Process of preparing imidazo[l,2-c] pyrimidine compounds

Abstract

The present disclosure relates to improved methods of making the PRC2 inhibitor 8-(4- ((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile, or a salt or solvate thereof.

Description

WSGR Docket No. 47134-780.601PROCESS OF PREPARING IMIDAZO[l,2-c] PYRIMIDINE COMPOUNDS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 760,517 filed on February 19, 2025, and U.S. Provisional Application No. filed 63 / 970,035 on January 28, 2026; which are hereby incorporated by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] The Poly comb Repressive Complex 2 (PRC2) is a multiprotein complex that contributes to the epigenetic silencing of target genes to regulate development and homeostasis The PRC2 complex is comprised of three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). Two additional non-essential subunits, AEBP2, and RbAp48, function to promote the enzymatic activity of the PRC2 complex (e.g. , see Cao et al., (2002) Science 298: 1039-1043). The dysregulation of PRC2 methyltransferase activity can lead to tumorigenesis in a wide range of cancers including prostate cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, and hematological malignancies. PRC2 is composed of two druggable subunits: EED and EZH2. The pharmacologic properties of some EZH2 inhibitor compounds may require high doses that achieve only partial target inhibition in subjects suffering from cancer. Additionally, preclinical studies suggest drug resistance to EZH2 inhibitors may develop via EZH1 bypass compensation or acquired mutations in EZH2. Allosteric inhibition of EED impacts the assembly, stabilization, and activation of PRC2, and may have benefits over EZH2 -mediated inhibition of PRC2. Therefore, there is a need to develop improved methods of synthesis of said compounds, that exhibit inhibition of the EED subunit of PRC2 for the treatment of cancer in subjects.BRIEF SUMMARY OF THE INVENTION

[0003] Described herein are improved methods of making the PRC2 inhibitor of Formula (I), 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile, or a salt or solvate thereof:

[0004] In one aspect, described herein is a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprising reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst to afford the compound of Formula (I)WSGR Docket No. 47134-780.601wherein:X in the compound of Formula (II) is halogen or -OS(O)2RX;Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3; andY in the compound of Formula (III) is -B(OR1)2 or -BF3K;wherein when Y is -B(OR1)2, each R1is independently hydrogen or Ci-Ce alkyl, or both R1together with the atoms to which they are attached form a 5-12 membered heterocycle.

[0005] In a second aspect, described herein is a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprising reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(dimethylamino)phosphonium hexafluorophosphate to afford the compound of Formula (II)wherein X in the compounds of Formula (V) and Formula (II) are the same and are halogen or - 0S(0)2RX, wherein Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3.

[0006] Also described herein is substantially pure compound of Formula (I)or a salt or solvate thereof, comprising from 0.01% to 5% by weight of palladium impurities.

[0007] Also described herein is substantially pure compound of Formula (I)WSGR Docket No. 47134-780.601or a salt or solvate thereof, comprising from 0.01% to 5% by weight of a compound of Formula (VI)salt or solvate thereof.

[0008] Also described herein is substantially pure compound of Formula (I),or a salt or solvate thereof, comprising from 0.01% to 5% by weight of a compound of Formula (Ila)salt or solvate thereof.

[0009] Also described herein is substantially pure compound of Formula (II)(IDor a salt or solvate thereof,wherein X is halogen or -OS(O)2RX, comprising from 0.01% to 5% by weight of a compound ofFormula (salt or solvate thereof.

[0010] Also described herein is substantially pure compound of Formula (II)WSGR Docket No. 47134-780.601or a salt or solvate thereof, wherein X is halogen or -OS(O)2RX, comprising from 0.01% to 5% by weightof a compound of Formula (salt or solvate thereof.

[0011] Also described herein is solvate of a compound of Formula (II)or a salt or solvate thereof, wherein X is halogen or -OS(O)2RX.INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTIONCertain Terminology

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0014] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0015] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.

[0016] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment ofWSGR Docket No. 47134-780.601any composition of mater, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0017] As used herein, Ci-Cxincludes C1-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, / .so-propyl. / 7-butyl. zso-butyl, sec-butyl, and / -butyl. As used herein, “alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about six carbon atoms, wherein an sp3-hybridized carbon of the alkyl residue is atached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Ce alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. “Aryl” refers to a radical derived from an aromatic monocyclic or multi cyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon atoms unless otherwise specified (z. e., from 6 to 18 carbon atoms), where at least one of the rings in the ring system is fully unsaturated, (i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory). The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. In some embodiments, the aryl is a Ce-Cio aryl. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, the aryl is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl,WSGR Docket No. 47134-780.601aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2. -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rfis independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0018] “Cycloalkyl” refers to a stable, partially, or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non- aromatic ring atom), bridged ring systems, and / or spirocyclic ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3-to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclofl. l.l]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2. l.l]hexane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “cycloalkyr is meant to include cycloalkyl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylallyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rfis independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0019] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.WSGR Docket No. 47134-780.601

[0020] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1.2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0021] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2.2.2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0022] A "Heterocycle" refers to a stable 3- to 18-membered non-aromatic ring that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, sulfur, and boron. Unless stated otherwise specifically in the specification, a heterocycle is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocycle are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycle is partially or fully saturated. The heterocycle is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycles include, but are not limited to, dioxolane, thienyl[l,3]dithiane, decahydroisoquinoline, imidazoline, imidazolidine, isothiazolidine, isoxazolidine, morpholine, octahydroindole, octahydroisoindole, 2-oxopiperazine, 2-oxopiperidine, 2-oxopyrrolidine, oxazolidine, piperidine, piperazine, 4-piperidone, pyrrolidine, pyrazolidine, quinuclidine, thiazolidine, tetrahydrofurane, trithiane, tetrahydropyrane, thiomorpholine, thiamorpholine, 1-oxo-thiomorpholine, 1,1-dioxo-thiomorpholine, 1,3,2-dioxaborolane, 1,3,2-dioxaborinane, and oxazaborolidin-5-one. Unless stated otherwise specifically in the specification, the term "heterocycle" is meant to include heterocycle rings as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O )tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2)and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight orWSGR Docket No. 47134-780.601branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0023] “Heteroaryl” refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a monocyclic heteroaryl, or a monocyclic 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6,5-fused bicyclic heteroaryl. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a Ci-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is aCi-Cs heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9 heteroaryl. The heteroatom(s) in the heteroaryl radical is optionally oxidized. The carbon atom(s) in the heteroaryl is optionally oxidized. Two non-limiting examples of heteroaryl radicals that are oxidized and are encompassed by the term heteroaryl are pyridone and pyridine N-oxide. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rfis independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.WSGR Docket No. 47134-780.601

[0024] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono- substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono- substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and / or synthetically non-feasible.

[0025] The term “pre- catalyst” is employed herein to refer to a molecular species that is not an intermediate in a catalytic cycle but allows the generation of an active, competent catalytic species.

[0026] The term “salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. These salts can be prepared by addition of an inorganic acid or an organic acid to the free base. These salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the tike. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, pheny 1 -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesul Ionic acid, salicylic acid, and the tike. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconate^ and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997). These salts can also be prepared by addition of an inorganic base or an organic base to the free acid. In some embodiments, salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the tike. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,WSGR Docket No. 47134-780.601di cyclohexylamine, lysine, arginine, histidine, caffeine, procaine, X.X-di benzyl ethylenedi amine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, JV-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, / V-ethy l pi peridine, polyamine resins and the like. See Berge et al., supra.

[0027] The term “solvate” refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with solvents such as water, ethanol, and the like. “Hydrates” are formed when the solvent is water, or “alcoholates” are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in unsolvated as well as solvated forms. The term “substantially pure,” as used herein, means those compounds, salts, or solvates disclosed herein that comprise less than a recited amount of other organic or inorganic compounds or materials, including, but not limited to, unreacted starting materials, unreacted or excess chemical reagents, synthesis by-products, or solvents that are present following the conduct of one or more of steps of a chemical synthesis or during the isolation of a chemical compound.Improved methods of synthesis

[0028] Disclosed herein, in certain embodiments, is a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprising reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst to afford the compound of Formula (I)wherein:X in the compound of Formula (II) is halogen or -OS(O)2RX;Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3; andY in the compound of Formula (III) is -B(OR1)2 or -BF3K;wherein when Y is -B(OR1)2, each R1is independently hydrogen or Ci-Ce alkyl, or both R1together with the atoms to which they are attached form a 5-12 membered heterocycle.

