) , 3.73 (s, 3H) , 2.24-2.19 (m, 6H) , 2.18 (d, J= 1.9 Hz, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.68, 159.05 (d, J= 243.2 Hz), 154.94, 154.81,

148.90, 138.26, 129.63 (d, J= 5.3 Hz), 125.69, 124.72, 124.59 (d, J = 18.6 Hz), 123.83, 114.59 (d, J = 23.3 Hz) , 80.26, 59.81, 53.58, 28.22, 14.51, 13.18, 10.40; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -121.37; HRMS (ESI-TOF) m/z Calcd for C ₂ iH ₂₈ FN ₂ 0 ₃ [M+H] ⁺ : 375.2078, found: 375.2079.

tert-butyl (2-fluoro-4-methoxyphenyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (It)

Red liquid, rotameric mixture, ratio of the rotamers = 75/25; ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.06 (brs, 1H) , 7.18 (s, 0.25H), 7.00 (d, J= 9.1 Hz, 0.75H), 6.63-6.44 (m, 2H) , 5.02-4.75 (m, 2H) , 3.73 (s, 3H) , 3.72 (s, 3H) , 2.26 (s, 3H) , 2.19 (s, 3H) , 1.52-1.31 (m, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture: δ 163.81, 159.63, 159.41,

159.20, 159.16, 159.03, 158.95, 158.01, 157.76, 154.96, 154.81, 154.66, 148.69, 130.50, 129.73, 125.28, 124.99, 124.42, 122.33, 122.24, 109.53, 108.98, 101.75, 101.59, 80.62, 80.22, 76.79, 59.73, 55.48, 53.61, 52.77, 28.10, 13.17, 10.52; ¹³ C NMR (150 MHz, CDC1 ₃ ) for major isomer: δ 163.81, 159.03, 158.95, 158.58 (d, J = 248.7 Hz) , 154.74 (d, J = 22.2 Hz), 148.69, 129.73, 125.28, 124.99, 122.29 (d, J= 13.1 Hz), 108.98, 101.67 (d, J= 24.2 Hz), 80.22, 59.73, 55.48, 52.77, 28.10, 13.17, 10.52; ¹⁹ F NMR (376 MHz, CDCI ₃ ) for major isomer: δ -119.19; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) for minor isomer: δ -118.92; HRMS (ESI-TOF) m/z Calcd for C ₂₁ H ₂₈ F ₂ 0 ₄ [M+H] ⁺ : 391.2028, found: 391.2028.

Methyl 3- ( ( fcert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -2-methylbenzoate (lu)

Colorless liquid, rotameric mixture, ratio of the rotamers = 70/30; ½ NMR (400 MHz, CDC1 ₃ ) δ 8.09 (brs, 1H) , 7.72 (d, J = 7.8 Hz, 1H) , 7.47 (s, 0.3H), 7.21 (d, J = 7.8 Hz, 0.7H), 7.16-7.00 (m, 1H) , 5.16 (d, J = 14.9 Hz, 1H) , 4.66- 4.30 (m, 1H) , 3.87 (s, 3H) , 3.71 (s, 3H) , 2.50-2.30 (m, 3H) , 2.20 (s, 6H) , 1.52-1.28 (m, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture, resonances for the minor

rotamerthe the minor rotamer are enclosed in parenthesis (): δ 168.05, 163.75 (163.65), 154.70 (154.79), 154.48, 148.89, 141.94 (142.56), 137.93 (138.10), 132.50 (132.90), 130.91 (131.28), 129.15, 125.50 (125.79), 124.98, 124.86 (123.85), 80.07, 59.72, 52.44 (53.27), 51.85, 28.16, 15.07, 13.17, 10.61; HRMS (ESI-TOF) m/z Calcd for C ₂ 3H _{31 2} 05 [M+H] ⁺ : 415.2227, found: 415.2226.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) - methyl) (naphthalen-l-yl) carbamate (lv)

Colorless solid, rotameric mixture, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.11 (s, 1H) , 7.87 (s, 1H) , 7.84-7.77 (m, 1H) , 7.70 (d, J = 8.2 Hz, 1H) , 7.52-7.39 (m, 2H) , 7.38-7.18 (m, 2H) , 5.37 (d, J= 15.2 Hz, 1H) , 4.66 (d, J= 15.1 Hz, 1H) , 3.66 (s, 3H) , 2.17 (s, 3H) , 2.13 (s, 3H) , 1.70-1.05 (m, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture, resonances for the minor rotamer are enclosed in parenthesis (): δ 163.63, 155.46, 154.99, 148.89, 138.66, 134.23, 130.76, 128.14, 127.27, 126.37, 125.99, 125.66, 125.32, 124.75, 124.66, 122.88, 79.93, 59.69, 53.00 (53.86), 28.06, 13.13, 10.54; HRMS (ESI-TOF) m/z Calcd for C ₂ H _{29 2} O ₃ [M+H] ⁺ : 393.2173, found: 393.2173.

tert-butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) - methyl) (naphthalen-2-yl) carbamate (lw)

Colorless solid, mp = 81 °C, ¾ NMR (400 MHz, CDC1 ₃ ) δ (s, 1H) , 7.78-7.72 (m, 1H) , 7.72-7.67 (m, 2H) , 7.65 (s 1H) , 7.44 (d, J= 8.6 Hz, 1H) , 7.42-7.34 (m, 2H) , 5.03 2H) , 3.71 (s, 3H) , 2.23 (s, 3H) , 2.19 (s, 3H) , 1.41 (s 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.66, 154.99, 154.78, 17028116

148.97, 140.41, 133.41, 131.37, 127.73, 127.70, 127.37, 126.03, 125.78, 125.36, 124.67, 123.75, 123.52, 80.43, 59.80, 53.63, 28.25, 13.17, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂ 4H _{29 2} 0 ₃ [M+H] ⁺ : 393.2173, found: 393.2172.

tert-Butyl (3- ( ( ( tert-butyldimethylsilyl) oxy) methyl) - phenyl) ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - carbamate (lx)

Light yellow liquid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 7.23-7.15 (m, 2H) , 7.12 (d, J= 7.9 Hz, 1H) , 7.06 (d, J= 7.5 Hz, 1H) , 4.91 (s, 2H) , 4.66 (s, 2H) , 3.72 (s, 3H) , 2.24-2.16 (m, 6H) , 1.39 (s, 9H) , 0.89 (s, 9H) , 0.04 (s, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.60, 155.03, 154.79, 148.95, 142.79, 141.69, 128.05, 124.93, 124.55, 123.81, 123.61, 123.03, 80.17, 64.61, 64.59, 59.81, 53.46, 28.24, 25.88, 25.86, 18.32, 13.17, 10.34, -5.33; HRMS (ESI-TOF) m/z Calcd for C ₂ 7H43N20 ₄ Si [M+H] ⁺ : 487.2987, found: 487.2986.

tert-Butyl (3-benzylpheny1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (ly)

Colorless liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.11 (s, 1H) , 7.28-7.20 (m, 2H) , 7.20-6.99 (m, 6H) , 6.91 (d, J = 7.1 Hz, 1H) , 4.89 (s, 2H) , 3.89 (s, 2H) , 3.69 (s, 3H) , 2.19 (s, 3H), 2.18 (s, 3H) , 1.36 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.64, 155.04, 154.72, 148.88, 142.70, 141.02, 140.89, 128.85, 128.35, 128.29, 127.34, 126.19, 125.94, 124.60, 123.96, 123.82, 80.21, 59.79, 53.44, 41.62, 28.21, 13.20, 10.39; HRMS (ESI-TOF) m/z Calcd for C2 ₇ H33N2O3 [M+H] ⁺ :

433.2486, found: 433.2484.

tert-Butyl [1,1' -biphenyl] -3-yl ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (lz)

Light yellow liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H), 7.52-7.46 (m, 2H) , 7.44 (s, 1H) , 7.42-7.36 (m, 2H) , 7.36-7.27 (m, 3H) , 7.23 (d, J = 8.3 Hz, 1H) , 4.97 (s, 2H) , 3.71 (s, 3H) , 2.22 (s, 3H) , 2.20 (s, 3H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.68, 155.08, 154.72, 148.97, 143.09, 141.32, 140.87, 128.61, 127.19, 127.07, 125.43, 125.32, 124.70, 124.30, 123.82, 80.33, 59.81, 53.46, 28.28, 13.18, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₃ i ₂ 03 [M+H] ⁺ : 419.2329, found: 419.2327.

tert-Butyl (3-bromopheny1) ( (4-methoxy-3 , 5-dimethylpyridin- 2-yl) methyl) carbamate (laa)

Colorless solid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.45 (s, 1H) , 7.26-7.18 (m, 2H) , 7.10 (t, J = 8.0 Hz, 1H) , 4.87 (s, 2H) , 3.74 (s, 3H) , 2.22 (s, 3H) , 2.20 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.68, 154.57, 154.33, 149.04, 149.03, 144.29, 129.46, 128.43, 125.00, 124.79, 123.53, 121.55, 80.74, 59.88, 53.21, 28.18, 13.21, 10.36; HRMS (ESI-TOF) m/z Calcd for C ₂₀ H ₂₆ BrN ₂ O ₃ [M+H] ⁺ :

421.1121, found: 421.1121.

Preparation of Heterocyclic-Amine Substrates 28116

S2a and S2b were synthesized following the General

Procedure A; Aminothiophenes bearing Boc-protecting group S2c-e were commercial available; Boc-protected amines S2f- 1 were synthesized following the General Procedure B.

Substrates 2a-l were synthesized following the general procedure .

General procedure A for synthesis of Boc-protected amines

S2 : To a solution of amine (5 mmol) in THF (20 mL) was added a solution of sodium bis (trimethylsilyl) amide (2.5 N in THF) slowly at -15 °C under nitrogen, and the resulting mixture was stirred for 30 min at the same temperature.

Next, (Boc) ₂ 0 (1.1 equiv.) was added at the same

temperature. The reaction mixture was allowed to warm up to room temperature. After the reaction was completed, the resulting mixture was diluted with EtOAc (50 mL) , and the organic phase was washed with water (50 mL) and then brine (50 mL) , dried over MgS0 ₄ , and concentrated in vacuo. Purification of the residue by flash

chromatography on silica gel gave S2. [Demont ert al . , Med. Chem., 58:5649-5673 (2015) .]

General procedure B for synthesis of Boc-protected amines

S2 : To a solution of amine in ethanol was added (Boc) ₂ 0 (1.1 equiv.) at room temperature. After the reaction was completed, the solution was concentrated under vacuum to afford the Boc-protected amines in high yield. The Boc- protected amines were used for next step without further purification. [Vilaivan, Tetrahedron Lett 47:6739-6742

(2005) . ]

General procedure for synthesis of substrates 2a-l: To a solution of Boc-protected amine S2 (1.2 equiv.) in DMF was added NaH (3.0 equiv.) at 0 °C, and the resulting mixture TU 2017/028116 was allowed to warm up to room temperature for 30 minutes.

The mixture was cooled to 0 °C again, then 2-chloromethyl- 4-methoxy-3, 5-dimethylpyridine hydrochloride (1.0 equiv.) was added into the mixture slowly. The resulting mixture was allowed to warm to room temperature for another 12 hours . After the reaction completed, EtOAc was added to dilute the reaction mixture, then the organic phase was washed with water, brine and dried over Na ₂ S0 . After concentrated in vacuo, the residue was purified by flash chromatography on silica gel to afford 2.

tert-Butyl (2-chloropyridin-3-yl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (2a)

Colorless solid, rotameric mixture, ratio of the rotamers = 76/24; ² H NMR (400 MHz, CDC1 ₃ ) δ 8.22 (d, J = 4.7 Hz, 1H) , 8.13 (s, 0.24H), 8.07 (s, 0.76H), 7.92 (s, 0.24H), 7.66 (d, J = 7.7 Hz, 0.76H), 7.22-7.10 (m, 1H) , 5.16 (d, J = 15.4 Hz, 1H) , 4.72-4.38 (m, 1H) , 3.73 (s, 3H) , 2.27 (s, 3H) , 2.20 (s, 3H) , 1.50-1.29 (m, 9H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) for major isomer: δ 163.86, 154.04, 153.75, 150.49, 148.80, 147.43, 139.21, 136.43, 125.23, 125.07, 122.51, 81.02, 59.75, 51.62, 28.03, 13.17, 10.66; HRMS (ESI-TOF) m/z Calcd for dgHzsClNsOa [M+H] ⁺ : 378.1579, found: 378.1579.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (6- methoxypyridin-2-yl) carbamate (2b)

Light yellow liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.12 (s, 1H) , 7.50 (t, J = 7.9 Hz, 1H) , 7.38 (d, J = 7.9 Hz, 1H) , 6.37 (d, J= 7.9 Hz, 1H) , 5.20 (s, 2H) , 3.72 (s, 3H) , 3.62

(s, 3H) , 2.24 (s, 3H) , 2.19 (s, 3H) , 1.43 (s, 9H) ; ¹³ C MR (150 MHz, CDC1 ₃ ) δ 163.32, 162.09, 155.91, 154.45, 152.20, 148.85, 139.43, 123.84, 122.42, 110.75, 104.67, 80.95, 59.82, 52.84, 49.28, 28.15, 13.13, 10.32; HRMS (ESI-TOF) m/z Calcd for C ₂₀ H ₂₈ N ₃ O4 [M+H] ⁺ : 374.2074, found: 374.2073.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2- yl) methyl) (thiophen-2-yl) carbamate (2c)

Light yellow liquid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 6.89 (d, J= 5.5 Hz, 1H) , 6.73 (dd, J = 5.6, 3.8 Hz, 1H) , 6.57 (d, J= 3.6 Hz, 1H) , 4.96 (s, 2H) , 3.73 (s, 3H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.46 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 163.71, 154.15, 154.00, 149.00, 145.12, 124.83, 124.21, 123.75, 120.38, 116.32, 81.52, 59.85, 53.87, 28.16, 13.19, 10.26; HRMS (ESI-TOF) m/z Calcd for

C18H25N2O3S [M+H] ⁺ : 349.1580, found: 349.1579.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2- yl) methyl) (thiophen-3-yl) carbamate (2d)

Light yellow liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 7.12-7.08 (m, 1H) , 7.06 (s, 1H) , 6.91 (s, 1H) , 4.90 (s, 2H) , 3.73 (s, 3H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.44 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.67, 154.80, 154.25, 149.00, 141.18, 125.41, 124.68, 123.61, 123.18, 114.83, 80.65, 59.84, 53.33, 28.23, 13.18, 10.27; HRMS (ESI-TOF) m/z Calcd for [M+H] ⁺ : 349.1580, found: 349.1581.

Methyl 3- ( ( er -butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) thiophene-2 -carboxylate <2e)

Light yellow liquid, rotameric mixture, ratio of rotamers = 34/64, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.20-7.98 (m, 1H) , 7.37- 7.16 (m, 1H) , 6.99 (s, 0.34H), 6.76 (s, 0.66H), 5.14-4.68 (m, 2H) , 3.84 (s, 3H) , 3.72 (s, 3H) , 2.25 (s, 3H) , 2.20 (s, 3H) , 1.50-1.28 (m, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture, resonances for the minor rotamer are enclosed in parenthesis () : δ 163.74 (163.60), 161.44 (161.32), 154.71 (155.16), 154.07 (154.16), 148.67

(148.75), 144.92 (145.84), 128.91 (129.28), 128.51

(128.78), 124.97 (125.02), 124.78 (124.71), 123.92, 80.28 (80.62), 59.75, 52.49 (53.43), 51.83, 28.08, 13.15, 10.50; HRMS (ESI-TOF) m/z Calcd for C20H27N2O5S [M+H] ⁺ : 407.1635, found: 407.1635.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2- yl) methyl) (quinolin-5-yl) carbamate (2f)

Red liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.88 (dd, J = 4.2, 1.6 Hz, 1H) , 8.27 (s, 1H) , 8.09 (s, 1H) , 7.98 (d, J = 8.5 Hz, 1H) , 7.59 (t, J = 7.9 Hz, 1H) , 7.38 (dd, J = 8.5, 4.2 Hz, 2H) , 5.21 (d, J = 15.3 Hz, 1H) , 4.80 (d, J = 15.2 Hz, 1H) , 3.67 (s, 3H) , 2.17 (s, 6H) , 1.25 (brs, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 163.73, 155.09, 154.54, 150.19, 148.97, 148.73, 138.85, 131.91, 128.89, 128.74, 126.24, 125.75, 124.95, 124.53, 120.89, 80.46, 59.75, 53.26, 28.07, 13.16, 6

10.60; HRMS (ESI-TOF) m/z Calcd for C ₂₃ H ₂₈ N ₃ 0 ₃ [M+H] ⁺ :

394.2125, found: 394.2124.

terfc-Butyl (l-acetylindolin-6-yl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (2g)

Light yellow solid, mp = 140 °C, rotameric mixture, ratio of rotamer = 22/78, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.18-8.08 (m, 1.78H), 7.15 (s, 0.22H), 7.08 (d, J= 7.4 Hz, 0.22H), 7.00 (d, J = 8.0 Hz, 0.78H), 6.96-6.85 (m, 1H) , 4.95-4.84 (m, 2H) , 4.09 (t, J= 8.1 Hz, 0.44H), 4.02 (t, J= 8.4 Hz, 1.56H), 3.72 (s, 3H) , 3.11 (t, J= 8.5 Hz, 1.56H), 2.98 (t, J= 8.5 Hz, 0.44H), 2.32-2.14 (m, 9H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture, resonances for the minor rotamer are enclosed in parenthesis (): δ 168.34 (168.19), 163.61 (163.68), 155.12 (154.97), 154.79 ,

148.78 (148.86), 142.93 (142.18), 142.08 (141.68) , 128.43 (131.15), 125.15 , 124.52 (124.79), 123.75 (123.89),

122.25 (121.66), 115.85 (113.80), 80.16 (80.38), 59.79 , 53.55 (53.60), 49.18 (48.33), 28.21 , 27.56 (26.39), 24.11 (24.31), 13.15 , 10.44 (10.39); HRMS (ESI-TOF) m/z Calcd for C ₂₄ H ₃₂ N:A [M+H] ⁺ : 426.2387, found: 426.2387.

te t-Butyl 6- ( ( te t-butoxycarbony1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -lH-indole-l-carboxylate (2h)

Colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.11 (s, 1H) , 7.95 (s, 1H) , 7.53 (d, J= 3.7 Hz, 1H) , 7.38 (d, J= 8.3 Hz, 1H) , 7.12 (d, J= 8.4 Hz, 1H) , 6.47 (d, J= 3.7 Hz, 1H) , 4.99 (s, 2H) , 3.72 (s, 3H) , 2.23 (s, 3H) , 2.19 (s, 3H) , 1.59 (s, 9H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.73, 154.75, 154.55, 149.01, 143.94, 139.80, 139.25, 124.81, 123.72, 123.58, 123.39, 120.34, 111.99, 84.65, 80.74, 59.85, 53.78, 28.20, 28.01, 13.19, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂₇ H _{36 3} 0 ₅ [M+H] ⁺ : 482.2649, found: 482.2650.

tert-Butyl 4- (( tert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -lH-indole-l-carboxylate

(2i)

Colorless solid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.10 (s, 1H) , 7.97 (d, J= 8.3 Hz, 1H) , 7.52 (d, J= 3.8 Hz, 1H) , 7.15 (t, J= 8.0 Hz, 1H) , 7.01 (s, 1H) , 6.52 (d, J= 3.7 Hz, 1H) , 4.99 (s, 2H) , 3.68 (s, 3H) , 2.18 (s, 6H) , 1.65 (s, 9H) , 1.35 (brs, 9H) ; ¹³ C NMR (150 MHz, CDCl ₃ ) δ 163.59, 154.98, 154.85, 149.65, 148.85, 135.80, 134.93, 128.51, 125.42, 124.68, 124.33, 124.16, 121.07, 113.58, 105.56, 83.62, 80.08, 59.70, 53.18, 28.16, 28.13, 13.14, 10.52; HRMS (ESI-TOF) m/z Calcd for C ₂₇ H ₃₆ N ₃ 0 ₅ [M+H] ⁺ : 482.2649, found: 482.2649.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (l-methyl-lH-indazol-6-yl) carbamate (2j)

Colorless solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 7.87 (s, 1H), 7.55 (d, J= 8.6 Hz, 1H) , 7.33 (s, 1H) , 7 (d, J= 8.6 Hz, 1H) , 4.99 (s, 2H) , 3.98 (s, 3H) , 3.73 ( 3H) , 2.24 (s, 3H) , 2.21 (s, 3H) , 1.40 (s, 9H) ; ^1J C NMR (150

MHz, CDC1 ₃ ) δ 163.70, 155.02, 154.81, 148.94, 141.45, 140.01, 132.47, 124.76, 123.84, 121.90, 120.82, 120.45, 106.53, 80.50, 59.84, 53.92, 35.50, 28.25, 13.21, 10.46;

HRMS (ESI-TOF) m/z Calcd for C22H29 4O3 [M+H] ⁺ : 397.2234, found: 397.2234.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - (4-oxo-2-phenyl-4H-chromen-6-y1) carbamate (2k)

Yellow solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 7.99 (d, J = 2.6 Hz, 1H) , 7.94-7.87 (m, 2H) , 7.78 (d, J = 9.1 Hz, 1H) , 7.57-7.49 (m, 3H) , 7.47 (d, J= 9.0 Hz, 1H) , 6.77 (s, 1H) , 4.98 (s, 2H) , 3.74 (s, 3H) , 2.24 (s, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 177.99, 163.75, 163.22, 154.50, 153.76, 149.03, 140.32, 133.36, 131.73, 131.53, 128.99, 126.22, 124.84, 123.84, 123.68, 121.85, 117.95, 107.19, 80.83, 59.89, 53.24, 28.18, 13.19, 10.42; HRMS (ESI-TOF) m/z Calcd for C ₂ 9H3i ₂ 0 ₅ [M+H] ⁺ :

487.2227, found: 487.2226.

fcert-Butyl (2 , 3-dihydrobenzo [b] [1 , 4] dioxin-6-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (21)

Colorless solid, Η NMR (500 MHz, CDCl ₃ ) δ 8.15 (s, 1H) , 6.78 (s, 1H) , 6.70 (s, 2H) , 4.84 (s, 2H) , 4.19 (s, 4H) , 3.72 (s, 3H) , 2.21 (s, 3H) , 2.19 (s, 3H) , 1.39 (s, 9H) ; NMR (150 MHz, CDC1 ₃ ) δ 163.62, 155.05, 154.99, 148.92, 142.85, 141.48, 136.34, 124.59, 123.75, 120.17, 116.54, 115.81, 80.10, 64.24, 64.19, 59.82, 53.68, 28.25, 13.18, 10.37; HRMS (ESI-TOF) m/z Calcd for C ₂ 2H ₂ 9 ₂ 05 [M+H] ^† :

401.2071, found: 401.2071.

Preparation of Phenol Substrates

3a-l

2- (Chloromethyl) -3-methylpyridine was synthesized

following the literature. [Narendara et al . , Synthetic Commun, 34:1097-1103 (2004)]

General Procedure for Preparation of Phenol Substrates :

Phenol derivative (10 mmol) and K ₂ C0 ₃ (20 mmol) were added to a 100 mL round bottom flask equipped with a reflux condenser and diluted with 20 mL MeCN. Next,

2- ( chloromethyl ) -3-methylpyridine (12 mmol) was added to the mixture via syringe and the reaction mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with 2 N NaOH three times. The resulting solution was dried over sodium sulfate, concentrated by rotatory evaporation and purified by silica gel chromatography to afford the desired phenol substrate Compounds 3a-l.

3a

3-Methy1-2- ( (m-tolyloxy) methyl) pyridine (3a)

Light yellow liquid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.45 (d, J = 4.8 Hz, 1H) , 7.51 (d, J = 7.7 Hz, 1H) , 7.21-7.13 (m, 2H) , 6.82-6.88 (m, 2H) , 6.78 (d, J = 7.5 Hz, 1H) , 5.20 (s, 2H) , 2.43 (s, 3H) , 2.33 (s, 3H) ; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.70, 154.40, 146.47, 139.42, 138.37, 133.26, 129.11,

123.35, 121.79, 115.69, 111.61, 70.73, 21.48, 18.14; HRMS

(ESI-TOF) m/z Calcd for C ₁₄ H ₁₅ O [M+H] ⁺ : 214.1226, found: 214.1228.

3b

2- ( (3-Methoxyphenoxy) methyl) -3-methylpyridine (3b)

Light yellow liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.45 (d, J = 4.7 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H) , 7.23-7.10 (m, 2H) , 6.66-6.59 (m, 2H) , 6.52 (dd, J = 8.3, 2.4 Hz, 1H) , 5.19 (s, 2H) , 3.78 (s, 3H) , 2.42 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 160.75, 159.96, 154.24, 146.57, 138.39, 133.21, 129.81, 123.41, 106.93, 106.75, 101.26, 70.83, 55.23, 18.14; HRMS (ESI-TOF) m/z Calcd for C ₄ H ₁₆ N0 ₂ [M+H] ⁺ :

230.1176, found: 230.1180.

3c

2- ( (3- (1 , 3-Dioxolan-2-yl)phenoxy) methyl) -3-methylpyridine (3c)

Clear liquid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.45 (d, J = 4.7 Hz, 1H) , 7.50 (d, J = 7.7 Hz, 1H) , 7.33-7.27 (m, 1H) , 7.21-7.15 (m, 2H) , 7.09 (d, J = 7.5 Hz, 1H) , 7.05 (dd, J = 8.2, 2.7 Hz, 1H) , 5.81 (s, 1H) , 5.23 (s, 2H) , 4.16-3.97 (m, 4H) , 2.42 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 158.64, 154.04, 146.37, 139.42, 138.27, 133.16, 129.31, 123.32, 118.96, 115.54, 112.55, 103.32, 103.31, 70.71, 65.09, 18.01; HRMS (ESI-TOF) m/z Calcd for Ci ₆ Hi ₈ N0 ₃ [M+H] ⁺ :

272.1281, found: 272.1284.

3d

3-Methyl-2- (phenoxymethyl) pyridine (3d)

Clear liquid, ² H NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, J = 4.7 Hz, 1H) , 7.49 (d, J = 7.6 Hz, 1H) , 7.31-7.23 (m, 2H) , 7.16 (dd, J = 7.7, 4.8 Hz, 1H) , 7.06-7.00 (m, 2H) , 6.94 (t, J = 7.6, 1H) 5.20 (s, 2H) , 2.41 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 158.63, 154.26, 146.46, 138.30, 133.17, 129.32, 123.32, 120.88, 114.76, 70.73, 18.07; HRMS (ESI-TOF) m/z Calcd for Ci ₃ H ₁₄ NO [M+H] ⁺ : 200.1070, found: 200.1073.

3e

3-Methyl-2- ( (o-tolyloxy) methyl) pyridine (3e)

Light yellow liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, J = 4.9 Hz, 1H) , 7.52 (d, J = 7.2 Hz, 1H) , 7.19 (dd, J = 7.7, 4.9 Hz, 1H) , 7.16-7.10 (m, 2H) , 7.03 (d, J = 8.1 Hz, 1H) , 6.86 (t, J = 7.4 Hz, 1H) , 5.22 (s, 2H) , 2.45 (s, 3H) , 2.22 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 156.74, 154.66, 146.37, 138.37, 133.46, 130.62, 126.82, 126.75, 123.35, 120.54, 111.51, 71.16, 18.14, 16.23; HRMS (ESI-TOF) m/z Calcd for Ci ₄ H ₁₆ NO [M+H] ⁺ : 214.1226, found: 214.1236.

2- ( (2-Isopropylphenoxy) methyl) -3-methylpyridine (3f)

Clear liquid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.45 (d, J = 4.4, Hz, 1H) , 7.52 (d, J = 8.0 Hz, 1H) , 7.24 - 7.16 (m, 2H) , 7.14 (d, J = 7.2 Hz, 1H) , 7.07 (d, J = 8.1 Hz, 1H) , 6.94 (t, J = 7.4 Hz, 1H) , 5.22 (s, 2H) 3.34 (sep, J = 6.9 Hz, 2017/028116

1H) , 2.45 (s, 3H) , 1.18 (d, J = 6.9 Hz, 6H) ; ^1J C NMR (100 MHz, CDC1 ₃ ) δ 155.77, 154.74, 146.44, 138.35, 137.20,

133.43, 126.50, 126.05, 123.38, 120.86, 111.81, 71.31, 26.36, 22.90, 18.16; HRMS (ESI-TOF) m/z Calcd for Ci ₆ H ₁₉ NO [M+H] ⁺ : 242.1539, found: 242.1539.

3g

2- ( (2-Methoxyphenoxy) methyl) -3-methylpyridine (3g)

Yellow liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.32 (d, J = 4.4 Hz, 1H) , 7.37 (d, J = 7.6 Hz, 1H) , 7.04 (dd, J = 7.7, 4.8 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H) , 6.85-6.74 (m, 3H) , 5.16 (s, 2H) , 3.73 (s, 3H) , 2.36 (s, 3H) ; ¹³ C NMR (100 MHz, CDCI ₃ ) δ 154.25, 149.65, 147.97, 146.22, 138.26, 133.36, 123.19, 121.41, 120.62, 114.42, 111.69, 71.86, 55.66, 18.02; HRMS (ESI-TOF) m/z Calcd for C ₁₄ Hi ₆ N0 ₂ [M+H] ⁺ :

230.1176, found: 230.1179.

3h

2- ( (2-Chlorophenoxy) methyl) -3-methylpyridine (3h)

Colorless solid, ^λ Ε NMR (400 MHz, CDC1 ₃ ) δ 8.43 (d, J = 4.8 Hz, 1H) , 7.52 (d, J = 7.7 Hz, 1H) , 7.34 (d, J = 8.0 Hz, 1H) , 7.23-7.14 (m, 3H) , 6.92-6.84 (m, 1H) , 5.31 (s, 2H) , 2.49 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 153.98, 153.78, 146.24, 138.62, 133.90, 130.25, 127.65, 123.60, 122.95, 121.59, 114.23, 72.02, 18.22; HRMS (ESI-TOF) m/z Calcd for C ₁₃ H ₁₃ C1N0 [M+H] ⁺ : 234.0680, found: 234.0682.

3i

3-Methyl-2- ( ( (5,6,7 , 8-tetrahydronaphthalen-l- yl) oxy) methyl) yridine (3i)

Orange solid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, J = 4.7 Hz, 1H) , 7.51 (d, J = 7.6 Hz, 1H) , 7.19 (dd, J = 7.6, 4.8 Hz, 1H) , 7.06 (t, J = 7.9 Hz, 1H) , 6.86 (d, J = 8.0 Hz, 1H) , 6.71 (d, J = 7.6 Hz, 1H) , 5.21 (s, 2H) , 2.75 (t, J = 5.1 Hz, 2H) , 2.66 (t, J = 6.3 Hz, 2H) , 2.44 (s, 3H) , 1.84- 1.68 (m, J= 3.3 Hz, 4H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ

156.34, 154.77, 146.34, 138.49, 138.35, 133.49, 126.13, 125.62, 123.32, 121.62, 108.20, 71.06, 29.61, 23.10, 22.79, 22.75, 18.20; HRMS (ESI-TOF) m/z Calcd for C ₁₇ H ₂₀ NO [M+H] ⁺ : 254.1539, found: 254.1537.

3j

3-Methy1-2- ( (naphthalen-l-yloxy) methyl) pyridine (3j)

Orange liguid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.48 (d, J = 4.9 Hz, 1H) , 8.25 (d, J = 8.2 Hz, 1H) , 7.78 (d, J = 8.1 Hz, 1H) , 7.54 (d, J = 7.6 Hz, 1H) , 7.50-7.42 (m, 3H) , 7.38 (t, J = 7.9 Hz, 1H) , 7.27-7.20 (m, 1H) , 7.05 (d, J = 7.5 Hz, 1H) , 5.42 (s, 2H) , 2.48 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 154.40, 154.31, 146.40, 138.54, 134.49, 133.69, 127.43, 126.31, 125.85, 125.64, 125.14, 123.52, 122.00, 120.46, 105.40, 71.32, 18.27; HRMS (ESI-TOF) m/z Calcd for C ₁₇ H ₁₆ NO [M+H] ⁺ : 250.1226, found: 250.1228.

3k P T/US2017/028116

2- ( ( (2 , 3-Dihydro-lH-inden-5~yl) oxy) methyl) -3- methylpyridine (3k)

Yellow liquid, ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, J = 4.8 Hz, 1H) , 7.51 (d, J = 7.5 Hz, 1H) , 7.18 (dd, J = 7.7, 4.8 Hz, 1H) , 7.11 (d, J = 8.2 Hz, 1H) , 6.92 (s, 1H) , 6.81 (dd, J = 8.0, 2.2 Hz, 1H) , 5.18 (s, 2H) , 2.92 - 2.79 (m, 4H) , 2.43 (s, 3H) , 2.06 (p, J = 7.4 Hz, 2H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 157.60, 154.53, 146.38, 145.64, 138.43, 136.52, 133.33, 124.66, 123.34, 112.78, 110.91, 71.05, 33.13, 31.95, 25.77, 18.16; HRMS (ESI-TOF) m/z Calcd for C ₁₆ H ₁₈ NO [M+H] ⁺ : 240.1383, found: 240.1386.

31

2- ( (4-Methoxyphenoxy) methyl) -3-methylpyridine (31)

Light yellow liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, J = 4.8 Hz, 1H) , 7.50 (d, J = 7.6 Hz, 1H) , 7.18 (dd, J = 7.7, 4.8 Hz, 1H) , 6.96 (d, J = 9.0 Hz , 2H) , 6.82 (d, J = 9.0 Hz, 2H) , 5.16 (s, 2H) , 3.76 (s, 3H) , 2.43 (s, 3H) ; ¹³ C NMR (100 MHz, CDCI ₃ ) δ 154.53, 154.00, 152.87, 146.56, 138.37, 133.21, 123.36, 115.85, 114.58, 71.55, 55.68, 18.17; HRMS (ESI-TOF) m/z Calcd for Ci ₄ Hi ₆ 0 ₂ [M+H] ⁺ : 230.1176, found: 230.1179.

Preparation of Other Heterocyclic Substrates

S7

2 ,4-Dimethyl-3- (2-pyridylmethyl) -3-pentanol (S7)

n-BuLi (1.6 M in hexane, 13 mL, 20 mmol) was slowly added to a solution of 2-picoline ( 2.0 mL, 20 mmol) in

tetrahydrofuran (20 mL) at -30 °C and the reaction mixture was stirred for 30 minutes. Diisopropyl ketone (3.4 mL, 24 mmol) was then added, the reaction mixture was stirred for 2 hours at ambient temperature. Water (30 mL) was added, and the product was extracted with ethyl acetate (3 x 20 mL) . The combined organic layer was dried over sodium sulfate, and concentrated in vacuo. Silica gel column purification (Hexane : EtOAc = 3 : 1) gave the pyridyl alcohol S7 (3.5 g, 17 mmol) in 85% yield.

