Nickel-catalyzed suzuki-miyaura coupling for process synthesis

Abstract

The present disclosure relates to nickel-based catalysts for Suzuki -Miy aura coupling reactions. In particular, the present disclosure provides a process for making a compound of Formula (III): where 0 G), R, R, m and n are as defined herein, using nickel-based catalysts as described herein.

Description

NICKEL-CATALYZED SUZUKI-MIYAURA COUPLING FOR PROCESS SYNTHESIS CROSS REFERENCE TO RELATED APPLICATION

[0001] This patent application claims the benefit of U.S. Provisional Application Nos.63 / 790,319, filed on April 17, 2025, and 63 / 676,056, filed on July 26, 2024, the disclosure of each of which is incorporated by reference herein in its entirety. STATEMENT AS TO FEDERALLY FUNDED RESEARCH

[0002] This invention was made with government support under R01 GM127778 awarded bythe National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION

[0003] The present disclosure relates to nickel-catalyzed Suzuki-Miyaura coupling of aryland / or heteroaryl compounds for process synthesis. BACKGROUND

[0004] Biaryl and heteroaryl motifs are prevalent in pharmaceutical products. The aromaticscaffolds provide a platform for the strategic spatial arrangement of substituents, imparting binding affinity and selectivity. Moreover, the aromatic and heteroaromatic rings themselves can engage in various non-covalent interactions with targets, such as p-p stacking, hydrogen bonding, and dipole interactions. The modern synthesis of aromatic frameworks often employs palladium- catalyzed Suzuki–Miyaura Coupling (Pd-SMC) between aryl electrophiles, such as halides, and arylboron nucleophiles to construct Csp2–Csp2bonds (Figure 1A) (Miyaura et al., “Palladium- Catalyzed Cross-Coupling Reactions of Organoboron Compounds,” Chem. Rev.95(7):2457–2483 (1995); Suzuki, A., “Cross-Coupling Reactions of Organoboranes: An Easy Way to Construct C– C Bonds (Nobel Lecture),” Angew. Chem. Int. Ed.50(30):6722–6737 (2011)). The growing focus on sustainable pharmaceutical production with a minimal environmental impact, along with the motivation to reduce process costs, has led to an increase of interest in pursuing non-precious metal alternatives to the Pd-SMC process (Bryan et al., “Key Green Chemistry Research Areas from a Pharmaceutical Manufacturers’ Perspective Revisited,” Green Chem.20(22):5082–5103 (2018)). Nickel, belonging to the same group as palladium, emerges as a potential substitute (Percec et al., “Aryl Mesylates in Metal Catalyzed Homocoupling and Cross-Coupling Reactions. 2. Suzuki-Type Nickel-Catalyzed Cross-Coupling of Aryl Arenesulfonates and Aryl Mesylates with Arylboronic Acids,” J. Org. Chem.60(4):1060–1065 (1995); Saito et al., “Synthesis of Biaryls via a Nickel(0)-Catalyzed Cross-Coupling Reaction of Chloroarenes with Arylboronic Acids,” J. Org. Chem.62(23):8024–8030 (1997); Inada et al., “Synthesis of Biaryls via Cross-Coupling Reaction of Arylboronic Acids with Aryl Chlorides Catalyzed by NiCl2 / Triphenylphosphine Complexes,” Tetrahedron 56(44):8657–8660 (2000); Ramgren et al., “Nickel-Catalyzed Suzuki–Miyaura Couplings in Green Solvents,” Org. Lett.15(15):3950-3953 (2013); Han, F.-S., “Transition-Metal- Catalyzed Suzuki–Miyaura Cross-Coupling Reactions: A Remarkable Advance from Palladium to Nickel Catalysts,” Chem. Soc. Rev.42(12):5270–5298 (2013); Malapit et al., “Base-Free Nickel- Catalysed Decarbonylative Suzuki–Miyaura Coupling of Acid Fluorides.” Nature 563(7729):100– 104 (2018); Hazari et al., “Well-Defined Nickel and Palladium Precatalysts for Cross-Coupling,” Nat. Rev. Chem. 1(3):25 (2017)). However, implementing Ni-SMC in process synthesis poses challenges, including the requirement for high catalyst loading (typically ranging from 5-10 mol%) (Chirik et al., “Collaboration as a Key to Advance Capabilities for Earth-Abundant Metal Catalysis,” Org. Process Res. Dev. 27(7):1160–1184 (2023)), which offsets the price benefit, a slow reaction rate (Cooper et al., “Nickel Versus Palladium in Cross-Coupling Catalysis: On the Role of Substrate Coordination to Zerovalent Metal Complexes,” Synthesis 52(4):565–573 (2020)), and a limited scope of heteroarenes (Figure 1B) (West et al., “Ni vs. Pd in Suzuki– Miyaura Sp2–Sp2Cross-Coupling: A Head-to-Head Study in a Comparable Precatalyst / Ligand System,” Org. Biomol. Chem. 17(20):5055–5059 (2019); Cooper et al., “Inhibition of (Dppf)Nickel-Catalysed Suzuki–Miyaura Cross-Coupling Reactions by α-Halo-N-Heterocycles,” Chem. Sci. 12:(42):14074–14082 (2021)). The latter limitation may arise from the potential catalyst poisoning through coordination.