[0029] In some embodiments, the palladium pre-catalyst is bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), for example in an amount of about 1 to 3 mol%, about 1 to 2 mol%, or less. In some embodiments the reaction is conducted for 1 to 8 hours or 2 to 7 hours, e.g., 3 to 6 hours, to be complete or substantially complete. In some embodiments, the reactionWSGR Docket No. 47134-780.601mixture further comprises a phosphate base, e.g., potassium phosphate tribasic K3PO4. In some embodiments, the reaction mixture does not comprise a phosphine ligand such as XPhos.

[0030] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the compound of Formula (II) is a solvate. In some embodiments, the compound of Formula (II) is a solvate of N,N-dimethylformamide.

[0031] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, in the compound of Formula (II), or a salt or solvate thereof, X is a halogen. In some embodiments, in the compound of Formula (II), or a salt or solvate thereof, X is chlorine, bromine or iodine. In some embodiments, in the compound of Formula (II), or a salt or solvate thereof, X is chlorine. In some embodiments, in the compound of Formula (II), or a salt or solvate thereof, X is bromine. In some embodiments, in the compound of Formula (II), or a salt or solvate thereof, X is iodine. In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, in the compound of Formula (II), or a salt or solvate thereof, X is -OS(O)2RX, wherein Rxis Ci-Ce alkyl or Ce-C10 aryl. In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, in the compound of Formula (II), or a salt or solvate thereof, X is -OS(O)2CF3.

[0032] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, in the compound of Formula (III), or a salt or solvate thereof, Y is B(OR1)2. In some embodiments, in the compound of Formula (III), or a salt or solvate thereof, each R1is hydrogen. In some embodiments, in the compound of Formula (III), or a salt or solvate thereof, Y is B(OH)2. In some embodiments, in the compound of Formula (III), or a salt or solvate thereof, each R1is Ci-Ce alkyl. In some embodiments, in the compound of Formula (III), or a salt or solvate thereof, each R1is methyl. In some embodiments, in the compound of Formula (III), or a salt or solvate thereof, both R1together with the atoms to which they are attached form an unsubstituted or substituted 5-12 membered heterocycle. In some embodiments, in the compound of Formula (III), or a salt or solvate thereof, both R1together with the atoms to which they are attached form a 5-12 membered heterocycle derived from methyliminodiacetic acid. In some embodiments, in the compound of Formula (III), or a salt or solvate thereof, both R1together with the atoms to which they are attached form a 5-12 membered heterocycle derived from 2,3-dimethylbutane-2,3-diol In some embodiments, in the compound of Formula (III), or asalt or solvate thereof,some embodiments, in the compound of Formula (III), or asalt or solvate thereof,salt or solvate thereof. In some embodiments, thecompound of Formula (III), or a salt or solvate thereof,salt or aWSGR Docket No. 47134-780.601solvate thereof. In some embodiments, the compound of Formula (III), or a salt or solvate thereof, issalt or a solvate thereof.

[0033] In some embodiments of a method of preparing a compound of Formula (I), or a salt or a solvate thereof, the palladium pre-catalyst is a palladium (0) pre-catalyst or a palladium (II) pre-catalyst. In some embodiments, the palladium pre-catalyst is a palladium (0) pre-catalyst. In some embodiments, the palladium (0) pre-catalyst is selected from tetrakis(triphenylphosphine)palladium (0), palladium (0) on carbon, tris(dibenzylideneacetone)dipalladium (0), and bis(dibenzylideneacetone)palladium (0). In some embodiments, the palladium (0) pre-catalyst is tetrakis(triphenylphosphine)palladium (0). In some embodiments, the palladium (0) pre-catalyst is palladium (0) on carbon. In some embodiments, the palladium (0) pre-catalyst is tris(dibenzylideneacetone)dipalladium (0). In some embodiments, the palladium (0) pre-catalyst is bis(dibenzylideneacetone)palladium (0). In some embodiments, the palladium pre-catalyst is a palladium (II) pre-catalyst. In some embodiments, the palladium (II) pre-catalyst is selected from Pd (II)-NHC (NHC=N-heterocyclic carbene; pyridine-enhanced precatalyst, preparation, stabilization, and initiation (PEPPSI) complexes), palladium (II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium (II) dichloride, and[l,l'-bis(diphenylphosphino)ferrocene] palladium (II) di chloride. In some embodiments, the palladium (II) pre-catalyst is Pd (II)-NHC (NHC=N-heterocyclic carbene; pyridine-enhanced precatalyst, preparation, stabilization, and initiation (PEPPSI) complexes). In some embodiments, the palladium (II) pre-catalyst is palladium(II) acetate. In some embodiments, the palladium (II) pre-catalyst is palladium(II) chloride. In some embodiments, the palladium (II) pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride. In some embodiments, the palladium (II) pre-catalyst is [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. In some embodiments, the palladium (II) pre-catalyst is bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).

[0034] In some embodiments, the palladium (II) pre-catalyst is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) di chloride, and [1,1 '-bis(diphenylphosphino)ferrocene] palladium(n) dichloride, optionally wherein the palladium(II) pre-catalyst is bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).

[0035] In some embodiments, the palladium (II) pre-catalyst is bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), optionally wherein the reaction is conducted for 3-6 hours.

[0036] In some embodiments, the palladium pre-catalyst is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) dichloride,[l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, XPhosPdG3, tBuBrettPhosPdG3, SPhosPdG3, cataCXium®APdG3, BrettPhosPdG3,WSGR Docket No. 47134-780.601tBuXPhosPdG3, [(1, 3, 5, 7-Tetramethyl-6-phenyl-2, 4, 6-trioxa-6-phosphaadamantane)-2-(2'-amino-l, l'-biphenyl)]palladium(II)methanesulfonate, JackiePhosPdG3, CPhosPdG3, XantPhosPdG3, RuPhosPdG3, APhosPdG3, RockPhosPdG3, AdBrettPhosPdG3, Neopentyl(t-Bu)2PPdG3, TrixiePhosPdG3, N-XantPhosPdG3, DTBPF-Pd-G3, DPPFPdG3, DavePhos-Pd-G3, RuPhosPdG4, SPhosPdG4, BrettPhosPdG4, XPhosPdG4, APhosPdG4, rac-BINAPPdG4, P(t-Bu)3PdG4, (t-Bu)PhCPhosPdG4, cataCXiumPdG4, CPhosPdG4, CyJohnPhosPdG4, DavePhosPdG4, DPPFPdG4, EPhosPdG4, MorDalPhosPdG4, Neopentyl(tBu)2PPdG4, PCy3PdG4, (tBu)2PMePdG4, (tBu)2PPhPdG4, l,3,5,7-Tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantanePdG4.

[0037] In some embodiments, the palladium pre-catalyst is selected from palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II)dichloride, [1, l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, XPhosPdG3, tBuBrettPhosPdG3, SPhosPdG3, cataCXium®APdG3, BrettPhosPdG3, tBuXPhosPdG3, [(1, 3, 5, 7-Tetramethyl-6-phenyl-2, 4, 6-trioxa-6-phosphaadamantane)-2-(2'-amino-l, 1'-biphenyl)]palladium(n)methanesulfonate, JackiePhosPdG3, CPhosPdG3, XantPhosPdG3, RuPhosPdG3, APhosPdG3, RockPhosPdG3, AdBrettPhosPdG3, Neopentyl(t-Bu)2PPdG3, TrixiePhosPdG3, N-XantPhosPdG3, DTBPF-Pd-G3, DPPFPdG3, DavePhos-Pd-G3, RuPhosPdG4, SPhosPdG4, BrettPhosPdG4, XPhosPdG4, APhosPdG4, rac-BINAPPdG4, P(t-Bu)3PdG4, (t-Bu)PhCPhosPdG4, cataCXiumPdG4, CPhosPdG4, CyJohnPhosPdG4, DavePhosPdG4, DPPFPdG4, EPhosPdG4, MorDalPhosPdG4, Neopentyl(tBu)2PPdG4, PCy3PdG4, (tBu)2PMePdG4, (tBu)2PPhPdG4, 1, 3,5,7-Tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantanePdG4.