Methyl 2- (pyridin-2-ylmethyl) benzoate (4b) [Niwa et al . , Angew. Chem. Int. Ed. 46:2643-2645 (2007) .]

Cesium carbonate (0.714 g, 2.0 mmol) was placed in a 50-mL two-necked reaction flask. Cesium carbonate was dried in vacuo with heating with a heat gun for 2 minutes. The flask was then filled with argon using standard Schlenk technique. Palladium trifluoroacetate (34 mg, 0.10 mmol), tricyclohexylphosphine (53 mg, 0.20 mmol), xylene (10 mL) , pyridyl alcohol S7 (0.414 g, 2.0 mmol), and methyl 2- iodobenzoate (576 mg, 2.2 mmol) were sequentially added at room temperature. The resulting mixture was heated at reflux for 10 hours. After the mixture was cooled to room temperature, water (30 mL) was added. The product was extracted with ethyl acetate (30 mL ^χ 3) . The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. Silica gel column purification

(Hexane : EtOAc = 5 : 1) gave product Compound 4b (272 mg, 1.2 mmol) in 60% yield. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.53

(d, J = 4.6 Hz, 1H) , 7.93 (d, J = 7.8 Hz, 1H) , 7.54 (td, J = 7.7, 1.9 Hz, 1H) , 7.50-7.42 (m, 1H) , 7.36-7.28 (m, 2H) , 7.13-7.02 (m, 2H) , 4.56 (s, 2H) , 3.81 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 167.93, 160.81, 149.15, 140.44, 136.28, 132.12, 131.98, 130.72, 129.96, 126.54, 122.96, 120.99, 51.91, 42.52; HRMS (ESI-TOF) m/z Calcd for C ₁₄ H ₁₄ N0 ₂ [M+H] ⁺ : 228.1019, found: 228.1019.

4c

2-Benzyl-3-methylpyridine (4c)

Anhydrous cobalt (II) acetylacetonate (77 mg, 0.30 mmol) was placed in a 50 mL flask. Anhydrous dioxane (10 mL) was then added under argon. After the solution became red, benzylmagnesium chloride (2.0 M in THF, 4.5 mL, 9.0 mmol) was added at 0 °C. The mixture was stirred for about 5 minutes at 25 °C. Then, 2-bromo-3-methylpyridine (526 mg, 3.0 mmol) was added dropwise to the reaction mixture. After stiring for 2 hours at 25 °C, the reaction mixture was poured into water. The products were

extracted with ethyl acetate (3 ^χ 30 mL) and the combined organic layers were dried over sodium sulfate and

concentrated. Purification of the crude product by silica gel column chromatography (Hexane: EtOAc = 4 : 1) provided the corresponding product Compound 4c (384 mg, 2.1 mmol) in 70% yield. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.42 (d, J = 4.6 Hz, 1H) , 7.40 (d, J = 7.5 Hz, 1H) , 7.25 (t, J = 7.5 Hz, 2H) , 7.22-7.13 (m, 3H) , 7.07 (dd, J = 7.6, 4.9 Hz, 1H) , 4.19 (s, 2H) , 2.24 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 158.76, 146.74, 138.99, 137.96, 131.70, 128.61, 128.33, 126.04, 121.66, 42.21, 18.92; HRMS (ESI-TOF) m/z Calcd for Ci ₃ H ₁₄ N [M+H] ⁺ : 184.1121, found: 184.1121.

4d

2-Benzyl-5-methylpyridine (4d) [Ohmiya et al . , Chem. Lett., 33:1240-1241 (2004) .]

Anhydrous cobalt (II) acetylacetonate (77 mg, 0.30 mmol) was placed in a 50 mL flask. Anhydrous dioxane (10 mL) was then added under argon. After the solution became red, benzylmagnesium chloride (2 M in THF, 4.5 mL, 9.0 mmol) was added at 0 °C . The mixture was stirred for about 5 minutes at 25 °C . Then, 2-bromo-5-methylpyridine (526 mg, 3.0 mmol) was added dropwise to the reaction mixture. After being stirred for 2 hours at 25 °C, the reaction mixture was poured into water. The products were extracted with ethyl acetate (30 mix 3) . The combined organic layers were dried over sodium sulfate and

concentrated. Purification of the crude product by silica gel column chromatography (Hexane: EtOAc = 4 : 1) provided the corresponding product Compound 4d (455 mg, 2.4 mmol) in 83% yield. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.52 (s, 1H) , 7.57- 7.50 (m, 1H) , 7.49-7.38 (m, 4H) , 7.38-7.32 (m, 1H) , 7.15 (d, J = 7.9 Hz, 1H) , 4.27 (s, 2H) , 2.43 (s, 3H) ; ¹³ C NMR (100 MHz, cdcl ₃ ) δ 157.96, 149.60, 139.77, 137.09, 130.43, 128.98, 128.49, 126.22, 122.53, 44.18, 17.98; HRMS (ESI- TOF) m/z Calcd for Ci ₃ Hi ₄ N [M+H] ⁺ : 184.1121, found:

4e

2-benzylpyrimidine (4e)

According ^' to procedure for Compound 4c, Compound 4e was afforded in 83% yield using 2- (bromomethyl) yrimidine . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J = 4.9 Hz, 2H) , 7.36 (d, J = 7.6 Hz, 2H) , 7.30 (t, J = 7.5 Hz, 2H) , 7.22 (t, J = 7.3 Hz, 1H) , 7.12 (t, J = 4.9 Hz, 1H) , 4.30 (s, 2H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 170.03, 157.29, 138.19, 129.12, 128.52, 126.57, 118.63, 46.05; HRMS (ESI-TOF) m/z Calcd

[M+H] ⁺ : 171.0917, found: 171.0916.

2-Benzylpyrazine (4f)

According to procedure for Compound 4c, Compound 4f was afforded in 70% yield using 2- (bromomethyl ) pyrazine . ½ NMR (400 MHz, CDC1 ₃ ) δ 8.50 (t, J = 2.0 Hz, 1H) , 8.47 (s, 1H) , 8.40 (d, J = 2.5 Hz, 1H) , 7.36 - 7.20 (m, 5H) , 4.17 (s, 2H) ; ¹³ C NMR (100 MHz, cdcl ₃ ) δ 156.44, 144.73, 144.04, 142.34, 138.08, 128.96, 128.72, 126.72, 41.94; HRMS (ESI-

TOF) m/z Calcd for C _u Hn ₂ [M+H] ⁺ : 171.0917, found:

171.0917.

1-Benzyl-lH-pyrazole (4g) [Kumpulainen et al . , Adv. Synth. Catal. 356:1555-1561 (2014) .]

A round bottomed flask was charged with pyrazole (504 mg, 12.6 mmol) , benzyl bromide (1.0 mL, 8.4 mmol) , potassium carbonate (1.738 g, 12.6 mmol), potassium iodide (70 mg, 0.043 mmol) and dimethylformamide (10 mL) . The mixture was heated to 80 °C for 13 hours. The reaction mixture was allowed to cool to room temperature and poured into a beaker containing water (20 mL) and ethyl acetate (50 mL) . Next, the phases were separated and aqueous phase was extracted with ethyl acetate (50 mL) . Combined organic extracts were dried with anhydrous sodium sulfate and solvents were evaporated. Purification by silica gel column chromatography (Hexane : EtOAc = 20 : 1) provided the corresponding product (796 mg, 5.0 mmol) in 60% yield. ¾ NMR (600 MHz, CDC1 ₃ ) δ 7.58 (d, J = 1.9 Hz, 1H) , 7.40 (d, J = 2.3 Hz, 1H) , 7.39-7.34 (m, 2H) , 7.34-7.30 (m, 1H) , 7.26-7.22 (m, 2H) , 6.31 (t, J = 2.1 Hz, 1H) , 5.35 (s, 2H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 139.43, 136.59, 129.12, 128.69, 127.89, 127.52, 105.86, 55.82; HRMS (ESI-TOF) m/z Calcd for Ci ₀ H N ₂ [M+H] ⁺ : 159.0917, found: 159.0917.

4h

N-phenyl-N- (pyridin-2-yl) acetamide (4h) [Wang et al . , Tetrahedron Lett 55:7121-7123 (2014) .]

A 10 mL flask equipped with a magnetic stir bar and a Teflon valve was charged withCul (19 mg, 1 mol%) , pyridin- 2-amine (1.41 g, 15 mmol), and KOtBu (2.12 g, 20 mmol) . The tube was evacuated and backfilled with argon. Under a counter flow of argon, 1,4-dioxane (25 iriL) andbromobenzene (1.57 g, 10 mmol) were added via syringe and the tube was sealed. The reaction mixture was allowed to stir at 110 °C for 24 hours. The mixture was cooled to room

temperature and 5.0 mL of brine was added. Subsequently, the mixture was extracted with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered and the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel (hexanes : EtOAc = 8 : 1) to give the secondary amine as a colorless solid (1.35 g, 8.2 mmol) in 82% yield.

NaH (60% in mineral oil, 50 mg, 1.2 mmol) was added into the solution of secondary amine (170 mg, 10 mmol) in THF. The reaction mixture was stirred at room temperature for 30 minutes. Then acetyl chloride (110 mg, 1.5 mmol) was added and the reaction was monitored by TLC. Upon completion, the mixture was extracted with ethyl acetate

(3x30 mL) . The combined organic phases were washed with brine and dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (Hexanes : EtOAc = 20 : 1) to give the title product Compound 4h (174 mg, 0.85 mmol) in 85% yield. ¹ H NMR (600 MHz, CDC1 ₃ ) δ 8.43 (dd, J= 4.9, 1.9 Hz, 1H) , 7.71 (td, J= 7.8, 2.0 Hz, 1H) , 7.46 (d, J= 8.4 Hz, 1H) , 7.44-7.38 (m, 2H) , 7.33 (d, J= 7.5 Hz, 1H) , 7.32-7.27 (m, 2H) , 7.13 (dd, J = 7.0, 5.1 Hz, 1H) , 2.11 (s, 3H) ¹³ C NMR

(150 MHz, CDC1 ₃ ) δ 170.89, 155.18, 148.74, 141.96, 137.86, 129.38, 128.31, 127.54, 121.38, 121.13, 24.21; HRMS (ESI- TOF) m/z Calcd for C ₁₃ H ₁₃ N ₂ 0 [M+H] ⁺ : 213.1022, found:

213.1021.

4i tert-Butyl phenyl (pyrimidin-2-yl) carbamate (4i) [Qian et al., Eur. J. Org. Chem. 4837-4843 (2014) .]

To an oven-dried flask containing aniline (1.39 g, 15.0 mmol) was added a solution of 2-chloro-pyrimidine (1.14 g,

10.0 mmol) and acetic acid (0.6 g, 10 mmol) in 1,4-dioxane

(30.0 mL) . The reaction mixture was stirred at 110 °C overnight. Upon completion, the mixture was extracted with CH ₂ C1 ₂ (3x30 mL) . The combined organic phases were washed with brine, dried over sodium sulfate and

concentrated. The crude product was purified by column chromatography on silica gel (hexanes : EtOAc = 5 : 1) to give the secondary amine as a colorless solid (1.28 g, 7.5 mmol) in 75% yield.

The secondary amine (513 mg, 3.0 mmol) was dissolved in anhydrous DMF (30 mL) , and the solution was cooled to 0 °C in an ice/water bath. Sodium hydride (132 mg, 60% suspension in oil, 3.3 mmol) was added in portions. The suspension was stirred vigorously for an additional 20 minutes while maintaining the temperature below 5 °C and then (Boc) ₂ 0 (719 mg, 3.3 mmol) was added dropwise. After stirring for 30 minutes, the reaction mixture was brought to room temperature over a 1 hour period before water (5.0 mL) was added. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (3 ^χ 30 mL) . The organic layer was separated and extracted with water, 0.1 M HC1, sat. aqueous NaHC0 ₃ solution, and brine, then dried and concentrated. The resulting residue was then purified by silica gel chromatography (Hexanes : EtOAc = 10 : 1) to afford Compound 4i (650 mg, 80%) as a clear, colorless oil.

^X H NMR (400 MHz, CDC1 ₃ ) δ 8.66 (d, J = 4.8 Hz, 2H) , 7.44- 7.35 (m, 2H) , 7.32-7.26 (m, 1H) , 7.25-7.20 (m, 2H) , 7.04 (t, J = 4.8 Hz, 1H) , 1.45 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 161.35, 158.21, 153.16, 141.25, 128.95, 127.69, 126.84, 117.14, 82.04, 28.05; HRMS (ESI-TOF) m/z Calcd for

C ₁₅ Hi ₈ N ₃ 0 ₂ [M+H] ⁺ : 272.1394, found: 272.1394.

1-Benzyl-lH-indazole and 2-Benzyl-2H-indazole

[Shumeiko et al . , Russ. J. Org. Chem. 42:294-295 (2006) .] A round-bottom flask was charged with indazole (1.18 g, 10.0 mmol) , benzyl bromide (1.44 mL, 10.0 mmol), potassium hydroxide (0.56 g, 10.0 mmol), tetrabutylammonium chloride

(189 mg, 0.5 mmol) and toluene (50 mL) . The mixture was heated to 110 °C overnight (about 18 hours) . The reaction mixture was allowed to cool to room temperature and poured into a beaker containing water (20 mL) and ethyl acetate

(50 mL) . Phases were separated and the aqueous phase was extracted with ethyl acetate (50 mL) . Combined organic extracts were dried over anhydrous sodium sulfate and solvents were evaporated. The resulting residue was then purified by silica gel column chromatography (Hexanes: EtOAc = 20:1 - 10:1) to provide the corresponding

1-benzyl-lH-indazole 4k (1.1 g, 5.5 mmol) in 55% yield and

2-benzyl-2ff-indazole 4k' (561 mg, 2.7 mmol) in 27% yield.

2-Benzyl-2H-indazole (4j)

½ NMR (400 MHz, CDC1 ₃ ) δ 7.89-7.85 (m, 1H) , 7.73 (d, J = 8.8 Hz, 1H) , 7.61 (d, J = 8.4 Hz, 1H) , 7.38-7.30 (m, 3H) , 7.30-7.23 (m, 3H) , 7.06 (dd, J = 8.3, 6.7 Hz, 1H) , 5.58 (s, 2H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 148.90, 135.73, 128.87, 128.32, 127.92, 125.91, 122.78, 122.06, 121.71, 120.09, 117.50, 57.47; HRMS (ESI-TOF) m/z Calcd for C ₁₄ H ₁₃ N ₂ [M+H] ⁺ : 209.1073, found: 209.1074.

4k

1-Benzyl-lH-indazole (4k)

½ NMR (600 MHz, CDC1 ₃ ) δ 8.04 (d, J = 0.9 Hz, 1H) , 7.74 (dt, J = 8.1, 1.0 Hz, 1H) , 7.36-7.31 (m, 2H) , 7.30-7.26 (m, 2H) , 7.26-7.23 (m, 1H) , 7.21-7.19 (m, 1H) , 7.19-7.17 (m, 1H) , 7.15-7.12 (m, 1H) , 5.60 (s, 2H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 139.52, 136.86, 133.36, 128.69, 127.70, 127.14, 126.35, 124.34, 121.12, 120.61, 109.26, 52.95; HRMS (ESI- TOF) m/z Calcd for Ci ₄ H ₁₃ N ₂ [M+H] ⁺ : 209.1073, found:

209.1074. -Benzylisoquinoline (41)

41

Anhydrous cobalt (II) acetylacetonate (77 mg, 0.30 mmol) was placed in a 50 mL flask. Anhydrous 1,4-dioxane (10 itiL) was then added under argon. After the solution became red, benzylmagnesium chloride (2 M in THF solution, 4.5 mL, 9.0 mmol) was added at 0 °C. The mixture was stirred for about 5 minutes at 25 °C. Next, 2-chloroquinoline (491 mg, 3.0 mmol) was added dropwise to the reaction mixture. After being stirred for 2 hours at 25 °C, the reaction mixture was poured into water. The products were extracted with ethyl acetate (3 χ 30 mL) . The combined organic layers were dried over sodium sulfate and

concentrated. Purification of the crude product by silica gel column chromatography (Hexanes: EtOAc = 4 : 1) provided the corresponding product Compound 41 (328 mg, 1.5 mmol) in 50% yield. ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.09 (d, J = 8.5 Hz, 1H) , 7.99 (d, J = 8.5 Hz, 1H) , 7.73 (d, J = 8.2 Hz, 1H) , 7.68 (t, J = 7.6 Hz, 1H) , 7.47 (t, J = 7.5 Hz, 1H) , 7.33-7.25 (m, 4H) , 7.25-7.16 (m, 2H) , 4.34 (s, 2H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 161.14, 147.74, 139.15, 136.42, 129.41, 129.15, 128.92, 128.56, 127.44, 126.70, 126.42, 125.91, 121.46, 45.50; HRMS (ESI-TOF) m/z Calcd for C ₁₆ Hi ₄ N [M+H] ⁺ : 220.1121, found: 220.1121.

Synthesis of Substrates Bearing Different Protecting Groups

S3a-3i were synthesized following a similar procedure to make substrate 1. The protected amines were prepared as previously described. [Pialat et al . , Org. Lett. 15:1764-1767 (2013); Brasche et al . , Org. Lett.

10:2207-2210 (2008); Wipf et al . , Org. Lett. 10:4383-4386 (2008); Imanishi et al., Adv. Synth. Catal. 354:771-776 (2012); Gawande et al . , Green Chem. 13:3355-3359 (2011); Johnson et al . , J. Org. Chem. 68:5300-5309 (2003); and Le Peraet al . , Tetrahedron 62:100-6106 (2006) .]

N- (Pyridin-2-ylmethyl) -N- (m-tolyl) acetamide (S3a)

Colorless liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.49 (d, J = 4.9 Hz, 1H) , 7.64 (td, J = 7.7, 1.8 Hz, 1H) , 7.38 (d, J = 7.8 Hz, 1H) , 7.20 (t, J = 7.7 Hz, 1H) , 7.14 (dd, J = 7.5, 5.0 Hz, 1H) , 7.09 (d, J = 7.6 Hz, 1H) , 6.97 (s, 1H) , 6.92 (d, J = 7.9 Hz, 1H) , 5.02 (s, 2H) , 2.31 (s, 3H) , 1.95 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 170.69, 157.40, 149.02, 143.16, 139.55, 136.44, 129.22, 128.59, 128.31, 124.85, 122.40, 122.03, 54.87, 22.57, 21.20; HRMS (ESI-TOF) m/z Calcd for C ₁₅ H ₁₇ N ₂ 0 [M+H] ⁺ : 241.1335, found: 241.1335.

N- (Pyridin-2-ylmethyl) -N- (m-tolyl) pivalamide (S3b)

Colorless liquid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.46 (d, J - 4.8 Hz, 1H) , 7.65 (td, J = 7.7, 1.8 Hz, 1H) , 7.39 (d, J 7.8 Hz, 1H) , 7.21 - 7.05 (m, 3H) , 6.99 (s, 1H) , 6.95 (d, = 7.8 Hz, 1H) , 4.95 (s, 2H) , 2.30 (s, 3H) , 1.07 (s, 9H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 177.81, 157.95, 148.84, 143.71 138.86, 136.35, 130.05, 128.62, 128.59, 126.50, 122.23, 121.82, 58.48, 40.96, 29.46, 21.17; HRMS (ESI-TOF) m/z Calcd for C ₁₈ H ₂₃ N ₂ 0 [M+H] ⁺ : 283.1805, found: 283.1805.

fcerfc-Butyl (pyridin-2-ylmethyl) (m-tolyl) carbamate (S3c)

Colorless liquid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.53 (d, J = 4.6 Hz, 1H) , 7.66 (td, J = 7.7, 1.8 Hz, 1H) , 7.36 (d, J = 7.9 Hz, 1H) , 7.20-7.09 (m, 3H) , 7.06 (d, J = 8.0 Hz, 1H) , 6.96 (d, J = 7.4 Hz, 1H) , 4.96 (s, 2H) , 2.30 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (100 MHz, cdcl ₃ ) δ 158.73, 154.67, 149.09, 142.87, 138.39, 136.46, 128.35, 126.41, 126.36, 122.80, 121.79, 120.73, 80.59, 55.92, 28.17, 21.33; HRMS (ESI-TOF) m/z Calcd for Ci ₈ H ₂₃ N ₂ 0 ₂ [M+H] ⁺ : 299.1754, found: 299.1754.

Benzyl (pyridin-2-ylmethyl) (m-tolyl) carbamate (S3d)

Colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.52 (d, J = 4.7 Hz, 1H) , 7.60 (t, J = 7.6 Hz, 1H) , 7.33-7.25 (m, 4H) , 7.25-7.11 (m, 4H) , 7.09 (s, 1H) , 7.05 (d, J = 7.6 Hz, 1H) , 6.99 (d, J = 7.6 Hz, 1H) , 5.18 (s, 2H) , 5.00 (s, 2H) , 2.29 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 157.83, 155.60, 149.20, 142.14, 138.65, 136.52, 136.40, 128.57, 128.29, 127.80, 127.63, 127.18, 126.94, 123.26, 122.00, 121.25, 67.37, 56.10, 21.29; HRMS (ESI-TOF) m/z Calcd for C ₂ iH ₂ iN ₂ 0 ₂ [M+H] ⁺ : 333.1598, found: 333.1598.

2,2, 2-Trichloroethyl (pyridin-2-ylraethyl) (m-tolyl) - carbamate (S3e)

Colorless solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.54 (d, J = 4 Hz, 1H) , 7.66 (t, J = 7.7 Hz, 1H) , 7.38 (d, J = 7.8 Hz, 1H) , 7.25-7.06 (m, 4H) , 7.03 (d, J = 7.5 Hz, 1H) , 5.05 ( 2H) , 4.79 (s, 2H) , 2.31 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) 157.16, 154.02, 149.35, 142.16, 141.00, 138.78, 136.61, 128.65, 127.70, 126.36, 123.82, 122.24, 121.66, 95.39, 77.25, 77.04, 76.83, 75.20, 56.43, 21.30; HRMS (ESI-TOF) m/z Calcd for Ci ₆ H ₁₆ Cl ₃ N ₂ 0 ₂ [M+H] ⁺ : 373.0272, found:

373.0271.

(9H-Fluoren-9-yl) methyl (pyridin-2-ylmethyl) (m-tolyl) - carbamate (S3f)

Light yellow solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.52 (d, J = 4.8 Hz, 1H) , 7.69 (d, J = 7.6 Hz, 2H) , 7.62 (t, J = 7.6 Hz, 1H) , 7.34 (t, J = 7.5 Hz, 2H) , 7.30-7.21 (m, 3H) , 7.21-7.12 (m, 4H) , 7.11-7.02 (d, J = 6.3 Hz, 2H) , 6.99 (d, J = 6.9 Hz, 1H) , 4.97 (s, 2H) , 4.45 (d, J = 7.0 Hz, 2H) , 4.10 (t, J = 7.0 Hz, 1H) , 2.32 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 157.65, 155.75, 149.23, 143.71, 141.89, 141.19, 138.84, 136.57, 128.73, 127.51, 126.86, 125.09, 124.26, 122.07, 121.54, 119.78, 67.60, 56.08, 47.11, 21.32; HRMS (ESI-TOF) m/z Calcd for C ₂ 8H ₂₅ N ₂ 02 [M+H] ⁺ : 421.1911, found: 421.1911.

N- (Pyridin-2-ylmethy1) -N- (m-tolyl) methanesulfonamide (S3g)

Light yellow solid, ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.49 (d, J= 4.7 Hz, 1H) , 7.64 (td, J= 7.7, 1.8 Hz, 1H) , 7.45 (d, J= 7.9 Hz, 1H) , 7.24-7.11 (m, 4H) , 7.06 (d, J= 7.3 Hz, 1H) , 5.01 (s, 2H) , 3.04 (s, 3H) , 2.30 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 156.70, 149.06, 139.37, 136.70, 129.07, 128.82, 128.75, 124.96, 122.46, 122.35, 56.53, 38.13, 21.28; HRMS (ESI-TOF) m/z Calcd for C14H17 2O2S [M+H] ⁺ : 277.1005, found: 277.1005.

1 ,1 , 1-Trifluoro-W- (pyridin-2-ylmethy1) -N- (m-tolyl) - methanesulfonamide (S3h)

Yellow solid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.48 (d, J= 4.8 Hz, 1H) , 7.68 (td, J= 7.7, 1.8 Hz, 1H) , 7.45 (d, J= 7.8 Hz, 1H) , 7.24-7.15 (m, 2H) , 7.14-7.04 (m, 3H) , 5.07 (s, 2H) , 2.30 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 154.65 , 149.38 , 139.53 , 136.84 , 129.97 , 129.42 , 129.10 , 125.91 , 122.99 , 122.61 , 120.46 (q, J= 324.2 Hz), 58.52 , 21.22; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -73.54; HRMS (ESI-TOF) m/z Calcd for C^H^FsNzOzS [M+H] ⁺ : 331.0723, found: 331.0723.

4-Nitro-N- (pyridin-2-ylmethyl) -N-

(m-tolyl) benzenesulfonamide (S3i) Light yellow solid, ¾ NMR (400 MHz , CDC1 ₃ ) δ 8.41 (d, J = 4.7 Hz, 1H) , 8.30 (d, J = 8.7 Hz, 2H) , 7.81 (d, J = 8.7 Hz, 2H) , 7.66 (td, J = 7.7, 1.7 Hz, 1H) , 7.52 (d, J = 7.9 Hz, 1H) , 7.17-7.09 (m, 2H) , 7.06 (d, J = 7.6 Hz, 1H) , 6.96 (s, 1H) , 6.83 (d, J = 7.7 Hz, 1H) , 4.93 (s, 2H) , 2.26 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 155.77, 150.05, 149.06, 144.00, 139.35, 138.44, 136.76, 129.34, 129.22, 128.96, 125.09, 123.93, 122.62, 122.44, 56.87, 21.22; HRMS (ESI- TOF) /z Calcd for C ₁₉ Hi ₈ N ₃ 0 ₄ S [M+H] ⁺ : 384.1013, found:

384.1013.

Synthesis of Substrates Bearing Different Directing Gr ups

S5a-5e were synthesized following a similar

procedure to prepare substrate 1.

terfc-Butyl (quinolin-2-ylmethyl) (m-tolyl) carbamate (S5a)

Light yellow solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.15 (d, J = 8.5 Hz, 1H) , 8.02 (d, J = 8.5 Hz, 1H) , 7.80 (d, J = 8.1 Hz, 1H) , 7.72-7.66 (m, 1H) , 7.55-7.47 (m, 2H) , 7.21-7.12 (m, 2H) , 7.09 (d, J = 8.1 Hz, 1H) , 6.95 (d, J = 7.3 Hz, 1H) , 5.13 (s, 2H) , 2.29 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 159.14, 154.91, 147.63, 142.84, 138.47, 136.63, 129.51, 128.97, 128.42, 127.53, 127.16, 126.62, 126.57, 126.09, 123.04, 118.88, 80.73, 56.48, 28.22, 21.37; HRMS (ESI-TOF) m/z Calcd for C22H25N2O2 [M+H] ⁺ :

349.1911, found: 349.1911.

terfc-Butyl (quinolin-2-ylmethyl) (m-tolyl) carbamate (S5b)

Light yellow solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 7.55 (t, J = 7.7 Hz, 1H) , 7.19-7.10 (m, 3H) , 7.07 (d, J = 8.1 Hz, 1H) , 7.00 (d, J = 7.6 Hz, 1H) , 6.95 (d, J = 7.4 Hz, 1H) , 4.92 (s, 2H) , 2.51 (s, 3H) , 2.30 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 158.07, 157.70, 154.71, 142.95, 138.32, 136.68, 128.31, 126.36, 126.32, 122.76, 121.23, 117.34, 80.53, 55.96, 28.18, 24.34, 21.34; HRMS (ESI-TOF) m/z Calcd for C ₁₉ H _{25 2} O ₂ [M+H] ⁺ : 313.1911, found: 313.1911.

tert-Butyl ( (3-methylpyridin-2-yl) methyl) (m-tolyl) - carbamate (S5c)

Light yellow solid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.37 (d, J = 4.6 Hz, 1H) , 7.38 (d, J = 7.6 Hz, 1H) , 7.16 - 7.00 (m, 4H) , 6.92 (d, J = 7.4 Hz, 1H) , 4.93 (s, 2H) , 2.30 (s, 3H) , 2.27 (s, 3H) , 1.37 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 155.32, 154.74, 146.51, 142.81, 138.05, 137.46, 130.61, 128.06, 126.85, 126.26, 123.39, 121.90, 80.10, 53.44, 28.16, 21.29, 18.00; HRMS (ESI-TOF) m/z Calcd for C ₁₉ H ₂₅ N ₂ 0 ₂ [M+H] ⁺ : 313.1911, found: 313.1911.

tert-Butyl ( (3-methoxy-4- (2,2 , 2-trifluoroethoxy) pyridin-: yl)methyl) (m-tolyl) carbamate (S5d)

Colorless solid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.31 (d, J = 5 Hz, 1H), 7.16-6.98 (m, 3H) , 6.92 (d, J = 7.4 Hz, 1H) , 6. J (d, J = 5.6 Hz , 1H) , 4.93 (s, 2H) , 4.37 (q, J = 7.9 Hz,

2H) , 2.27 (s, 3H) , 2.20 (s, 3H) , Ί.38 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 161.13 , 157.09 , 154.73 , 147.71 , 142.75 , 138.09 , 128.08 , 126.81 , 126.30 , 123.38 , 122.98 (q, J = 278.34 Hz), 119.92 , 105.10 , 80.21 , 65.31 (q, J = 36.2 Hz), 53.37 , 28.18 , 21.30 , 9.64; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -74.21; HRMS (ESI-TOF) /z Calcd for CaiHzeFa zC^ [M+H] ⁺ : 411.1890, found: 411.1890.

terfc-Butyl ( (3 , -dimethoxypyridin-2-yl) methyl) (m-tolyl) - carbamate (S5e)

Colorless solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.21 (d, J = 5.5 Hz, 1H) , 7.19-7.03 (m, 3H) , 6.91 (d, J = 7.0 Ηζ, ΙΗ), 6.74 (d, J = 5.5 Hz, 1H) , 4.97 (s, 2H) , 3.88 (s, 3H) , 3.78 (s, 3H) , 2.28 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 157.99, 154.90, 151.47, 145.59, 143.22, 142.90, 138.01, 128.04, 126.85, 126.11, 123.41, 106.49, 79.97, 60.41, 55.54, 50.72, 28.24, 21.33; HRMS (ESI-TOF) m/z Calcd for C ₂ oH27N ₂ 0 ₄ [M+H] ⁺ : 359.1965, found: 359.1964.

Synthesis of MPAHP Ligands

Ligands L12-19 were synthesized from commercially

available amines S9. In cases where the amines were not commercially available, the free amines S9 were

synthesized by the reduction of the nitro group.

Reduction: In a 100 mL round bottom flask, S8 (10.0 mmol) ,

10% Pd/C (1.0 mmol) were added and the flask was sealed with a rubber stopper. Next, 50 mL methanol was added under nitrogen. The nitrogen was removed and the flask was back filled with hydrogen three times. Then a hydrogen balloon was left on the flask and the reaction mixture was stirred for 16 hours at room temperature.

After the 16 hours, the reaction mixture was filtered through a pad of Celite® and the solvent was evaporated to obtain the pure amino product in quantitative yields.

Acetyl protection: In a 50 mL round bottom flask, S9 (8.0 mmol), acetic anhydride (9.6 mmol) and 20 mL toluene were added and the reaction mixture was refluxed for 16 hours. The solvent was removed and the residue was washed with diethyl ether (5.0 mL) twice to remove impurities. The left over residue was recrystallized with methanol to obtain the product.

L12

N- (2-Hydroxypyridin-3-yl) acetamide (L12)

Black solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.89 (s, 1H) , 9.18 (s, 1H) , 8.20 (dd, J = 7.4, 1.8 Hz, 1H) , 7.06 (dd, J = 6.6, 1.9 Hz, 1H) , 6.18 (t, J = 6.9 Hz, 1H) , 2.11 (s, 3H) ; ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 169.30, 157.25, 129.45, 127.53, 123.25, 105.20, 24.00; HRMS (ESI-TOF) m/z Calcd for C ₇ H ₉ N ₂ 0 ₂ [M+H] ⁺ : 153.0659, found: 153.0659.

L13

fcerfc-Butyl (2-hydroxypyridin-3-yl) carbamate (L13)

Beige solid, ½ NMR (400 ^' MHz, DMSO-d ₆ ) δ 11.91 (s, 1H) , 7.79 (dd, J = 7.1, 2.0 Hz, 1H) , 7.68 (s, 1H) , 7.03 (dd, = 6.6, 1.8 Hz, 1H) , 6.21 (t, J = 6.9 Hz, 1H) , 1.45 (s, 9H) ; ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 157.01, 152.11, 129.01 126.59, 120.66, 105.35, 80.01, 27.88; HRMS (ESI-TOF) m/ Calcd for Ci ₀ H _{15 2} O3 [M+H] ⁺ : 211.1077, found: 211.1077. NHAc

ΌΗ

L14

N- (2-Hydroxy-5- (trifluoromethyl) pyridin-3-yl) acetamide (L14)

Beige solid, ^X H NMR (400 MHz , DMSO-d ₆ ) δ 12.51 (s, 1H) , 9.55 (s, 1H) , 8.41 (d, J= 2.6 Hz, 1H) , 7.69-7.61 (m, 1H) , 2.15 (s, 3H) ; ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 170.23, 157.16, 130.11, 127.64 (q, J= 4.7 Hz), 123.86 (q, J= 269.5 Hz), 116.81, 107.23 (q, J = 34.1 Hz), 24.00; ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -60.60; HRMS (ESI-TOF) m/z Calcd for C ₈ H ₈ F ₃ N ₂ 0 ₂ [M+H] ⁺ : 221.0532, found: 221.0532.

L15

N- (2-Hydroxy- 6- (trifluoromethyl) pyridin-3-yl) acetamide (L15)

Beige solid, ½ NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (s, 1H) , 8. (d, J= 7.9 Hz, 1H) , 7.13 (d, J= 7.9 Hz, 1H) , 2.15 (s, 3H) ; ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 169.98, 155.31, 132.92, 127.74, 124.99, 121.16 (q, J= 272.7 Hz), 110.60, 23.99; ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -65.22; HRMS (ESI-TOF) m/z Calcd for C ₈ HgF _{3 2} 0 ₂ [M+H] ⁺ : 221.0532, found: 221.0532.

L16

N- (2-Hydroxy-5-methylpyridin-3-yl) acetamide (L16)

Colorless solid, ^X H NMR (400 MHz, DMS0-d ₆ ) δ 11.68 (s, 1H) , 9.15 (s, 1H) , 8.11 (d, J= 2.4 Hz, 1H) , 6.85 (dd, J= 2.3, 1.2 Hz, 1H) , 2.10 (s, 3H) , 2.01 (d, J= 1.1 Hz, 3H) ; ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 169.27, 156.32, 128.89, 125.50, 124.50, 113.60, 24.03, 17.10; HRMS (ESI-TOF) m/z Calcd for CgHn zOz [M+H] ⁺ : 167.0815, found: 167.0815.