[0005] Accordingly, there is an unmet need in the art for novel nickel-based catalysts that canbe used in Suzuki–Miyaura Coupling reactions and address the above limitations. SUMMARY OF THE INVENTION

[0006] Various non-limiting aspects and embodiments of the invention are described below.

[0007] In one aspect, provided herein is a process for making a compound of Formula (I):wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12 alkyl, PPh2C1-6 alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1- 6 alkyl, and N(C1-6 alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1-6alkyl, -C(O)C1-6alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6alkyl; R5is independently at each occurrence C1-6alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4. This process comprises: providing a nickel salt comprising NiX2; providing a phosphorus containing compound of Formula (II):reacting the nickel salt with the phosphorus containing compound in a solvent in a presence of a base under conditions effective to form a compound of Formula (I).

[0008] In another aspect, provided herein is a process for making a compound of Formula (I):wherein X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1- 6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1- 6 alkyl, -C(O)C1-6alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6alkyl; R5is independently at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; andc is 1, 2, 3, or 4. This process comprises: providing a nickel salt comprising NiX2; providing a phosphorus containing compound of Formula (II): andreacting the nickel salt with the phosphorus containing compound in a solvent in a presence of a base under conditions effective to form a compound of Formula (I).

[0009] In another aspect, provided herein is a composition comprising:a nickel salt comprising NiX2, wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12 alkyl, PPh2C1-6 alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2; and a phosphorus containing compound of Formula (II):wherein Y is absent or, if present, is –C(R3)(R4)- or -O-; Z is selected from the group consisting of -OH, -OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O- Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 timeswith one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is H or C1-6 alkyl; R4is H or C1-6alkyl; R5is independently at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4.

[0010] In yet another aspect, provided herein is a composition comprising:a nickel salt comprising NiX2, wherein X is independently at each occurrence a halogen, -OC(O)C1-12 alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2; and a phosphorus containing compound of Formula (II):wherein Y is absent or, if present, is –C(R3)(R4)- or -O-; Z is selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O- Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 timeswith one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is H or C1-6 alkyl; R4is H or C1-6alkyl; R5is independently at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4.

[0011] In yet another aspect, provided herein is a process for making a compound of Formula(III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6alkyl, -OC1-6alkyl, -C(O)C1-6alkyl, C(O)OH, and -S(O)2C1-6alkyl, wherein C1-6 alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5. This process comprises: providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formproviding a compound of Formula (I):wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl;R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the compound of Formula (I) under conditions effective to produce the compound of Formula (III).

[0012] In a further aspect, provided herein is a process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6alkyl, -OC1-6alkyl, -C(O)C1-6alkyl, C(O)OH, and -S(O)2C1-6alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5. This process comprises:providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formproviding a compound of Formula (I): whereinX is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6alkyl, -C(O)C1-6alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 timeswith one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the compound of Formula (I) under conditions effective to produce the compound of Formula (III).

[0013] In yet another aspect, provided herein is a process for making a compound of Formula(III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3;m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5. This process comprises: providing a compound of Formula (VI)wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6 alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1-6alkyl, -C(O)C1-6alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6alkyl; R5is independently selected at each occurrence C1-6alkyl; a is 0, 1, or 2;b is 1 or 2; and c is 1, 2, 3, or 4, providing a compound of Formula (IV)wherein Hal is halogen; and reacting the compound of Formula (VI) with the compound of Formula (IV) under conditions effective to produce the compound of Formula (III).