[0038] In some embodiments of a method of preparing a compound of Formula (I), or a salt or a solvate thereof, the reaction mixture further comprises a phosphine ligand. In some embodiments the phosphine ligand is selected from tricyclohexylphosphine, tri-tert-butylphosphine, tri(o-tolyl)phosphine, tri(2-furyl)phosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), dicyclohexyl[2',4',6'-tris( 1 -methylethyl) [1,1 '-biphenyl] -2-yl] phosphine (XPhos), [4-(N,N-dimethylamino)phenyl] di-t-butylphosphine (Amphos), and di(l-adamantyl)-n-butylphosphine. In some embodiments the phosphine ligand is tri cyclohexylphosphine. In some embodiments the phosphine ligand is tri-tert-butylphosphine. In some embodiments the phosphine ligand is tri(o-tolyl)phosphine. In some embodiments the phosphine ligand is tri cyclohexylphosphine. In some embodiments the phosphine ligand is tri(2-furyl)phosphine. In some embodiments the phosphine ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos). In some embodiments the phosphine ligand is dicyclohexyl[2',4', 6'-tris( 1 -methylethyl) [1,1'-biphenyl] -2-yl] phosphine (XPhos). In some embodiments the phosphine ligand is [4-(N,N-dimethylamino)phenyl]di-t-butylphosphine (Amphos). In some embodiments the phosphine ligand is di ( 1 -adamantyl)-n-butylphosphine.

[0039] In some embodiments of a method of preparing a compound of Formula (I), or a salt or a solvate thereof, the reaction mixture further comprises one or more solvents. In some embodiments, the one or more solvents comprise one or more aprotic solvents. In some embodiments, the one or more aproticWSGR Docket No. 47134-780.601solvents are selected from one or more ethereal solvents and one or more amide solvents. In some embodiments, the solvent comprises one or more ethereal solvents. In some embodiments, the one or more ethereal solvents comprises a cyclic ether, a non-cyclic ether, or a mixture of a cyclic ether and a non-cyclic ether. In some embodiments, the solvent comprises a cyclic ether. In some embodiments, the cyclic ether solvent is tetrahydrofuran, dioxane, or 2-methyltetrahydrofuran, or a mixture thereof In some embodiments, the one or more aprotic solvents is one or more amide solvents. In some embodiments, the one or more amide solvents is selected from N,N-diethylformamide, l,3-dimethyl-2-imidazolidinone, dimethylacetamide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, formamide, and N-methyl-2-pyrrolidone. In some embodiments, the amide solvent is N,N-diethylformamide. In some embodiments, the amide solvent is l,3-dimethyl-2-imidazolidinone. In some embodiments, the amide solvent is dimethylacetamide. In some embodiments, the amide solvent is N,N-dimethylformamide. In some embodiments the amide solvent is, N,N'-dimethylpropyleneurea. In some embodiments, the amide solvent is formamide. In some embodiments, the amide solvent is N-methyl-2-pyrrolidone.

[0040] In some embodiments of a method of preparing a compound of Formula (I), or a salt thereof, the reaction mixture further comprises a base. In some embodiments, the base is selected from a fluoride base, carbonate base, a bicarbonate base, a hydroxide base, an alkoxide base, a phosphate base, and an amine-containing base, or a mixture thereof. In some embodiments, the base is a fluoride base. In some embodiments, the fluoride base is sodium fluoride, potassium fluoride, or cesium fluoride. In some embodiments, the base is a phosphate base, e.g., potassium phosphate tribasic K3PO4. In some embodiments, the base is a carbonate base. In some embodiments, the base is sodium carbonate or potassium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is a bicarbonate base. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is a hydroxide base. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the base is cesium hydroxide. In some embodiments, the base is an alkoxide base. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is a phosphate base. In some embodiments, the base is an amine-containing base. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the base is a combination of two or more of a carbonate base, a bicarbonate base, a hydroxide base, an alkoxide base, a phosphate base, and an amine-containing base.

[0041] In some embodiments of a method of preparing a compound of Formula (I), or a salt or a solvate thereof, the method further comprises isolating the compound of Formula (I) from the reaction mixture to afford substantially pure compound of Formula (I). In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.01% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.05% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.1% to 5%WSGR Docket No. 47134-780.601by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.2% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or asalt or solvate thereof, comprises from 0.4% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.5% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.6% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.7% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.8% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or asalt or solvate thereof, comprises from 0.9% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 1% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 2% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 3% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 4% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.1% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.2% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.3% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.4% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.6% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.7% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.8% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.9% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.25% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.5% by weight of palladium impurities. In some embodiments, theWSGR Docket No. 47134-780.601substantially pure compound of Formula (I), or asalt or solvate thereof, comprises about 1.75% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.25% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.50% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.75% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.25 % by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.50% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.75% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.25 by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.50% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.75% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 5% by weight of palladium impurities.

[0042] In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.01% to 5% by weight of a compound of Formula (VI)salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.05% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.1% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.2% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, theWSGR Docket No. 47134-780.601substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.4% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.5% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.6% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.7% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.8% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.9% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 1% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 2% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 3% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 4% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.1% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.2% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.3% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.4% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.6% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.7% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.8% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.9% by weightWSGR Docket No. 47134-780.601of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.25% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.75% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.25% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.75% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula(I), orasalt or solvate thereof, comprises about 3.25% by weight of acompound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.75% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.25% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.75% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 5% by weight of a compound of Formula (VI), or a salt or solvate thereof.

[0043] Also provided herein is a compound of Formula (salt or solvate thereof.WSGR Docket No. 47134-780.601

[0044] In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.01% to 5% by weight of a compound of Formula (Ila)salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.05% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.1% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.2% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.4% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.5% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.6% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.7% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.8% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.9% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 1% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 2% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 3% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 4% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof.In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.1% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.2% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments,WSGR Docket No. 47134-780.601the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.3% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.4% by weight of a compound of Formula (II), ora salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.5% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.6% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.7% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.8% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.9% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.25% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.5% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.75% by weight of a compound of Formula (II), ora salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.25% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.5% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.75% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.25% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.5% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.75% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pureWSGR Docket No. 47134-780.601compound of Formula(I), orasalt or solvate thereof, comprises about 4.25% by weight of acompound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.5% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.75% by weight of a compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 5% by weight of a compound of Formula (II), or a salt or solvate thereof

[0045] Disclosed herein, in certain embodiments, is a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprising reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(dimethylamino)phosphonium hexafluorophosphate to afford the compound of Formula (II), or a salt or solvate thereof,wherein X in the compounds of Formula (V), or a salt or solvate thereof, and Formula (II), or a salt or solvate thereof, are the same and are halogen or -OS(O)2RX, wherein Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3.

[0046] In some embodiments, the reaction mixture comprises bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBrOP), for example in an amount of about 1.5 equivalents, about 1.3 equivalents to about 1 equivalent, or less. In some embodiments, the reaction is conducted at a temperature range of 40 °C to 70 °C, such as 45 °C to 65 °C, or 50 °C to 60 °C, e.g., 60 °C. In some embodiments the reaction is conducted for 1 to 4 hours, e.g., 2 to 3 hours, to be complete or substantially complete. In some embodiments, the reaction mixture comprises an amine- containing base, e.g., tri ethylamine. In some embodiments, Compound IV is in a salt form, without a need for converting it to a freebase form for the reaction. In some embodiments, the reaction mixture comprises 2-methyltetrahydrofuran as a solvent, less volume used as the temperature rises, e.g., 5-10 volumes or 7 volumes at 60 ± 5 °C.