L17

N- (2-Hydroxy-4-methylpyridin-3-yl) acetamide (L17)

Colorless solid, ¾ NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H) , 9.08 (s, 1H) , 7.16 (d, J= 6.7 Hz, 1H) , 6.06 (d, J= 6.7 Hz, 1H) , 1.99 (s, 3H) , 1.97 (s, 3H) ; ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 167.97, 159.90, 145.60, 130.99, 125.64, 107.86, 22.75, 18.49; HRMS (ESI-TOF) m/z Calcd for C ₈ H _u N ₂ 0 ₂ [M+H] ⁺ : 167.0815, found: 167.0815.

L18

N- (4-Hydroxy-2 , 6-dimethylpyridin-3-y1) acetamide (L18)

Colorless solid, ^X H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H) , 8.84 (s, 1H) , 5.91 (s, 1H) , 2.17 (s, 3H) , 2.04 (s, 3H) , 1.96 (s, 3H) ; ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 174.23, 168.04, 145.41, 142.63, 122.97, 113.63, 22.77, 18.35, 16.19; HRMS (ESI-TOF) m/z Calcd for C ₉ Hi ₃ N ₂ 0 ₂ [M+H] ⁺ : 181.0972, found: 181.0972.

L19

N- (2-Hydroxyquinolin-3-yl) acetamide (L19)

Beige solid, ¾ NMR (400 MHz, DMSO-d ₆ ) δ 12.22 (s, 1H) , 9.43 (s, 1H) , 8.63 (s, 1H) , 7.62 (d, J= 7.8 Hz, 1H) , 7.43-7.35 (m, 1H) , 7.28 (d, J= 8.1 Hz, 1H) , 7.17 (t, J = 7.5 Hz, 1H) , 2.18 (s, 3H) ; ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 169.70, 157.43, 134.32, 128.76, 128.10, 127.25, 122.41, 120.49, 119.72, 114.87, 24.11; HRMS (ESI-TOF) m/z Calcd for C _n HiiN ₂ 02 [M+H] ⁺ : 203.0815, found: 203.0815.

L24

To a solution of amine (2.0 mmol) and 1-adamantanecarbonyl chloride (437.1 mg, 2.2 mmol) in DCM (10.0 mL) was added griethylamine (0.56 mL, 4.0 mmol) at 0 °C.

The mixture was allowed to warm to room temperature and stirred at room temperature. After the reaction was completed, the solvent was removed under vacuum and the resulting residue was then purified by silica gel

chromatography to afford L24 as a colorless solid.

(3r, 5r, 7r) -N- (2-Hydroxy-5- (trifluoromethyl) pyridin-3- yl) adamantane-l-carboxamide (L24)

Colorless solid, ¾ NMR (400 MHz , CDC1 ₃ ) δ 12.80 (brs, 1H) , 8.76 (d, J = 2.4 Hz, 1H) , 8.56 (s, 1H) , 7.50 (s, 1H) , 2.13 (s, 3H) , 2.07-1.90 (m, 6H) , 1.84-1.69 (m, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 177.36, 159.30, 129.79, 125.78, 125.32, 125.28, 125.24, 125.20, 123.99, 122.20, 120.41, 119.15, 112.65, 112.41, 112.18, 111.95, 42.05, 39.10, 38.74, 36.43, 36.32, 28.00, 27.86; HRMS (ESI-TOF) m/z Calcd for C ₁₇ H ₂ oF _{3 2} 0 ₂ [M+H] ⁺ : 341.1471, found: 341.1474.

L25

2 , 2 , 2-Trifluoro-N- (2-hydroxy-5- (trifluoromethyl) pyridin-3- yl) acetamide (L25)

Colorless solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.66 (brs, 2H) , 8.12 (d, J = 2.6 Hz, 1H) , 7.98-7.88 (m, 1H) ; ¹³ C NMR

(150 MHz, DMSO-d ₆ ) δ 157.45 , 155.22 (q, J = 37.5 Hz), 132.36 (q, J = 5.3 Hz), 126.82 , 124.67 (q, J = 3.0 Hz), 123.52 (q, J = 269.6 Hz), 115.37 (q, J = 286.2 Hz), 106.75

(q, J = 34.5 Hz); HRMS (ESI-TOF) m/z Calcd for C ₈ H ₅ F ₆ N ₂ 0 ₂

[M+H] ⁺ : 275.0250, found: 275.0250. Condition Screening

Ligand screened

Me hyl 3 ' -methyl-5 ' - (N- (pyridin-2-ylmethy1) acetamido) - [1,1' -biphenyl] -2-carboxylate (S4a)

Colorless liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.50 (d, J = 4.8 Hz, 1H) , 7.82 (d, J = 7.7 Hz, 1H) , 7.67 (t, J = 7.5 Hz, 1H) , 7.51 (t, J = 7.5 Hz, 1H) , 7.41 (t, J = 6.9 Hz, 2H) , 7.26 (d, J = 6.9 Hz, 1H) , 7.20-7.13 (m, 1H) , 7.07 (s, 1H) , 6.98 (s, 1H) , 6.90 (s, 1H) , 5.05 (s, 2H) , 3.60 (s, 3H) , 2.36 (s, 3H) , 2.02 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 170.85, 168.42, 157.30, 148.81, 142.85, 142.64, 141.45, 139.37, 136.77, 131.33, 130.56, 130.50, 129.91, 128.59, 127.47, 127.03, 125.32, 122.39, 122.14, 54.85, 51.94, 22.64, 21.29; HRMS (ESI-TOF) m/z Calcd for CzaHzsNzOs [M+H] ⁺ : 375.1703, found: 375.1703.

Methyl 3 ' -methyl-5 ' - (N- (pyridin-2-ylmethyl) pivalamido) - [1,1' -biphenyl] -2-carboxylate (S4b)

Colorless liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.48 (d, J = 4.4 Hz, 1H) , 7.81 (d, J = 7.7 Hz, 1H) , 7.66 (td, J = 7.8, 1.8 Hz, 1H) , 7.49 (t, J = 7.2 Hz, 1H) , 7.43-7.37 (m, 2H) , 7.21-7.11 (m, 2H) , 7.04-6.98 (m, 2H) , 6.92 (s, 1H) , 4.98 (s, 2H) , 3.56 (s, 3H) , 2.34 (s, 3H) , 1.12 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 177.91, 168.61, 157.94, 148.84, 143.60, 142.35, 141.50, 138.56, 136.59, 131.27, 130.63, 130.53, 129.88, 128.84, 128.73, 127.43, 126.57, 122.25, 121.94, 58.58, 51.89, 41.09, 29.60, 21.26; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₂₉ N ₂ 0 ₃ [M+H] ⁺ : 417.2173, found: 417.2172.

Methyl 3 ' - ( ( te t-butoxycarbonyl) (pyridin-2-ylmethyl) - amino) -5 ' -methyl- [1,1' -biphenyl] -2-carboxylate (S4c)

Colorless liquid, ^λ NMR (400 MHz, CDC1 ₃ ) δ 8.54 (d, J = 4.8 Hz, 1H) , 7.76 (d, J = 7.7 Hz, 1H) , 7.69 (t, J = 7.7 Hz, 1H) , 7.49 (t, J = 7.5 Hz, 1H) , 7.41-7.35 (m, 2H) , 7.32 (d, J = 7.6 Hz, 1H) , 7.22-7.15 (m, 1H) , 7.11 (s, 1H) , 7.06 (s, 1H) , 6.93 (s, 1H) , 4.99 (s, 2H) , 3.57 (s, 3H) , 2.34 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.09, 158.62, 154.60, 148.87, 142.66, 141.80, 141.58, 138.13, 136.77, 131.10, 130.92, 130.55, 129.61, 127.14, 126.53, 125.36, 123.13, 121.90, 120.81, 80.68, 55.92, 51.89, 28.18, 21.38; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₂₉ N ₂ 0 ₄ [M+H] ⁺ : 433.2122, found: 433.2122.

Methyl 3 ' - ( ( (benzyloxy) carbonyl) (pyridin-2-ylmethyl) - amino) -5 ' -methyl- [1,1' -biphenyl] -2-carboxylate (S4d)

Colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.53 (d, J = 4.9 Hz, 1H) , 7.77 (d, J = 7.7 Hz, 1H) , 7.62 (t, J = 7.8 Hz, 1H) , 7.48 (t, J = 7.5 Hz, 1H) , 7.38 (t, J = 7.6 Hz, 1H) , 7.35-7.18 (m, 7H) , 7.18-7.12 (m, 1H) , 7.09 (s, 1H) , 7.05 (s, 1H) , 6.96 (s, 1H) , 5.18 (s, 2H) , 5.03 (s, 2H) , 3.50 (s, 3H) , 2.33 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.02, 157.82, 155.59, 149.25, 141.97, 141.81, 141.65, 138.36, 136.61, 136.35, 131.15, 131.13, 130.87, 130.56, 129.68, 128.32, 127.85, 127.68, 127.23, 127.19, 125.72, 123.60, 122.05, 121.22, 67.47, 56.19, 51.87, 21.36; HRMS

(ESI-TOF) m/z Calcd for C29H27 2O4 [M+H] ⁺ : 467.1965, found: 467.1965.

Directing group

Methyl 3 ' - ( ( tert-butoxycarbonyl) ( (3-methylpyridin-2-yl) - methyl) amino) -5 ' -methyl- [1,1' -bipheny1] -2-carboxylate (S6c)

Colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.39 (d, J = 4.4 Hz, 1H) , 7.74 (d, J= 7.7 Hz, 1H) , 7.47 (t, J= 7.1 Hz, 1H) , 7.42-7.33 (m, 2H) , 7.30 (d, J = 7.6 Hz, 1H) , 7.12 (s, 1H) , 7.10-7.03 (m, 2H) , 6.89 (s, 1H) , 4.93 (s, 2H) , 3.57 (s, 3H) , 2.31 (s, 3H) , 2.30 (s, 3H) , 1.36 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.26, 155.35, 154.68, 146.58, 142.78, 141.97, 141.19, 137.69, 137.45, 131.02, 130.93, 130.56, 129.53, 126.98, 126.33, 125.88, 123.55, 121.90, 80.12, 53.50, 51.81, 28.18, 21.34, 18.03; HRMS (ESI-TOF) m/z Calcd for C27H31 2O4 [M+H] ⁺ : 447.2278, found: 447.2278.

Methyl 3 ' - ( ( tert-butoxycarbonyl) ( (3-methoxy-4- (2,2,2- trifluoroethoxy) pyridin-2-yl) methyl) amino) -5 ' -methyl- [1,1' -bipheny1] -2-carboxylate (S6d)

Colorless liquid, ¹ R NMR (400 MHz, CDC1 ₃ ) δ 8.34 (d, J = 5.6 Hz, 1H) , 7.75 (d, J = 7.5 Hz, 1H) , 7.47 (t, J= 7.5 Hz, 1H) , 7.36 (t, J= 7.3 Hz, 1H) , 7.30 (d, J= 7.5 Hz, 1H) , 7.10 (s, 1H) , 7.06 (s, 1H) , 6.89 (s, 1H) , 6.60 (d, J = 5.6 Hz, 1H) , 4.94 (s, 2H) , 4.37 (q, J = 7.9 Hz, 2H) , 3.59 (s, 3H) , 2.32 (s, 3H) , 2.20 (s, 3H) , 1.37 (s, 9H) , NMR (150 MHz, CDC1 ₃ ) δ 169.22, 161.11, 157.10, 154.67, 147.78, 142.73, 141.97, 141.18, 137.70, 131.04, 130.91, 130.55, 129.55, 127.00, 126.34, 125.83, 123.49, 122.99 J = 277.9 Hz), 119.77, 105.10, 80.19, 65.33 (q, J = 36 Hz), 53.41, 51.81, 28.19, 21.34, 9.64; ¹⁹ F NMR (376 MHz CDC1 ₃ ) δ -74.20; HRMS (ESI-TOF) m/z Calcd for C29H32F3 2O [M+H] ⁺ : 545.2258, found: 545.2258.

Methyl 3 ' - ( ( e fc-butoxycarbonyl) ( (3 , 4-dimethoxypyridin-2- yl) methyl) amino) -5 ' -methyl- [1,1' -biphenyl] -2-carboxylate (S6e)

Colorless liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.23 (d, J = 5.5 Hz, 1H) , 7.74 (d, J = 7.5 Hz, 1H) , 7.47 (t, J = 7.5 Hz, 1H) , 7.40-7.28 (m, 2H) , 7.14 (s, 1H) , 7.11 (s, 1H) , 6.89 (s, 1H) , 6.75 (d, J = 5.5 Hz, 1H) , 4.98 (s, 2H) , 3.89 (s, 3H) , 3.80 (s, 3H) , 3.58 (s, 3H) , 2.32 (s, 3H) , 1.37 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.31, 157.99, 154.82, 151.39, 145.57, 143.14, 142.81, 141.99, 141.15, 137.65, 131.01, 131.00, 130.94, 130.58, 129.52, 126.94, 126.21, 125.89, 123.52, 106.51, 80.00, 60.40, 55.55, 51.84, 50.86, 28.22, 21.35; HRMS (ESI-TOF) m/z Calcd for CzeHssNzOg [M+H] ⁺ : 493.2333, found: 493.2332.

Mefca-Arylation of Anilines

General Procedure for me a-Ar lation of Anilines:

Substrate 1 (0.1 mmol) , Ar-I (0.2 mmol), Pd(0Ac) ₂ (2.2 mg,

10 mol%), L12 (3.0 mg, 20 mol%) , AgOAc (50.1 mg, 0.3 mmol), 2-Norbornene (14.1 mg, 0.15 mmol) or NBE-C0 ₂ Me

(21.6 mg, 0.15 mmol) and DCE (0.5 mL) were added to a 2 dram vial. The vial was capped and closed tightly. Then the reaction mixture was then stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resulted solution was concentrated and purified by preparative TLC to afford the desired arylated product. {In cases where mono:di ratios are possible, the selectivity was determined by ¹ H

NMR. )

Methyl 3 ' - ( ( fcert-butoxycarbonyl) ( (4-me hoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ' -methyl- [1,1'- biphenyl] -2-carboxylate (5a)

Substrate la was arylated following the general meta- arylation procedure using 2-norbornene . After

purification by preparative thin-layer chromatography, Compound 5a was obtained in 98% yield as a light yellow liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.74 (d, J = 7.6 Hz, 1H) , 7.47 (t, J = 7.4 Hz, 1H) , 7.36 (t, J = 7.5 Hz, 1H) , 7.27 (d, J = 9.1 Hz, 1H) , 7.09 (s, 1H) , 7.02 (s, 1H) , 6.87 (s, 1H) , 4.90 (s, 2H) , 3.71 (s, 3H) , 3.57 (s, 3H) , 2.31 (s, 3H) , 2.21 (s, 6H) , 1.38 (s, 9H) ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.24, 163.59, 155.18, 154.67, 148.91, 142.61, 141.97, 141.13, 137.63, 131.00, 130.92, 130.54, 129.52, 126.97, 126.33, 125.93, 124.54, 123.64, 123.57, 80.09, 59.79, 53.54, 51.77, 28.22, 21.33, 13.16, 10.38;HRMS (ESI-TOF) m/z Calcd for C29H35 2O5 [M+H] ⁺ :

491.2540, found: 491.2540.

Methyl 3 ' - ( ( te t-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ' -methoxy- [1,1' -biphenyl] -2-carboxyla e (5b)

Substrate lb was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 5b was obtained in 97% yield as a colorless liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.75 (dd, J = 7.7, 1.5 Hz, 1H) , 7.48 (td, J = 7.5, 1.5 Hz, 1H) , 7.37 (td, J = 7.6, 1.4 Hz, 1H) , 7.30 (d, J = 7.4 Hz, 1H) , 6.86 (s, 1H) , 6.83 (s, 1H) , 6.62 (t, J = 1.9 Hz, 1H) , 4.91 (s, 2H) , 3.75 (s, 3H) , 3.71 (s, 3H) , 3.59 (s, 3H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (126 MHz, CDC1 ₃ ) δ 169.10, 163.62, 159.09, 155.01, 154.56, 148.91, 143.74, 142.09, 141.80, 131.00, 130.45, 129.49, 127.15, 124.58, 123.60, 119.21, 111.54, 111.26, 80.23, 59.79, 55.31, 53.46, 51.85, 28.23, 13.14, 10.36; HRMS (ESI-TOF) m/z Calcd for C ₂ 9H3 _{5 2} 0 ₆ [M+H] ⁺ : 507.2490, found: 507.2490.

Methyl 3 ¹ - ( ( te t-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ¹ - (methylthio)

[1,1' -biphenyl] -2-carboxylate (5c)

Substrate lc was arylated following the general me arylation procedure using 2-norbornene. After purification by preparative thin-layer chromatography, Compound 5c was obtained in 73% yield as a colorless liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.77 (d, = 7.7 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7. Hz, 1H) , 7.30 (d, J = 7.6 Hz, 1H) , 7.18 (s, 1H) , 7.03 (s 1H), 6.95 (s, 1H) , 4.90 (s, 2H) , 3.72 (s, 3H) , 3.59 (s, 3H) , 2.42 (s, 3H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.98, 163.62, 154.91, 154.50, 148.96, 143.14, 141.75, 141.41, 137.98, 131.14, 130.87, 130.50, 129.66, 127.31, 124.65, 123.64, 123.53, 80.36, 59.83, 53.37, 51.88, 28.23, 15.90, 13.17, 10.38; HRMS ( ES I -TOF ) m/z Calcd for CzgHagNzOsS [M+H] ⁺ : 523.2261, found: 523.2261.

Methyl 3 ' - (benzyl ( ter -butoxycarbonyl) amino) -5 ' - ( ( tert- butoxycarbonyl) ( (4-methoxy-3 , 5-dimethyl -pyridin-2- yl) methyl) amino) -[1,1' -bipheny1] -2-carboxylate (5d)

Substrate Id was arylated following the general meta- arylation procedure using 2-norbornene . After

purification by preparative thin-layer chromatography, Compound 5d was obtained in 89% yield as a colorless solid. ^λ η NMR (400 MHz, CDC1 ₃ ) δ 8.11 (s, 1H) , 7.75 (d, J = 7.7 Hz, 1H) , 7.46 (t, J = 7.4 Hz, 1H) , 7.36 (t, J = 7.5 Hz, 1H) , 7.30-7.15 (m, 6H) , 7.11 (s, 1H) , 7.05 (s, 1H) , 6.89 (s, 1H) , 4.84 (s, 2H) , 4.78 (s, 2H) , 3.70 (s, 3H) , 3.49 (s, 3H) , 2.19 (s, 3H) , 2.16 (s, 3H) , 1.37 (s, 9H) , 1.36 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.82, 163.59, 154.82, 154.49, 154.47, 148.94, 142.97, 142.38, 141.48, 141.42, 138.51, 131.07, 130.84, 130.55, 129.65, 128.26, 127.27, 127.20, 126.91, 124.55, 124.08, 123.91, 123.46, 123.16, 80.41, 80.26, 59.80, 53.94, 53.38, 51.75, 28.21, 28.18, 13.15, 10.32; HRMS (ESI-TOF) m/z Calcd for C ₄ oH4 _{8 3} 07 [M+H] ⁺ : 682.3487, found: 682.3486.

Methyl 3 ' - ( ( tert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ' -fluoro- [1,1' -biphenyl] -2-carboxylate (5e)

Substrate le was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 5e was obtained in 94% yield as a colorless solid, mp = 97 °C, ¾ NMR (400 MHz, CDC1 ₃ ) - δ 8.18 (s, 1H) , 7.80 (dd, J = 7.7, 1.4 Hz, 1H) , 7.50 (td, J = 7.6, 1.5 Hz, 1H) , 7.40 (td, J = 7.6, 1.3 Hz, 1H) , 7.29 (dd, J = 7.7, 1.4 Hz, 1H) , 7.11-7.00 (m, 2H) , 6.83-6.75 (m, 1H) , 4.89 (s, 2H) , 3.73 (s, 3H) , 3.62 (s, 3H) , 2.22 (s, 3H) , 2.20 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.59, 163.64, 161.86 (d, J = 244.6 Hz) , 154.63, 154.28, 149.03, 144.18 (d, J = 10.2 Hz), 142.71 (d, J = 9.7 Hz), 140.98 (d, J = 1.8 Hz), 131.28, 130.65, 130.50, 129.83, 127.56, 124.72, 123.39, 122.00, 112.39 (d, J = 22.4 Hz), 80.65, 59.84, 53.29, 51.92, 28.17, 13.18, 10.32; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -114.11; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₃₂ F ₂ 05 [M+H] ⁺ : 495.2290, found: 495.2289.

Methyl 3 ' - ( ( tert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ' -chloro-

[1,1' -biphenyl] -2-carboxylate (5f) Substrate If was arylated following the general meta- arylation procedure using 2-norbornene . After

purification by preparative thin-layer chromatography, Compound 5f was obtained in 92% yield as a colorless solid, mp = 98 °C, ¹ R NMR (400 MHz, CDC1 ₃ ) δ 8.21 (s, 1H) , 7.82 (d, J = 7.7 Hz, 1H) , 7.51 (t, J = 7.5 Hz, 1H) , 7.41 (t, J = 7.5 Hz, 1H) , 7.36-7.28 (m, 2H) , 7.18 (s, 1H) , 7.05 (s, 1H) , 5.01 (s, 2H) , 3.78 (s, 3H) , 3.63 (s, 3H) , 2.25 (s, 3H) , 2.24 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.38, 165.08, 154.14, 153.64, 147.26, 143.18, 142.84, 140.70, 133.18, 131.43, 130.64, 130.42, 129.95, 127.68, 125.79, 125.55, 125.31, 124.82, 81.08, 60.11, 52.20, 51.92, 28.16, 28.13, 13.43, 10.58; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₃₂ CI ₂ O ₅ [M+H] ⁺ : 511.1994, found: 511.1994.

Methyl 3 ' - ( ( fce.rt-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ¹ - (trifluoromethyl) - [1,1' -biphenyl] -2-carboxylate (5g)

Substrate lg was arylated following the general meta- arylation procedure using NBE-C0 ₂ Me. After purification by preparative thin-layer chromatography, Compound 5g was obtained in 94% yield as a colorless liquid. ^λ Ε NMR (400 MHz, CDCI ₃ ) δ 8.17 (s, 1H) , 7.85 (d, J = 7.6 Hz, 1H) , 7.57 (s, 1H) , 7.53 (t, J = 7.3 Hz, 1H) , 7.48 (s, 1H) , 7.43 (t, J = 7.5 Hz, 1H) , 7.35-7.28 (m, 2H) , 4.93 (s, 2H) , 3.72 (s, 3H) , 3.59 (s, 3H) , 2.21 (s, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 168.40, 163.70, 154.52, 154.22, 149.07, 143.32, 142.18, 140.70, 131.48, 130.63, 130.57, 130.18 (q, J = 32.5 Hz), 130.12, 129.39, 127.81, 124.82, 123.85 (q, J = 272.8 Hz), 123.47, 122.18, 122.07 ( q, J = 3.8 Hz), 80.87, 59.84, 53.13, 51.85, 28.15, 13.18, 10.36; ¹⁹ F NMR U 2017/028116

(376 MHz, CDCI ₃ ) δ -62.70; HRMS (ESI-TOF) m/z Calcd for

C29H32F ₃ N ₂ 05 [M+H] ⁺ : 545.2258, found: 545.2259.

Dimethyl 5 ' - ( ( te fc-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -[1,1* -bipheny1] - 2,3' -dicarboxylate (5h)

Substrate lh was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 5h was obtained in 94% yield as a colorless solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 7.95 (s, 1H) , 7.84 (d, J = 7.6 Hz, 1H) , 7.75 (s, 1H) , 7.56-7.45 (m, 2H) , 7.41 (t, J = 7.6 Hz, 1H) , 7.30 (d, J = 7.6 Hz, 1H) , 4.93 (s, 2H) , 3.88 (s, 3H) , 3.72 (s, 3H) , 3.58 (s, 3H) , 2.22 (s, 3H) , 2.21 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 168.41, 166.57, 163.67, 154.70, 154.38, 149.00, 142.92, 141.68, 141.21, 131.37, 130.99, 130.71, 130.43, 130.01, 127.54, 126.56, 126.36, 124.71, 123.54, 80.60, 59.81, 53.18, 52.10, 51.83, 28.16, 13.16, 10.38; HRMS (ESI-TOF) m/z Calcd for Ca^^O, [M+H] ⁺ : 535.2439, found: 535.2439.

5i

Methyl 3 ' -benzoyl-5 ' - ( ( tert-butoxycarbony1) ( (4-methoxy- 3 , 5-dimethylpyridin-2-yl) methyl) amino) -[1,1' -biphenyl] -2- carboxylate (5i)

Substrate li was arylated following the general meta- arylation procedure using 2-norbornene. After purification by preparative thin-layer chromatography, Compound 5i was obtained in 93% yield as a colorless solid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 7.84 (d, J = 7.7 Hz, 1H) , 7.80 (s, 1H) , 7.78 (s, 1H) , 7.70 (s, 1H) , 7.61-7.37 (m, 7H) , 7.33 (d, J = 7.6 Hz, 1H) , 4.95 (s, 2H) , 3.71 (s, 3H) , 3.63 (s, 3H) , 2.21 (s, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 195.85, 168.29, 163.68, 154.67, 154.43, 148.98, 142.87, 141.50, 141.26, 137.35, 137.33, 132.36, 131.42, 130.82, 130.48, 130.41, 130.05, 130.02, 128.18, 127.56, 127.13, 126.67, 124.71, 123.52, 80.63, 59.83, 53.20, 51.89, 28.19, 13.18, 10.37; HRMS (ESI-TOF) m/z Calcd for C3 ₅ H3 _{7 2} 0 ₅ [M+H] ⁺ : 581.2646, found: 581.2646.

Methyl 3 ¹ - ( ( ert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ' -cyano- [1,1'- biphenyl] -2-carboxylate (5j )

Substrate lj was arylated following the general meta- arylation procedure using NBE-C0 ₂ Me. After purification by preparative thin-layer chromatography, Compound 5j was obtained in 93% yield as a colorless solid, mp = 106 °C, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.89 (d, J = 7.7 Hz, 1H) , 7.62 (s, 1H) , 7.60-7.50 (m, 2H) , 7.45 (t, J = 7.6 Hz, 1H) , 7.33 (s, 1H) , 7.28 (d, J = 9.0 Hz, 1H) , 4.88 (s, 2H) , 3.75 (s, 3H) , 3.65 (s, 3H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 1.38 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 167.80, 163.70, 154.19, 154.05, 149.12, 143.79, 142.73, 140.27, 131.68, 130.88, 130.67, 130.31, 130.10, 128.52, 128.08, 124.90, 123.22, 118.55, 111.81, 81.11, 59.88, 53.00, 51.99, 28.10, 13.20, 10.28; HRMS (ESI-TOF) m/z Calcd for Czcfe sOg [M+H] ⁺ : 502.2336, found: 502.2336. TU 2017/028116

Methyl 3 ' - ( ( te fc-butoxycarbony1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ' -nitroll , 1 ¹ -biphenyl] -2-carboxylate (5k)

Substrate lk was arylated following the general meta- arylation procedure using NBE-C0 ₂ Me. After purification by preparative thin-layer chromatography, Compound 5k was obtained in 89% yield as a light yellow solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.20 (q, J = 2.1 Hz, 1H) , 8.18 (s, 1H) , 7.96-7.88 (m, 2H) , 7.67 (s, 1H) , 7.56 (t, J = 7.5 Hz, 1H) , 7.46 (t, J = 7.5 Hz, 1H) , 7.33 (d, J = 7.6 Hz, 1H) , 4.93 (s, 2H) , 3.75 (s, 3H) , 3.65 (s, 3H) , 2.23 (s, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 167.74, 163.75, 154.21, 154.02, 149.15, 147.71, 143.89, 142.56, 140.27, 132.22, 131.76, 130.75, 130.40, 130.08, 128.19, 124.93, 123.33, 119.80, 81.27, 59.90, 52.96, 52.02, 28.11, 13.22, 10.34; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H _{32 3} 0 ₇ [M+H] ⁺ : 522.2235, found: 522.2235.

51

Dimethyl 5 ' - ( ( tert-butoxycarbony1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) - [Ι,Ι'^',Ι' ¹ - terphenyl] -2,2' ¹ -dicarboxylate (51)

Substrate 11 was arylated following the general meta- arylation procedure using 2-norbornene. Analysis of crude reaction mixture by ¹ E NMR showed the selectivity of mono- and di- products (mono:di < 20:1). After purification by preparative thin-layer chromatography, Compound 51 was T/US2017/028116 obtained in 92% yield as a light yellow liquid. Ή N R (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.78 (dd, J = 7.7, 1.4 Hz, 2H) , 7.49 (td, J = 7.5, 1.5 Hz, 2H) , 7.38 (td, J = 7.6, 1.3 Hz, 2H) , 7.34 (s, 1H) , 7.32 (s, 1H) , 7.29-7.21 (m, 2H) , 7.01 (t, J = 1.7 Hz, 1H) , 4.93 (s, 2H) , 3.70 (s, 3H) , 3.61 (s, 6H) , 2.21 (s, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 168.99, 163.58, 155.04, 154.55, 148.94, 142.56, 141.68, 141.13, 131.09, 130.93, 130.64, 129.68, 127.17, 125.60, 125.36, 124.58, 123.52, 80.18, 59.79, 53.50, 51.84, 28.21, 13.15, 10.37; HRMS (ESI-TOF) m/z Calcd for C ₃₆ H _{39 2} 0 ₇ [M+H] ⁺ : 611.2752, found: 611.2754.

Methyl 3 ' - ( ( te t-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-y1) methy1) amino) -4 ¹ -methy1- [1,1' -biphenyl] -2-carboxylate (5m)

Substrate lm was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 5m was obtained in 81% yield as a colorless liquid. Rotameric mixture, ratio of the rotamers = 70/30; ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.11 (s, 1H) , 7.73 (d, J = 7.7 Hz, 1H) , 7.44 (t, J = 7.5 Hz, 1H) , 7.34 (t, J = 7.6 Hz, 1H) , 7.31-6.98 (m, 3.3H), 6.86 (s, 0.7H), 5.26 (d, J = 14.9 Hz, 0.7H), 5.18-5.04 (m, 0.3H), 4.51 (d, J = 14.7 Hz, 1H) , 3.66 (s, 3H) , 3.55 (s, 3H) , 2.33-2.12 (m, 9H) , 1.38

(s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture, resonances for the minor rotamer are enclosed in

parenthesis () : δ 169.20 (169.50), 163.76 (163.54), 155.07

(155.34), 154.75 (154.09), 148.88, 141.49 (141.25),

140.41, 139.11, 134.90 (135.29), 130.95, 130.86, 130.47, 130.27, 129.89, 129.59, 128.31, 126.87, 124.95 (124.65), 123.71, 79.77 (79.90), 59.69, 52.52 (53.54), 51.72 (51.84) , 28.22, 17.31 (17.52) , 13.13, 10.61; HRMS (ESI- TOF) m/z Calcd for CzgHssNzOs [M+H] ⁺ : 491.2540, found:

491.2540.

Methyl 3 ' - ( ( te t-butoxycarbony1) ( (4-me hoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -4 ' -methoxy- [1,1' -biphenyl] -2-carboxylate (5n)

Substrate In was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 5n was obtained in 84% yield as a colorless liquid. Rotameric mixture, ratio of the rotamers = 75/25; ^l R NMR (400 MHz, CDC1 ₃ ) δ 8.07 (s, 1H) , 7.70 (d, J = 7.6 Hz, 1H) , 7.42 (t, J = 7.6 Hz, 1H) , 7.32 (t, J = 7.5 Hz, 1H) , 7.26-6.76 (m, 4H) , 5.33 (s, 0.75H), 4.91-4.30 (m, 1.25H), 3.83 (s, 3H) , 3.67 (s, 3H) , 3.55 (s, 3H) , 2.26 (s, 3H) , 2.19 (s, 3H) , 1.49-1.30 (m, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture: δ 169.56, 169.35, 163.76, 163.59, 155.70, 155.53, 155.24, 154.82, 154.49, 148.62, 141.28, 133.15, 132.99, 130.88, 130.85, 130.63, 130.45, 130.38, 129.53, 127.78, 127.71, 126.68, 126.62, 125.28, 124.84, 124.56, 124.19, 111.22, 110.42, 79.98, 79.51, 59.70, 55.72, 55.31, 53.50, 52.50, 51.86, 51.70, 28.19, 13.11, 10.58; HRMS (ESI-TOF) m/z Calcd for ¾ ₉ Η _{35 2} 0 ₆ [M+H] ⁺ :

507.2490, found: 507.2491.

2017/028116

Methyl 3 ' - ( ( te -butoxycarbonyl) ( (4-methoxy-3 , 5- dimeth lpyridin-2-yl) methyl) amino) -4 ' -fluoro- [1,1' -biphenyl] -2-carboxylate (5o)

Substrate lo was arylated following the general meta- arylation procedure using 2-norbornene . After

purification by preparative thin-layer chromatography, Compound 5o was obtained in 90% yield as a colorless liquid. Rotameric mixture, ratio of the rotamers = 75/25; ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.10 (s, 1H) , 7.77 (dd, J = 7.7, 1.4 Hz, 1H) , 7.47 ^' (td, J = 7.5, 1.5 Hz, 1H) , 7.37 (t, J = 7.3 Hz, 1H) , 7.25-6.91 (m, 4H) , 4.94 (s, 2H) , 3.70 (s, 3H) , 3.56 (s, 3H) , 2.26 (s, 3H) , 2.19 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.85, 163.77, 157.50 (d, J = 249.6 Hz), 154.68, 154.23, 148.77, 140.84, 137.07 (d, J = 3.7 Hz), 131.16, 130.73, 130.55, 129.80, 129.50,

129.36, 129.28, 127.78 (d, J = 7.8 Hz), 127.24, 124.96, 115.06 (d, J = 21.6 Hz), 80.50, 59.74, 52.70, 51.74,

28.07, 13.14, 10.48; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) for major isomer: δ -123.17; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) for minor isomer: δ -122.57; HRMS (ESI-TOF) m/z Calcd for C28H32F 2O5 [M+H] ⁺ : 495.2290, found: 495.2291.