[0014] In yet another aspect, provided herein is a process for making a compound of Formula(III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5. This process comprises: providing a compound of Formula (VI)wherein X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, providing a compound of Formula (IV)wherein Hal is halogen; and reacting the compound of Formula (VI) with the compound of Formula (IV) under conditions effective to produce the compound of Formula (III).

[0015] In a further aspect, provided herein is a process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6 alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6 alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5. This process comprises: providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formproviding a nickel salt comprising NiX2, wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; providing a phosphorus containing compound of Formula (II):wherein Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, - C(O)NC1-6 alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionallysubstituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6alkyl; R5is independently selected at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the nickel salt and the compound of Formula (II) under conditions effective to produce the compound of Formula (III).

[0016] In yet another aspect, provided herein is a process for making a compound of Formula(III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6alkyl, -OC1-6alkyl, -C(O)C1-6alkyl, C(O)OH, and -S(O)2C1-6alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5. This process comprises:providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formproviding a nickel salt comprising NiX2, wherein X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6 alkyl)2; providing a phosphorus containing compound of Formula (II):wherein Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-;Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, - C(O)NC1-6 alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the nickel salt and the compound of Formula (II) under conditions effective to produce the compound of Formula (III).

[0017] These and other aspects of the present invention will become apparent to those skilled inthe art after a reading of the following detailed description of the invention, including the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figures 1A-1D show Suzuki-Miyaura Coupling (SMC) in the synthesis ofpharmaceutical products (Figure 1A), challenges faced in Ni-SMC (Figure 1B), mechanistic inquiries regarding transmetalation (Figure 1C), and proposed scaffolding ligand for promoting transmetalation (Figure 1D).

[0019] Figure 2 shows comparison between the SMC of 4-bromoacetophenone (4) and B(p-Tol)Pin (5) using 0.5 mol% Ni(cod)2 and 2 mol% ProPhos and the “hydrolysis” of B(p-Tol)Pin(5) without the electrophile 4 and the catalyst. Condition: [4] = 0.5 M, 60oC.

[0020] Figure 3 shows 31P{1H} NMR (162.04 MHz, C6D6) spectrum of the crude mixturecontaining complexes Ni(PPh2CH2CH2CH2OH)4 (12) and Ni(PPh2CH2CH2CH2OH)2(cod) (11).

[0021] Figure 4 shows 31P{1H} NMR (162.04 MHz, C6D6:THF = 1:4) spectrum of the crudemixture containing Ni(PPh2CH2CH2CH2OH)4(12), Ni(PPh2CH2CH2CH2OH)2(cod) (11), Ni(PPh2CH2CH2CH2OH)4(THF) and other unidentified species.

[0022] Figures 5A-5C show partial 1H / 31P{1H}-HMBC NMR (500.20 MHz, C6D6) spectra forthe isolated [Ni(PPh2Me)(m-OH)(o-Tol)]2(16), showing the correlations in four isomeric Ni hydroxo-bridged dinuclear complexes.

[0023] Figure 6 shows 13C{1H} NMR (125.79 MHz, C6D6) spectrum of complex[Ni(PPh2Me)(m-OH)(o-Tol)]2 (16). Deuterated solvent (^).

[0024] Figure 7 shows 31P{1H} NMR (162.04 MHz, C6D6) spectrum of the reaction of complexNi(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with 4-OMe-PhB(OH)2(22, 5.0 equiv) at rt.

[0025] Figure 8 shows partial 1H / 31P{1H}-HMBC NMR (500.20 MHz, C6D6) spectrum for thereaction complex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with 4-OMe-PhB(OH)2 (22, 5.0 equiv) at rt, showing the correlations between the P nuclei and its adjacent CH2protons on the proposed P-C-O-B ligand. The correlations due to complex 23 are heavily overlapped with those due to complex 21.

[0026] Figure 9 shows partial 1H COSY (400.30 MHz, C6D6) spectrum for the reaction ofcomplex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with 22 (5.0 equiv) at rt, showing the correlations of CH3 protons on the phosphine ligand.

[0027] Figure 10 shows 11B NMR (160.48 MHz, C6D6) spectra for the reaction mixture ofcomplex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with 22 at rt (top) and the free boronic acid 22 (bottom).

[0028] Figure 11 shows 31P{1H} NMR (162.04 MHz, C6D6) spectrum of the reaction ofcomplex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with BPh(OH)2(6, 5.0 equiv) at rt. This reaction mixture is more complicated than the reaction observed with 4-methoxyphenylboronic acid 22, unidentified species is marked as green dots.