[0047] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, X in the compounds of Formula (V), or a salt or solvate thereof, and Formula (II), or a salt or solvate thereof, is halogen. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, X in the compounds of Formula (V), or a salt or solvate thereof, and Formula (II), or a salt or solvate thereof, is chlorine, bromine, or iodine. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, X in the compounds of Formula (V), or a salt or solvate thereof, and Formula (II), or a salt or solvate thereof, is chlorine. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, X in the compounds ofWSGR Docket No. 47134-780.601Formula (V), or a salt or solvate thereof, and Formula (II), or a salt or solvate thereof, is bromine. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, X in the compounds of Formula (V), or a salt or solvate thereof, and Formula (II), or a salt or solvate thereof, is iodine. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, X in the compounds of Formula (V), or a salt or solvate thereof, and Formula (II), or a salt or solvate thereof, is -OS(O)2CF3. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, X in the compounds of Formula (V), or a salt or solvate thereof, and Formula (II), or a salt or solvate thereof, is -OS(O)2RX, wherein Rxis Ci-Ce alkyl or Ce-Cio aryl.

[0048] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the reaction mixture further comprises one or more solvent. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more solvents comprises acetonitrile, one or more ethereal solvents, or one or more halogenated solvents. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more solvents comprises acetonitrile. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more solvents comprises one or more ethereal solvents. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more ethereal solvents comprises a cyclic ether, a non-cyclic ether, or a mixture of a cyclic ether and a non-cyclic ether. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more ethereal solvents comprises a cyclic ether. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more cyclic ether solvents is tetrahydrofuran, dioxane, or 2-methyltetrahydrofuran, or a mixture thereof. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more cyclic ether solvents is tetrahydrofuran. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more cyclic ether solvents is dioxane. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more cyclic ether solvents is 2-methyltetrahydrofuran. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more cyclic ether solvent is a combination of tetrahydrofuran and dioxane. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more cyclic ether solvent is a combination of tetrahydrofuran and 2-methyltetrahydrofuran. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more cyclic ether solvent is a combination of dioxane and 2-methyltetrahydrofuran. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the solvent comprises one or more halogenated solvents. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the one or more halogenated solvents comprises di chloromethane, 1,1 -di chloroethane, 1,2-di chloroethane, 1,1,1 ,2-tetrachloroethane, 1 , 1,2, 2 -tetrachloroethane, 1 ,1 ,2- tri chloro- 1 ,2, 2- trifluoroethane, 1,1,1 -tri chloroethane, and 1,1,2-trichloroethane. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the halogenated solvent is di chloromethane. InWSGR Docket No. 47134-780.601some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the halogenated solvent is 1,1 -di chloroethane. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the halogenated solvent is 1,2-di chloroethane. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the halogenated solvent is 1,1,1,2-tetrachloroethane. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the halogenated solvent is 1, 1,2,2-tetrachloroethane. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the halogenated solvent is l,l,2-trichloro-l,2,2-trifluoroethane. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the halogenated solvent is 1,1,1 -tri chloroethane. In some embodiments of amethod of preparing a compound of Formula (II), or a salt or solvate thereof, the halogenated solvent is 1, 1,2-tri chloroethane.

[0049] In some embodiments of amethod of preparing a compound of Formula (II), or a salt or solvate thereof, the reaction mixture further comprises a base. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the base is selected from a carbonate base, a bicarbonate based, a hydroxide base, an alkoxide base, a phosphate base, and an amine-containing base, or a mixture thereof. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the base is a carbonate base. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the base is a bicarbonate base. In some embodiments of amethod of preparing a compound of Formula (II), or a salt or solvate thereof, the base is a hydroxide base. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the base is an alkoxide base. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the base is a phosphate base. In some embodiments of amethod of preparing a compound of Formula (II), or a salt or solvate thereof, the base is an amine-containing base. In some embodiments of amethod of preparing a compound of Formula (II), or a salt or solvate thereof, the amine-containing base is N,N-diisopropylethylamine or triethylamine. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the amine-containing base is N,N-diisopropylethylamine. In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the amine-containing base is tri ethylamine.

[0050] In some embodiments of amethod of preparing a compound of Formula (II), or a salt or solvate thereof, the compound of F ormula (IV), or a salt or solvate thereof, is used in the reaction in the form of a salt. In some embodiments, the compound of Formula (IV) is used in the reaction in the form of a hydrochloride salt or a hydrobromide salt. In some embodiments, the compound of Formula (IV) is used in the reaction in the form of a hydrochloride salt. In some embodiments, the compound of Formula (IV) is used in the reaction in the form of a hydrobromide salt.

[0051] In some embodiments of amethod of preparing a compound of Formula (II), or a salt or solvate thereof, the reaction mixture comprises bromotris(pyrrolidino)phosphonium hexafluorophosphate. In some embodiments, the bromotris(pyrrolidino)phosphonium hexafluorophosphate comprises less than 5% by weight of pyrrolidine. In some embodiments, the bromotris(pyrrolidino)phosphoniumWSGR Docket No. 47134-780.601hexafluorophosphate comprises less than 4% by weight of pyrrolidine. In some embodiments, the bromotris(pyrrolidino)phosphonium hexafluorophosphate comprises less than 3% by weight of pyrrolidine. In some embodiments, the bromotris(pyrrolidino)phosphonium hexafluorophosphate comprises less than 2% by weight of pyrrolidine. In some embodiments, the bromotris(pyrrolidino)phosphonium hexafluorophosphate comprises less than 1% by weight of pyrrolidine. In some embodiments, the reaction mixture comprises bromotris(dimethylamino)phosphonium hexafluorophosphate. In some embodiments, the bromotris(dimethylamino)phosphonium hexafluorophosphate comprises less than 5% by weight of dimethylamine. In some embodiments, the bromotris(dimethylamino)phosphonium hexafluorophosphate comprises less than 4% by weight of dimethylamine. In some embodiments, the bromotris(dimethylamino)phosphonium hexafluorophosphate comprises less than 3% by weight of dimethylamine. In some embodiments, the bromotris(dimethylamino)phosphonium hexafluorophosphate comprises less than 2% by weight of dimethylamine. In some embodiments, the bromotris(dimethylamino)phosphonium hexafluorophosphate comprises less than 1% by weight of dimethylamine.

[0052] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the reaction is conducted at a temperature range of 45 °C to 65 °C, optionally 50 °C or 60 °C. In some embodiments, the reaction is conducted at a temperature range of 45 °C to 65 °C. In some embodiments, the reaction is conducted at a temperature range of 50 °C or 60 °C.

[0053] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the reaction is conducted for 1 to 4 hours, optionally 2 to 3 hours. In some embodiments, the reaction is conducted for 1 to 4 hours. In some embodiments, the reaction is conducted for 2 to 3 hours.

[0054] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method further comprises isolating the compound of Formula (II), or a salt or solvate thereof, from the reaction mixture to afford substantially pure compound of Formula (II), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), is in the form of a solvate. In some embodiments, the substantially pure compound of Formula (II) is in the form of a solvate of N,N-dimethylformamide. In some embodiments, the isolating comprises adding an aqueous acid to the reaction mixture, optionally wherein the aqueous acid is citric acid, acetic, formic, or phosphoric acid. In some embodiments, the aqueous acid is citric acid. In some embodiments, the aqueous acid is added when the reaction mixture is at a temperature range of 40 °C to 70 °C, such as 45 °C to 65 °C, optionally 50 °C or 60 °C.

[0055] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises fromWSGR Docket No. 47134-780.6010.01% to 5% by weight of a compound of Formula (salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 0.05% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 0.1% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 0.2% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 0.4% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 0.5% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 0.6% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 0.7% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II) comprises from 0.8% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 0.9% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 1% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 2% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 3% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises from 4% to 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or a solvate thereof, comprises 5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.1% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.2% by weight of a compound of FormulaWSGR Docket No. 47134-780.601(Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.3% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.4% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.6% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.7% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.8% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.9% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.25% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or asalt or solvate thereof, comprises about 1.5% by weight of acompound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.75% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.25% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.75% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or asalt or solvate thereof, comprises about 3.25% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.75% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4% by weight of a compound of Formula (Va), or a salt or solvateWSGR Docket No. 47134-780.601thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.25% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.75% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 5% by weight of a compound of Formula (Va), or a salt or solvate thereof.