5p

Dimethyl 5 ¹ - ( ( ter -butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -2 ' -fluoro- [1 , 1 ' : 3 ' , 1 ¹ ' - terphenyl] -2,2' ' -dicarboxylate (5p)

Substrate lp was arylated following the general meta- arylation procedure using 2-norbornene. Analysis of the crude reaction mixture by ¹ H NMR showed the selectivity of mono- and di- products (mono:di < 20:1) . After

purification by preparative thin-layer chromatography, Compound 5p was obtained in 90% yield as a light yellow solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.91 (d, J = 7.7 Hz, 2H) , 7.53 (t, J = 7.5 Hz, 2H) , 7.41 (t, J = 7.6 Hz, 2H) , 7.29 (d, J = 7.7 Hz, 2H) , 7.18 (s, 2H) , 4.95 (s, 2H) , 3.70 (s, 3H) , 3.64 (s, 6H) , 2.21 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 167.79, 163.69, 154.99, 154.58, 153.56 (d, J = 244.3 Hz) , 148.91, 138.04, 136.02, 131.52, 131.42, 130.96, 130.01, 128.54 (d, J = 18.4 Hz), 127.98, 127.80, 124.74, 123.92, 80.29, 59.78, 53.54, 51.87, 28.24, 13.16, 10.44; ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ - 123.88; HRMS (ESI-TOF) m/z Calcd for C ₃₆ H ₃₈ FN ₂ 0 ₇ [M+H] ⁺ :

629.2658, found: 629.2657.

Methyl 5 ¹ - ( ( tert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -2 ' -methoxy- [1,1' -biphenyl] -2-carboxylate (5q)

Substrate lq was arylated following the general me ta- arylation procedure using 2-norbornene. Analysis of crude reaction mixture by ¹ H NMR showed the selectivity of mono- arid di - products {mono : di > 20:1) . After purification by preparative thin-layer chromatography, Compound 5q was obtained in 64% yield as a colorless liquid. ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 7.83 (d, J = 7.7 Hz, 1H) , 7.50

(t, J = 7.5 Hz, 1H) , 7.37 (t, J = 7.6 Hz, 1H) , 7.16 (brs, 2H) , 7.01 (s, 1H) , 6.73 (d, J = 8.7 Hz, 1H) , 4.93 (brs, 2H) , 3.70 (s, 3H) , 3.65 (s, 3H) , 3.56 (s, 3H) , 2. 30-2.10

(m, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.60, 163.75, 155.29, 154.99, 153.89, 148.84, 138.17, 135.35, 131.60, 131.49, 131.20, 130.30, 129.32, 128.85, 127.12, 126.88, 124.74, 124.39, 109.71, 80.03, 59.79, 55.35, 53.66, 51.48, 28.30, 13.17, 10.51; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H ₃ 5 ₂ 0 ₆ [M+H] ⁺ : 507.2490, found: 507.2491.

Methyl 2- (6- ( ( e t-butoxycarbonyl) ( (4-methoxy-3 ,5- dimethylpyridin-2-yl) methyl) amino) benzo [d] [1 , 3] dioxol-4- yl) benzoate (5r)

Substrate lr was arylated following the general meta- arylation procedure using 2-norbornene . After

purification by preparative thin-layer chromatography, Compound 5r was obtained in 83% yield as a light yellow liquid. ^X H NMR (400 MHz , CDC1 ₃ ) δ 8.18 (s, 1H) , 7.86 (d, J = 7.7 Hz, 1H) , 7.51 (t, J = 7.5 Hz, 1H) , 7.39 (t, J = 7.6 Hz, 1H) , 7.30 (d, J = 7.7 Hz, 1H) , 6.81 (s, 1H) , 6.68 (s, 1H) , 5.87 (s, 2H) , 4.88 (s, 2H) , 3.71 (s, 3H) , 3.67 (s, 3H) , 2.22 (s, 3H) , 2.21 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.36, 163.70, 155.02, 154.92, 148.85, 146.61, 142.64, 136.74, 135.93, 131.57, 130.88, 130.76, 130.06, 127.66, 124.71, 123.99, 121.88, 120.87, 107.96, 101.15, 80.15, 59.79, 53.76, 51.89, 28.24, 13.16, 10.41; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H _{33 2} O ₇ [M+H] ⁺ : 521.2282, found: 521.2283.

Methyl 5 ¹ - ( ( tert-butoxycarbonyl) ( (4-methoxy~3 , 5- dimethylpyridin-2-yl) methyl) amino) -2 ' -fluoro-3 ' -methyl- [1,1' -biphenyl] -2-carboxylate (5s)

Substrate Is was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 5s was obtained in 94% yield as a light yellow liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.92 (d, J 6

= 7.7 Hz, 1H) , 7.52 (td, J = 7.6, 1.4 Hz, 1H) , 7.41 (t, J

= 7.6 Hz, 1H) , 7.23 (d, J = 7.6 Hz, 1H) , 7.10 (s, 1H) , 6.96 (s, 1H) , 4.90 (s, 2H) , 3.71 (s, 3H) , 3.63 (s, 3H) , 2.21 (d, J = 2.3 Hz, 9H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) 5 167.87, 163.69, 155.58 (d, J = 243.2 Hz), 155.03, 154.69, 148.85, 137.86, 136.35, 131.58, 131.32, 130.77, 129.96, 128.67 (d, J = 5.1 Hz), 128.35 (d, J = 18.1 Hz), 127.66, 126.39, 124.71, 124.08 (d, J = 19.5 Hz), 123.89, 80.20, 59.78, 53.57, 51.74, 28.22, 14.66 (d, J = 4.0 Hz), 13.15, 10.41; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -124.82; HRMS (ESI-TOF) m/z Calcd for C ₂₉ E _3i FN ₂ 0 ₅ [M+H] ⁺ : 509.2446, found: 509.2447.

Methyl 5 '-(( te t-butoxycarbonyl) ( (4-methoxy~3 , 5- dime h lpyridin-2-yl) methyl) amino) -4 ' -fluoro-2 ¹ -methoxy- [1,1' -biphenyl] -2-carboxylate (5t)

Substrate It was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 5t was obtained in 92% yield as a colorless solid. Rotameric mixture, ratio of the rotamers = 76/24; ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.09 (s, 1H) , 7.82 (d, J = 7.7 Hz, 1H) , 7.47 (t, J = 7.5 Hz, 1H) , 7.36 (t, J = 7.6 Hz, 1H) , 7.14 (s, 0.48H), 6.99 (s, 0.76H), 6.83 (s, 0.76H), 6.54 (d, J = 11.7 Hz, 1H) , 5.30-4.60 (m, 2H) , 3.68 (s, 3H) , 3.64 (s, 3H) , 3.56 (s, 3H) , 2.27 (s, 3H) , 2.20 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture: δ 168.42, 163.89, 163.80, 158.89, 157.23, 155.41, 155.35, 155.02, 154.66, 154.29, 148.71, 137.20, 131.49, 131.12, 130.76, 130.71, 130.56, 129.44, 127.23, 125.97, 125.40, 125.07, 124.87, 124.36, 121.96, 121.54, 121.46, 99.03, 98.88, 98.52, 98.35, 80.59, 59.71, 55.55, 53.83, 52.66, 51.41, 28.12, 13.14, 10.57; ⁱ⁹ F NMR (376 MHz, CDC1 ₃ ) for major isomer: δ -119.67; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) for minor isomer: δ -118.80; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H ₃₄ F ₂ 0 ₆ [M+H] ⁺ : 525.2395, found: 525.2395.

Dimethyl 5 ' - ( ( te t-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -4 ' -methyl- [1,1' -biphenyl] -2,3' -dicarboxylate (5u)

Substrate lu was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 5u was obtained in 92% yield as a colorless liquid. Rotameric mixture, ratio of the rotamers = 74/26; ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.22-8.05 (m, 1H) , 7.79 (d, J = 7.7 Hz, 1H), 7.70 (s, 0.74H), 7.59 (d, J = 3.7 Hz, 0.26H), 7.47 (t, J = 7.5 Hz, 1H) , 7.38 (t, J = 7.6 Hz, 1H) , 7.34- 7.04 (m, 2H) , 5.35-5.05 (m, 1H) , 4.54-4.30 (m, 1H) , 3.87 (s, 3H) , 3.67 (s, 3H) , 3.55 (s, 3H) , 2.57-2.38 (m, 3H) , 2.27-2.15 (m, 6H) , 1.37 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture: δ 169.05, 168.64, 167.81, 163.78, 163.55, 155.01, 154.64, 154.30, 148.94, 142.67, 141.82,

140.66, 138.61, 137.22, 136.92, 132.94, 132.41, 131.20, 130.57, 130.50, 129.93, 129.13, 127.38, 124.99, 124.77,

124.67, 123.49, 80.13, 59.70, 53.43, 52.55, 51.92, 51.75, 28.17, 15.00, 13.12, 10.61; HRMS (ESI-TOF) m/z Calcd for C ₃ iH ₃₇ N ₂ 0 ₇ [M+H] ⁺ : 549.2595, found: 549.2596.

5v Methyl 2- (4- ( ( ert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) naphthalen-2-yl) benzoate (5v)

Substrate lv was arylated following the general meta- arylation procedure using 2-norbornene . After

purification by preparative thin-layer chromatography, Compound 5v was obtained in 92% yield as a colorless solid. Rotameric mixture, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.13

(s, 1H) , 7.92 (s, 1H) , 7.87-7.77 (m, 2H) , 7.66 (s, 1H) , 7.56-7.44 (m, 3H) , 7.40 (t, J = 7.5 Hz, 1H) , 7.34-7.18 (m, 2H) , 5.56-5.18 (m, 1H) , 4.61 (d, J = 15.2 Hz, 1H) , 3.63

(s, 3H) , 3.46 (s, 3H) , 2.18 (s, 3H) , 2.16 (s, 3H) , 1.56- 1.14 (m, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture: δ 169.07, 163.64, 155.33, 155.03, 148.96, 141.59, 138.49, 138.37, 134.01, 131.13, 131.01, 130.80, 129.82, 128.36, 127.66, 127.20, 126.76, 126.17, 126.07, 124.76, 124.46, 123.31, 122.91, 79.96, 59.67, 53.15, 51.75, 50.06, 28.07, 13.10, 10.52; HRMS (ESI-TOF) m/z Calcd for C ₃₂ H _{35 2} O ₅ [M+H] ⁺ : 527.2540, found: 527.2541.

Methyl 2- (3- (( ert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) naphthalene-1- yl) benzoate (5w)

Substrate l was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography Compound 5w was obtained in 92% yield as a colorless solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 8.00 (d, J = 7.8 Hz, 1H) , 7.74 (d, J = 8.1 Hz, 1H) , 7.66 (s, 1H) , 7.58 (t, J = 7.3 Hz, 1H) , 7.49 (t, J = 7.6 Hz, 1H) , 7.41-7.22 (m, 5H) , 5.06 (s, 2H) , 3.70 (s, 3H) , 3.23 (s, 3H) , 2.24 (s, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 167.79, 163.68, 155.11, 154.65, 148.94, 14U.85, 139.61, 139.57, 133.26, 131.79, 131.61, 131.43, 130.13, 130.00, 128.09, 127.57, 126.09, 125.60, 125.52, 125.10, 124.67, 123.85, 122.79, 80.40, 59.81, 53.70, 51.56, 28.27, 13.17, 10.48; HRMS (ESI-TOF) m/z Calcd for C ₃₂ H ₃₅ N ₂ 05 [M+H] ⁺ : 527.2540, found: 527.2538.

Mefca-Arylation of Heterocycle-Containing Aromatic Amines

General Procedures for mefca-Arylation of Heterocycle- Containing Aromatic Amines:

Substrate 2 (0.1 mmol) , Ar-I (0.2 mmol) , Pd(0Ac) ₂ (2.2 mg, 10 mol%) , L12 (3.0 mg, 20 mol%) , AgOAc (50.1 mg, 0.3 mmol), 2-Norbornene (14.1 mg, 0.15 mmol) or NBE-C0 ₂ Me (21.6 mg, 0.15 mmol) and DCE (0.5 mL) were added to a 2- dram vial. The vial was capped and closed tightly. Then the reaction mixture was then stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resultant solution was concentrated and purified by preparative TLC plate to afford the desired arylated product.

6a

Methyl 2- (5- ( ( fcerfc-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -6 -chloropyridin-3- yl) benzoate (6a) Substrate 2a was arylated following the general meta- arylation procedure using NBE-C0 ₂ Me. After purification by preparative thin-layer chromatography, Compound 6a was obtained in 53% yield as a colorless liquid. Rotameric mixture, ratio of the rotamers = 77/23; ½ NMR (400 MHz, CDC1 ₃ ) δ 8.25-8.12 (m, 1H) , 8.10 (s, 0.77H), 7.99 (s, 0.23H), 7.92 (d, J = 7.7 Hz, 1H) , 7.65 (s, 0.77H), 7.55 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.27 (s, 0.46H), 7.17 (d, J = 7.6 Hz, 0.77H), 5.24 (d, J = 15.5 Hz, 1H) , 4.56 (d, J = 15.5 Hz, 1H) , 3.71 (s, 3H) , 3.60 (s, 3H) , 2.33-2.23 (m, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) rotameric mixture: δ 167.98, 167.68, 163.94, 163.69, 154.64, 154.12, 153.79, 149.03, 148.91, 148.78, 146.47, 140.22, 138.99, 137.15, 136.54, 136.33, 135.68, 131.78, 130.84, 130.60, 130.46, 130.29, 128.36, 128.26, 125.26, 124.97, 124.86, 123.59, 81.08, 59.79, 52.51, 51.91, 51.67, 28.09, 13.18, 10.67, 10.50; HRMS (ESI-TOF) m/z Calcd for C ₂ 7H ₃₁ C1N ₃ 0 ₅ [M+H] ⁺ : 512.1947, found: 512.1946.

Methyl 2- (2- ( ( tert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -6-methoxypyridin-4- yl)benzoate (6b)

Substrate 2b was arylated following the general meta- arylation procedure using 2-norbornene . After

purification by preparative thin-layer chromatography, Compound 6b was obtained in 72% yield as a colorless liquid. Only 4% NMR yield was obtained in the absence of L12. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.13 (s, 1H) , 7.83 (d, J = 7.6 Hz, 1H) , 7.51 (t, J = 7.5 Hz, 1H) , 7.46-7.39 (m, 2H) , 7.36 (d, J = 7.5 Hz, 1H) , 6.32 (s, 1H) , 5.24 (s, 2H) , 3.73 (s, 3H) , 3.69 (s, 3H) , 3.65 (s, 3H) , 2.26 (s, 3H) , 2.21 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.27,

163.33, 161.85, 156.03, 154.28, 153.00, 151.84, 148.82, 140.63, 131.35, 130.42, 130.26, 129.83, 127.90, 123.82, 122.36, 110.87, 104.23, 80.92, 59.83, 53.00, 52.05, 49.35, 28.13, 13.14, 10.34; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H _{34 3} 0 ₆ [M+H] ⁺ : 508.2442, found: 508.2442.

Methyl 2- (5- ( ( te t-butoxycarbony1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -thiophen-3-yl) benzoate (6c)

Substrate 2c was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 6c was obtained in 79% yield as a colorless liquid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.30 (s, 1H) , 7.71 (d, J = 7.7 Hz, 1H), 7.56-7.39 (m, 2H) , 7.34 (t, J = 7.4 Hz, 1H) , 6.97 (s, 1H) , 6.80 (s, 1H) , 5.48 (s, 2H) , 3.96 (s, 3H) , 3.73 (s, 3H) , 2.35 (s, 6H) , 1.50 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.58, 168.72, 153.40, 150.44, 141.74, 138.94, 136.46, 131.35, 130.71, 130.40, 129.44, 128.83, 128.72, 128.13, 127.24, 123.99, 118.73, 82.96, 60.92, 52.06, 49.86, 28.09, 14.16, 11.10; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₃ i ₂ 0 ₅ S [M+H] ⁺ : 483.1948, found: 483.1949.

6d

Methyl 2- (4- ( ( ter -butoxycarbony1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -thiophen-2-yl) benzoate (6d) Substrate 2d was arylated following the general meta- arylation procedure using NBE-C0 ₂ Me. After purification by preparative thin-layer chromatography, Compound 6d was obtained in 56% yield as a colorless liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.19 (s, 1H) , 7.66 (d, J = 7.6 Hz, 1H) , 7.49-7.39 (m, 2H) , 7.39-7.32 (m, 1H) , 7.07 (s, 1H) , 6.96 (s, 1H) , 4.91 (s, 2H) , 3.74 (s, 3H) , 3.70 (s, 3H) , 2.26- 2.19 (m, 6H) , 1.44 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.04, 163.69, 154.77, 154.18, 149.05, 140.87, 139.46, 134.13, 131.51, 130.88, 129.27, 127.64, 124.68, 123.50, 115.39, 80.72, 59.86, 53.21, 52.13, 28.25, 13.20, 10.29; HRMS (ESI-TOF) m/z Calcd for C26H31N2O5S [M+H] ⁺ : 483.1948, found: 483.1948.

Methyl 3- ( ( fcert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5- (2- (methoxycarbonyl) - phenyl) thiophene-2-carboxylate (6e)

Substrate 2e was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 6e was obtained in 65% yield as a colorless liquid. Rotameric mixture, ratio of the rotamers = 65/35; R NMR (400 MHz, CDC1 ₃ ) δ 8.13 (s, 1H) , 7.73 (d, J = 7.6 Hz, 1H) , 7.48 (t, J = 7.5 Hz, 1H) , 7.45-7.29 (m, 2H) , 7.06 (s, 0.35H), 6.80 (s, 0.65H), 5.20-4.60 (m, 2H) , 3.85 (s, 3H) , 3.72 (s, 3H) , 3.66 (s, 3H) , 2.26 (s, 3H) , 2.20 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) rotameric mixture: δ 168.16, 167.85, 163.31, 163.14, 161.03, 160.90, 154.89, 154.29, 153.70, 132.81, 131.11, 131.03, 130.72, 130.38, 129.28, 128.41, 128.18, 128.10, 127.77, 124.49, 124.38, 124.28, 124.12, 124.05, 123.05, 79.91, 59.37, 53.02, 52.14, 51.79, 51.68, 51.47, 27.72, 12.74, 10.07; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₃₃ N ₂ 0 ₇ S [M+H] ⁺ : 541.2003, found: 541.2003.

Methyl 2- (5- ( ( fcert-butoxycarbonyl) ( (4-methoxy-3 ,5- dimethylpyridin-2-yl) methyl) amino) -quinolin-7-yl) benzoate (6f)

Substrate 2f was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 6f was obtained in 76% yield as a red liquid. ¹ H NMR (400 MHz , CDC1 ₃ ) δ 8.91 (dd, J = 4.2, 1.6 Hz, 1H) , 8.34 (d, J = 8.4 Hz, 1H) , 8.12 (s, 1H) , 7.97 (s, 1H) , 7.87 (d, J = 7.6 Hz, 1H) , 7.55 (t, J = 7.3 Hz, 1H) , 7.51-7.30 (m, 4H) , 5.24 (d, J = 15.5 Hz, 1H) , 4.76 (d, J = 15.3 Hz, 1H) , 3.65 (s, 3H) , 3.52 (s, 3H) , 2.28-2.10 (m, 6H) , 1.54- 1.10 (m, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.50, 163.67, 154.97, 154.56, 150.52, 148.99, 148.57, 142.19, 141.25, 138.52, 132.00, 131.46, 130.91, 130.66, 130.17, 127.65, 127.48, 126.97, 125.23, 124.87, 124.23, 120.86, 80.44, 59.72, 53.40, 51.82, 28.08, 13.12, 10.51; HRMS (ESI-TOF) m/z Calcd for Csi^^Os [M+H] ⁺ : 528.2493, found: 528.2493.

6g

Methyl 2- (l-acetyl-6- ( ( fcert-butoxycarbonyl) ( (4-me

3 , 5-dimethylpyridin-2-yl) methyl) -amino) -indolin-4

benzoate (6g) Substrate 2g was arylated following the general meta- arylation procedure using 2-norbornene . After

purification by preparative thin-layer chromatography, Compound 6g was obtained in 89% yield as a light yellow solid. Rotameric mixture, ratio of the rotamers = 78/22; mp = 79 °C, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.20-8.08 (m, 1.78H), 7.96-7.84 (m, 1H) , 7.50 (t, J = 7.6 Hz, 1H) , 7.40 (t, J = 7.6 Hz, 1H) , 7.26-7.09 (m, 1.22H), 6.74 (s, 1H) , 5.00-4.80

(m, 2H) , 4.12-3.90 (m, 2H) , 3.70 (s, 2H) , 3.66-3.52 (m, 3H) , 2.82 (t, J = 8.4 Hz, 1.56H), 2.69 (t, J = 8.4 Hz, 0.44H), 2.38-2.08 (m, 9H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) resonances for the minor rotamer are enclosed in parenthesis () : δ 168.46 (168.29), 167.88 (167.52), 163.60

(163.66), 155.15 (155.03), 154.68, 148.74 (148.82),

142.41, 142.00 (141.16), 140.54 (140.45), 137.49 (138.91), 131.49 (131.67), 130.52 (130.47), 130.13 (129.85), 129.97

(129.28), 127.41 (127.61), 126.70, 124.50 (124.75),

123.90, 122.52 (121.91), 114.62 (112.46), 80.12 (80.33), 59.74 (59.79), 53.54, 51.87 (51.92), 49.12 (48.19), 28.21, 26.81 (25.60), 24.14 (24.36), 13.12, 10.45 (10.37); HRMS

(ESI-TOF) m/z Calcd for C ₃ 2H3 _{8 3} 0 ₆ [M+H] ⁺ : 560.2755, found: 560.2755.

6h

tert-Butyl 6- ( ( fcert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-y1) methy1) amino) -4- (2- (methoxycarbonyl) - phenyl) -1H-indole-1-carboxylate (6h)

Substrate 2h was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 6h was obtained in 66% yield as a colorless solid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 7.99 (s, 1H) , 7.89 (d, J = 7.7 Hz, 1H) , 7.57-7.47 (m, 2H) , 7.43 (t, J = 7.6 Hz, 1H) , 7.31 (d, J = 7.5 Hz, 1H) , 7.03 (s, 1H) , 6.22 (d, J = 3.7 Hz, 1H) , 5.01 (s, 2H) , 3.71 (s, 3H) , 3.42 (s, 3H) , 2.24 (s, 3H) , 2.20 (s, 3H) , 1.60 (s, 9H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.58, 163.70, 155.30, 154.94, 149.55, 148.84, 140.23, 139.22, 134.48, 133.59, 131.39, 131.32, 131.14, 129.92, 127.36, 127.32, 126.33, 124.64, 124.05, 122.40, 112.86, 105.68, 83.59, 80.08, 59.76, 54.11, 51.88, 28.27, 28.04, 13.12, 10.50; HRMS (ESI-TOF) m/z Calcd for C ₃₅ H ₄ 2 ₃ 0 ₇ [M+H] ⁺ : 616.3017, found: 616.3018.

terfc-Butyl 4- ( ( te t-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -6- (2- (me hoxycarbonyl) - phenyl) -1H-indole-1-carboxylate (6i)

Substrate 2i was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 6i as obtained in 51% yield as a colorless solid. ^L H NMR (400 MHz, CDC1 ₃ ) δ 8.13 (s, 1H) , 8.01 (s, 1H) , 7.75 (d, J = 7.7 Hz, 1H) , 7.56 (d, J = 3.7 Hz, 1H) , 7.48 (t, J = 7.4 Hz, 1H) , 7.41-7.28 (m, 2H) , 7.02 (brs, 1H) , 6.58 (d, J = 3.7 Hz, 1H) , 4.97 (brs, 2H) , 3.66 (s, 3H) , 3.54 (s, 3H) , 2.18 (s, 6H) , 1.64 (s, 9H) , 1.35 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.41, 163.58, 155.02, 154.78, 149.61, 148.93, 142.31, 137.48, 135.73, 134.72, 131.18, 130.97,

130.92, 129.65, 127.71, 126.83, 125.87, 124.67, 124.15,

121.93, 113.59, 105.71, 83.78, 80.07, 59.72, 53.36, 51.76, 28.20, 28.13, 13.15, 10.50; HRMS (ESI-TOF) m/z Calcd for C ₃₅ H ₄₂ N ₃ 0 ₇ [M+H] ⁺ : 616.3017, found: 616.3018.

6j

Methyl 2- (6- ( ( tejrfc-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -1-methyl-lH-indazol- 4-yl)benzoate (6j)

Substrate 2j was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 6j as obtained in 90% yield as a colorless solid, mp = 79 °C, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.90 (d, J = 7.7 Hz, 1H) , 7.63 (s, 1H) , 7.56 (t, J = 7.5 Hz, 1H) , 7.46 (t, J = 7.6 Hz, 1H) , 7.39 (d, J = 7.6 Hz, 1H) , 7.35 (s, 1H) , 6.98 (s, 1H) , 5.00 (s, 2H) , 4.00 (s, 3H) , 3.71 (s, 3H) , 3.44 (s, 3H) , 2.24 (s, 3H) , 2.22 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.39, 163.70, 155.05, 154.71, 148.89, 141.40, 139.77, 139.61, 134.29, 131.56, 131.45, 131.09, 131.02, 130.00, 127.64, 124.73, 123.79, 121.46, 120.66, 105.64, 80.43, 59.80, 53.89, 51.89, 35.65, 28.23, 13.17, 10.45; HRMS (ESI-TOF) m/z Calcd for C ₃₀ H ₃₅ N ₄ O ₅ ^' [M+H] ⁺ : 531.2602, found: 531.2604.

6k

Methyl 2- (6- (( e t-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -4-oxo-2-phenyl-4fl- chromen-8-yl) benzoate (6k)

Substrate 2k was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 6k was obtained in 87% yield as a colorless solid. ¾ NMR (400 MHz , CDC1 ₃ ) δ 8.16 (s, 1H) , 8.11 (d, J = 7.7 Hz, 1H) , 8.01 (d, J = 2.6 Hz, 1H) , 7.78-7.62 (m, 2H) , 7.61-7.49 (m, 3H) , 7.48-7.33 (m, 4H) , 6.77 (s, 1H) , 5.02 (q, J = 15.1, 14.2 Hz, 2H) , 3.74 (s, 3H) , 3.40 (s, 3H) , 2.25 (s, 3H) , 2.21 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 178.08, 167.21, 163.75, 162.67, 154.60, 154.40, 150.81, 149.03, 139.91, 136.59, 134.50, 133.25, 132.19, 131.89, 131.69, 131.39, 131.27, 130.74, 130.52, 130.27, 128.83, 128.39, 126.00, 124.81, 123.70, 123.49, 120.74, 106.72, 80.78, 59.88, 53.26, 51.70, 28.20, 13.19, 10.44; HRMS (ESI-TOF) m/z Calcd for C ₃ 7H3 _{7 2} 07 [M+H] ⁺ : 621.2595, found: 621.2596.

61

Methyl 2- (7- ( ( fcert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-y1) methyl) amino) -2 , 3- dihydrobenzo [±>] [1 , 4] dioxin-5-yl) benzoate (61)

Substrate 21 was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 61 was obtained in 91% yield as a colorless solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.84 (d, J =

7.7 Hz, 1H) , 7.50 (t, J = 7.5 Hz, 1H) , 7.36 (s, 1H) , 7.21 (d, J = 6.4 Hz, 1H) , 6.81 (s, 1H) , 6.67 (s, 1H) , 4.89 (s, 2H) , 4.15 (dd, J = 5.6, 2.8 Hz, 2H) , 4.09 (dd, J = 5.7,

2.8 Hz, 2H) , 3.71 (s, 3H) , 3.64 (s, 3H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.41, 163.63, 155.14, 154.84, 148.86, 142.40, 138.20, 137.39, 135.73, 131.50, 131.39, 131.22, 129.88, 129.41, 127.28, 124.60, 123.90, 120.95, 115.08, 80.03, 64.11, 64.02, 59.77, 53.66, 51.62, 28.25, 13.14, 10.39; HRMS (ESI-TOF) m/z Calcd for C ₃ oH ₃₅ N ₂ 0 ₇ [M+H] ⁺ : 535.2439, found: 535.2438. Meta-Arylation of Phenols

3a-l 7a-l

General Procedure for meta-Arylation of Phenols : Substrate

3 (0.2 mmol), Ar-I (0.6 mmol) , Pd(0Ac) ₂ (4.5 mg, 10 mol%), L14 (4.4 mg, 10 mol%) , AgOAc (100.0 mg, 0.6 mmol), NBE- C0 ₂ Me (45.6 mg, 0.3 mmol) and CHC1 ₃ (1.0 mL) were added to a 50 mL schlenk tube. The tube was capped and closed tightly. The reaction mixture was then stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was passed through a pad of Celite® with EtOAc as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC plate to afford the desired arylated product. {In cases where mono:di ratios are possible, the selectivity was determined by ¹ H NMR.)

7a

Methyl 3 ' -methyl-5 ' - ( (3-methylpyridin-2-yl) methoxy) - [1 , 1 ¹ - biphenyl] -2-carboxylate (7a)

Substrate 3a was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7a was obtained in 87% yield as a light yellow liquid. ¹ R NMR

(400 MHz, CDCI ₃ ) 5 8.45 (d, J = 4.4 Hz, 1H) , 7.77 (d, J = 7.5 Hz, 1H) , 7.54-7.45 (m, 1H) , 7.41-7.34 (m, 2H) , 7.19

(dd, J = 7.7, 4.8 Hz, 2H) , 6.86 (s, 1H) , 6.80 (s, 1H) , 6.74 (s, 1H) , 5.20 (s, 2H) , 3.63 (s, 3H) , 2.43 (s, 3H) , 2.36 (s, 3H) ; ¹³ C NMR (100 MHz , CDC1 ₃ ) δ 169.26, 158.48,

154.32, 146.55, 142.35, 142.13, 139.01, 138.34, 133.22, 131.04, 131.02, 130.46, 129.49, 127.06, 123.38, 122.02, 114.56, 111.92, 70.81, 51.92, 21.53, 18.16; HRMS (ESI-TOF) m/z Calcd for C ₂₂ H ₂₂ O ₃ [M+H] ⁺ : 348.1594, found: 348.1598.

7b

Methyl 3 ' -me hoxy-5 ' - ( (3-methylpyridin-2-yl) methoxy) - [1,1' -biphenyl] -2-carboxylate (7b)

Substrate 3b was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7b was obtained in 91% yield as a light yellow liquid ¹ H NMR (400 MHz, CDCI ₃ ) 5 8.45 (d, J= 4.7 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H) , 7.54-7.46 (m, 2H) , 7.42-7.35 (m, 2H) , 7.19 (dd, J = 7.7, 4.8 Hz, 1H) , 6.26-6.58 (m, 2H) , 6.48 (s, 1H) , 5.19 (s, 2H) , 3.79 (s, 3H) , 3.64 (s, 3H) , 2.42 (s, 3H) ; ¹³ C NMR (100 MHz, CDCI ₃ ) δ 169.18, 160.32, 159.56, 154.14, 146.61, 143.23, 142.00, 138.36, 133.17, 131.09, 131.05, 130.34, 129.47, 127.24, 123.42, 107.40, 107.03, 100.18, 70.86, 55.33, 51.99, 18.14; HRMS (ESI-TOF) m/z Calcd for C ₂₂ H ₂₂ NO ₄ [M+H] ⁺ : 364.1543, found: 364.1552.

7c

Methyl 3 ' - (1 ,3-dioxolan-2-yl) -5 ' - ( (3-methylpyridin-2- yl) methoxy) -[1,1' -biphenyl] -2-carboxylate (7c)

Substrate 3c was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7c was obtained in 53% yield as a clear liquid. ¹ H NMR (400 MHz , CDC1 ₃ ) δ 8.45 (d, J = 4.8 Hz, 1H) , 7.79 (d, J = 7.6 Hz, 1H) , 7.55-7.46 (m, 2H) , 7.43-7.34 (m, 2H) , 7.19 (dd, J = 7.7, 4.8 Hz, 1H) , 7.16 (s, 1H) , 7.03 (s, 1H) , 7.01 (t, J = 1.9 Hz, 1H) ; 5.82 (s, 1H) , 5.23 (s, 2H) , 4.16-3.95 (m, 4H) , 3.61 (s, 3H) , 2.43 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 169.21, 158.58, 154.15, 146.61, 142.68, 141.68, 139.35, 138.39, 133.30, 131.15, 131.06, 130.54, 129.68, 127.31, 123.48, 119.50, 115.78, 111.57, 103.46, 71.00, 65.27, 51.98, 18.20; HRMS (ESI-TOF) m/z Calcd for C ₂ 4H _Z4 0 ₅ [M+H] ⁺ : 406.1649, found: 406.1656.

7d

Methyl 3 ' - ( (3-methylpyridin-2-yl) methoxy) -[1,1" -biphenyl] - 2-carboxylate (7d)

Substrate 3d was arylated following the general me ta- arylation procedure for phenols. Analysis of crude reaction mixture by ¹ H NMR showed the selectivity of mono- arid di- products {mono i d! = 1:1) . After purification by preparative thin-layer chromatography, Compound 7d was obtained in 38% yield as a clear liquid. ¾ NMR (400 MHz, CDCI ₃ ) δ 8.45 (d, J = 4.3 Hz, 1H) , 7.81-7.77 (m, 1H) , 7.54-7.49 (m, 2H) , 7.40 (td, J = 7.6, 1.3 Hz, 1H) , 7.38- 7.35 (m, 1H) , 7.30 (t, J = 7.9 Hz, 1H) , 7.19 (dd, J = 7.7, 4.8 Hz, 1H) , 7.03 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H) , 7.00

(s, 1H) , 6.90 (ddd, J = 7.5, 1.7, 0.9 Hz, 1H) , 5.22 (s, 2H) , 3.62 (s, 3H) , 2.44 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 169.15, 158.53, 154.28, 146.61, 142.68, 142.10, 138.40, 133.27, 131.15, 130.99, 130.55, 129.64, 128.99, 127.20, 123.44, 121.24, 114.99, 113.63, 70.89, 51.95, 18.20; HRMS

(ESI-TOF) m/z Calcd for C ₂₁ H ₂₀ O ₃ [M+H] ⁺ : 334.1438, found: 334.1443.

7d'

Dimethyl 5'- ( (3-methylpyridin-2-yl) methoxy) -[1,1' :3',1"- terphenyl] -2,2' ' -dicarboxylate (7d' )

Substrate 3d was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7d' was obtained in 40% yield as a clear liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.45 (d, J = 4.9 Hz, 1H) , 7.81-7.76 (m, 2H) , 7.55-7.48 (m, 3H) , 7.43-7.37 (m, 4H) , 7.20 (dd, J = 7.7, 4.8 Hz, 1H) , 6.99 (s, 2H) , 6.86 (s, 1H) , 5.23 (s, 2H) , 3.65 (s, 6H) , 2.44 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 169.09, 158.22, 154.11, 146.58, 142.40, 141.86, 138.43, 133.25, 131.13, 131.05, 130.58, 129.67, 127.27, 123.47, 121.51, 113.81, 70.88, 51.98, 18.19; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H ₂₆ N0 ₅ [M+H] ⁺ : 468.1805, found: 468.1809.