[0056] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the substantially pure compound of Formula (II) comprises from 0.01% to 5% by weight of acompound of Formula (salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 0.05% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 0.1% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 0.2% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or asalt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 0.4% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or asalt or solvate thereof, comprises from 0.5% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or asalt or solvate thereof, comprises from 0.6% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 0.7% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 0.8% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or asalt or solvate thereof, comprises from 0.9% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 1% to 5% byWSGR Docket No. 47134-780.601weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 2% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 3% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises from 4% to 5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises 5% by weight of a compound of Formula (VII), or a salt or solvate thereof.

[0057] In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.1% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.2% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.3% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.4% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.6% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.7% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.8% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.9% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.25% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.75% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.25% by weight of a compound of Formula (VII), or a salt orWSGR Docket No. 47134-780.601solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.75% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.25% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.75% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.25% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.75% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 5% by weight of a compound of Formula (VII), or a salt or solvate thereof.

[0058] Disclosed herein, in certain embodiments, is a substantially pure compound of Formula (I):or a salt or solvate thereof, comprising from 0.01% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.01% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.05% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.1% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.2% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of palladium impurities. In someWSGR Docket No. 47134-780.601embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.4% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or asalt or solvate thereof, comprises from 0.5% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.6% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.7% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.8% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.9% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or asalt or solvate thereof, comprises from 1% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 2% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 3% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 4% to 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), ora salt or solvate thereof, comprises 5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.1% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.2% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or asalt or solvate thereof, comprises about 0.3% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.4% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or asalt or solvate thereof, comprises about 0.5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.6% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or asalt or solvate thereof, comprises about 0.7% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.8% by weight of palladium impurities. In some embodiments, the substantially pure compound of F ormula (I), or a salt or solvate thereof, comprises about 0.9% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.25% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.75% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvateWSGR Docket No. 47134-780.601thereof, comprises about 2% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.25% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.75% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.25% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.75% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.25% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.5% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.75% by weight of palladium impurities. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 5% by weight of palladium impurities.

[0059] Also provided herein is a compound of F ormula (or a salt or solvate thereof.

[0060] Disclosed herein, in certain embodiments, is substantially pure compound of Formula (I),or a salt or solvate thereof, comprising from 0.01% to 5% by weight of a compound of Formula (VI)salt or solvate thereof. In some embodiments, theWSGR Docket No. 47134-780.601substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.05% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.1% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.2% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.4% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.5% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.6% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.7% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.8% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.9% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 1% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 2% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 3% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 4% to 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises 5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.1% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.2% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.3% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt orWSGR Docket No. 47134-780.601solvate thereof, comprises about 0.4% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.6% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.7% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.8% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.9% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.25% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.75% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.25% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.75% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula(I), orasalt or solvate thereof, comprises about 3.25% by weight of acompound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.75% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.25% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof,WSGR Docket No. 47134-780.601comprises about 4.5% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.75% by weight of a compound of Formula (VI), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 5% by weight of a compound of Formula (VI), or a salt or solvate thereof.

[0061] Also provided herein is a compound of Formula (VIII),salt or solvate thereof.

[0062] Also provided herein, in certain embodiments, is substantially pure compound of Formula (I),or a salt or solvate thereof, comprising from 0.01% to 5% by weight of a compound of Formula (VIII),salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.05% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.1% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.2% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.4% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.5% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.6% to 5% byWSGR Docket No. 47134-780.601weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.7% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.8% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.9% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 1% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 2% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 3% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 4% to 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula(I), orasalt or solvate thereof, comprises about 0.1% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.2% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.3% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.4% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.6% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.7% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.8% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.9% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.25% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, theWSGR Docket No. 47134-780.601substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.75% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.25% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.75% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3% by weight of a compound of F ormula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.25% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.75% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.25% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.5% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.75% by weight of a compound of Formula (VIII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 5% by weight of a compound of Formula (VIII), or a salt or solvate thereof

[0063] Disclosed herein, in certain embodiments, is substantially pure compound of Formula (I),WSGR Docket No. 47134-780.601or a salt or solvate thereof, comprising from 0.01% to 5% by weight of a compound of Formula (Ila),salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.05% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.1% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.2% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.3% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.4% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.5% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.6% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.7% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.8% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 0.9% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula(I), orasalt or solvate thereof, comprises from 1% to 5% by weight of acompound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 2% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 3% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises from 4% to 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises 5% by weight of a compound of Formula (Ila), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.1% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprisesWSGR Docket No. 47134-780.601about 0.2% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.3% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.4% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.5% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.6% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.7% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.8% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 0.9% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.25% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 1.5% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula(I), orasalt or solvate thereof, comprises about 1.75% by weight of acompound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.25% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.5% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 2.75% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.25% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.5% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 3.75% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In someWSGR Docket No. 47134-780.601embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.25% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 4.5% by weight of a compound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula(I), orasalt or solvate thereof, comprises about 4.75% by weight of acompound of Formula (IIA), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (I), or a salt or solvate thereof, comprises about 5% by weight of a compound of Formula (IIA), or a salt or solvate thereof.

[0064] Disclosed herein, in certain embodiments, is substantially pure compound of Formula (II), N -X°'Y II^N^N^'NCN i), or a salt or solvate thereof,wherein X is halogen or -OS(O)2RX, comprising from 0.01% to 5% by weight of a compound of Formulasalt or solvate thereof. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (Va), or a salt or solvate thereof, is halogen. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (Va), or a salt or solvate thereof, is chlorine. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (Va), or a salt or solvate thereof, is bromine. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (Va), or a salt or solvate thereof, is iodine. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (Va), or a salt or solvate thereof, is -OS(O)2CF3. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (Va), or a salt or solvate thereof, is -OS(O)2RX, wherein Rxis Ci-Ce alkyl or Ce-Cio aryl. In some embodiments, the substantially pure compound of formula (II), is in the form of a solvate. In some embodiments, the substantially pure compound of formula (II) is in the form of a solvate ofN,N-dimethylformamide. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.1% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.2% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.3% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof,WSGR Docket No. 47134-780.601comprises about 0.4% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.6% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.7% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.8% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.9% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.25% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.5% by weight of acompound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.75% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.25% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.75% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.25% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.75% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.25% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprisesWSGR Docket No. 47134-780.601about 4.5% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.75% by weight of a compound of Formula (Va), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 5% by weight of a compound of Formula (Va), or a salt or solvate thereof.

[0065] Disclosed herein, in certain embodiments, is substantially pure compound of Formula (II),or a salt or solvate thereof, wherein X is halogen or -OS(O)2RX, comprising from 0.01% to 5% by weightof a compound of Formula (salt or solvate thereof. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (VII), or a salt or solvate thereof is halogen. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (VII), or a salt or solvate thereof, is chlorine. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (VII), or a salt or solvate thereof, is bromine. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (VII), or a salt or solvate thereof, is iodine. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (VII), or a salt or solvate thereof, is -OS(O)2CF3. In some embodiments, X in compounds of Formula (II), or a salt or solvate thereof, and Formula (VII), or a salt or solvate thereof, is -OS(O)2RX, wherein Rxis Ci-Ce alkyl or Ce-Cio aryl. In some embodiments, the substantially pure compound of formula (II) is in the form of a solvate. In some embodiments, the substantially pure compound of formula (II) is in the form of a solvate of N,N-dimethylformamide. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.1% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.2% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.3% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.4% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II),WSGR Docket No. 47134-780.601or a salt or solvate thereof, comprises about 0.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.6% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.7% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.8% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 0.9% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.25% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 1.75% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.25% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 2.75% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.25% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 3.75% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.25% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 4.5% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pureWSGR Docket No. 47134-780.601compound of Formula (II), or a salt or solvate thereof, comprises about 4.75% by weight of a compound of Formula (VII), or a salt or solvate thereof. In some embodiments, the substantially pure compound of Formula (II), or a salt or solvate thereof, comprises about 5% by weight of a compound of Formula (VII), or a salt or solvate thereof.

[0066] Disclosed herein, in certain embodiments, is a solvate of a compound of Formula (II),wherein X is halogen or -OS(O)2RX, wherein Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3. In some embodiments, X in solvate of a compound of Formula (II) is halogen. In some embodiments, X in solvate of a compound of Formula (II) is bromine or iodine. In some embodiments, X in solvate of a compound of Formula (II) is iodine. In some embodiments, X in solvate of a compound of Formula (II) is chlorine. In some embodiments, X in solvate of a compound of Formula (II) is iodine. In some embodiments, X in solvate of a compound of Formula (II) is bromine. In some embodiments, X in solvate of a compound of Formula (II) is -OS(O)2CF3. In some embodiments, X in solvate of a compound of Formula (II) is -OS(O)2RX, wherein Rxis Ci-Ce alkyl or Ce-Cio aryl. In some embodiments, the solvate of a compound of Formula (II) is in the form of a solvate of N,N-dimethylformamide.

[0067] Disclosed herein, in certain embodiments, is a compound of Formula (or a salt or solvate thereof, wherein X is halogen or -OS(O)2RX, wherein Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3. In some embodiments, X is halogen. In some embodiments, X is chlorine. In some embodiments, X is bromine. In some embodiments, X is iodine. In some embodiments, X is -OS(O)2CF3. In some embodiments, X is OS(O)2RX, wherein Rxis Ci-Ce alkyl or Ce-Cio aryl.Embodiments

[0068] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst to afford the compound of Formula (I), wherein X in the compound of Formula (II) is halogen, Y in the compound of Formula (III) is -B(OR1)2, wherein both R1together with the atoms to which they are attached form an unsubstituted or substituted 5-12 membered heterocycle, the palladium pre-catalyst is a Pd(O) pre-catalyst, and includes a phosphine ligand.

[0069] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst to afford the compound of Formula (I), wherein X in the compound of Formula (II) is bromine,compound of Formula (, the palladium pre-catalyst is Pd(OAc)2, and the phosphine ligand is X-Phos.

[0070] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst to afford the compound of Formula (I), wherein X in the compound of Formula (II) is bromine,compound of Formula (, the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, including a base and an ethereal solvent.

[0071] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, a base and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is chlorine, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0072] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, a base and a solvent, to afford the compound of Formula (I), wherein X in the compound of Formula (II) is bromine, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0073] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0074] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X in the compound of Formula (II) is -OS(O)2CF3, compound of Formula (III) is, the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0075] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent afford the compound of Formula (I), wherein X in thecompound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0076] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0077] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0078] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0079] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0080] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0081] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-WSGR Docket No. 47134-780.601catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0082] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0083] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formula, the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0084] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is chlorine, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0085] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0086] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0087] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X in the compound of Formula (II) is -OS(O)2CF3, compound of Formula (III) is, the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0088] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.WSGR Docket No. 47134-780.601

[0089] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0090] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0091] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X in the compound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0092] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X in the compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0093] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0094] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0095] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0096] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formula (, the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0097] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is chlorine, compound of Formula (the palladium pre-catalyst is palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0098] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formula (the palladium pre-catalyst is palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0099] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0100] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X in the compound of Formula (II) is -OS(O)2CF3, compound of Formula (III) is, the palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.WSGR Docket No. 47134-780.601

[0101] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0102] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0103] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formula (the palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0104] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formulapalladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0105] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0106] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0107] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0108] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0109] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formula, the palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0110] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is chlorine, compound of Formula (the palladium pre-catalyst is palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0111] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formula (the palladium pre-catalyst is palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0112] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formula (the palladium pre-catalyst is Pd(OAc)2, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.WSGR Docket No. 47134-780.601

[0113] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X in the compound of Formula (II) is -OS(O)2CF3, compound of Formula (III) is, the palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0114] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0115] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0116] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formula (the palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.WSGR Docket No. 47134-780.601

[0117] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0118] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0119] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0120] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.WSGR Docket No. 47134-780.601

[0121] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is iodine, compound of Formulathe palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0122] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a phosphine ligand, abase, and a solvent, to afford the compound of Formula (I), wherein X inthe compound of Formula (II) is -OS(O)2CF3, compound of Formula, the palladium pre-catalyst is Palladium(II) chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0123] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is chlorine, compound of Formula< the palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0124] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula< the palladium pre-WSGR Docket No. 47134-780.601catalyst is [1 J’-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0125] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0126] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0127] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0128] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalystWSGR Docket No. 47134-780.601is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0129] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0130] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0131] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formulathe palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0132] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (, the palladium pre-WSGR Docket No. 47134-780.601catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0133] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0134] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0135] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0136] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is chlorine, compound of Formulathe palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0137] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0138] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0139] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0140] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0141] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0142] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0143] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0144] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is iodine, compound of Formulathe palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0145] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (, the palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0146] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0147] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0148] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0149] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is chlorine, compound of Formulathe palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0150] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0151] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0152] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of<the palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0153] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre- catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0154] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is bis(triphenylphosphine)palladium(n) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0155] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre- catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0156] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-WSGR Docket No. 47134-780.601catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0157] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formulathe palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0158] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (, the palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0159] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of"Formula (II) is bromine, compound of Formula (the palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0160] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is iodine, compound of Formula (the palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0161] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is sodium carbonate and the solvent is 2-Me THF.

[0162] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is chlorine, compound of Formulathe palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0163] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0164] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-WSGR Docket No. 47134-780.601catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0165] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0166] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0167] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0168] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-WSGR Docket No. 47134-780.601catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0169] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0170] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formulathe palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0171] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (, the palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0172] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is bromine, compound of Formula (the palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0173] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0174] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of" Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is bis(triphenylphosphine)palladium(II) dichloride, the base is potassium carbonate and the solvent is 2-Me THF.

[0175] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is chlorine, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0176] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-WSGR Docket No. 47134-780.601catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0177] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0178] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0179] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0180] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is tetrakis(triphenylphosphine)pa!ladium(0)the base is sodium carbonate and the solvent is 2-Me THF.

[0181] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (the palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0182] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0183] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0184] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is -OS(O)2CF3, compound of Formula (, the palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0185] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of < <Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2 -Me THF.

[0186] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0187] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of < < Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0188] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is chlorine, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0189] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2- Me THF.

[0190] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is tetrakis(triphenylphosphine)palladium(0), the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0191] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0192] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium precatalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0193] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0)the base is potassium carbonate and the solvent is 2-Me THF.

[0194] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium precatalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0195] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2- Me THF.

[0196] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is iodine, compound of Formulathe palladium precatalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0197] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (, the palladium precatalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0198] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium precatalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0199] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2- Me THF.

[0200] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is tetrakis(triphenylphosphine)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0201] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is chlorine, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0202] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0203] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0204] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0205] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2 -Me THF.

[0206] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0)the base is sodium carbonate and the solvent is 2-Me THF.

[0207] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0208] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is bromine, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2 -Me THF.

[0209] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2 -Me THF.

[0210] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (, the palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2 -Me THF.

[0211] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of < <Formula (II) is bromine, compound of Formula (the palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2 -Me THF.

[0212] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is iodine, compound of Formula (the palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2 -Me THF.

[0213] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of" Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0214] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is chlorine, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0215] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2- Me THF.

[0216] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-WSGR Docket No. 47134-780.601catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0217] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0218] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2- Me THF.

[0219] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formulathe palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0)the base is potassium carbonate and the solvent is 2-Me THF.

[0220] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is tris(dihenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0221] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0222] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formulathe palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0223] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (, the palladium pre-catalyst is tris(dibenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0224] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is bromine, compound of Formula (the palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0225] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is tris(dibenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0226] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of" Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is tris(dihenzylideneacetone)dipalladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0227] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is chlorine, compound of Formulathe palladium pre-catalyst is his(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0228] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-WSGR Docket No. 47134-780.601catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0229] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the phosphine ligand is X-Phos, the base is sodium carbonate and the solvent is 2-Me THF.