7e

Methyl 4 ' -methyl-3 ' - ( (3-methylpyridin-2-yl) methoxy) - [1,1 ¹ - biphenyl] -2-carboxylate (7e)

Substrate 3e was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7e was obtained in 85% yield as a light yellow liquid. ^X H NMR (400 MHz, CDCI ₃ ) δ 8.44 (d, J = 4.6 Hz, 1H) , 7.78 (d, J = 7.6 Hz, 1H) , 7.55-7.47 (m, 2H) , 7.42-7.33 (m, 2H) , 7.20 (dd, J = 7.7, 4.8 Hz, 1H) , 7.15 (d, J = 7.5 Hz, 1H) , 7.01 (s, 1H) , 6.82 (d, J = 7.6 Hz, 1H) , 5.21 (s, 2H) , 3.64 (d, J = 0.7 Hz, 3H) , 2.45 (s, 3H) , 2.25 (s, 3H) ; ¹³ C NMR (100 MHz, CDCI ₃ ) δ 169.32, 156.53, 154.54, 146.49, 142.29, 139.95, 138.32, 133.39, 131.09, 131.00, 130.62, 130.27, 129.54, 126.94, 125.90, 123.39, 120.64, 111.72, 71.19, 51.97, 18.16, 16.08; HRMS (ESI-TOF) m/z Calcd for C ₂₂ H ₂₂ O ₃ [M+H] ⁺ : 348.1594, found: 348.1597.

7f

Methyl 4 ' -isopropyl-3 ' - ( (3-methylpyridin-2-yl) methoxy) - [1,1' -biphenyl] -2-carboxylate (7f)

Substrate 3f was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7f was obtained in 89% yield as clear liquid. ¾ NMR (400 MHz, CDCI ₃ ) δ 8.44 (d, J = 4.6 Hz, 1H) , 7.77 (d, J = 7.2 Hz, 1H) , 7.56-7.46 (m, 2H) , 7.42-7.35 (m, 2H) , 7.26-7.16 (m, 2H) , 7.04 (s, 1H) , 6.89 (d, J = 7.8 Hz, 1H) , 5.20 (s, 2H) , 3.63 (s, 3H) , 3.34 (hept, J = 7.0 Hz, 1H) , 2.45 (s, 3H) , 1.20 (d, J = 6.9 Hz, 6H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ

169.43, 155.58, 154.58, 146.52, 142.18, 139.50, 138.28, 136.18, 133.32, 131.09, 131.03, 130.59, 129.49, 126.90, 125.70, 123.39, 120.94, 111.96, 71.28, 51.93, 26.36, 22.84, 18.14; HRMS (ESI-TOF) m/z Calcd for C ₂₄ H ₂₆ 0 ₃ [M+H] ⁺ : 376.1907, found: 376.1907.

Methyl 4 ' -methoxy-3 ¹ - ( (3-methylpyridin-2-yl) methoxy) - [1,1' -biphenyl] -2-carboxylate (7g) Substrate 3g was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7g was obtained in 54% yield as a light yellow liquid. ½ NMR (400 MHz, CDC13) δ 8.42 (d, J = 4.9 Hz, 1H) , 7.76 (d, J = 7.7 Hz, 1H) , 7.53-7.47 (m, 2H) , 7.37 (t, J = 7.6 Hz, 1H) , 7.32 (d, J = 7.7 Hz, 1H) , 7.17 (dd, J = 7.7, 4.8 Hz, 1H) , 7.07 (d, J = 1.2 Hz, 1H) , 6.94-6.84 (m, 2H) , 5.25 (s, 2H) , 3.88 (s, 3H) , 3.63 (s, 3H) , 2.47 (s, 3H) ; ¹³ C NMR (100 MHz, CDC13) δ 169.39, 154.26, 149.19, 147.74, 146.49, 141.84, 138.36, 133.85, 133.43, 131.08, 130.96, 130.63, 129.58, 126.81, 123.35, 121.44, 114.84, 111.27, 72.02, 55.89, 51.96, 18.20; HRMS (ESI-TOF) m/z Calcd for C ₂₂ H ₂₂ 0 ₄ [M+H] ⁺ : 364.1543, found: 364.1547.

7h

Methyl 4 ' -chloro-3 ' - ( (3-methylpyridin-2-yl) methoxy) - [1,1 '- biphenyl] -2-carboxylate (7h)

Substrate 3h was arylated following a slightly modified jneta-arylation procedure for phenols. For this substrate, L12 was used in place of L14 and the reaction was run for 36 hours. After purification by preparative thin-layer chromatography, Compound 7h was obtained in 81% yield as a colorless solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.42 (d, J = 4.7 Hz, 1H) , 7.83 (d, J = 7.7 Hz, 1H) , 7.56-7.49 (m, 2H) , 7.42 (t, J = 7.6 Hz, 1H) , 7.35 (d, J = 8.1 Hz, 1H) , 7.30 (d, J = 7.7 Hz, 1H) , 7.20 (dd, J = 7.7, 4.8 Hz, 1H) , 7.14 (d, J = 1.9 Hz, 1H) , 6.82 (dd, J = 8.1, 1.9 Hz, 1H) , 5.29 (s, 2H) , 3.62 (s, 3H) , 2.50 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 168.71, 153.72, 153.63, 146.40, 141.40, 141.18, 138.50, 133.78, 131.33, 130.65, 130.56, 129.89, 129.65, 127.48, 123.60, 122.11, 121.68, 114.38, 72.13, 51.98, 18.23; HRMS (ESI-TOF) m/z Calcd for C ₂₁ H ₁₉ C1N0 ₃ [M+H] ⁺ : 368.1048, found:

368.1053.

7i

Methyl 2- (4- ( (3-methylpyridin-2-yl) methoxy) -5,6,7,8- tetrahydronaphthalen-2-yl) benzoate (7i)

Substrate 3i was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7i was obtained in 90% yield as a light yellow liquid. ^X H NMR

(400 MHz, CDC1 ₃ ) δ 8.43 (d, J = 4.7 Hz, 1H) , 7.75 (d, J = 7.9 Hz, 1H) , 7.54-7.46 m, 2H) , 7.41-7.33 (m, 2H) , 7.18

(dd, J = 7.6, 4.8 Hz, 1H) , 6.82 (s, 1H) , 6.68 (s, 1H) , 5.17 (s, 2H) , 3.66 (s, 3H) , 2.78-2.74 (m, 2H) , 2.71-2.65

(m, 2H) , 2.43 (s, 3H) , 1.82-1.72 m, 4H) ; ¹³ C NMR (100 MHz, CDCI ₃ ) δ 169.50, 156.15, 154.63, 146.45, 142.35, 138.65, 138.27, 138.14, 133.37, 131.08, 130.98, 130.58, 129.38, 126.80, 125.29, 123.33, 121.58, 108.53, 71.05, 51.99, 29.67, 23.04, 22.79, 22.70, 18.19; HRMS (ESI-TOF) m/z Calcd for C ₂₅ H ₂₆ N0 ₃ [M+H] ⁺ : 388.1907, found: 388.1910.

7j

Methyl 2- (4- ( (3-methylpyridin-2-yl) methoxy) naphthalen-2- yl) benzoate (7j)

Substrate 3j was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7j was obtained in 87% yield as a yellow liquid. ½ NMR (400 MHz, CDCI ₃ ) δ 8.47 (d, J = 4.8, 1.5 Hz, 1H) , 8.24 (d, J = 8.2 Hz, 1H) , 7.84 (dd, J = 7.6Hz, 1H) , 7.79 (d, J = 8.0 Hz, 1H) , 7.59-7.52 (m, 2H) , 7.51-7.40 (m, 4H) , 7.39 (s, 1H) , 7.23 (dd, J = 7.7, 4.9 Hz, 1H) , 7.02 (d, J = 1.4 Hz, 1H) , 5.38 (s, 2H) , 3.55 (s, 3H) , 2.47 (s, 3H) ; ¹³ C NMR (100 MHz, CDCI ₃ ) δ 169.27, 154.25, 154.04, 146.57, 142.43, 139.06, 138.40, 134.23, 133.52, 131.19, 131.15, 130.84, 129.71, 127.66, 127.22, 126.70, 125.25, 124.76, 123.52, 121.98, 119.70, 106.67, 71.33, 51.97, 18.23; HRMS (ESI-TOF) m/z Calcd for C ₂₅ H ₂₂ O ₃ [M+H] ⁺ : 384.1594, found: 384.1598.

7k

Methyl 2- (6- ( (3-methylpyridin-2-yl) methoxy) -2 , 3-dihydro- lH-inden-4-yl)benzoate (7k)

Substrate 3k was arylated following the general meta- arylation procedure for phenols. After purification by preparative thin-layer chromatography, Compound 7k was obtained in 42% yield as a clear liquid. ^X H NMR (400 MHz, CDCI3 ) δ 8.44 (d, J = 4.9 Hz, 1H) , 7.88 (d, J = 7.8 Hz, 1H) , 7.54-7.48 (m, 2H) , 7.39 (t, J = 7.6 Hz, 1H) , 7.31- 7.23 (m, 1H) , 7.18 (dd, J = 7.7, 4.8 Hz, 1H) , 6.92 (s, 1H) , 6.69 (d, J = 2.3 Hz, 1H) , 5.18 (s, 2H) , 3.62 (s, 3H) , 2.93 (t, J = 7.4 Hz, 2H) , 2.55 (t, J = 7.3 Hz, 2H) , 2.43 (s, 3H) , 2.06 - 1.94 (m, 2H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 168.28, 157.49, 154.57, 146.50, 145.21, 142.14, 138.50, 138.34, 134.70, 133.27, 131.35, 130.67, 130.38, 129.80, 127.03, 123.32, 113.01, 109.93, 71.11, 51.94, 33.41, 31.11, 25.59, 18.21; HRMS (ESI-TOF) m/z Calcd for C24H2 NO3 [M+H] ⁺ : 374.1757, found: 374.1757.

71

Methyl 2 ' -methoxy-5 ' - ( (3-methylpyridin-2-yl) raethoxy) - [1,1' -biphenyl] -2-carboxylate (71)

Substrate 31 was arylated following the general meta- arylation procedure for phenols. Analysis of crude reaction mixture by ¹ H NMR showed the selectivity of mono- arid di- products (mono:di = 20>1) . After purification by preparative thin-layer chromatography, Compound 71 was obtained in 58% yield as a light yellow liquid. ¹ H NMR

(400 MHz, CDC1 ₃ ) δ 8.45 (d, J = 4.3 Hz, 1H) , 7.85 (dd, J = 7.7, 1.4 Hz, 1H) , 7.57-7.49 (m, 2H) , 7.39 (td, J = 7.6, 1.2 Hz, 1H) , 7.31 (dd, J = 7.6, 1.3 Hz, 1H) , 7.19 (dd, J = 7.6, 4.8 Hz, 1H) , 7.02-6.96 (m, 2H) , 6.80 (d, J = 8.5 Hz, 1H) , 5.19 (s, 2H) , 3.63-3.68 (m, 6H) , 2.44 (s, 3H) ; ¹³ C NMR

(100 MHz, CDCI ₃ ) δ 168.52, 154.52, 152.76, 150.57, 146.55, 138.40, 138.36, 133.23, 131.62, 131.51, 131.37, 131.20, 129.30, 127.18, 123.36, 117.34, 114.11, 111.00, 71.48, 55.73, 51.68, 18.21; HRMS (ESI-TOF) m/z Calcd for C ₂₂ H ₂₂ NO ₄

[M+H] ⁺ : 364.1543, found: 364.1543.

Meta-Arylation of Other Heterocyclic Substrates

General Procedure for meta-Arylation of Other Heterocycle Substrates: Substrate 4 (0.1 mmol) , methyl 2-iodobenzoate

(43.0 L, 0.3 mmol), Pd(OAc) ₂ (2.2 mg, 10 mol%) , L14 (4.4 mg, 20 mol%) , AgOAc (50.1 mg, 0.3 mmol), 2-Norbornene

(14.1 mg, 0.15 mmol) and CHC1 ₃ (1.0 mL) were added to a 2- dram vial. The vial was capped and closed tightly. Then the reaction mixture was then stirred at 90 °C for 24 hours. After cooling to room temperature, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resultant solution was concentrated and purified by preparative TLC to afford the desired arylated product. (In cases where mono:di ratios are possible , the selectivity was determined by ¹ H NMR. )

Methyl 3 ' - (pyridin-2-ylmethyl) -[1,1· -biphenyl] -2- carboxylate (8a)

Substrate 4a was arylated following the general meta- arylation procedure using 2-norbornene. Analysis of crude reaction mixture by ¹ H NMR showed the selectivity of mono- arid di- products (mono di = 2:1) . After purification by preparative thin-layer chromatography, Compounds 8a and 8a' were obtained in 92% total yield.

½ NMR (400 MHz, CDC1 ₃ ) δ 8.58-8.53 (m, 1H) , 7.79 (d, J = 7.5 Hz, 1H) , 7.58 (td, J = 7.7, 1.8 Hz, 1H) , 7.50 (t, J = 7.5 Hz, 1H) , 7.42-7.31 (m, 3H) , 7.30-7.24 (m, 1H) , 7.23- 7.16 (m, 2H) , 7.16-7.08 (m, 2H) , 4.19 (s, 2H) , 3.55 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.11, 160.85, 149.30, 142.23, 141.50, 139.17, 136.53, 131.15, 130.88, 130.64, 129.66, 129.10, 128.30, 128.04, 127.09, 126.38, 123.11, 121.25, 51.84, 44.62; HRMS (ESI-TOF) m/z Calcd for C ₂ oHi ₈ 0 ₂ [M+H] ⁺ : 304.1332, found: 304.1332.

Dimethyl 5 ' - (pyridin-2-ylmethy1) -[1,1' :3' ,1' ¹ -terphenyl] - 2 , 2 ^{1 ■} -dicarboxylate (8a')

¾ NMR (400 MHz, CDC1 ₃ ) δ 8.55 (d, J = 3.6 Hz, 1H) , 7.82- 7.76 (m, 2H) , 7.60 (td, J = 7.7, 1.8 Hz, 1H) , 7.54-7.47

(m, 2H) , 7.43-7.36 (m, 4H) , 7.20 (s, 2H) , 7.19-7.15 (m, 2H) , 7.12 (dd, J = 7.5, 5.0 Hz, 1H) , 4.23 (s, 2H) , 3.58

(s, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.10, 160.77, 149.30, 141.94, 141.44, 138.84, 136.54, 131.15, 131.02, 130.67, 129.70, 128.12, 127.19, 126.46, 123.13, 121.30, 51.87, 44.56; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₂₄ N0 ₄ [M+H] ⁺ :

438.1700, found: 438.1698.

Dimethyl 5 ' - (pyridin-2-ylmethyl) -[Ι,Ι' :3' ,1" -terphenyl] - 2,2'* -dicarboxylate (8b)

Substrate 4b was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 8b was obtained in 92% yield. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.55-8.49 (m, 1H) , 8.00 (d, J = 7.9 Hz, 1H) , 7.84 (dd, J = 7.7, 1.4 Hz, 1H) , 7.59-7.48 (m, 2H) , 7.42 (td, J = 7.6, 1.3 Hz, 1H) , 7.35 (dd, J = 7.6, 1.3 Hz, 1H) , 7.30- 7.24 (m, 2H) , 7.12-7.04 (m, 2H) , 4.61 (s, 2H) , 3.83 (s, 3H) , 3.59 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.53, 167.72, 160.74, 149.08, 145.28, 141.29, 140.29, 136.36, 132.08, 131.38, 130.72, 130.56, 130.54 , 129.98, 128.63, 127.70, 126.57, 122.88, 121.04, 51.96, 51.95, 42.53; HRMS (ESI-TOF) m/z Calcd for C ₂₂ H ₂₀ O ₄ [M+H] ⁺ : 362.1387, found: 362.1387.

Dimethyl 5 ' - ( (3-methylpyridin-2-yl) methyl) -[1,1':3',1''- terphenyl] -2,2' ¹ -dicarboxylate (8c' )

Substrate 4c was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, - Compound 8c' was obtained in 55% total yield as a sole product .

¾ NMR (400 MHz, CDC1 ₃ ) δ 8.42 (d, J = 4.5 Hz, 1H) , 7.77 (d, J = 7.5 Hz, 2H) , 7.49 (t, J = 7.5 Hz, 2H) , 7.43 (d, J = 7.3 Hz, 1H) , 7.41-7.34 (m, 4H) , 7.14-7.06 (m, 4H) , 4.26 (s, 2H) , 3.57 (s, 6H) , 2.29 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.11, 158.50, 146.81, 142.01, 141.26, 138.57, 138.06, 131.84, 131.12, 131.03, 130.69, 129.66, 127.59, 127.14, 126.23, 121.85, 51.85, 42.24, 19.06; HRMS (ESI- TOF) m/z Calcd for C ₂₉ H ₂₆ NO ₄ [M+H] ⁺ : 452.1856, found:

452.1856.

Dimethyl 5 ¹ - ( (5-methylpyridin-2-yl) methyl) -[1,1':3',1''- terpheny1] -2,2' ' -dicarboxylate (8d' )

Substrate 4d was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 8d' was obtained in 60% yield as a sole product. XH NMR (400 MHz, CDC1 ₃ ) δ 8.37 (d, J = 2.2 Hz, 1H) , 7.82 - 7.76 (m, 2H) , 7.50 (td, J = 7.5, 1.4 Hz, 2H) , 7.43-7.35 (m, 5H) , 7.18 (d, J = 1.6 Hz, 2H) , 7.14 (t, J = 1.6 Hz, 1H) , 7.05 (d, J = 7.9 Hz, 1H) , 4.18 (s, 2H) , 3.59 (s, 6H) , 2.29 (s, 3H) ; ^iJ C NMR (100 MHz, CDC1 ₃ ) δ 169.13, 157.76, 149.61, 141.99, 141.38, 139.18, 137.13, 131.13, 131.02, 130.69, 130.55, 129.69, 128.07, 127.17, 126.38, 122.61, 51.87, 44.07, 18.01; HRMS (ESI-TOF) m/z Calcd for C ₂ 9H ₂₆ 0 ₄ [M+H] ⁺ : 452.1856, found: 452.1855.

Methyl 3 ' - (pyrimidin-2-ylmethyl) -[1,1' -biphenyl] -2- carboxyl te (8e)

Substrate 4e was arylated following the general meta- arylation procedure using 2-norbornene. Analysis of crude reaction mixture by ¹ R NMR showed the selectivity of mono- and di- products (mono:di = 4:1). After purification by preparative thin-layer chromatography, Compouds 8e and 8e' were obtained in 64% total yield. ¹ H NMR (600 MHz, CDC1 ₃ ) δ 8.68 (d, J = 4.9 Hz, 2H) , 7.78 (ddd, J = 7.7, 1.4, 0.6 Hz, 1H) , 7.50 (td, J = 7.6, 1.4 Hz, 1H) ; 7.41-7.32 (m, 4H) , 7.31- 7.29 (m, 1H) , 7.18 (dt, J = 6.9, 1.8 Hz, 1H) , 7.13 (t, J = 4.9 Hz, 1H) , 4.33 (s, 2H) , 3.57 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.89, 169.20, 157.29, 142.20, 141.40, 137.99, 131.13, 130.93, 130.69, 129.65, 129.10, 128.20, 128.05, 127.08, 126.59, 118.69, 51.87, 45.99; HRMS (ESI-TOF) m/z Calcd for Ci ₉ H ₁₇ N ₂ 0 ₂ [M+H] ⁺ : 305.1285, found: 305.1284.

Dimethyl 5 ' - (pyrimidin-2-ylmethy1) -[Ι,Ι' :3' ,1' '- terphenyl] -2,2 ' ' -dicarboxylate (8e' )

½ NMR (400 MHz, CDC1 ₃ ) δ 8.69 (d, J = 4.9 Hz, 2H) , 7.79 (d, J = 7.5 Hz, 2H) , 7.50 (t, J = 7.5 Hz, 2H) , 7.42-7.36 (m, 4H) , 7.28 (s, 2H) , 7.26 (s, 1H) , 7.17-7.12 (m, 1H) , 4.36 (s, 2H) , 3.59 (s, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.75, 169.22, 157.29, 141.93, 141.28, 137.74, 131.14, 131.05, 130.72, 129.69, 128.06, 127.17, 126.63, 118.77, 51.89, 45.86; HRMS (ESI-TOF) m/z Calcd for C _Z7 H _{23 2} O ₄ [M+H] ⁺ : 439.1652, found: 439.1652.

Methyl 3 ' - (pyrazin-2-ylme hyl) -[1,1' -biphenyl] -2- carboxylate (8f)

Substrate 4f was arylated following the general meta- arylation procedure using 2-norbornene. Analysis of crude reaction mixture by ^X H NMR showed the selectivity of mono - arid di- products {mono di = 2:1). After purification by preparative thin-layer chromatography, Compounds 8f and 8f were obtained in 84% total yield.

^X H NMR (400 MHz, CDC1 ₃ ) δ 8.51 (d, J = 2.0 Hz, 1H) , 8.48 (s, 1H) , 8.42 (d, J = 2.5 Hz, 1H) , 7.81 (d, J = 7.9 Hz, 1H) , 7.51 (t, J = 7.4 Hz, 1H) , 7.40 (t, J = 8.0 Hz, 1H) , 7.35 (d, J = 7.6 Hz, 2H) , 7.24-7.18 (m, 1H) , 7.21 (d, J - 8.0 Hz, 2H) , 4.21 (s, 2H) , 3.59 (s, 3H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 168.97, 156.41, 144.78, 144.08, 142.41, 142.09, 141.83, 137.81, 131.23, 130.79, 130.66, 129.76, 129.02, 128.48, 127.92, 127.23, 126.83, 51.92, 41.96; HRMS (ESI- TOF) m/z Calcd for Ci ₉ Hi ₇ N ₂ 0 ₂ [M+H] ⁺ : 305.1285, found:

305.1285.

Dimethyl 5 ' - (pyrazin-2-ylmethyl) - [1 , 1 ¹ : 3 ¹ , 1 ' ' -terphenyl] 2 ,2 ' ' -dicarboxylate (8f' ) ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.52 (d, J = 1.6 Hz, 1H) , 8.49 (s, 1H) , 8.43 (d, J = 2.6 Hz, 1H) , 7.81 (d, J = 7.7 Hz, 2H) , 7.54-7.48 (m, 2H) , 7.44-7.36 (m, 4H) , 7.20 (s, 2H) , 7.17 (s, 1H) , 4.25 (s, 2H) , 3.61 (s, 6H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 168.97, 156.39, 144.81, 144.07, 142.45, 141.82, 141.76, 137.46, 131.24, 130.94, 130.70, 129.82, 128.01, 127.34, 126.91, 51.97, 41.95; HRMS (ESI-TOF) m/z Calcd for C ₂₇ H _{23 2} 0 ₄ [M+H] ⁺ : 439.1652, found: 439.1652.

M Uethy-l 3 ' - ( (lH-pyrazol-l-yl) methyl) -[1,1' -biphenyl] -2- carboxylate (8g)

Substrate 4g was arylated following the general meta- arylation procedure using 2-norbornene. Analysis of crude reaction mixture by ¹ E NMR showed the selectivity of mono- and di- products {mono:di = 1:2) . After purification by preparative thin-layer chromatography, Compounds 8g and 8g' were obtained in 84% total yield.

½ NMR (400 MHz, CDC1 ₃ ) δ 8.69 (d, J = 4.9 Hz, 2H) , 7.78 (d, J = 7.7 Hz, 1H) , 7.54-7.47 (m, 1H) , 7.42-7.28 (m, 5H) , 7.22 - 7.16 (m, 1H) , 7.14 (t, J = 4.9 Hz, 1H) , 4.33 (s, 2H) , 3.57 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.89, 169.22, 157.30, 142.20, 141.41, 137.99, 131.14, 130.92, 130.70, 129.66, 129.10, 128.21, 128.05, 127.08, 126.60, 118.70, 51.88, 45.98; HRMS (ESI-TOF) m/z Calcd for

Ci ₈ Hi ₇ N ₂ 0 ₂ [M+H] ⁺ : 293.1285, found: 293.1285.

Dimethyl 5 ' - ( (lH-pyrazol-l-yl) methyl) -[!,!' :3' ,1

terphenyl] -2,2' ' -dicarboxylate (8g' ) ¾ NMR (400 MHz, CDC1 ₃ ) δ 7.82 (d, J = 7.7 Hz, 2H) , 7.57- 7.48 (m, 3H) , 7.45-7.35 (m, 5H) , 7.22 (s, 1H) , 7.15 (s, 2H) , 6.29 (t, J = 2.2 Hz, 1H) , 5.39 (s, 2H) , 3.62 (s, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.80, 141.77, 141.64, 139.57, 136.00, 131.30, 130.82, 130.72, 129.88, 129.26, 128.10, 127.43, 126.71, 106.00, 55.79, 51.99; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₂ 3 ₂ 04 [M+H] ⁺ : 427.1652, found: 427.1652.

Methyl 3 ' - (N- (pyridin-2-yl) acetamido) -[1,1' -biphenyl] -2- carboxylate (8h)

Substrate 4h was arylated following the general meta- arylation procedure using 2-norbornene . After

purification by preparative thin-layer chromatography, Compound 8h was obtained in 60% yield as a sole product. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.47-8.40 (m, 1H) , 7.83 (dd, J = 7.7, 1.4 Hz, 1H) , 7.72 (td, J = 7.8, 2.0 Hz, 1H) , 7.57- 7.35 (m, 5H) , 7.35-7.28 (m, 2H) , 7.22 (t, J = 2.0 Hz, 1H) , 7.17-7.10 (m, IE), 3.59 (s, 3H) , 2.15 (s, 3E) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 171.03, 168.60, 155.16, 148.74, 142.68, 141.62, 141.37, 137.92, 131.38, 130.72, 130.60, 129.95, 129.14, 128.61, 127.52, 127.23, 121.43, 121.16, 51.97, 24.29; HRMS (ESI-TOF) m/z Calcd for C ₂ iH ₁₉ N ₂ 03 [M+H] ⁺ :

347.1390, found: 347.1389.

Methyl 3 ' - ( ( terfc-butoxycarbonyl) (pyrimidin-2-yl) amino) - [1,1' -biphenyl] -2-carboxylate (8i)

Substrate 4i was arylated following the general meta- arylation procedure using 2-norbornene. After purification by preparative thin-layer chromatography, 8i was obtained in 50% yield as a sole product. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.66 (d, J = 4.8 Hz, 2H) , 7.82-7.77 (m, 1H) , 7.51 (td, J = 7.6, 1.4 Hz, 1H) , 7.45-7.34 (m, 3H) , 7.26-7.21 (m, 2H) , 7.15 (t, J = 2.0 Hz, 1H) , 7.05 (t, J = 4.8 Hz, 1H) , 3.61 (s, 3H) , 1.46 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.03, 161.28, 158.23, 153.14, 142.15, 141.49, 141.01, 131.21, 130.97, 130.62, 130.05, 129.77, 128.53, 127.61, 127.34, 126.79, 126.56, 117.27, 82.07, 51.95, 28.07; HRMS (ESI- TOF) m/z Calcd for C ₂ 3H _{24 3} 0 ₄ [M+H] ⁺ : 406.1761, found:

406.1761.

Methyl 3' - ( (2H-indazol-2-yl) methyl) - [1,1 ' -biphenyl] -2- carboxylate (8j )

Substrate 4j was arylated following the general meta- arylation procedure using 2-norbornene. Analysis of crude reaction mixture by ¹ H NMR showed the selectivity of mono- arid di- products (mono:di = 3:1) . After purification by preparative thin-layer chromatography, Compounds 8j and 8j' were obtained in 74% total yield. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.05 (d, J = 0.9 Hz, 1H) , 7.82-7.76 (m, 1H) , 7.78-7.70 (m, 1H) , 7.49 (td, J = 7.5, 1.4 Hz, 1H) , 7.43- 7.27 (m, 5H) , 7.24-7.10 (m, 4H) , 5.64 (s, 2H) , 3.47 (d, J = 0.5 Hz, 3H) ; ¹³ C NMR (100 MHz , CDC1 ₃ ) δ 168.82, 141.96, 141.83, 139.52, 136.68, 133.39, 131.24, 130.75, 130.68, 129.79, 128.43, 127.80, 127.28, 127.22, 126.38, 126.12, 124.38, 121.14, 120.64, 109.29, 52.96, 51.80; HRMS (ESI- TOF) m/z Calcd for C ₂₂ H ₁₉ N ₂ 0 ₂ [M+H] ⁺ : 343.1441, found:

343.1442.

Dimethyl 5 ¹ - ( (2H-indazol-2-yl) methyl) -[1,1' :3' ,1' '- terphenyl] -2,2' ' -dicarboxylate (8j ' )

½ NMR (400 MHz , CDC1 ₃ ) δ 8.04 (s, 1H) , 7.79 (d, J = 7.5 Hz, 2H) , 7.74 (d, J = 8.0 Hz, 1H) , 7.49 (t, J = 7.3 Hz, 2H) , 7.43-7.31 (m, 6H) , 7.15 (d, J = 11.4 Hz, 4H) , 5.66 (s, 2H) , 3.49 (s, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.82, 141.73, 141.66, 139.49, 136.42, 133.40, 131.23, 130.88, 130.72, 129.83, 127.90, 127.37, 126.38, 126.25, 124.42, 121.16, 120.67, 109.33, 52.97, 51.82; HRMS ( ES I -TOF) m/z Calcd for C ₃ oH _{25 2} 0 ₄ [M+H] ⁺ : 477.1809, found: 477.1810.

Methyl 3 ' - ( (lH-indazol-l-yl) methyl) -[1,1' -biphenyl] -2- carboxylate (8k)

Substrate 4k was arylated following the general me ta- arylation procedure using 2-norbornene. Analysis of crude reaction mixture by ½ NMR showed the selectivity of mono - arid di - products [mono i di = 3:1) . After purification by preparative thin-layer chromatography, 8k and 8k' was obtained in 50% total yield.

¹ H' NMR (400 MHz, CDC1 ₃ ) δ 8.04 (s, 1H) , 7.79 (d, J = 7.5 Hz, 1H) , 7.74 (d, J = 8.1 Hz, 1H) , 7.48 (td, J = 7.6, 1.4 Hz, 1H) , 7.41-7.26 (m, 5H) , 7.24-7.10 (m, 4H) , 5.63 (s, 2H) , 3.47 (s, 3H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 168.81, 141.94, 141.81, 139.51, 136.68, 133.38, 131.23, 130.74, 130.67, 129.78, 128.43, 127.79, 127.26, 127.21, 126.37, 126.11, 124.37, 121.13, 120.63, 109.28, 52.94, 51.79; HRMS (ESI-TOF ) m/z Calcd for C^HigNzOz [M+H] ⁺ : 343.1441, found: 343.1440.

Dimethyl 5 ¹ - ( (lH-indazol-l-yl) methyl) -[1,1' :3' ,1' '- terpheny1] -2,2' ' -dicarboxylate (8k' )

^X H NMR (400 MHz, CDC1 ₃ ) δ 8.04 (s, 1H) , 7.79 (d, J = 7.9 Hz, 2H) , 7.74 (d, J = 8.1 Hz, 1H) , 7.49 (t, J = 7.4 Hz, 2H) , 7.44-7.31 (m, 6H) , 7.20-7.10 (m, 4H) , 5.66 (s, 2H) , 3.49 (s, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.81, 141.73,

141.66, 139.49, 136.42, 133.40, 131.23, 130.88, 130.72, 129.83, 127.90, 127.37, 126.38, 126.25, 124.42, 121.16,

120.67, 109.33, 52.97, 51.82; HRMS (ESI-TOF) m/z Calcd for C ₃ oH _{25 2} 04 [M+H] ⁺ : 477.1809, found: 477.1808.

Dimethyl 5 ' - (isoquinolin-l-ylmethyl) -[1,1' :3 ' ,1 ' ' - terphenyl] -2,2' ' -dicarboxylate (81' )

Substrate 41 was arylated following the general meta- arylation procedure using 2-norbornene. After

purification by preparative thin-layer chromatography, Compound 81' was obtained in 78% yield as a sole product. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.49 (d, J = 5.7 Hz, 1H) , 8.21 (d, J = 8.4 Hz, 1H) , 7.82 (d, J = 8.1 Hz, 1H) , 7.76 (d, J = 1.1 Hz, 2H) , 7.64 (t, J = 7.5 Hz, 1H) , 7.60-7.53 (m, 2H) , 7.48 (t, J = 7.9 Hz, 2H) , 7.41-7.32 (m, 4H) , 7.22 (s, 2H) , 7.10 (s, 1H) , 4.73 (s, 2H) , 3.41 (s, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.07, 159.85, 142.02, 141.89, 141.41, 139.00, 136.61, 131.11, 131.03, 130.67, 129.86, 129.66, 127.57, 127.36, 127.23, 127.17, 127.14, 126.37, 125.90, 119.90, 51.70, 42.12; HRMS (ESI-TOF) m/z Calcd for C ₃₂ H ₂₆ O ₄

[M+H] + 488.1856, found: 488.1857.