[0230] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2- Me THF.

[0231] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0232] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is his(dibenzylideneacetone)palladium(0)the base is sodium carbonate and the solvent is 2-Me THF.

[0233] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (the palladium precatalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me

[0234] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0235] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0236] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is -OS(O)2CF3, compound of Formula (, the palladium precatalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0237] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of<"Formula (II) is bromine, compound of Formula (the palladium precatalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0238] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0239] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound of<Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the base is sodium carbonate and the solvent is 2-Me THF.

[0240] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is chlorine, compound of Formulathe palladium pre-catalyst is his(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0241] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2- Me THF.

[0242] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is his(dibenzylideneacetone)palladium(0), the phosphine ligand is X-Phos, the base is potassium carbonate and the solvent is 2-Me THF.

[0243] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is his(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0244] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium pre-catalyst is his(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0245] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0)the base is potassium carbonate and the solvent is 2-Me THF.

[0246] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formulathe palladium precatalyst is bis(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0247] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formulathe palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2- Me THF.

[0248] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is iodine, compound of Formulathe palladium precatalyst is his(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0249] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is -OS(O)2CF3, compound of Formula (, the palladium precatalyst is his(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0250] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is bromine, compound of Formula (the palladium precatalyst is his(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0251] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofFormula (II) is iodine, compound of Formula (the palladium precatalyst is his(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2- Me THF.

[0252] In some embodiments of a method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprises reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium precatalyst, a base, and a solvent, to afford the compound of Formula (I), wherein X in the compound ofWSGR Docket No. 47134-780.601Formula (II) is -OS(O)2CF3, compound of Formulathe palladium pre-catalyst is bis(dibenzylideneacetone)palladium(0), the base is potassium carbonate and the solvent is 2-Me THF.

[0253] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0254] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0255] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and acetonitrile to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0256] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0257] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0258] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0259] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0260] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphoniumhexafluorophosphate, N,N-diisopropyleihylamine, and2-MeTHF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0261] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphoniumhexafluorophosphate, N,N-diisopropyleihylamine, and2-MeTHF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0262] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 2-Me THF to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0263] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphoniumhexafluorophosphate, N,N-diisopropyleihylamine, and 2-Me THF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0264] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 2-MeWSGR Docket No. 47134-780.601THF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0265] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphoniumhexafluorophosphate, N,N-diisopropyleihylamine, and2-MeTHF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0266] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 2-Me THF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0267] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0268] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0269] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and tetrahydrofuran to afford the compound of F ormula (II), wherein X in the compounds of F ormula (V) and Formula (II) are the same and are bromine.

[0270] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.WSGR Docket No. 47134-780.601

[0271] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0272] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0273] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0274] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0275] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0276] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and dioxane to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0277] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0278] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0279] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0280] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0281] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 1,2-di chloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0282] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 1,2-di chloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0283] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 1,2-WSGR Docket No. 47134-780.601di chloroethane to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0284] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 1,2-di chloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0285] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 1,2-di chloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0286] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 1,2-di chloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0287] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, N,N-diisopropylethylamine, and 1,2-di chloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0288] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0289] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.WSGR Docket No. 47134-780.601

[0290] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, tri ethylamine, and acetonitrile to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0291] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0292] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0293] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0294] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and acetonitrile, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0295] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and 2-Me THF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0296] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and 2-Me THF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0297] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and 2-Me THF to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0298] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and 2-Me THF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0299] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and 2-Me THF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0300] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and 2-Me THF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0301] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and 2-Me THF, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0302] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and tetrahydrofuran, to affordWSGR Docket No. 47134-780.601the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0303] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0304] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and tetrahydrofuran to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0305] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0306] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0307] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0308] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and tetrahydrofuran, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.WSGR Docket No. 47134-780.601

[0309] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0310] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0311] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and dioxane to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0312] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0313] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0314] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0315] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with aWSGR Docket No. 47134-780.601compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and dioxane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0316] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and 1,2-dichloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are chlorine.

[0317] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and 1,2-dichloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0318] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and 1,2-dichloroethane to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are bromine.

[0319] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and 1,2-dichloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0320] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and 1,2-dichloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are iodine.

[0321] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate, triethylamine, and 1,2-dichloroethane, toWSGR Docket No. 47134-780.601afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.

[0322] In some embodiments of a method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprises reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(dimethylamino)phosphonium hexafluorophosphate, triethylamine, and 1,2-dichloroethane, to afford the compound of Formula (II), wherein X in the compounds of Formula (V) and Formula (II) are the same and are -OS(O)2CF3.Further Forms of Compounds

[0323] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0324] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In some embodiments, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0325] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0326] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may beWSGR Docket No. 47134-780.601labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine- 125 (125I) or carbon- 14 (14C). Isotopic substitution with2H,3H, “C,13C,14C,15C,12N,13N,15N,16N,170,180,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0327] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium- containing compounds are known in the art. In some embodiments deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem, 1981, 64(1-2), 9-32.

[0328] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Numbered Embodiments

[0329] Embodiment 1. A method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprising reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre-catalyst to afford the compound of Formula (I)wherein:X in the compound of Formula (II) is halogen or -OS(O)2RX;Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3; andY in the compound of Formula (III) is -B(OR1)2 or -BF3K;wherein when Y is -B(OR1)2, each R1is independently hydrogen or Ci-Ce alkyl, or both R1together with the atoms to which they are attached form an unsubstituted or substituted 5-12 membered heterocycle.

[0330] Embodiment 2. The method of embodiment 1, wherein the compound of Formula (II) is a solvate.

[0331] Embodiment 3. The method of embodiment 1 or 2, wherein the compound of Formula (II) is a N,N-dimethylformamide solvate.

[0332] Embodiment 4. The method of any one of embodiments 1 to 3, wherein in the compound of Formula (II), X is halogen.WSGR Docket No. 47134-780.601

[0333] Embodiment 5. The method of embodiment 4, wherein in the compound of Formula (II), X is chlorine, bromine, or iodine.

[0334] Embodiment 6. The method of embodiment 5, wherein in the compound of Formula (II), X is bromine.

[0335] Embodiment 7. The method of embodiment 5, wherein in the compound of Formula (II), X is iodine.

[0336] Embodiment 8. The method of any one of embodiments 1 to 3, wherein in the compound of Formula (II), X is -OS(O)2CF3.

[0337] Embodiment 9. The method of any one of embodiments 1 to 8, wherein Y in the compound of Formula (III) is -B(OR1)2

[0338] Embodiment 10. The method of embodiment 9, wherein each R1is hydrogen.

[0339] Embodiment 11. The method of embodiment 9, wherein each R1is Ci-Ce alkyl.

[0340] Embodiment 12. The method of embodiment 9, wherein Y in the compound of Formula (III) is -B(OR' )2. wherein both R1together with the atoms to which they are attached form an unsubstituted or substituted 5-12 membered heterocycle.

[0341] Embodiment 13. The method of embodiment 9, wherein the compound of Formula (III) issalt or solvate thereof.

[0342] Embodiment 14. The method of embodiment 12, wherein the 5-12 membered heterocycle is derived from methyliminodiacetic acid.

[0343] Embodiment 15. The method of any one of embodiments 1 to 14, wherein the palladium precatalyst is a palladium(O) pre-catalyst or a palladium(II) pre-catalyst.

[0344] Embodiment 16. The method of embodiment 15, wherein the palladium pre-catalyst is a palladium(O) pre-catalyst.

[0345] Embodiment 17. The method of embodiment 16, wherein palladium(O) pre-catalyst is selected from tetrakis(triphenylphosphine)palladium(0), palladium(O) on carbon, tris(dibenzylideneacetone)dipalladium(0), and bis(dibenzylideneacetone)palladium(0).

[0346] Embodiment 18. The method of embodiment 15, wherein the palladium pre-catalyst is a palladium(II) pre-catalyst.

[0347] Embodiment 19. The method of embodiment 18, wherein the palladium(II) pre-catalyst is selected from bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) dichloride, and[l,l'-bis(diphenylphosphino)ferrocene]palladium(II) di chloride, optionally wherein the palladium(II) pre-catalyst is bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).