Scope of Aryl Iodides

General Procedure for meta-Arylation of Anilines:

Substrate la (0.1 mmol), Ar-I (0.2 mmol) , Pd(OAc) ₂ (2.2 mg, 10 mol%), Ligand (3.0 mg, 20 mol%) , AgOAc (50.1 mg, 0.3 mmol), NBE-C0 ₂ Me (21.6 mg, 0.15 mmol) and DCE (0.5 iriL) were added to a 2-dram vial. The vial was capped and closed tightly. The reaction mixture was then stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC plate to afford the desired arylated product .

fcert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (5 methyl- [1 , 1 ' -biphenyl] -3-yl) carbamate (9a)

Following the general roeta-arylation procedure using NBE- C0 ₂ Me, Compound 9a was obtained in 87% yield as a

colorless liquid. *H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.47 (d, J = 7.5 Hz, 2H) , 7.38 (t, J = 7.5 Hz, 2H) , 7.29 (t, J = 7.3 Hz, 1H) , 7.23 (s, 1H) , 7.14 (s, 1H) , 7.07 (s, 1H) , 4.94 (s, 2H) , 3.71 (s, 3H) , 2.22 (s, 3H) , 2.21 (s, 3H) , 1.41 (s, 9H); ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.64, 155.20, 154.75, 148.96, 143.04, 141.14, 141.05, 138.35,

128.55, 127.08, 125.85, 125.23, 124.64, 123.74, 122.61, 80.25, 59.82, 53.55, 28.30, 21.46, 13.19, 10.44; HRMS (ESI-TOF) m/z Calcd for C27H33 2O3 [M+H] ⁺ : 433.2486, found: 433.2487.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (5- methyl-[l,l' : 4 ¹ ,1 ' ¹ -terphenyl] -3-yl) carbamate (9b)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9b was obtained in 79% yield as a

colorless solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.19 (s, 1H) , 7.62 (d, J = 8.0 Hz, 4H) , 7.56 (d, J = 8.1 Hz, 2H) , 7.44 (t, J = 7.6 Hz, 2H) , 7.34 (t, J = 7.3 Hz, 1H) , 7.29 (s, 1H) , 7.19 (s, 1H) , 7.09 (s, 1H) , 4.95 (s, 2H) , 3.72 (s, 3H) , 2.35 (s, 3H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.65, 155.20, 154.75, 148.97, 143.13, 140.67, 140.60, 139.94, 138.41, 137.83, 128.74, 127.41, 127.29, 127.25, 126.97, 125.97, 125.09, 124.65, 123.73, 122.48, 80.26, 59.82, 53.54, 28.30, 21.48, 13.19, 10.44; HRMS (ESI-TOF) m/z Calcd for C33H3 ₇ N2O3 [M+H] ⁺ : 509.2799, found: 509.2799.

ter-t-Butyl (4 ' , 5-dimethyl- [1,1' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9c)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9c was obtained in 82% yield as a colorless liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.37 (d, J = 7.9 Hz, 2H) , 7.23-7.21 (m, 3H) , 7.13 (s, 1H) , 7.04 (s, 1H) , 4.93 (s, 2H) , 3.71 (s, 3H) , 2.36 (s, 3H) , 2.32 (s, 3H) , 2.21 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.63, 155.21, 154.77, 148.94, 142.99, 141.04, 138.26, 138.15, 136.82, 129.26, 129.24, 126.89, 125.60, 125.04, 124.61, 123.73, 122.40, 80.20, 59.81, 53.55, 28.29, 28.26, 21.45, 21.05, 13.17, 10.42; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₃₅ N ₂ O ₃ [M+H] ⁺ : 447.2642, found: 447.2643.

terfc-Butyl ( ' - ( ( (tert-butyldimethylsilyl) oxy) methyl) -5- methyl- [1,1 ¹ -biphenyl] -3-yl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate ( 9d)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9d was obtained in 83% yield as a light yellow liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.44 (d, J = 8.1 Hz, 2H) , 7.33 (d, J = 8.1 Hz, 2H) , 7.21 (s, 1H) , 7.14 (s, 1H) , 7.05 (s, 1H) , 4.94 (s, 2H) , 4.76 (s, 2H) , 3.71 (s, 3H) , 2.33 (s, 3H) , 2.21 (s, 3H) , 2.21 (s, 3H) , 1.41 (s, 9H) , 0.95 (s, 9H) , 0.11 (s, 6H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 163.65, 155.19, 154.76, 148.95, 142.98, 140.98, 140.34, 139.66, 138.30, 126.89, 126.29, 125.75, 125.15, 124.64, 123.77, 122.51, 80.23, 64.73, 59.81, 53.54, 28.29, 25.95, 21.46, 18.42, 13.18, 10.44, -5.24; HRMS (ESI-TOF) m/z Calcd for C ₃ 4H4 _{9 2} 0 ₄ Si [M+H] ⁺ : 577.3456, found: 577.3456.

terfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - (4 ' -methoxy-5-methyl- [1,1' -biphenyl] -3-yl) carbamate (9e)

Following the general meta-arylation procedure using NBE C0 ₂ Me, Compound 9e was obtained in 81% yield as a

colorless liquid. ¾ NMR (400 MHz , CDC1 ₃ ) δ 8.17 (s, 1H) , 7.41 (d, J = 8.5 Hz, 2H) , 7.19 (s, 1H) , 7.10 (s, 1H) , 7. (s, 1H) , 6.92 (d, J = 8.5 Hz, 2H) , 4.93 (s, 2H) , 3.83 (s 3H) , 3.71 (s, 3H) , 2.32 (s, 3H) , 2.21 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.63, 158.98, 155.22, 154.77, 148.94, 143.01, 140.72, 138.27, 133.59, 128.06, 125.28, 124.82, 124.62, 123.74, 122.17, 113.98, 80.20, 59.82, 55.29, 53.55, 28.30, 21.46, 13.19, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H _{35 2} 0 ₄ [M+H] ⁺ : 463.2591, found: 463.2591.

tert-Butyl (4 ' - ( (tert-butyldimethylsilyl) oxy) -5-methy1- [1 , 1 ' -biphenyl] -3-yl) ( (4-methoxy-3 , 5-dimethyl-pyridin-2- yl) methyl) carbamate (9f)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9f was obtained in 65% yield as a

colorless liquid. ² H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.34 (d, J = 8.3 Hz, 2H) , 7.18 (s, 1H) , 7.10 (s, 1H) , 7.01 (s, 1H) , 6.84 (d, J = 8.2 Hz, 2H) , 4.94 (s, 2H) , 3.71 (s, 3H) , 2.31 (s, 3H) , 2.22 (s, 3H) , 2.21 (s, 3H) , 1.41 (s, 9H) , 0.99 (s, 9H) , 0.21 (s, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.66, 155.23, 155.11, 154.77, 148.92, 142.91, 140.82, 138.24, 134.12, 128.00, 125.30, 124.88, 124.64, 123.82, 122.24, 120.14, 80.19, 59.81, 53.55, 28.30, 25.68, 21.45, 18.21, 13.18, 10.45, -4.40; HRMS (ESI-TOF) m/z Calcd for C33H47N2O4 S1 [M+H] ⁺ : 563.3300, found: 563.3300.

text-Butyl (4 ' - ( (diethoxyphosphoryl) methyl) -5-methy1- [1,1' -biphenyl] -3-yl) ( (4-methoxy-3 , 5-dimethyl-pyridin-2- yl) methyl) carbamate (9g)

Following the general meta-arylation procedure using NBE- C0 ₂ e, Compound 9g was obtained in 92% yield as a

colorless liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.43 (d, J = 7.9 Hz, 2H) , 7.31 (dd, J = 8.3, 2.5 Hz, 2H) , 7.23 (s, 1H) , 7.13 (s, 1H) , 7.06 (s, 1H) , 4.94 (s, 2H) , 4.12 - 3.94 (m, 4H) , 3.72 (s, 3H) , 3.17 (d, J = 21.6 Hz, 2H) , 2.33 (s, 3H) , 2.24-2.19 (m, 6H) , 1.41 (s, 9H) , 1.26 (t, J = 7.0 Hz, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.63, 155.14, 154.72, 148.92, 143.06, 140.62, 139.56 (d, J = 4.1 Hz), 138.35, 130.43 (d, J = 9.0 Hz), 129.95 (d, J = 6.6 Hz), 127.15 (d, J = 3.3 Hz), 125.84, 125.03, 124.63, 123.71, 122.39, 80.25, 62.12 (d, J = 7.1 Hz), 59.81, 53.50, 33.36 (d, J = 138.4 Hz), 28.26, 21.43, 16.35 (d, J = 6.2 Hz), 13.17, 10.41; HRMS (ESI-TOF) m/z Calcd for C32H44 2O6P [M+H] ⁺ : 583.2932, found: 583.2931.

terfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (5- methyl-4 ' - (methylthio) -[1,1' -biphenyl] -3-yl) carbamate (9h) Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9h was obtained in 70% yield as a

colorless liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.40 (d, J = 8.2 Hz, 2H) , 7.27 (d, J = 9.0 Hz, 2 H ) , 7.22 (s, 1H) , 7.12 (s, 1H) , 7.06 (s, 1H) , 4.93 (s, 2H) , 3.72 (s, 3H) , 2.50 (s, 3H) , 2.33 (s, 3H) , 2.21 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.65, 155.18, 154.74, 148.96, 143.14, 140.44, 138.42, 137.90, 137.33, 127.41, 126.80, 125.81, 124.87, 124.64, 123.72, 122.26, 80.27, 59.84, 53.54, 28.30, 21.47, 15.92, 13.20, 10.43; HRMS (ESI-TOF) m/z Calcd for C28H35N2O3S [M+H] ⁺ : 479.2363, found: 479.2362.

tert-Butyl (4 ¹ - (benzyl ( er -butoxycarbony1) amino) -5- methyl- [1,1' -biphenyl] -3-yl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate ( 9i)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9i was obtained in 80% yield as a

colorless solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 7.38 (d, J = 8.4 Hz, 2H) , .33-7.27 (m, 2H ) , 7.27-7.14 (m, 6H) , 7.10 (s, 1H) , 7.05 (s, 1H) , 4.92 (s, 2H) , 4.85 (s, 2H) , 3.70 (s, 3H) , 2.31 (s, 3H) , 2.24-2.16 m, 6H) , 1.43 (s, 9H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.63, 155.14, 154.74, 154.71, 148.94, 143.06, 141.90, 140.43, 138.61, 138.38, 138.33, 128.36, 127.29, 127.21, 127.02, 126.38, 125.79, 125.00, 124.61, 123.68, 122.39, 80.61, 80.24, 59.81, 53.89, 53.50, 28.26, 21.43, 13.17, 10.41; HRMS (ESI-TOF) m/z Calcd for C ₃ 9H4 ₈ N ₃ 05 [M+H] ⁺ : 638.3588, found: 638.3588.

text-Butyl (4 ' -fluoro-5-methyl- [1,1' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9j )

Following the general mefca-arylation procedure using NBE- C0 ₂ Me, Compound 9 was obtained in 92% yield as a

colorless liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.47 - 7.39 (m, 2H) , 7.21 (s, 1H) , 7.12 - 7.02 (m, 4H) , 4.93 (s, 2H) , 3.72 (s, 3H) , 2.33 (s, 3H) , 2.22 (s, 3H) , 2.21 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.65 , 162.31 (d, J = 246.4 Hz), 155.17 , 154.69 , 148.93 , 143.13 , 140.15 , 138.45 , 137.13 , 128.59 (d, J = 8.3 Hz), 125.82 , 125.05 , 124.65 , 123.71 , 122.45 , 115.38 (d, J = 21.1 Hz), 80.29 , 59.82 , 53.51 , 28.27 , 21.43 , 13.18 , 10.42; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -116.22; HRMS (ESI-TOF) m/z Calcd for C27H32F 2O3 [M+H] ⁺ : 451.2391, found: 451.2391.

fcert-Butyl (4 ' -chloro-5-methyl- [1,1' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9k)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9k was obtained in 83% yield as a

colorless liquid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.40 (d, J = 8.6 Hz, 2H) , 7.34 (d, J = 8.5 Hz, 2H) , 7.22 (s, 1H) , 7.10 (s, 1H) , 7.08 (s, 1H) , 4.93 (s, 2H) , 3.72 (s, 3H) , 2.33 (s, 3H) , 2.22 (s, 3H) , 2.21 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.66, 155.13, 154.67, 148.94, 143.20, 139.89, 139.48, 138.55, 133.14, 128.69, 128.30, 126.14, 124.98, 124.68, 123.71, 122.39, 80.33, 59.83, 53.49, 28.27, 21.44, 13.19, 10.42. HRMS (ESI-TOF) m/z Calcd for C ₂₇ H ₃₂ C1 ₂ 03 [M+H] ⁺ : 467.2096, found: 467.2096.

fcert-Butyl (4 ¹ -bromo-5-methyl- [1 , 1 ' -biphenyl] -3-yl) ((4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (91)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 91 was obtained in 82% yield as a

colorless solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.50 (d, J = 8.3 Hz, 2H) , 7.34 (d, J = 8.2 Hz, 2H) , 7.22 (s, 1H) , 7.12-7.05 (m, 2H) , 4.93 (s, 2H) , 3.72 (s, 3H) , 2.33 (s, 3H) , 2.25-2.18 (m, 6H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.66, 155.13, 154.67, 148.94, 143.24, 139.95, 139.90, 138.57, 131.64, 128.66, 126.20, 124.92, 124.67, 123.69, 122.35, 121.31, 80.33, 59.83, 53.49, 28.27, 21.43, 13.20, 10.42; HRMS (ESI-TOF) m/z Calcd for C ₂₇ H ₃₂ BrN ₂ 03 [M+H] ⁺ : 511.1591, found: 511.1592.

fcert-Butyl (4 ^■ -iodo-5-methyl- [1,1' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9m)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9m was obtained in 67% yield as a

colorless solid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 7.70 (d, J = 8.1 Hz, 2H) , 7.25-7.17 (m, 3H) , 7.09 (s, 2H) , 4.93 (s, 2H), 3.72 (s, 3H) , 2.33 (s, 3H) , 2.21 (s, 6H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.66, 155.12, 154.67, 148.95, 143.25, 140.56, 139.96, 138.59, 137.63, 128.94, 126.26, 124.87, 124.68, 123.71, 122.30, 92.81, 80.34, 59.84, 53.49, 28.27, 21.44, 13.20, 10.43; HRMS (ESI-TOF) m/z Calcd for 0 ₂₇ H ₃₂ lN ₂ 0 ₃ [M+H] ⁺ : 559.1452, found: 559.1451.

Methyl 3 ' - ( ( te t-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ' -methyl- [1,1'- biphenyl] -4-carboxylate (9n)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9n was obtained in 92% yield as a

colorless liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 8.05 (d, J = 8.2 Hz, 2H) , 7.54 (d, J = 8.2 Hz, 2H) , 7.29 (s, 1H) , 7.18 (s, 1H) , 7.12 (s, 1H) , 4.94 (s, 2H) , 3.93 (s, 3H) , 3.72 (s, 3H) , 2.35 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 166.96, 163.70, 155.08, 154.65, 148.92, 145.47, 143.22, 139.92, 138.63, 129.90, 128.69, 126.96, 126.73, 125.26, 124.73, 123.76, 122.71, 80.38, 59.83, 53.45, 52.06, 28.26, 21.43, 13.19, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H ₃₅ N ₂ O ₅ [M+H] ⁺ : 491.2540, found: 491.2541.

tert-Butyl ( ' -acetyl-5-methyl- [1,1' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9o)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9o was obtained in 87% yield as a colorless liquid. ¾ N R (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.98 (d, J = 8.2 Hz, 2H) , 7.57 (d, J = 8.2 Hz, 2H) , 7.31 (s, 1H) , 7.18 (s, 1H) , 7.13 (s, 1H) , 4.94 (s, 2H) , 3.72 (s, 3H) , 2.62 (s, 3H) , 2.35 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 197.71, 163.67, 155.08, 154.65, 148.95, 145.64, 143.31, 139.79, 138.66, 135.69, 128.72, 127.14, 126.79, 125.22, 124.70, 123.69, 122.68, 80.39, 59.83, 53.47, 28.26, 26.61, 21.44, 13.19, 10.42; HRMS (ESI-TOF) m/z Calcd for C ₂ 9H3 ₅ N ₂ 0 ₄ [M+H] ⁺ : 475.2591, found: 475.2591.

tert-Butyl (4 ' -formyl-5-me hyl- [1 , 1 ' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9p)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9p was obtained in 96% yield as a

colorless liquid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 10.03 (s, 1H) , 8.18 (s, 1H) , 7.90 (d, J = 8.1 Hz, 2H) , 7.64 (d, J = 8.1 Hz, 2H) , 7.33 (s, 1H) , 7.19 (s, 1H) , 7.15 (s, 1H) , 4.94 (s, 2H) , 3.73 (s, 3H) , 2.36 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 191.90, 163.69, 155.08, 154.63, 148.96, 147.08, 143.38, 139.65, 138.77, 135.05, 130.10, 127.62, 127.02, 125.31, 124.74, 123.71, 122.79, 80.44, 59.85, 53.47, 28.26, 21.45, 13.21, 10.44; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₃₃ N ₂ 0 ₄ [M+H] ⁺ :

461.2435, found: 461.2436.

fcert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (5- methyl-4 ' - (trifluoromethyl) -[1,1' -biphenyl] -3-yl) carbamate (9q)

Following the general jneta-arylation procedure using NBE- C0 ₂ Me, Compound 9q was obtained in 97% yield as a

colorless liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.64 (d, J = 8.2 Hz, 2H) , 7.58 (d, J = 8.2 Hz, 2H) , 7.29 (s, 1H) , 7.19-7.09 (m, 2H) , 4.94 (s, 2H) , 3.72 (s, 3H) , 2.35 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.68, 155.10, 154.65, 148.96, 144.57, 143.36, 139.68, 138.71, 129.14 (q, J = 32.6 Hz), 127.34, 126.70, 125.50 (q, J = 3.4 Hz), 125.22, 124.71, 124.21 (q, J = 271.8 Hz); 123.69, 122.69, 80.41, 59.84, 53.47, 28.26, 21.43, 13.20, 10.42; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -62.62; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H3 ₂ F ₃ N ₂ 03 [M+H] ⁺ : 501.2360, found: 501.2360.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (5- methyl-4 ' -nitro- [1,1' -biphenyl] -3-yl) carbamate (9r)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9r was obtained in 88% yield as a light yellow solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.24 (d, J = 8.6 Hz, 2H) , 8.18 (s, 1H) , 7.63 (d, J = 8.6 Hz, 2H) , 7.36 (s, 1H) , 7.22-7.15 (m, 2H) , 4.94 (s, 2H) , 3.74 (s, 3H) , 2.36 (s, 3H) , 2.23 (s, 3H) , 2.23 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.70, 155.02, 154.57, 148.96, 147.50, 146.91, 143.57, 138.96, 138.69, 127.72, 127.37, 125.24, 124.77, 123.92, 123.67, 122.76, 80.53, 59.87, 53.41, 28.24, 21.44, 13.22, 10.42; HRMS (ESI-TOF) m/z Calcd for C ₂₇ H ₃₂ N ₃ 0 ₅ [M+H] ⁺ : 478.2336, found: 478.2336.

fcert-Butyl (4 ' -cyano-5-methyl- [1,1' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9s)

Following the general jneta-arylation procedure using NBE- C0 ₂ Me, Compound 9s was obtained in 89% yield as a

colorless solid. ^λ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.67 (d, J = 8.2 Hz, 2H) , 7.58 (d, J = 8.3 Hz, 2H) , 7.31 (s, 1H) , 7.19-7.12 (m, 2H) , 4.93 (s, 2H) , 3.73 (s, 3H) , 2.35 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.70, 155.02, 154.57, 148.93, 145.53, 143.47, 139.11, 138.89, 132.41, 127.67, 127.12, 125.12, 124.76, 123.70, 122.61, 118.94, 110.68, 80.49, 59.86, 53.39, 28.24, 21.43, 13.21, 10.42; HRMS (ESI-TOF) m/z Calcd for C ₂ 8H3 _{2 3} 03 [M+H] ⁺ : 458.2438, found: 458.2438.

Methyl 3 ¹ - ( ( te fc-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5 ' -methyl- [1 , 1 ' - biphenyl] -3-carboxylate (9t)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9t was obtained in 88% yield as a

colorless liquid. ^λ Ε NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 2H) , 7.98 (d, J = 7.7 Hz, 1H) , 7.67 (d, J = 7.7 Hz, 1H) , 7.46 (t, J = 7.7 Hz, 1H) , 7.29 (s, 1H) , 7.17 (s, 1H) , 7.10 (s, 1H) , 4.95 (s, 2H) , 3.94 (s, 3H) , 3.72 (s, 3H) , 2.35 (s, 3H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 167.01, 163.68, 155.10, 154.69, 148.95, 143.19, 141.30, 140.03, 138.60, 131.50, 130.48, 128.66, 128.20, 126.24, 125.18, 124.69, 123.75, 122.64, 80.37,

59.83, 53.47, 52.13, 28.28, 21.44, 13.19, 10.44; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H _{35 2} O ₅ [M+H] ⁺ : 491.2540, found: 491.2541.

tert-Butyl (3 ' -fluoro-5-methyl- [1,1 ' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9u)

Following the general ineta-arylation procedure using NBE- C0 ₂ Me, Compound 9u was obtained in 86% yield as a

colorless liquid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.38-7.28 (m, 1H) , 7.25 (d, J = 6.2 Hz, 1H) , 7.20 (s, 1H) , 7.18-7.07 (m, 3H) , 6.98 (td, J = 7.7, 2.1 Hz, 1H) , 4.94 (s, 2H) , 3.72 (s, 3H) , 2.34 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.69 , 163.01 (d, J = 245.4 Hz), 155.15 , 154.68 , 148.97 , 143.33 (d, J = 7.6 Hz), 143.15 , 139.86 , 138.57 , 129.98 (d, J = 8.6 Hz), 126.47 , 125.14 , 124.73 , 123.79 , 122.68 (d, J = 2.6 Hz), 122.60 , 113.95 (d, J = 10.8 Hz), 113.81 (d, J = 9.9 Hz), 80.34 , 59.82 , 53.52 , 28.27 , 21.43 , 13.18 , 10.44; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -113.61; HRMS (ESI-TOF) m/z Calcd for C ₂₇ H ₃₂ FN ₂ 03 [M+H] ⁺ : 451.2391, found: 451.2391.

tert-Butyl (3 ' -iodo-5-methyl- [1,1' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9v)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9v was obtained in 74% yield as a light yellow solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.80 (d, J = 1.7 Hz, 1H) , 7.62 (d, J = 7.8 Hz, 1H) , 7.43 (d, J = 7.8 Hz, 1H) , 7.17 (s, 1H) , 7.14-7.06 (m, 3H) , 4.93 (s, 2H) , 3.73 (s, 3H) , 2.33 (s, 3H) , 2.22 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.70, 155.11, 154.67, 148.97, 143.29, 143.12, 139.53, 138.60, 136.08, 135.97, 130.22, 126.44, 126.34, 125.14, 124.73, 123.81, 122.59, 94.57, 80.37, 77.21, 59.88, 53.51, 28.29, 21.43, 13.25, 10.46; HRMS (ESI-TOF) m/z Calcd for C^Haal zOs [M+H] ⁺ :

559.1452, found: 559.1453.

9w

tert-Butyl (3 ' , 5-dimethyl- [1 , 1 ' -biphenyl] -3-yl) ( (4- methoxy-3 , 5-dime hylpyridin-2-yl) methyl) carbamate (9w)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9w was obtained in 82% yield as a

colorless liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.31-7.23 (m, 3H) , 7.20 (s, 1H) , 7.16-7.09 (m, 2H) , 7.05 (s, 1H) , 4.94 (s, 2H) , 3.71 (s, 3H) , 2.38 (s, 3H) , 2.33 (s, 3H) , 2.25-2.19 (m, 6H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.66, 155.23, 154.77, 148.94, 142.95, 141.26, 141.02, 138.28, 138.06, 128.44, 127.88, 127.83, 125.79, 125.27, 124.62, 124.17, 123.79, 122.67, 80.21, 59.81, 53.56, 28.30, 21.49, 21.45, 13.18, 10.44; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₃₅ N ₂ O ₃ [M+H] ⁺ : 447.2642, found: 447.2643.

9x fcerfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2- yl) methyl) (3 ' -methoxy-5-methyl- [1,1" -biphenyl] -3-yl) - carbamate (9x)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9x was obtained in 85% yield as a

colorless liquid. ¾ NMR (400 MHz , CDC1 ₃ ) δ 8.17 (s, 1H) , 7.29 (t, J = 7.9 Hz, 1H) , 7.21 (s, 1H) , 7.14 (s, 1H) , 7.11-7.02 (m, 2H) , 6.99 (t, J = 2.1 Hz, 1H) , 6.85 (dd, J = 8.2, 2.5 Hz, 1H) , 4.94 (s, 2H) , 3.83 (s, 3H) , 3.71 (s, 3H) , 2.33 (s, 3H) , 2.22 (s, 3H) , 2.21 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.66, 159.76, 155.18, 154.75, 148.95, 143.01, 142.59, 141.01, 138.34, 129.52, 126.05, 125.26, 124.66, 123.77, 122.67, 119.61, 112.80, 112.54, 80.25, 59.82, 55.24, 53.54, 28.30, 21.45, 13.18, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₃₅ N ₂ 0 ₄ [M+H] ⁺ :

463.2591, found: 463.2591.

tert-Butyl (2 ' -acetamido-5-methyl- [1,1' -biphenyl] -3- yl) ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9y)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9y was obtained in 91% yield as a

colorless solid. ^: Η NMR (400 MHz, CDC1 ₃ ) δ 8.32 (d, J = 8.3 Hz, 1H) , 8.16 (s, 1H) , 7.64 (s, 1H) , 7.32 (t, J = 7.8 Hz, 1H) , 7.25-7.17 (m, 2H) , 7.14-7.07 (m, 2H) , 6.94 (s, 1H) , 4.89 (s, 2H) , 3.74 (s, 3H) , 2.33 (s, 3H) , 2.23 (s, 6H) , 2.11 (s, 3H) , 1.35 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.01, 163.66, 155.11, 154.76, 148.93, 143.31, 139.42, 137.74, 135.06, 131.34, 129.69, 128.20, 127.12, 125.19, 124.70, 124.64, 123.33, 121.30, 80.44, 59.88, 53.27, 28.12, 24.53, 21.43, 13.20, 10.38; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H ₃₆ N ₃ 0 ₄ [M+H] ⁺ : 490.2700, found: 490.2700.

terfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methy1-5- (naphthalen-2-yl) phenyl) carbamate (9z)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9z was obtained in 76% yield as a

colorless liquid. ^X H NMR (400 MHz , CDC1 ₃ ) δ 8.19 (s, 1H) , 7.92 (s, 1H) , 7.89-7.81 (m, 3H) , 7.63 (dd, J = 8.6, 1.8 Hz, 1H) , 7.52-7.42 (m, 2H) , 7.36 (s, 1H) , 7.28 (s, 1H) , 7.10 (s, 1H) , 4.97 (s, 2H) , 3.71 (s, 3H) , 2.37 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.43 (s, 9H) . ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.68, 155.22, 154.77, 148.98, 143.14, 141.03, 138.48, 138.38, 133.54, 132.52, 128.17, 128.10, 127.56, 126.16, 125.98, 125.78, 125.67, 125.58, 125.48, 124.67, 123.79, 122.90, 80.29, 59.83, 53.57, 28.31, 21.50, 13.21, 10.47; HRMS (ESI-TOF) m/z Calcd for Ca^^Oa [M+H] ⁺ :

483.2642, found: 483.2642.

tert-Butyl (3-(benzo[d] [1 , 3] dioxol-5-yl) -5- methyIphenyl) ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - carbamate ( 9aa)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9aa was obtained in 72% yield as a colorless solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.13 (s, 1H) , 7.06 (s, 1H) , 7.03 (s, 1H) , 6.97-6.90 (m, 2H) , 6.82 (d, J = 7.8 Hz, 1H) , 5.97 (s, 2H) , 4.93 (s, 2H) , 3.72 (s, 3H) , 2.32 (s, 3H) , 2.22 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz , CDC1 ₃ ) δ 163.66, 155.21, 154.72, 148.95, 147.88, 146.88, 142.98, 140.83, 138.33, 135.44, 125.59, 124.99, 124.68, 123.79, 122.37, 120.51, 108.37, 107.62, 101.03, 80.24, 59.82, 53.54, 28.29, 21.44, 13.18, 10.43;

HRMS (ESI-TOF) m/z Calcd for C ₂₈ H _{33 2} O ₅ [M+H] ⁺ : 477.2384, found: 477.2384.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2- yl) methyl) (3 ' , 5 , 5 ' -trimethyl- [1,1 ' -biphenyl] -3-yl) - carbamate (9ab)

Following the general ineta-arylation procedure using NBE- C0 ₂ Me, Compound 9ab was obtained in 85% yield as a colorless liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.17 (s, 1H) , 7.12 (s, 1H) , 7.08 (s, 2H) , 7.04 (s, 1H) , 6.94 (s, 1H) , 4.94 (s, 2H) , 3.71 (s, 3H) , 2.34 (s, 6H) , 2.32 (s, 3H) , 2.21 (s, 6H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 163.66, 155.26, 154.79, 148.94, 142.85, 141.36, 141.04, 138.22, 137.98, 128.72, 125.74, 125.32, 125.01, 124.61, 123.83, 122.72, 80.19, 59.82, 53.58, 28.30, 21.44, 21.35, 13.19, 10.46; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H _{37 2} O ₃ [M+H] ⁺ : 461.2799, found: 461.2799.

9ac

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (5- methyl-3 ' ,5" -bis (trifluoromethyl) - [1 , 1 ' -biphenyl] -3- yl) carbamate (9ac) Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9ac was obtained in 94% yield as a light yellow liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.89 (s, 2H) , 7.81 (s, 1H) , 7.28 (s, 1H) , 7.19 (s, 1H) , 7.15 (s, 1H) , 4.95 (s, 2H) , 3.73 (s, 3H) , 2.37 (s, 3H) , 2.24 (s, 3H) , 2.22 (s, 3H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.80 , 154.97 , 154.60 , 148.96 , 143.61 , 143.15 , 139.22 , 138.13 , 131.87 (q, J = 33.3 Hz),

127.42 , 127.18 , 125.12 , 124.92 , 123.84 , 123.29 (q, J = 273.3 Hz), 122.81 , 120.72 , 80.64 , 59.85 , 53.43 , 28.26 , 21.43 , 13.17 , 10.46; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ - 63.09; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H ₃ iF _{6 2} 03 [M+H] ⁺ :

569.2233, found: 569.2233.

tert-Butyl (3 ¹ -chloro-4 ¹ -fluoro-5-methyl- [1,1' -biphenyl] 3-yl) ( (4-methoxy-3 , 5-dimeth lpyridin-2-yl) methyl) - carbamate (9ad)

Following the general meta-arylation procedure using NBE C0 ₂ Me, Compound 9ad was obtained in 82% yield as a colorless liquid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 1H) , 7.46 (dd, J = 7.0, 2.3 Hz, 1H) , 7.32 (ddd, J = 8.6, 4.6, 2.3 Hz, 1H) , 7.20-7.11 (m, 2H) , 7.10 (s, 1H) , 7.07 (s, 1H) , 4.93 (s, 2H) , 3.73 (s, 3H) , 2.33 (s, 3H) , 2.26-2.19 (m, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.72 157.48 (d, J = 248.7 Hz), 155.12 , 154.63 , 148.96 , 143.22 , 138.91 , 138.71 , 138.32 (d, J = 4.1 Hz),

129.14 , 126.70 (d, J = 6.9 Hz), 126.40 , 125.01 ,

124.77 , 123.80 , 122.47 , 120.97 (d, J = 17.8 Hz), 116. (d, J = 21.2 Hz), 80.41 , 59.86 , 53.49 , 28.27 , 21.42 13.21 , 10.45; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -118.58; HRMS (ESI-TOF) m/z Calcd for C27H31CI F 2O3 [M+H] ⁺ : 485.2002, found: 485.2002.

tert-Butyl (3- (2 , 3-dihydrobenzo [b] [1 , 4] dioxin-6-yl) -5- methyIpheny1) ( (4-methoxy-3 , 5-dimethylpyridin-2- yl) methyl) carbamate (9ae)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9ae was obtained in 82% yield as a colorless solid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.12 (s, 1H) , 7.08 (s, 1H) , 7.01 (s, 1H) , 6.98-6.93 (m, 2H) , 6.86 (d, J = 8.7 Hz, 1H) , 4.93 (s, 2H) , 4.26 (s, 4H) , 3.72 (s, 3H) , 2.31 (s, 3H) , 2.21 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 163.69, 155.18, 154.74, 148.91, 143.48, 142.99, 142.88, 140.49, 138.26, 134.63, 125.54, 124.90, 124.69, 123.85, 122.27, 120.07, 117.30, 115.77, 80.20, 64.40, 64.36, 59.80, 53.49, 28.29, 21.43, 13.16, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂₉ H ₃₅ N ₂ O ₅ [M+H] ⁺ :

491.2540, found: 491.2540.