[0348] Embodiment 20. The method of embodiment 19, wherein the palladium(II) pre-catalyst is palladium(II) acetate.WSGR Docket No. 47134-780.601

[0349] Embodiment 21. The method of embodiment 19, wherein the palladium(II) pre-catalyst is palladium(II) chloride.

[0350] Embodiment 22. The method of embodiment 19, wherein the palladium(II) pre-catalyst is bis(triphenylphosphine)palladium(II) di chloride.

[0351] Embodiment 23. The method of embodiment 19, wherein the palladium(II) pre-catalyst is [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

[0352] Embodiment 24. The method of embodiment 19, wherein the palladium(n) pre-catalyst is bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), optionally wherein the reaction is conducted for 3-6 hours.

[0353] Embodiment 25. The method of any one of embodiments 1 to 24, wherein the reaction mixture further comprises a phosphine ligand, wherein the phosphine ligand is selected from dicyclohexyl[2',4',6'-tris( 1 -methylethyl) [1,1 '-biphenyl] -2-yl] phosphine (XPhos), [4-(N,N-dimethylamino)phenyl] di-t-butylphosphine (Amphos), and di(l-adamantyl)-n- butylphosphine.

[0354] Embodiment 26. The method of embodiment 25, wherein the phosphine ligand is dicyclohexyl[2',4',6'-tris(l-methylethyl)[l,r-biphenyl]-2-yl]phosphine (XPhos).

[0355] Embodiment 27. The method of embodiment 25, wherein the phosphine ligand is [4-(N,N-dimethylamino)phenyl] di-t-butylphosphine (Amphos).

[0356] Embodiment 28. The method of embodiment 25, wherein the phosphine ligand is di(l -adamantyl)-n-butylphosphine.

[0357] Embodiment 29. The method of any one of embodiments 1 to 28, wherein the reaction mixture further comprises one or more solvents.

[0358] Embodiment 30. The method of embodiment 29, wherein the one or more solvents comprise one or more aprotic solvents.

[0359] Embodiment 31. The method of embodiment 30, wherein the one or more aprotic solvents are selected from one or more ethereal solvents and one or more amide solvents.

[0360] Embodiment 32. The method of embodiment 30, wherein the solvent comprises one or more ethereal solvents.

[0361] Embodiment 33. The method of embodiment 32, wherein the one or more ethereal solvents comprises a cyclic ether, a non-cyclic ether, or a mixture of a cyclic ether and a non-cyclic ether.

[0362] Embodiment 34. The method of embodiment 33, wherein the solvent comprises a cyclic ether.

[0363] Embodiment 35. The method of embodiment 34, wherein the cyclic ether is tetrahydrofuran, dioxane, or 2-methyltetrahydrofuran, or a mixture thereof.

[0364] Embodiment 36. The method of embodiment 31, wherein the one or more aprotic solvents is one or more amide solvents.

[0365] Embodiment 37. The method of embodiment 36, wherein the one or more amide solvents is selected from N,N-diethylformamide, l,3-dimethyl-2-imidazolidinone, dimethylacetamide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, formamide, and N-methyl-2-pyrrolidone.WSGR Docket No. 47134-780.601

[0366] Embodiment 38. The method of any one of embodiments 1 to 37, wherein the reaction mixture further comprises a base.

[0367] Embodiment 39. The method of embodiment 38, wherein the base is selected from a carbonate base, a bicarbonate base, a hydroxide base, an alkoxide base, a phosphate base, and an amine -containing base, or a mixture thereof.

[0368] Embodiment 40. The method of embodiment 39, wherein the base is a carbonate base.

[0369] Embodiment 41. The method of embodiment 40, wherein the carbonate base is sodium carbonate or potassium carbonate.

[0370] Embodiment 42. The method of embodiment 39, wherein the base is a phosphate base.

[0371] Embodiment 43. The method of embodiment 42, wherein the phosphate base is potassium phosphate tribasic.

[0372] Embodiment 44. The method of any one of embodiments 1 to 43, wherein the method further comprises isolating the compound of Formula (I), or a salt or solvate thereof, from the reaction mixture to afford substantially pure compound of Formula (I), or a salt or solvate thereof.

[0373] Embodiment 45. The method of embodiment 44, wherein the substantially pure compound of Formula (I) comprises from 0.01% to 5% by weight of palladium impurities.

[0374] Embodiment 46. The method of embodiment 44, wherein the substantially pure compound of Formula (I) comprises from 0.01% to 5% by weight of a compound of Formula (VI)salt or solvate thereof.

[0375] Embodiment 47. The method of embodiment 44, wherein the substantially pure compound of Formula (I) comprises from 0.01% to 5% by weight of a compound of Formula (Ila)salt or solvate thereof.

[0376] Embodiment 48. A method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprising reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(dimethylamino)phosphonium hexafluorophosphate to afford the compound of Formula (II)WSGR Docket No. 47134-780.601wherein X in the compounds of Formula (V) and Formula (II) are the same and are halogen or -OS(O)2RX, wherein Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3.

[0377] Embodiment 49. The method o...

Claims

WSGR Docket No. 47134-780.601CLAIMSWhat is claimed is:

1. A method of preparing a compound of Formula (I), or a salt or solvate thereof, the method comprising reacting a compound of Formula (II), or a salt or solvate thereof, with a compound of Formula (III), or a salt or solvate thereof, in a reaction mixture comprising a palladium pre- catalyst to afford the compound of Formula (I)>wherein:X in the compound of Formula (II) is halogen or -OS(O)2RX;Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3; andY in the compound of Formula (III) is -B(OR1)2 or -BF3K;wherein when Y is -B(OR1)2, each R1is independently hydrogen or Ci-Ce alkyl, or both R1together with the atoms to which they are attached form an unsubstituted or substituted 5-12 membered heterocycle.

2. The method of claim 1, wherein in the compound of Formula (II), X is halogen.

3. The method of claim 1 or 2, wherein the compound of Formula (III) isor a salt or solvate thereof.

4. The method of any one of claims 1 to 3, wherein the palladium pre-catalyst is a palladium(II) precatalyst.

5. The method of claim 4, wherein the palladium(II) pre-catalyst is selected from bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II), palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) dichloride, and[l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, optionally wherein the palladium(II) pre-catalyst is bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II).

6. The method of claim 4, wherein the palladium(II) pre-catalyst is bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II), optionally wherein the reaction is conducted for 3-6 hours.

7. The method of any one of claims 1-6, wherein the reaction mixture further comprises a base, and wherein the base is a phosphate base.WSGR Docket No. 47134-780.6018. The method of claim 7, wherein the phosphate base is potassium phosphate tribasic.

9. A method of preparing a compound of Formula (II), or a salt or solvate thereof, the method comprising reacting a compound of Formula (IV), or salt or solvate thereof, with a compound of Formula (V), or a salt or solvate thereof, in a reaction mixture comprising bromotris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(dimethylamino)phosphonium hexafluorophosphate to afford the compound of Formula (II)wherein X in the compounds of Formula (V) and Formula (II) are the same and are halogen or - OS(O)2RX, wherein Rxis Ci-Ce alkyl, Ce-Cio aryl, or -CF3.

10. The method of claim 9, wherein X in the compounds of Formula (V) and Formula (II) is halogen.

11. The method of claim 9 or 10, wherein the reaction mixture further comprises a base, and wherein the base comprises an amine- containing base.

12. The method of claim 11, wherein the amine- containing base is N,N-diisopropylethylamine or tri ethyl amine, optionally wherein the amine- containing base is triethylamine.

13. The method of any one of claims 9 to 12, wherein the reaction is conducted at a temperature range of 45 °C to 65 °C, optionally 50 °C or 60 °C.

14. The method of any one of claims 9 to 13, further comprising isolating the compound of Formula (II) from the reaction mixture, wherein the isolating comprises adding an aqueous acid to the reaction mixture, optionally wherein the aqueous acid is citric acid.

15. Substantially pure compound of Formula (I)or a salt or solvate thereof, comprising from 0.01% to 5% by weight of palladium impurities.

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