Ethyl 6- (3- ( ( fcert-butoxycarbonyl) ( (4-methoxy~3 , 5- dimethylpyridin-2-yl) methyl) amino) -5-methyIpheny1) -4-oxo- 4H-chromene-2-carboxylate (9af)

Following the general /neta-arylation procedure using NBE- C0 ₂ Me, Compound 9af was obtained in 80% yield as a light yellow solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.29 (d, J = 2.3 Hz, 1H) , 8.19 (s, 1H) , 7.89 (dd, J = 8.8, 2.3 Hz, 1H) , 7.64 (d, J = 8.8 Hz, 1H) , 7.34 (s, 1H) , 7.23 (s, 1H) , 7.17-7.10 (m, 2H) , 4.95 (s, 2H) , 4.48 (q, J = 7.1 Hz, 2H) , 3.73 (s, 3H) , 2.35 (s, 3H) , 2.24 (s, 3H) , 2.23 (s, 3H) , 1.45 (t, J = 7.1 Hz, 3H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 178.40, 163.69, 160.49, 155.23, 155.07, 154.62, 152.12, 148.96, 143.36, 138.95, 138.88, 138.83, 133.64, 126.70, 125.27, 124.76, 124.40, 123.75, 123.30, 122.62, 119.08, 114.64 _. , 80.41, 62.98, 59.85, 53.44, 28.25, 21.40, 14.06, 13.19, 10.45; HRMS (ESI-TOF) m/z Calcd for C3 ₃ H3 _{7 2} 0 ₇ [M+H] ⁺ : 573.2595, found: 573.2593.

terfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methy1-5- (l-tosyl-lH-indol-6-yl) henyl) carbamate (9ag)

Following the general ffieta-arylation procedure using NBE- C0 ₂ Me, Compound 9ag was obtained in 72% yield as a colorless solid, mp = 100 °C, ^X H NMR (400 MHz, CDCl ₃ ) δ 8.24 (s, 1H) , 8.12 (s, 1H) , 7.76 (d, J = 8.2 Hz, 2H) , 7.55 (d, J = 3.7 Hz, 1H) , 7.50 (d, J = 8.2 Hz, 1H) , 7.35 (dd, J = 8.2, 1.5 Hz, 1H) , 7.32 (s, 1H) , 7.22-7.16 (m, 3H) , 7.11 (s, 1H) , 6.63 (d, J = 3.6 Hz, 1H) , 4.98 (s, 2H) , 3.71 (s, 3H) , 2.37 (s, 3H) , 2.32 (s, 3H) , 2.24 (s, 3H) , 2.20 (s, 3H) , 1.44 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.66, 155.08, 154.79, 149.03, 144.88, 143.13, 141.30, 138.39, 138.00, 135.32, 135.21, 129.86, 129.81, 126.76, 126.69, 125.78, 125.46, 124.70, 123.64, 122.98, 122.80, 121.26, 111.92, 108.82, 80.33, 59.83, 53.48, 28.30, 21.51, 13.20, 10.42; HRMS (ESI-TOF) m/z Calcd for C36H40N3O5S [M+H] ⁺ :

626.2683, found: 626.2683.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-y1) methyl) (3- methyl-5- (l-tosyl-lH-indol-5-yl) henyl) carbamate (9ah)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9ah was obtained in 83% -yield as a colorless solid, mp = 92 °C, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.98 (d, J = 8.6 Hz, 1H) , 7.76 (d, J = 8.1 Hz, 2H) , 7.60 (s, 1H) , 7.55 (d, J = 3.7 Hz, 1H) , 7.43 (d, J = 8.2 Hz, 1H) , 7.27-7.19 (m, 3H) , 7.13 (s, 1H) , 7.05 (s, 1H), 6.65 (d, J = 3.7 Hz, 1H) , 4.94 (s, 2H) , 3.71 (s, 3H) , 2.33 (s, 3H) , 2.32 (s, 3H) , 2.25-2.17 (m, 6H) , 1.41 (s, 9H) ¹³ C NMR (150 MHz, CDCl ₃ ) δ 163.64, 155.20, 154.71, 148.92, 144.92, 143.02, 141.16, 138.35, 136.63, 135.21, 134.11, 131.12, 129.86, 126.80, 126.74, 125.59, 125.39, 124.62, 124.14, 123.74, 122.76, 119.72, 113.51, 109.27, 80.23, 59.81, 53.53, 28.27, 21.52, 21.44, 13.18, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₃₆ H ₄ oN ₃ 0 ₅ S [M+H] ⁺ : 626.2683, found: 626.2684.

tert-Butyl (3- (benzo [b] thiophen-2-yl) -5-methylpheny1) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9ai)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9ai was obtained in 84% yield as a colorless liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.19 (s, 1H) , 7.79 (d, J = 7.7 Hz, 1H) , 7.73 (d, J = 7.6 Hz, 1H) , 7.43 (s, 1H) , 7.39 (s, 1H) , 7.36-7.25 (m, 3H) , 7.07 (s, 1H) , 4.94 (s, 2H) , 3.72 (s, 3H) , 2.33 (s, 3H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 1.43 (s, 9H) ; ¹³ C NMR (150 MHz , CDC1 ₃ ) δ

163.69, 154.99, 154.63, 149.01, 144.10, 143.25, 140.57, 139.35, 138.68, 134.09, 126.83, 124.71, 124.39, 124.38, 124.17, 123.73, 123.44, 122.15, 122.08, 119.34, 80.46, 59.84, 53.35, 28.29, 21.38, 13.20, 10.44; HRMS (ESI-TOF) m/z Calcd for C29H33N2O3S [M+H] ⁺ : 489.2206, found: 489.2206.

tert-Butyl ( (4-methoxy-3 , 5-diraethylpyridin-2-yl) methyl) (3- methyl-5- (5-methylthiophen-2-yl) henyl) carbamate (9aj )

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9aj was obtained in 76% yield as a colorless liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.20 (s, 1H) , 7.10 (s, 1H) , 6.98 (d, J = 3.5 Hz, 1H) , 6.96

(s, 1H), 6.67 (d, J = 3.5 Hz, 1H) , 4.91 (s, 2H) , 3.71 (s, 3H) , 2.47 (s, 3H) , 2.28 (s, 3H) , 2.21 (s, 6H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.64, 155.06, 154.68, 148.97, 143.09, 141.82, 139.17, 138.44, 134.49, 125.98, 125.57, 124.62, 123.71, 123.48, 122.74, 121.10, 80.29, 59.82, 53.38, 28.28, 21.36, 15.40, 13.18, 10.42; HRMS

(ESI-TOF) m/z Calcd for C26H33N2O3S [M+H] ⁺ : 453.2206, found: 453.2206.

tert-Butyl (3- (5-acetylthiophen-2-yl) -5-methylphenyl) ( (4- methoxy-3,5-dimethylpyridin-2-yl) methyl) carbamate (9ak)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9ak was obtained in 98% yield as a colorless liquid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.61 (d, J = 3.9 Hz, 1H) , 7.34 (s, 1H) , 7.25-7.18 (m, 2H) , 7.12 (s, 1H) , 4.91 (s, 2H) , 3.74 ( s , 3H) , 2.54 (s, 3H) , 2.32 ( s , 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz , CDC1 ₃ ) δ 190.49, 163.69, 154.88, 154.50, 152.73, 148.99, 143.48, 142.79, 138.92, 133.32, 133.15, 127.62, 124.78, 124.08, 123.80, 123.65, 121.75, 80.52, 59.85, 53.30, 28.22, 26.47, 21.32, 13.19, 10.40; HRMS (ESI-TOF) m/z Calcd for C ₂₇ H _{33 2} O ₄ S [M+H] ⁺ : 481.2156, found: 481.2156.

terfc-Butyl (3- (5-formylfuran-2-yl) -5-methylpheny1) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9al)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9al was obtained in 87% yield as a colorless liquid. ¹ H NMR (400 MHz, CDC1 ₃ ) δ 9.61 (s, 1H) , 8.17 (s, 1H) , 7.52 (s, 1H) , 7.42 (s, 1H) , 7.28 (d, J = 3.8 Hz, 1H) , 7.14 (s, 1H) , 6.74 (d, J = 3.7 Hz, 1H) , 4.92 (s, 2H) , 3.74 (s, 3H) , 2.33 (s, 3H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 177.11, 163.71, 159.35, 154.89, 154.52, 151.84, 148.94, 143.46, 139.00, 128.93, 128.53, 124.76, 123.70, 123.52, 123.15, 120.87, 107.72, 80.54, 59.87, 53.29, 28.22, 21.30, 13.19, 10.44; HRMS . (ESI-TOF) m/z Calcd for C ₂₆ H ₃₁ N ₂ 0 ₅ [M+H] ⁺ :

451.2227, found: 451.2227.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methy1) ^' (3- methyl-5- (l-tosyl-lH-indazol-5-yl)phenyl) carbamate (9am)

Following the general ffleta-arylation procedure using NBE- C0 ₂ Me, Compound 9am was obtained in 63% yield as a light yellow solid ^, mp = 137 °C, ½ NMR (400 MHz, CDCl ₃ ) δ 8.24- 8.15 (m, 3H) , 7.87 (d, J = 8.2 Hz, 2H) , 7.75 (s, 1H) , 7.69 (dd, J = 8.7, 1.7 Hz, 1H), 7.29 (s, 1H) , 7.25 (d, J = 7.9 Hz, 2H), 7.14 (s, 1H), 7.10 (s, 1H) , 4.94 (s, 2H) , 3.72 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 163.67, 155.15, 154.65, 148.93, 145.37, 143.29, 141.55, 140.24, 139.58, 138.64, 137.76, 134.50, 129.83, 129.12, 127.50, 126.43, 126.02, 125.35, 124.68, 123.69, 122.78, 119.28, 113.20, 80.36, 59.84, 53.49, 28.26, 21.60, 21-45, 13.21, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₃₅ H ₃₉ N ₄ 0 ₅ S [M+H] ⁺ :

627.2636, found: 627.2635.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2 -yl) methyl) (3- methyl-5- (l-tosyl-lH-indazol-6-yl) phenyl) ca ba ate (9an)

Following the general .meta-arylation procedure using NBE- C0 ₂ Me, Compound 9an was obtained in 61% yield as a light yellow solid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.31 (s, 1H) , 8.24 (s, 1H), 8.16 (s, 1H), 7.86 (d, J= 8.2 Hz, 2H) , 7.67 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H) , 7 -41 (s, 1H) , 7.26-7.20 (m, 3H) , 7.17 (s, 1H) , 4.97 (s, 2 ) , 3.73 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H) , 2.25 (s, 313.), 2.22 (s, 3H) , 1.44 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) & 163.69, 155.02, 154.75, 149.04, 145.32, 143.40, 142. ^" 70, 141.11, 140.91, 140.40, 138.71, 134.55, 129.83, 127 _^ 51, 126.63, 125.66, 124.85, 124.74, 124.23, 123.62, 123- 12, 121.24, 111.17, 80.46, 59.86, 53.47, 28.28, 21.59, _. 21.48, 13.21, 10.43; HRMS (ESI-TOF) m/z Calcd for C35H39N4O5S [M+H] ⁺ :

627.2636, found: 627.2636.

tert-Butyl ( (4~methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methyl-5- (quinolin-3-yl) henyl) carbamate (9ao)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9ao was obtained in 54% yield as a colorless solid. ½ NMR (400 MHz, CDC1 ₃ ) δ 9.07 (d, J = 2.2 Hz, 1H) , 8.21 (d, J = 2.2 Hz, 1H) , 8.20 (s, 1H) , 8.11 (d, J = 8.5 Hz, 1H) , 7.85 (d, J = 8.1 Hz, 1H) , 7.70 (t, J = 7.7 Hz, 1H) , 7.56 (t, J = 7.5 Hz, 1H) , 7.43 (s, 1H) , 7.27 (s, 1H) , 7.19 (s, 1H) , 4.96 (s, 2H) , 3.73 (s, 3H) , 2.40 (s, 3H) , 2.24 (s, 3H) , 2.22 (s, 3H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 163.69, 155.04, 154.67, 149.94, 149.02, 147.26, 143.64, 138.96, 137.79, 133.70, 133.14, 129.25, 129.16, 127.94, 126.89, 126.62, 125.32, 124.74, 123.63, 122.75, 80.48, 59.86, 53.49, 28.29, 21.50, 13.22, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₃₀ H _{34 3} O ₃ [M+H] ⁺ : 484.2595, found: 484.2593.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methyl-5- (quinolin-6-yl)phenyl) carbamate (9ap)

Following the general meta-arylation procedure using 20 mol% of Pd(OAc) ₂ and 40 mol% of L12, Compound 9ap was obtained in 41% yield as a light yellow liquid. ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.90 (dd, J = 4.3, 1.7 Hz, 1H) , 8.22- 8.16 (m, 2H) , 8.12 (d, J = 8.7 Hz, 1H) , 7.91 (d, J = 2.0 Hz, 1H) , 7.87 (dd, J = 8.7, 2.1 Hz, 1H) , 7.41 (dd, J = 8.3, 4.2 Hz, 1H) , 7.39 (s, 1H) , 7.28 (s, 1H) , 7.13 (s, 1H) , 4.97 (s, 2H) , 3.73 (s, 3H) , 2.38 (s, 3H) , 2.24 (s, 3H) , 2.22 (s, 3H) , 1.43 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.72, 155.18, 154.72, 150.25, 148.98, 147.60, 143.29, 140.25, 139.18, 138.68, 136.20, 129.65, 129.25, 128.36, 126.37, 125.51, 125.39, 124.73, 123.81, 122.94, 121.39, 80.40, 59.86, 53.54, 28.31, 21.50, 13.22, 10.47; HRMS (ESI-TOF) m/z Calcd for C ₃ oH ₃₄ N ₃ 0 ₃ [M+H] ⁺ : 484.2595, found: 484.2592.

terfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methyl-5- (quinoxalin-6-yl) phenyl) carbamate (9aq)

Following the general ineta-arylation procedure using NBE- C0 ₂ Me, Compound 9aq was obtained in 63% yield as a yellow liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.85 (d, J = 1.8 Hz, 1H) , 8.82 (d, J = 1.8 Hz, 1H) , 8.19 (s, 2H) , 8.13 (d, J = 8.7 Hz, 1H) , 7.96 (dd, J = 8.8, 2.0 Hz, 1H) , 7.44 (s, 1H) , 7.32 (s, 1H) , 7.19 (s, 1H) , 4.97 (s, 2H) , 3.74 (s, 3H) , 2.39 (s, 3H) , 2.25 (s, 3H) , 2.23 (s, 3H) , 1.42 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.71, 155.09, 154.66, 149.01, 145.30, 144.62, 143.47, 143.17, 142.77, 142.29, 139.51, 138.86, 129.87, 129.58, 126.94, 126.75, 125.58, 124.78, 123.75, 122.97, 80.44, 59.86, 53.49, 28.28, 21.49; HRMS (ESI-TOF) m/z Calcd for C2 ₉ H ₃₃ N ₄ 0 ₃ [M+H] ⁺ : 485.2547, found: 485.2547.

terfc-Butyl (3- (2-fluoropyridin-4-yl) -5-methylphenyl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9ar)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9ar was obtained in 90% yield as a light yellow liquid. ½ NMR (400 MHz, CDCl ₃ ) δ 8.20 (d, J = 5.3 Hz, 1H) , 8.18 (s, 1H) , 7.33 (s, 1H) , 7.30 (d, J = 5.2 Hz, 1H) , 7.21 (s, 1H) , 7.18 (s, 1H) , 7.00 (s, 1H) , 4.93 (s, 2H) , 3.74 (s, 3H) , 2.36 (s, 3H) , 2.24 (s, 3H) , 2.23 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 164.36 (d, J = 237.8 Hz), 163.74, 154.94, 154.52, 153.98, 153.93, 148.96, 147.74 (d, J = 15.4 Hz), 143.61, 139.11, 136.99, 128.18, 124.87, 123.74, 122.46, 119.49 (d, J = 3.9 Hz), 107.00 (d, J = 38.3 Hz), 80.59, 59.86, 53.35, 28.23, 21.40, 13.20, 10.42; ¹ F NMR (376 MHz, CDC1 ₃ ) δ -68.68; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₃ iFN ₃ 0 ₃ [M+H] ⁺ : 452.2344, found: 452.2344.

terfc-Butyl (3- (2-chloropyridin-4-yl) -5-methylphenyl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9as)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9as was obtained in 96% yield as a colorless liquid. Only 9% NMR yield was obtained in the absence of L12. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.37 (d, J = 5.2 Hz, 1H) , 8.18 (s, 1H) , 7.41 (s, 1H) , 7.33 (dd, J = 5.2, 1.5 Hz, 1H) , 7.30 (s, lH) , 7.21 (s, 1H) , 7.16 (s, 1H) , 4.93 (s, 2H) , 3.74 (s, 3H) , 2.36 (s, 3H) , 2.24 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.74, 154.94, 154.50, 151.97, 151.44, 149.79, 148.96, 143.62, ijy.ib,

136.76, 128.20, 124.87, 124.84, 123.74, 122.47, 121.97, 120.46, 80.59, 59.87, 53.36, 28.22, 21.39, 13.21, 10.42; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₃₁ CI ₃ O ₃ [M+H] ⁺ : 468.2048, found: 468.2048.

terfc-Butyl (3- (2-bromopyridin-4-yl) -5-methylphenyl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9at)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9at was obtained in 56% yield as a light yellow liquid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.35 (d, J = 5.2 Hz, 1H) , 8.18 (s, 1H) , 7.57 (s, 1H) , 7.36 (dd, J = 5.2, 1.5 Hz, 1H) , 7.29 (s, 1H) , 7.20 (s, 1H) , 7.15 (s, 1H) , 4.93 (s, 2H) , 3.74 (s, 3H) , 2.36 (s, 3H) , 2.23 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.77, 154.92, 154.51, 151.18, 150.19, 148.95, 143.60, 142.70, 139.17, 136.64, 128.22, 125.78, 124.90, 124.88, 123.78, 122.49, 120.84, 80.62, 59.89, 53.34, 28.24, 21.40, 13.24, 10.44; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₃₁ Br ₃ 0 ₃ [M+H] ⁺ : 512.1543, found: 512.1540.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methyl-5- (2- (trifluoromethy1) pyridin-4-y1) -phenyl) - carbamate ( 9au)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9au was obtained in 93% yield as a light yellow liquid. *H NMR (400 MHz, CDC1 ₃ ) δ 8.72 (d, J = 5.1 Hz, 1H) , 8.18 (s, 1H) , 7.77 (s, 1H) , 7.60 (d, J = 3.5 Hz, 1H) , 7.39 (s, 1H) , 7.24 (s, 1H) , 7.21 (s, 1H) , 4.94 (s, 2H) , 3.74 (s, 3H) , 2.38 (s, 3H) , 2.24 (s, 3H) , 2.23 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.76, 154.90, 154.52, 150.27, 150.10, 148.96, 149.49 (q, J = 33.2 Hz ), 143.80, 139.32, 136.79, 128.33, 124.88, 124.86, 124.10, 123.73, 122.54, 121.61 (q, J = 274.4 Hz), 118.40 (q, J = 3.0 Hz), 80.67, 59.86, 53.34, 28.23, 21.41, 13.18, 10.42; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -68.23; HRMS (ESI-TOF) m/z Calcd for [M+H] ⁺ : 502.2312, found: 502.2312.

text-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methyl-5- (2-methylpyridin-4-y1) phenyl) carbamate (9av)

Following the general meta-arylation procedure using 20 mol% of Pd(OAc) ₂ and 40 mol% of L12, Compound 9av was obtained in 42% yield as a colorless , liquid. ^: H NMR (400 MHz, CDC1 ₃ ) δ 8.48 (d, J = 5.2 Hz, 1H) , 8.18 (s, 1H) , 7.31 (s, 1H) , 7.26 (s, 1H) , 7.20 (d, J = 5.2 Hz, 1H) , 7.17 (s, 1H) , 7.16 (s, 1H) , 4.93 (s, 2H) , 3.73 (s, 3H) , 2.59 (s, 3H) , 2.35 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.69, 158.62, 155.06, 154.60, 149.38, 148.95, 148.54, 143.40, 138.81, 138.38, 127.42, 124.93, 124.73, 123.72, 122.47, 121.15, 118.82, 80.44, 59.84, 53.44, 28.26, 24.52, 21.42, 13.20, 10.43; HRMS (ESI-TOF) m/z Calcd for Ca^NsOa [M+H] ⁺ : 448.2595, found: 448.2596.

terfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- (2-methoxypyridin-4-yl) -5-methylphen 1) carbamate (9aw)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9aw was obtained in 55% yield as a colorless liquid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 8.15 (d, J = 5.4 Hz, 1H) , 7.26 (s, 1H) , 7.16 (s, 2H) , 7.00 (dd, J = 5.4, 1.5 Hz, 1H) , 6.81 (s, 1H) , 4.93 (s, 2H) , 3.96 (s, 3H) , 3.73 (s, 3H) , 2.34 (s, 3H) , 2.22 (s, 6H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 164.75, 163.73, 155.03, 154.61, 151.08, 148.97, 147.00, 143.32, 138.77, 138.21, 127.54, 124.94, 124.80, 123.77, 122.46, 115.38, 108.37, 80.46, 59.84, 53.46, 53.43, 28.26, 21.42, 13.20, 10.43; HRMS (ESI-TOF) m/z Calcd for ^' C ²⁷ H ³ N ³ 0 ⁴ [M+H] ⁺ :

464.2544, found: 464.2544.

Methyl 4- (3- ( ( fcert-butoxycarbony1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5-meth l-phenyl) -2- chloronicotinate (9ax)

Following the general ffieta-arylation procedure using NBE- C0 ₂ Me, Compound 9ax was obtained in 51% yield as a colorless liquid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.41 (d, J = 5.1 Hz, 1H) , 8.18 (s, 1H) , 7.24-7.19 (m, 2H) , 7.17 (s, 1H) , 6.96 (s, 1H) , 4.88 (s, 2H), 3.74 (s, 3H) , 3.70 (s, 3H) , 2.32 (s, 3H) , 2.225 (s, 3H) , 2.217 (s, 3H) , 1.37 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 166.19, 163.68, 154.86, 154.45, 150.21, 149.72, 148.97, 147.93, 143.57, 138.86, 136.58, 128.83, 127.89, 125.55, 124.74, 123.48, 123.09, 123.05, 80.52, 59.88, 53.32, 52.70, 28.18, 21.36, 13.22, 10.37; HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₃₃ C1N ₃ 0 ₅ [M+H] ⁺ : 526.2103, found: 526.2103.

tert-Butyl (3- (6-fluoropyridin-3-yl) -5-methylphenyl) ( (4- methoxy-3 , 5-dime hylpyridin-2-yl) methyl) carbamate ( 9ay)

Following the general meta-arylation procedure using NBE- C0 ₂ Me, Compound 9ay was obtained in 52% yield as a colorless liquid. H NMR (400 MHz , CDC1 ₃ ) δ 8.30 (d, J = 2.6 Hz, 1H) , 8.17 (s, 1H) , 7.88 (td, J = 8.0, 2.6 Hz, 1H) , 7.26 (s, 1H) , 7.15 (s, 1H) , 7.08 (s, 1H) , 6.95 (dd, J = 8.5, 3.0 Hz, 1H) , 4.93 (s, 2H) , 3.73 (s, 3H) , 2.35 (s, 3H) , 2.26-2.20 (m, 6H) , 1.40 (s, 9H) ; ¹³ C NMR (126 MHz, CDC1 ₃ ) δ 163.70, 162.98 (d, J = 238.4 Hz), 155.02, 154.60, 148.97, 145.74 (d, J = 14.9 Hz), 143.59, 139.68 (d, J = 7.8 Hz), 138.95, 136.60, 134.70 (d, J = 4.6 Hz), 126.67, 124.93, 124.75, 123.64, 122.41, 109.22 (d, J = 37.5 Hz), 80.48, 59.85, 53.44, 28.25, 21.42, 13.20, 10.41; ¹⁹ F NMR (376 MHz, CDCI ₃ ) δ -71.02; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₃₁ F ₃ O ₃ [M+H] ⁺ : 452.2344, found: 452.2344.

tert-Butyl (3- (6-chloropyridin-3-yl) -5-methylphenyl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9az)

Following the general jneta-arylation procedure using NBE- C0 ₂ Me, Compound 9az was obtained in 52% yield as a colorless solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.49 (d, J = 2.5 Hz, 1H) , 8.17 (s, 1H) , 7.75 (dd, J = 8.2, 2.6 Hz, 1H) , 7.34 (d, J = 8.3 Hz, 1H) , 7.28 (s, 1H) , 7.16 (s, 1H) , 7.09 (s, 1H) , 4.92 (s, 2H) , 3.73 (s, 3H) , 2.35 (s, 3H) , 2.22 (s, 6H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.70, 154.96, 154.59, 150.12, 148.98, 147.93, 143.68, 139.05, 137.15, 136.39, 135.51, 126.93, 124.87, 124.77, 124.04, 123.64, 122.34, 80.54, 59.87, 53.41, 28.24, 21.43, 13.21, 10.40; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₃₁ C1N ₃ 03 [M+H] ⁺ :

468.2048, found: 468.2048.

fcerfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - (3-methyl-5- (6- (trifluoromethyl) pyridin-2-yl) - phenyl) carbamate (9ba)

Following the general JTieta-arylation procedure using 20 mol% of Pd(OAc) ₂ nd 40 mol% of L12, Compound 9ba was obtained in 84% yield as a red liquid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 7.86 (t, J = 7.8 Hz, 1H) , 7.80 (d, J = 8.0 Hz, 1H) , 7.74 (s, 1H) , 7.62 (s, 1H) , 7.56 (d, J = 7.5 Hz, 1H) , 7.18 (s, 1H) , 4.97 (s, 2H) , 3.71 (s, 3H) , 2.36 (s, 3H) , 2.24 (s, 3H) , 2.20 (s, 3H) , 1.43 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.77, 157.56, 154.95, 154.71, 148.86, 147.93 (q, J = 34.2 Hz), 143.17, 138.72, 137.86, 137.73, 128.28, 124.93, 124.76, 123.89, 122.84, 122.68, 121.51 (q, J = 274.5 Hz), 118.35 (q, J = 2.8 Hz), 80.50, 59.82, 53.25, 28.23, 21.45, 13.16, 10.44; HRMS (ESI-TOF) m/z Calcd for C27H31F3N3O3 [M+H] ⁺ : 502.2312, found: 502.2312.

tert-Butyl (2 ' -chloro-6-methoxy- [4 ,4 ' -bipyridin] -2-yl) ( (4- methoxy-3,5-dimethylpyridin-2-yl) methyl) carbamate (9bb)

Substrate 2b was arylated following the general meta- arylation procedure using 20 mol% of Pd(OAc) ₂ and 40 mol% of L12. After purification by preparative thin-layer chromatography, Compound 9bb was obtained in 40% yield as a colorless solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, J = 5.2 Hz, 1H) , 8.12 (s, 1H) , 7.78 (s, 1H) , 7.55 (s, 1H) , 7.44 (dd, J = 5.2, 1.5 Hz, 1H) , 6.55 (s, 1H) , 5.26 (s, 2H) , 3.74 (s, 3H) , 3.65 (s, 3H) , 2.27 (s, 3H) , 2.21 (s, 3H) , 1.45 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) & 163.38,

162.79, 155.60, 154.34, 153.17, 152.24, 150.12, 149.73, 148.92, 148.15, 123.97, 122.26, 122.23, 120.60, 108.40, 102.43, 81.45, 59.88, 53.22, 48.92, 28.16, 13.17, 10.34; HRMS (ESI-TOF) m/z Calcd for C25H30CIN4O4 [M+H] ⁺ : 485.1950, found: 485.1950.

tert-Butyl 4- (( ert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) mino) -6- (2-chloro-pyridin-4- yl) -lH-indole-l-carboxylate (9bc)

Substrate 2i was arylated following the general meta- arylation procedure using 20 mol% of Pd(OAc) ₂ and 40 mol% of L12. After purification by preparative thin-layer chromatography, Compound 9bc was obtained in 48% yield as a colorless solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.41-8.31 (m, 2H) , 8.13 (s, 1H) , 7.61 (d, J = 3.7 Hz, 1H) , 7.42 (s, 1H) , 7.39 (d, J = 5.2 Hz, 1H) , 7.21 (s, 1H) , 6.58 (d, J = 3.7 Hz, 1H) , 5.02 (s, 2H) , 3.71 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.68 (s, 9H) , 1.37 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.83, 154.94, 154.56, 152.00, 151.86, 149.75, 149.35, 148.90, 136.46, 135.52, 132.83, 129.57, 127.15, 125.08, 124.60, 121.95, 120.53, 112.49, 105.52, 84.22, 80.54, 59.82, 53.19, 28.18, 28.12, 13.21, 10.62; HRMS (ESI-TOF) m/z Calcd for C ₃₂ H ₃₈ C1 ₄ 0 ₅ [M+H] ⁺ : 593.2525, found: 593.2522.

terfc-Butyl (8- (2-chloropyridin- -y1) -2 , 3-dihydrobenzo [b]

[1,4] dioxin-6-yl) ( (4-methoxy-3 , 5-dimethyl-pyridin-2- yl) methyl) carbamate ( 9bd)

Substrate 21 was arylated following the general meta- arylation procedure. After purification by preparative thin-layer chromatography, Compound 9bd was obtained in 52% yield as a colorless solid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.35 (d, J = 5.2 Hz, 1H) , 8.17 (s, 1H) , 7.39 (s, 1H) , 7.

(d, J = 5.2 Hz, 1H) , 6.92 (s, 1H) , 6.78 (s, 1H) , 4.86 (s 2H) , 4.24 (s, 4H) , 3.74 (s, 3H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.78, 154.92, 154.72, 151.27, 149.10, 148.92, 148.27, 143.53, 138.83, 136.28, 125.60, 124.89, 124.36, 123.90, 122.86, 121.00, 117.09, 80.50, 64.34, 63.99, 59.88, 53.56, 28.25 13.23, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂₇ H ₃₁ CI ₃ O ₅

[M+H] ⁺ : 512.1947, found: 512.1948.

terfc-Butyl (4- (2-chloropyridin-4-yl) thiophen-2-yl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) carbamate (9be)

Substrate 2c was arylated following the general meta- arylation procedure. After purification by preparative thin-layer chromatography, Compound 9be was obtained in 93% yield as a yellow solid. ¹ R NMR (400 MHz, CDC1 ₃ ) δ 8.30 (d, J = 5.2 Hz, 1H) , 8.20 (s, 1H) , 7.36 (s, 1H) , 7.29-7.22 (m, 2H) , 6.92 (s, 1H) , 5.03 (s, 2H) , 3.75 (s, 3H) , 2.23 (s, 6H) , 1.48 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.86, 153.64, 153.46, 152.08, 149.83, 149.05, 146.81, 145.94, 134.60, 125.14, 123.73, 120.55, 119.14, 118.02, 112.98, 82.30, 59.91, 53.42, 28.12, 13.23, 10.29; HRMS (ESI-TOF) m/z Calcd for C ₂ 3H2 ₇ C1 30 ₃ S [M+H] ⁺ : 460.1456, found:

460.1456.

tert-Butyl ( (4-methoxy~3 , 5-dime h lpyridin-2-yl) methyl) (4- (2- (trifluorometh 1) yridin-4-y1) thiophen-2 -yl) carbamate (9bf)

Substrate 2c was arylated following the general meta- arylation procedure. After purification by preparative thin-layer chromatography, Compound 9bf was obtained in 80% yield as a yellow solid. ½ NMR (400 MHz, CDC1 ₃ ) δ 8.64 (d, J = 5.2 Hz, 1H) , 8.21 (s, 1H) , 7.70 (s, 1H) , 7.52 (d, J = 5.0 Hz, 1H) , 7.31 (s, 1H) , 6.99 (s, 1H) , 5.05 (s, 2H) , 3.75 (s, 3H) , 2.27-2.20 (m, 6H) , 1.49 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.92, 153.69, 153.46, 150.38, 149.08, 148. 72 (q, J = 34.7 Hz), 147.03, 144.65, 134.71, 125.22, 123.81, 122.65, 121.60 (q, J = 274.3 Hz), 118.52, 117.08 (d, J = 3.4 Hz), 112.86, 82.42, 59.93, 53.44, 28.15, 13.24, 10.32; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -68.37; HRMS (ESI- TOF) m/z Calcd for C24H27F3N3O3S [M+H] ⁺ : 494.1720, found: 494.1718.

tert-Butyl (5-acetyl- [2 , 3 ' -bithiophen] -5 ' -yl) ( (4-methoxy- 3 , 5-dimethylpyridin-2-yl) methyl) carbamate ( 9bg)

Substrate 2c was arylated following the general meta- arylation procedure. After purification by preparative thin-layer chromatography, Compound 9bg was obtained in 47% yield as a yellow solid. ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.19 (s, 1H) , 7.56 (d, J = 3.9 Hz, 1H) , 7.11 (s, 1H) , 7.07 (d, J = 3.9 Hz, 1H) , 6.83 (s, 1H) , 5.00 (s, 2H) , 3.75 (s, 3H) , 2.52 (s, 3H) , 2.23 (s, 6H) , 1.48 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 190.47, 163.83, 153.61, 153.55, 149.12, 148.08, 146.41, 141.70, 133.34, 131.48, 125.08, 123.66, 123.36, 116.57, 113.35, 82.24, 59.94, 53.39, 28.15, 26.45, 13.24, 10.29; HRMS (ESI-TOF) m/z Calcd for C24H29N2O ₄ S2 [M+H] ⁺ :

473.1563, found: 473.1564.

Ethyl 6- (5- ( ( terfc-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) thiophen-3-yl) -4-oxo-

4H-chromene-2-carboxylate (9bh)

Substrate 2c was arylated following the general meta- arylation procedure. After purification by preparative thin-layer chromatography, Compound 9bh was obtained in 41% yield as a yellow solid. ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.25-8.18 (m, 2H) , 7.87 (dd, J = 8.8, 2.3 Hz, 1H) , 7.59 (d, J = 8.8 Hz, 1H) , 7.14 (s, 1H) , 7.10 (s, 1H) , 6.98 (s, 1H) , 5.03 (s, 2H) , 4.47 (q, J = 7.2 Hz, 2H) , 3.76 (s, 3H) , 2.25 (s, 3H) , 2.23 (s, 3H) , 1.47 (s, 9H) , 1.44 (t, J = 7.2 Hz, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 178.43, 163.81, 160.49, 154.87, 153.82, 153.65, 152.09, 149.13, 146.50, 136.66, 134.12, 132.60, 125.02, 124.46, 123.63, 121.85, 119.12, 115.84, 114.55, 113.82, 82.02, 62.98, 59.93, 53.55, 28.16, 14.07, 13.23, 10.33; HRMS (ESI-TOF) m/z Calcd for

C ₃₀ H ₃₃ N ₂ O ₇ S [M+H] ⁺ : 565.2003, found: 565.2002.

Lenalidomide

11, 61 % yield

General Procedures for meta-Arylation of Lenalidomide:

Substrate (0.05 mmol) , Ar-I (0.1 mmol) , Pd(0Ac) ₂ (1.1 mg, 10 mol%), L12 (1.5 mg, 20 mol%) , AgOAc (25.0 mg, 0.15 mmol), NBE-C0 ₂ Me (11.4 mg, 0.075 mmol) and DCE (0.5 mL) were added to a 2-dram vial. The vial was capped and closed tightly. The reaction mixture was then stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC plate to afford the desired arylated product in 61% yield as a colorless solid.

11

Colorless solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.20 (s, 1H) , 8.15 (s, 1H) , 7.85 (d, J= 7.7 Hz, 1H) , 7.71 (s, 1H) , 7.53 (t, J = 7.5 Hz, 1H) , 7.43 (t, J = 7.6 Hz, 1H) , 7.33 (d, J = 5.7 Hz, 1H) , 5.25 (dd, J= 13.3, 5.1 Hz, 1H) , 4.89 (s, 2H) , 4.66 (d, J= 16.5 Hz, 1H) , 4.51 (d, J = 16.5 Hz, 1H) , 3.71 (s, 3H) , 3.58 (s, 3H) , 3.00-2.78 (m, 2H) , 2.38 (qd, J = 13.6, 13.0, 4.7 Hz, 1H) , 2.29-2.14 (m, 7H) , 1.36 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 170.70, 168.99, 168.46,

168.02, 163.38, 153.82, 153.25, 148.36, 142.11, 140.57, 138.02, 137.33, 131.90, 131.07, 130.42, 130.15, 130.07, 129.73, 127.24, 124.61, 121.49, 80.50, 59.45, 52.42, 51.43, 51.35, 45.99, 31.15, 27.72, 23.05, 12.80, 9.95;

HRMS (ESI-TOF) m/z Calcd for C ₃ 5H3 ₉ N ₄ 0 ₈ [M+H] ⁺ : 643.2762, found: 643.2762.

3.15 eta-Arylation of Anilines without Sliver

5a, 82% yield

General procedure for arylation of la without sliver using methyl 2-iodobenzoate as coupling partner on gram scale :

Substrate la (35.6 mg, 0.1 mmol) , methyl 2-iodobenzoate (30 μΐι, 0.2 mmol), Pd(OAc) ₂ (1.2 mg, 5 mol%), L12 (1.5 mg, 10 mol%), CsOAc (57.6 mg, 0.3 mmol), NBE-C0 ₂ Me (21.6 mg, 0.15 mmol), and t-Amyl-OH (0.2 mL) were added to a 2-dram vial. The vial was capped and closed tightly. Then the reaction mixture was stirred at 100 °C for 24 hours.

After cooling to room temperature, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC to afford the desired product Compound 5a in 82% yield.

f-Amy - , 16 ours

General procedure for arylation of la without sliver using iodobenzene as coupling partner : Substrate la (35.6 mg, 0.1 ramol) , iodobenzene (23 ]iL, 0.2 mmol) , Pd(OAc) ₂ (1.2 mg, 5 mol%), L17 (1.5 mg, 10 mol%), CsOAc (57.6 mg, 0.3 mmol), NBE-C0 ₂ Me (21.6 mg, 0.15 mmol), and t-Amyl-OH (0.2 mL) were added to a 2-dram vial. The vial was capped and closed tightly. Then the reaction mixture was stirred at 100 °C for 15 hours. After cooling to room temperature, the mixture was diluted by DCM (5.0 mL) and stirred for 10 minutes. The mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble

precipitate. After concentration, CsOAc (57.6 mg, 0.3 mmol), Pd(OAc) ₂ (1.2 mg, 5 moll) and t~Amyl-OH (0.2 mL) were added into a 2-dram vial with the residue. The vial was capped and closed tightly, the reaction mixture was then stirred at 100 °C for another 16 hours. After cooling to room temperature, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC to afford the desired product Compound 9a in 73% yield.

Mefca-Amination of Anilines

General procedure for amination of anilines:

Substrate 1 or 2 (0.1 mmol), aminating reagent (0.15 mmol), Pd(OAc) ₂ (2.2 mg, 10 mol%), L24 (3.4 mg, 10 mol%) , AgOAc (33.4 mg, 0.2 mmol), NBE-C0 ₂ Me (21.6 mg, 0.15 mmol), K3PO4 (62.8 mg, 0.3 mmol) and DCM (1.0 mL) were added to a 2-dram vial. The vial was capped and closed tightly.

Then the reaction mixture was then stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC to afford the desired product Compound 10.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methy1-5-morpholinopheny1) carbamate (10a)

Substrate la was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound 10a was obtained in 77% yield as a colorless liquid, ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 6.63 (s, 1H) , 6.60 (s, 1H) , 6.49 (s, 1H) , 4.87 (s, 2H) , 3.80 (t, J = 4.8 Hz, 4H) , 3.72 (s, 3H) , 3.04 (t, J = 4.8 Hz, 4H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.59, 155.36, 154.75, 151.28, 148.87, 143.53, 138.55, 124.54, 123.72, 119.03, 114.16, 111.84, 80.06, 66.90, 59.81, 53.60, 49.52, 28.29, 21.72, 13.19, 10.42; HRMS (ESI-TOF) m/z Calcd for C ₂ 5H3 _{6 3} 0 ₄ [M+H] ⁺ : 442.2700, found: 442.2700.

tert-Butyl ( (4-methoxy-3 , 5-diraethylpyridin-2-yl) methyl) (3- methoxy-5-morpholinophenyl) carbamate (10b)

Substrate lb was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound 10b was obtained in 65% yield as a colorless liquid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 6.46 (s, 1H) , 6.37 (s, 1H) , 6.22 (t, J = 2.2 Hz, 1H) , 4.88 (s, 2H) , 3.80 (t, J = 4.7 Hz, 4H) , 3.72 (s, 3H) , 3.70 (s, 3H) , 3.05 (t, J = 4.6 Hz, 4H) , 2.21 (s, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ

163.57, 160.15, 155.20, 154.64, 152.11, 148.88, 144.47, 124.57, 123.70, 107.47, 103.88, 99.79, 80.17, 66.81, 59.82, 55.20, 53.57, 49.31, 28.29, 13.19, 10.41; HRMS (ESI-TOF) m/z Calcd for C ₂ 5H3 _{6 3} 05 [M+H] ⁺ : 458.2649, found: 458.2650.

terfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- (methylthio) -5-morpholinopheny1) -carbamate (10c)

Substrate lc was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound 10c was obtained in 57% yield as a colorless solid, ^λ Ε NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 6.67 (s, 1H) , 6.65 (s, 1H) , 6.57 (t, J = 2.0 Hz, 1H) , 4.87 (s, 2H) , 3.84-3.76 (m, 4H) , 3.72 (s, 3H) , 3.10-3.01 (m, 4H), 2.38 (s, 3H) , 2.21 (s, 3H) , 2.19 (s, 3H) , 1.40 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.63, 155.09, 154.59, 151.51, 148.89, 144.05, 138.70, 124.67, 123.76, 116.61, 111.87, 111.62, 80.31, 66.79, 59.85, 53.43, 49.24, 28.29, 16.01, 13.20, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂₅ H ₃₆ N ₃ 0 ₄ S [M+H] ⁺ : 474.2421, found: 474.2421.

tert-Butyl (3-fluoro-5-morpho1inopheny1) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (lOd)

Substrate le was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound lOd was obtained in 63% yield as a colorless liquid, ¾ NMR (400 MHz , CDC1 ₃ ) δ 8.16 (s, 1H) , 6.65 (s, 1H) , 6.51 (dt, J = 10.0, 2.1 Hz, 1H) , 6.35 (dt, J = 11.7, 2.3 Hz, 1H) , 4.86 (s, 2H) , 3.84- 3.77 (m, 4H) , 3.73 (s, 3H) , 3.10-3.03 (m, 4H) , 2.22 (s, 3H) , 2.20 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDCl ₃ ) δ 164.00, 163.65, 162.40, 154.84, 152.24, 152.16, 148.93, 144.78, 144.69, 124.72, 123.61, 109.47, 105.05, 104.89, 99.91, 99.74, 80.54, 66.64, 59.85, 53.35, 28.21, 13.20, 10.37; HRMS (ESI-TOF) m/z Calcd for C24H33F 3O4 [M+H] ⁺ :

446.2450, found: 446.2452.

fcert-Butyl (3-chloro-5-morpholinophenyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (lOe)

Substrate If was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound lOe was obtained in 63% yield as a colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 6.77 (s, 2H) , 6.63 (t, J = 2.1 Hz, 1H) , 4.85 (s, 2H) , 3.84-3.77 (m, 4H) , 3.73 (s, 3H) ^' , 3.10-3.02 (m, 4H) , 2.22 (s, 3H) , 2.20 (s, 3H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDCI ₃ ) δ 163.66, 154.80, 154.35, 151.92, 148.94, 144.54, 134.17, 124.75, 123.62, 117.94, 112.84, 112.50, 80.58, 66.66, 59.86, 53.30, 48.87, 28.22, 13.21, 10.39; HRMS (ESI-TOF) m/z Calcd for C ₂₄ H ₃₃ CIN ₃ O ₄ [M+H] ⁺ : 462.2154, found: 462.2155.

Methyl 3- ( ( te t-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5-morpholino-benzoate (10f)

Substrate lh was aminated following the general meta- amination procedure using Pd(OAc) ₂ (3.4 mg, 15 mol%), L24 (5.1 mg, 15 mol%), AgOAc (50.1 mg, 0.3 mmol) and NBE-C0 ₂ e (45.7 mg, 0.3 mmol). After purification by preparative thin-layer chromatography, Compound lOf was obtained in 60% yield as a colorless solid, *H NMR (400 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 7.42 (s, 1H) , 7.36-7.32 (m, 1H) , 7.08 (s, IH) , 4.91 (s, 2H) , 3.86 (s, 3H) , 3.84-3.80 (m, 4H) , 3.72 (s, 3H) , 3.15-3.08 (m, 4H) , 2.23-2.19 (m, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 166.97, 163.71, 154.89, 154.48, 151.26, 148.90, 143.71, 130.80, 124.78, 123.86, 119.26, 118.86, 113.76, 80.55, 66.74, 59.85, 53.24, 52.09, 49.06, 28.23, 13.21, 10.46; HRMS (ESI-TOF) m/z Calcd for C ₂ 6H3 _{6 3} O _g [M+H] ⁺ : 486.2599, found: 486.2600.

terfc-Butyl (l-acetyl-4-morpholinoindolin-6-yl) ( (4-methoxy- 3 , 5-dimethylpyridin-2-yl) methyl) carbamate (lOg)

Substrate 2g was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound lOg was obtained in 76% yield as a light yellow solid, Rotameric mixture, ratio of the rotamers = 74/26; ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 7.87 (s, 0.74H), 6.86 (s, 0.26H), 6.68-6.52 (m, IH) , 4.97-4.81 (m, 2H) , 4.09 (t, J = 8.4 Hz, 0.52H), 4.01 (t, J = 8.2 Hz, 1.48H), 3.84-3.76 (m, 4H) , 3.76-3.69 (m, 3H) , 3.02 (t, J = 8.3 Hz, 1.42H), 2.97-2.82 (m,

4.52H), 2.28-2.13 (m, 9H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) resonances for the minor rotamer are enclosed in parenthesis () : δ 168.21, 163.64 (163.71), 155.27 (155.13), 154.74, 148.77 (148.88), 147.80, 143.81, 143.21

(142.78), 124.56 (124.83), 123.96 (123.43), 120.93, 112.74 (111.75), 110.80 (108.80), 80.22 (80.41), 67.15 (67.10), 59.82, 53.53 (53.68), 50.91 (50.71), 49.41 (48.60), 28.29, 26.61 (25.61), 24.21 (24.00), 13.18, 10.48 (10.45); HRMS (ESI-TOF) m/z Calcd for C ₂₈ H ₃₉ N ₄ O ₅ [M+H] ⁺ : 511.2915, found: 511.2914.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2- l) methyl) (1- methyl-4-morpholino-lH-indazol-6-yl) -carbamate (lOh)

Substrate 2j was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound lOh was obtained in 62% yield as a colorless solid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 7.86-7.79 (m, 2H) , 6.93 (s, 1H) , 6.44 (s, 1H) , 4.95 (s, 2H) , 3.94 (s, 3H) , 3.92-3.88 (m, 4H) , 3.73 (s, 3H) , 3.25-3.16 (m, 4H) , 2.23 (s, 3H) , 2.22 (s, 3H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.67, 155.14, 154.75, 148.88, 145.25, 142.42, 141.34, 130.99, 124.73, 123.82, 115.44, 106.64, 100.31, 80.40, 66.89, 59.83, 53.94, 51.40, 35.64, 2-8.29, 13.21, 10.48; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H ₃₆ N ₅ 04 [M+H] ⁺ : 482.2762, found: 482.2766.

tert-Butyl 6- ( ( tert-butoxycarbonyl) ( (4-me hoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -4-morpholino-lH-indole-

1-carboxylate (lOi) Substrate 2h was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound lOi was obtained in 53% yield as a colorless solid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.12 (s, 1H) , 7.67 (s, 1H) , 7.49 (d, J = 3.7 Hz, 1H) , 6.66 (s, 1H) , 6.48 (d, J = 3.7 Hz, 1H) , 4.97 (s, 2H) , 3.89 (t, J = 4.5 Hz, 4H) , 3.72 (s, 3H) , 3.06 (t, J = 4.6 Hz, 4H) , 2.23 (s, 3H) , 2.20 (s, 3H) , 1.57 (s, 9H) , 1.41 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.67, 155.32, 154.97, 149.52, 148.85, 144.70, 140.07, 135.82, 124.76, 124.63, 124.02, 121.87, 110.77, 108.56, 105.03, 83.54, 80.10, 67.12, 59.78, 54.13, 52.06, 28.34, 28.02, 28.01, 13.15, 10.50; HRMS (ESI-TOF) m/z Calcd for C ₃ iH43 ₄ 0 ₆ [M+H] ⁺ : 567.3177, found: 567.3179.

tert-Butyl 4- (( te -butoxycarbonyl) ( (4-methoxy-3 , 5- dime hylpyridin-2-yl) methyl) amino) -6-morpholino-lH-indole- 1-carboxylate (10j)

Substrate 2i was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound lOj was obtained in 44% yield as a colorless solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.11 (s, 1H) , 7.60 (s, 1H) , 7.38 (d, J = 3.7 Hz, 1H) , 6.69 (s, 1H) , 6.41 (d, J = 3.8 Hz, 1H) , 4.95 (s, 2H) , 3.86-3.78 (m, 4H) , 3.68 (s, 3H) , 3.12-3.01 (m, 4H) , 2.23-2.13 (m, 6H) , 1.64 (s, 9H) , 1.35 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.63, 155.23, 154.80, 149.81, 149.28, 148.83, 136.84, 135.05, 124.71, 124.42, 124.05, 122.23, 112.58, 105.50, 101.10, 83.29, 80.10, 66.95, 59.75, 53.28, 50.54, 28.22, 28.17, 13.16, 10.57; HRMS (ESI-TOF) m/z Calcd for C ₃₁ H ₄₃ N ₄ 0 ₆ [M+H] ⁺ : 567.3177, found: 567.3174.

10k

tert-Butyl (3- (2 , 6-dimethylmorpholino) -5-methylphenyl) ( (4- methoxy-3 , 5-dimethylpyridin-2-yl) methyl) -carbamate (10k)

Substrate la was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound 10k was obtained in 81% yield as a colorless liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ

8.15 (s, 1H) , 6.57 (s, 2H) , 6.48 (s, 1H) , 4.87 (s, 2H) , 3.80-3.67 (m, 5H) , 3.30 (d, J = 10.4 Hz, 2H) , 2.31 (t, J = 11.1 Hz, 2H) , 2.25-2.18 (m, 9H) , 1.39 (s, 9H) , 1.23 (s, 3H) , 1.21 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.58, 155.40, 154.76, 150.94, 148.83, 143.42, 138.55, 124.52, 123.79, 118.79, 114.24, 112.01, 80.02, 71.55, 59.81, 54.99, 53.62, 28.28, 21.71, 19.01, 13.18, 10.43; HRMS (ESI-TOF) m/z Calcd for C^H^NsC^ [M+H] ⁺ : 470.3013, found: 470.3014.

tert-Butyl 4- (3- ( (fcert-butoxycarbonyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) amino) -5- methylphenyl) piperazine-l-carboxylate (101)

Substrate la was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound 101 was obtained in 84% yield as a colorless solid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 6.63 (s, 1H) , 6.61 (s, 1H) , 6.50 (s, 1H) , 4.87 (s, 2H) , 3.72 (s, 3H) , 3.52 (t, J = 5.1 Hz, 4H) , 3. (t, J = 5.2 Hz, 4H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 2.20 (s 3H) , 1.48 (s, 9H) , 1.39 (s, 9H) ; ^1J C NMR (150 MHz, CDC1 ₃ ) δ 163.56, 155.30, 154.67, 151.23, 148.85, 143.46, 138.54, 124.54, 123.68, 119.20, 115.09, 112.60, 80.06, 79.78, 59.80, 53.57, 49.53, 44.01, 42.98, 28.38, 28.26, 21.68, 13.18, 10.40; HRMS (ESI-TOF) m/z Calcd for C ₃ oH45N ₄ 0 ₅ [M+H] ⁺ : 541.3384, found: 541.3387.

fcerfc-Butyl (3- (1 , 1-dioxidothiomorpholi.no) -5-methylpheny1) - ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) -carbamate (10m)

Substrate la was aminated following the general meta- amination procedure. After purification by preparative thin-layer chromatography, Compound 10m was obtained in 70% yield as a light yellow solid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 6.71 (s, 1H) , 6.66 (s, 1H) , 6.48 (s, 1H) , 4.87 (s, 2H) , 3.81-3.69 (m, 7H) , 3.07-2.98 (m, 4H) , 2.24 (s, 3H) , 2.23-2.19 (m, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.64, 155.16, 154.51, 148.83, 147.34, 143.93, 139.30, 124.76, 123.78, 119.61, 114.42, 112.37, 80.32, 59.85, 53.40, 50.33, 47.62, 28.24, 21.74, 13.21, 10.42; HRMS (ESI-TOF) m/z Calcd for C25H36 3O5S [M+H] ⁺ : 490.2370, found: 490.2368.

tert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methyl-5-thiomorpholinophenyl) carbamate (10n) Substrate la was aminated following the general meta- amination procedure using Pd(OAc) ₂ (3.4 mg, 15 mol%), L24 (5.1 mg, 15 mol%), AgOAc (50.1 mg, 0.3 mmol) and NBE-C0 ₂ Me (45.7 mg, 0.3 mmol) . After purification by preparative thin-layer chromatography, Compound 10η was ^' obtained in 62% yield as a colorless solid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 6.58 (s, 2H) , 6.47 (s, 1H) , 4.87 (s, 2H) , 3.72 (s, 3H) , 3.45-3.38 (m, 4H) , 2.71-2.64 (m, 4H) , 2.24- 2.18 (m, 9H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.61, 155.34, 154.74, 151.33, 148.85, 143.49, 138.66, 124.60, 123.78, 118.82, 115.65, 113.26, 80.10, 59.84, 53.59, 52.27, 28.30, 26.79, 21.71, 13.21, 10.44; HRMS (ESI-TOF) m/z Calcd for C25H36N3O3S [M+H] ⁺ : 458.2472, found: 458.2469.

terfc-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (3- methyl-5- (4-oxopiperidin-l-yl) phenyl) -carbamate (lOo)

Substrate la was aminated following the general meta- amination procedure using Pd(OAc) ₂ (3.4 mg, 15 mol%), L24 (5.1 mg, 15 mol%), AgOAc (50.1 mg, 0.3 mmol) and NBE-C0 ₂ Me (45.7 mg, 0.3 mmol) . After purification by preparative thin-layer chromatography, Compound lOo was obtained in 53% yield as a colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.14 (s, 1H) , 6.71 (s, 1H) , 6.61 (s, 1H) , 6.56 (s, 1H) , 4.88 (s, 2H) , 3.73 (s, 3H) , 3.50 (t, J = 6.0 Hz, 4H) , 2.47 (t, J = 6.0 Hz, 4H) , 2.25 (s, 3H) , 2.21 (s, 6H) , 1.39 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 208.41, 163.61, 155.33, 154.69, 148.97, 148.83, 143.73, 138.94, 124.63, 123.77, 118.81, 114.26, 112.10, 80.16, 59.84, 53.57, 49.00, 40.69, 28.29, 21.77, 13.20, 10.43; HRMS (ESI-TOF) m/z Calcd for C ₂₆ H _{36 3} O ₄ [M+H] ⁺ : 454.2700, found: 454.2699. Meta-Alkynylation of Anilines

General procedure for alkynylation of anilines :

Substrate 1 or 2 (0.1 mmol) , alkynylating reagent (52.2 mg, 0.2 mmol), Pd(OAc) ₂ (2.2 mg, 10 mol%), L25 (8.2 mg, 30 mol%), Ag ₂ C0 ₃ (41.1 mg, 0.15 mmol), NBE-C0 ₂ Me (38.0 mg, 0.25 mmol), LiF (5.2 mg, 0.2 mmol) and DCM (1.0 mL) were added to a 2-dram vial. The vial was capped and closed tightly. Then the reaction mixture was then stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC to afford the desired product Compound 14.

fcerfc-Butyl ( (4-methoxy-3 , 5-dime hylpyridin-2-yl) methyl) (3- methyl-5- ( ( riisopropylsilyl) ethynyl) phenyl) -carbamate (14a)

Substrate la was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 14a was obtained in 72% yield as a colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 7.11 (s, 1H) , 7.05 (s, 2H) , 4.87 (s, 2H) , 3.72 (s, 3H) , 2.24 (s, 3H) , 2.21 (s, 6H) , 1.40 (s, 9H) , 1.10 (s, 21H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.70, 154.94, 154.59, 148.95, 142.57, 138.08, 129.93, 127.64, 127.31, 124.69, 123.75, 123.25, 107.04, 89.82, 80.42, 59.83, 53.32, 28.22, 21.10, 18.63, 13.18, 11.29, 10.44; HRMS (ESI-TOF) m/z Calcd for CszH^NzOsSi [M+H] ⁺ : 537.3507, found: 537.3506.

tert-Butyl ( (4-methoxy-3 , 5-dime hylpyridin-2-yl) methyl) (3- methoxy-5- ( (triisopropylsilyl) ethynyl) phenyl) -carbamate (14b)

Substrate lb was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 14b was obtained in 62% yield as a colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.16 (s, 1H) , 6.94 (s, 1H) , 6.83 (s, 1H) , 6.75 (s, 1H) , 4.87 (s, 2H) , 3.73 (s, 3H) , 3.72 (s, 3H) , 2.23-2.18 (m, 6H) , 1.41 (s, 9H) , 1.10 (s, 21H) ; ¹³ C NMR (150 MHz, CDCl ₃ ) δ 163.70, 159.17, 154.78, 154.49, 148.97, 143.84, 124.70, 123.95, 123.70, 122.97, 114.24, 113.82, 106.82, 90.18, 80.56, 59.84, 55.39, 53.26, 28.23, 18.63, 13.18, 11.27, 10.41; HRMS (ESI-TOF) m/z Calcd for C32H49N2O4S1 [M+H] ⁺ :

553.3456, found: 553.3457.

tert-Butyl (3- ( ( ( fcert-Butyldimethylsilyl) oxy) methyl) -5- ( (triisopropylsilyl) ethynyl) phenyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) carbamate (14c)

Substrate lx was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 14c was obtained in 70% yield as a colorless liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 7.20 (s, 1H) , 7.19-7.14 (m, 2H) , 4.88 (s, 2H) , 4.62 (s, 2H) , 3.72 (s, 3H) , 2.23-2.17 (m, 6H) , 1.40 (s, 9H) , 1.10 (s, 21H) , 0.89 (s, 9H) , 0.04 (s, 6H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.67, 154.81, 154.61, 149.02, 142.77, 141.83, 128.46, 126.71, 124.63, 124.27, 123.63, 123.26, 107.06, 90.03, 80.45, 64.15, 59.82, 53.28, 28.23, 25.86, 18.63, 18.31, 13.17, 11.29, 10.39, -5.35; HRMS (ESI-TOF) m/z Calcd for CseHsaNzC^Siz [M+H] ⁺ : 667.4321, found:

667. 322.

terfc-Butyl (3-benzyl-5- ( ( riisopropylsilyl) ethynyl) - phenyl) ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - carbamate (14d)

Substrate ly was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 14d was obtained in 50% yield as a colorless liquid, ¹ R NMR (400 MHz, CDC1 ₃ ) δ 8.09 (s, 1H) , 7.28-7.22 (m, 2H) , 7.18 (t, J = 7.2 Hz, 1H) , 7.14 (s, 1H) , 7.11-7.05 (m, 3H) , 7.00 (s, 1H) , 4.86 (s, 2H) , 3.86 (s, 2H) , 3.69 (s, 3H) , 2.19 (s, 3H) , 2.17 (s, 3H) , 1.36 (s, 9H) , 1.09 (s, 21H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.72, 154.80, 154.56, 148.94, 142.65, 141.02, 140.40, 129.77, 128.85, 128.39, 128.10, 127.89, 126.10, 124.69, 123.86, 123.56, 106.87, 90.22, 80.49, 59.82, 53.22, 41.40, 28.21, 18.64, 13.20, 11.29, 10.44; HRMS (ESI-TOF) m/z Calcd for C ₃₈ H ₅₃ N ₂ O ₃ S 1 [M+H] ⁺ : 613.3820, found: 613.3820.

fcert-Butyl ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) (5- ( (triisopropy1silyl) ethynyl) -[1,1' -biphenyl] -3 - yl) carbamate (14e)

Substrate lz was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 14e was obtained in 61% yield as a colorless liquid, ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.48 (d, J = 7.6 Hz, 2H) , 7.45-7.36 (m, 4H) , 7.33 (d, J = 7.2 Hz, 1H) , 7.31 (s, 1H) , 4.94 (s, 2H) , 3.71 (s, 3H) , 2.22 (s, 3H) , 2.21 (s, 3H) , 1.43 (s, 9H) , 1.12 (s, 21H); ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.76, 154.86, 154.55, 149.02, 143.01, 141.45, 140.14, 128.90, 128.68, 127.99, 127.53, 127.10, 126.01 , 124.81 , 123.89, 106.78, 90.51, 80.62, 59.83, 53.28, 28.29, 28.26, 18.65, 13.19, 11.30, 10.48; HRMS (ESI-TOF) m/z Calcd for C3 ₇ H ₅₁ 20 ₃ Si [M+H] ⁺ :

599.3663, found: 599.3662.

terfc-Butyl (3-fluoro-5- ( (triisopropylsilyl) ethynyl) - phenyl) ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) methyl) - carbamate (14f)

Substrate le was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 14f was obtained in 44% yield as a colorless liquid, ½ NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.15 (s, 1H) , 7.03 (d, J = 10.3 Hz, 1H) , 6.92 (d, J = 8.1 Hz, 1H) , 4.86 (s, 2H) , 3.73 (s, 3H) , 2.22 (s, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) , 1.10 (s, 21H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.74 , 161.84 (d, J = 245.3 Hz), 154.42 , 154.21 , 149.09 , 144.41 (d, J = 11.1 Hz),

125.76 , 124.84 , 124.54 (d, J = 10.9 Hz), 123.53 , 115.79 (d, J = 23.0 Hz), 114.50 (d, J = 23.3 Hz), 105.59 (d, J = 3.3 Hz), 91.74 , 80.96 , 59.88 , 53.09 , 28.18 , 18.60 , 13.20 11.23 10.38; HRMS (ESI-TOF) m/z Calcd for

C ₃₁ H ₄₆ FN ₂ 0 ₃ Si [ +H] + 541.3256, found: 541.3257.

tert-Butyl (3-chloro-5-

( (triisopropylsilyl) ethynyl) phenyl) ( (4-methoxy-3 , 5- dimethylpyridin-2-yl) methyl) -carbamate (14g)

Substrate If was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 14g was obtained in 59% yield as a colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.28 (s, 1H) , 7.27-2.24 (m, 1H) , 7.20 (s, 1H) , 4.85 (s, 2H) , 3.73 (s, 3H) , 2.22 (s, 3H) , 2.20 (s, 3H) , 1.40 (s, 9H) , 1.10 (s, 21H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.75, 154.40, 154.18, 149.10, 144.00, 133.45, 128.83, 128.22, 127.03, 124.85, 124.70, 123.53, 105.31, 92.05, 80.98, 59.89, 53.06, 28.17, 18.61, 13.20, 11.23, 10.39; HRMS (ESI-TOF) m/z Calcd for C ₃ iH ₄₆ ClN ₂ 0 ₃ Si [M+H] ⁺ : 557.2961, found: 557.2960.

tert-Butyl (3-bromo-5- ( (triisopropylsilyl) ethynyl) - phenyl) ( (4-methoxy-3 , 5-dimethylpyridin-2-y1) methyl) - carbamate (14h)

Substrate laa was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 14h was obtained in 56% yield as a colorless liquid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.17 (s, 1H) , 7.43 (s, 1H) , 7.35 (s, 1H) , 7.29 (s, 1H) , 4. b£> [s, 2H) , 3.73 (s, 3H) , 2.22 (s, 3H) , 2.2(

1.40 (s, 9H) , 1.10 (s, 21H); ^iJ C NMR (151 MHz, CDC1 ₃ ) δ 163.76, 154.38, 154.16, 149.10, 144.04, 131.65, 129.88, 128.69, 125.00, 124.86, 123.55, 121.16, 105.14, 92.19, 81.00, 59.89, 53.05, 28.17, 18.61, 13.20, 11.23, 10.40;

HRMS (ESI-TOF) m/z Calcd for C ₃₁ H4 ₆ Br ₂ 0 ₃ Si [M+H] ⁺ : 601.2456, found: 601.2456.

terfc-Butyl ( (4-methoxy-3 , 5-dime hylpyridin-2-yl) methyl) (1- methyl-4- ( (triisopropylsilyl) ethynyl) -1H -indazol-6- yl) carbamate (14i)

Substrate 2j was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 14i was obtained in 53% yield as a colorless solid, ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 7.96 (s, 1H) , 7.35 (s, 1H) , 7.17 (s, 1H) , 4.95 (s, 2H) , 3.98 (s, 3H) , 3.72 (s, 3H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 1.41 (s, 9H) , 1.15 (s, 21H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 163.79, 154.81, 154.68, 148.93, 141.15, 139.74, 132.28, 125.06, 124.86, 123.91, 123.35, 115.60, 107.69, 103.86, 94.66, 80.72, 59.84, 53.70, 35.69, 28.23, 18.66, 13.18, 11.26, 10.50; HRMS (ESI-TOF) m/z Calcd for C ₃₃ H4 _{9 4} 0 ₃ Si [M+H] ⁺ : 577.3568, found: 577.3568.

tert-Butyl (l-acetyl-4- ( (triisopropylsilyl) ethynyl) - indolin-6-yl) ( (4-methoxy-3 , 5-dimethylpyridin-2-yl) - methyl) carbamate (14j) Substrate 2g was alkynylated following the general meta- alkynylation procedure. After purification by preparative thin-layer chromatography, Compound 1 j was obtained in 46% yield as a light yellow solid, Rotameric mixture, ratio of the rotamers = 84/16; ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.15 (s, 1H) , 8.11 (s, 0.84H), 7.19 (s, 0.16H), 6.97 (s, 1H) , 4.93-4.82 (m, 2H) , 4.18-4.96 (m, 2H) , 3.72 (s, 3H) , 3.17 (t, J = 8.5 Hz, 1.68H), 3.05 (t, J = 8.4 Hz, 0.32H) , 2.33-2.14 (m, 9H) , 1.40 (s, 9H) , 1.10 (s, 21H) ; ¹³ C MR (150 MHz, CDC1 ₃ ) resonances for the minor rotamer are enclosed in parenthesis () : ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 168.55 (168.27), 163.74, 154.98 (154.84), 154.67, 148.88, 142.87 (142.36), 142.27 (141.67), 131.84 (134.48), 125.21 (124.90), 124.68 (124.64), 123.98, 119.35 (120.76), 116.60 (114.42), 104.10 (103.69), 94.27 (95.13), 80.46 (80.63), 59.82, 53.49, 48.97 (48.06), 28.24, 27.72 (26.48), 24.11 (24.34), 18.62, 13.17, 11.18, 10.52 (10.45); HRMS (ESI- TOF) m/z Calcd for C ₃₅ H _{52 3} 0 ₄ Si [M+H] ⁺ : 606.3722, found:

606.3722.

3.18 Meta-Arylation of Phenylacetic Acid

General procedure for arylation of phenylacetic acid:

2-Methyl phenylacetic acid (0.1 mmol) , Ar-I (0.25 mmol) , Pd(OAc) ₂ (2.2 mg, 10 mol%) , L24 (6.8 mg, 20 mol%), Ag ₂ C0 ₃ (20.7 mg, 0.075 mmol), NBE-C0 ₂ Me (38.0 mg, 0.25 mmol), K ₂ HPO ₄ (35 mg, 0.2 mmol) and HFIP (1.0 mL) were added to a 10 mL vial. The vial was capped and closed tightly. Then the reaction mixture was first stirred at room temperature for 5 minutes and then heated to 100 °C for 24 hours.

After cooling to room temperature, 0.05 mL HOAc was added.

Then the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC using 2:1 hexanes : EtOAc (with 1% HOAc) as the eluent to afford the desired product Compound 15.

2- (4 , 4 ¹ -dimethyl- [1,1' -biphenyl] -3-yl) acetic acid

Colorless solid, ^X H NMR (400 MHz , CDC1 ₃ ) δ 7.46 (d, J = 8.0 Hz, 2H) , 7.43-7.36 (m, 2H) , 7.27-7.15 (m, 3H) , 3.72 (s, 2H) , 2.38 (s, 3H) , 2.35 (s, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 177.3, 139.2, 137.8, 136.9, 135.7, 132.3, 130.8, 129.4, 128.9, 126.8, 126.2, 39.0, 21.1, 19.2; HRMS (ESI-TOF) m/z Calcd for C ₁₆ Hi ₇ 0 ₂ ⁺ [M+H] ⁺ : 241.1223, found: 241.1223.

Gram-Scale Reaction for meta-Arylation of Anilines

4.0 mmol 8.0 mmol 1.82 g, 93% yield

Compound la (1.43 g, 4.0 mmol), methyl 4-iodobenzoate (2.1 g, 8.0 mmol), Pd(OAc) ₂ (44.8 mg, 0.2 mmol, 5 mol%), Ligand L12 (30.4 mg, 0.2 mmol, 5 mol%), AgOAc (2.0 g, 12.0 mmol), NBE-C0 ₂ Me (608.8 mg, 4.0 mmol) and DCE (10.0 mL) were added to a 150 mL sealed tube. Then the reaction mixture was stirred at 100 °C for 48 hours. After cooling to room temperature, the mixture was passed through a pad of

Celite® with DCM as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by silica gel column chromatography to afford the desired arylated product in 93% yield as a colorless liquid.

Directing Group Removal for Amines c

General procedure for directing group removal from amines :

To a solution of 9n (981.2 mg, 2.0 mmol) in DCM (8.0 mL) was added TFA (1.2 mL, 16.0 mmol) at room temperature. The mixture was stirring at room temperature for another 24 hours. The resulting solution was diluted by DCM (50 mL) , and washed by with a saturated sodium carbonate solution. The aqueous phase was extracted with DCM (3x10 mL) . The combined organic phases were dried by Na ₂ S0 ₄ and concentrated to afford a solid, which was used for next step without purification.

To a mixture of the solid amine obtained in the previous step (39.0 mg, 0.1 mmol), was added DDQ (22.7 mg, 0.1 mmol), DCM/H ₂ 0 (0.6 mL/0.2 mL) and Boc ₂ 0 (69 0.3 mmol) . The mixture was stirred at room temperature for another 24 hours. Next, the mixture was passed through a pad of Celite® with DCM as the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified by preparative TLC to afford the desired arylated product (Hexane/EA = 3/1) as a colorless solid (25.2 mg, 74% yield).

Methyl 3 ' - ( ( tert-butoxycarbonyl) amino) -5 ' -methyl- [1,1'- biphenyl] -4-carboxylate (12)

¾ NMR (400 MHz, CDC1 ₃ ) δ 8.09 (d, J= 8.3 Hz, 2H) , 7.65 (d, J= 8.4 Hz, 2H) , 7.47 (s, 1H) , 7.25 (s, 1H) , 7.12 (s, 1H) , 6.60 (s, 1H) , 3.95 (s, 3H) , 2.41 (s, 3H) , 1.55 (s, 9H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 167.00, 152.74, 145.45, 140.75, 139.45, 138.85, 129.96, 128.88, 127.07, 127.04, 122.83, 118.79, 114.53, 80.61, 52.09, 28.33, 21.57.

Directing Group Removal for Phenol

7e 13

General Procedure for directing group hydrogenolysis (phenols): Substrate 7e (0.1 mmol) and 10% Pd/C (30.0 mg) , were charged to a 10 mL vial equipped with a stir bar and a rubber septa. The vial was evacuated and purged with nitrogen, followed by addition of 2.0 mL of MeOH. The vial was then placed in an autoclave with a needle piercing the septa. The autoclave was purged with hydrogen three times then filled to a pressure of 30 bar H ₂ . The autoclave was placed on a stirring plate at room temperature overnight with good stirring. The resulting solution was diluted with EtOAc (5.0 mL) and passed through a plug of Celite® with EtOAc as the eluent. The filtrate was concentrated and purified by preparative TLC to provide the desired phenol 13 in 79% yield.

13 Methyl 4 ' -methyl-3 ' - ( (3-methylpyridin-2-yl) methoxy) -[1,1'- biphenyl] -2-carboxylate (13)

Colorless solid, ^X H NMR (400 MHz , CDC1 ₃ ) δ 7.77 (d, J = 7.7 Hz, 1H) , 7.53-7.44 (t, J = 7.6 Hz, 1H) , 7.41-7.32 (m, 2H) , 7.13 (d, J = 7.6 Hz, 1H) , 6.79 (dd, J = 7.5, 1.7 Hz, 1H) , 6.74 (d, J = 1.7 Hz, 1H) , 5.02 (s, 1H) , 3.68 (s, 3H) , 2.28 (S, 3H) ; ¹³ C NMR (150 MHz, CDC1 ₃ ) δ 169.56, 153.56, 141.87, 140.18, 131.17, 130.84, 130.69, 130.53, 129.53, 127.02, 122.91, 120.66, 114.86, 52.12, 15.56; HRMS (ESI-TOF) m/z Calcd for C ₁₅ H ₁₄ O ₃ [M+H] ⁺ : 243.1016, found: 243.1017.

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Each of the patents, patent applications and articles cited herein is incorporated by reference.

The foregoing description and the examples are intended as illustrative and are not to be taken as limiting. Still other variations within the spirit and scope of this invention are possible and will readily present themselves to those skilled in the art.