[0029] Figures 12A-12C show 1H NMR (400.30 MHz, C6D6) spectra of: BPh(OH)2 (6) (Figure12A), which undergoes an equilibrium with its corresponding boroxine and H2O in C6D6 (Antoft- Finch et al., “N,N-Diethyl O-Carbamate: Directed Metalation Group and Orthogonal Suzuki−Miyaura Cross-Coupling Partner,” J. Am. Chem. Soc. 131(49):17750–17752 (2009), which is hereby incorporated by reference in its entirety); the reaction of complex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with 6 (5.0 equiv) at rt (Figure 12B); isolated complex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) (Figure 12C). The blue arrows indicate the peak shifts of the boronic acid 6, and the green arrow indicates the peak shift of 21.

[0030] Figures 13A-13C show 31P{1H} NMR (162.04 MHz, C6D6) spectra of: isolated ofcomplex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) (Figure 13A); the reaction of complex 21 with B(p-Tol)Pin (5, 1.2 equiv) at rt after 2 hours (Figure 13B); the reaction of complex 21 with B(p- Tol)Pin (5, 1.2 equiv) at rt after 24 hours (Figure 13C).

[0031] Figure 14 shows 31P{1H} NMR (162.04 MHz, C6D6) spectra of the reaction of complexNi(PPh2Me)2Cl(o-Tol) (13) with 4-OMe-PhB(OH)2(22, 5.0 equiv) at rt, showing some decomposition of the Ni complex overtime.

[0032] Figure 15 shows 31P{1H} NMR (162.04 MHz, C6D6) spectra of the reaction ofNi(PPh2Me)2Cl(o-Tol) (13) with BPh(OH)2(6, 5.0 equiv) at rt, showing minor decomposition of the Ni complex overtime.

[0033] Figures 16A-16C show 1H NMR (400.30 MHz, C6D6) spectra of: 4-OMe-PhB(OH)222(Figure 16A); the reaction of 9 with 6 at rt (Figure 16B); and isolated ProPhos 9 (Figure 16C).

[0034] Figure 17 shows 31P{1H} NMR (162.04 MHz, C6D6) spectra of the reaction of 9 (red)with 22 at rt.

[0035] Figure 18 shows 1H NMR (400.30 MHz, C6D6) and 31P{1H} NMR (162.04 MHz, C6D6)spectra of the reaction of 9 (red) with 22 at variable temperatures.

[0036] Figures 19A-19C show 31P{1H} NMR (162.04 MHz, C6D6) spectra of: isolated ProPhos9 (Figure 19A); the ligand substitution mixture of Ni(TMEDA)Cl(o-Tol) (S9) with ProPhos 9 (Figure 19B); and the reaction mixture of Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) with KOH in THF / H2O (Figure 19C).

[0037] Figures 20A-20B show 1H NMR (400.30 MHz, C6D6) spectrum of free ProPhos 9(Figure 20A) and the reaction of the reaction mixture of Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21)with KOH in THF / H2O (Figure 20B), showing the shift of the signals due to OH and its adjacent CH protons at 24 with respect to free 9.

[0038] Figure 21 shows 1H NMR (400.30 MHz, C6D6) spectrum of the mixture conationcomplex 24, showing no Ni bridging OH formed (i.e., “empty” upfield region) and diagnostic signals in the tentatively assigned complexes. ProPhos ligand though O-coordination (^).

[0039] Figure 22 shows 31P{1H} NMR (162.04 MHz, C6D6) spectra of the reaction of themixture containing Ni(^2-PPh2CH2CH2CH2O)(o-Tol)(ProPhos) (24) with BPh(OH)2 (6) and the resulting biaryl products. L = ProPhos.

[0040] Figure 23 shows stoichiometric transmetalation of complex Ni(PPh2Me)2Cl(o-Tol) (13)with B(p-Tol)Pin (5), BPh(OH)2(6) and KB[(p-Tol)Pin(OH)] (15). %Yields of products 19 and 20 determined by GC.

[0041] Figure 24 shows stoichiometric transmetalation of complex [Ni(PPh2Me)(^-OH)(o-Tol)]2 (16) with B(p-Tol)Pin (5), BPh(OH)2 (6) and KB[(p-Tol)Pin(OH)] (15). %Yields of products 19 and 20 determined by GC.

[0042] Figures 25A-25C show 1H NMR (400.30 MHz, C6D6) spectra of: BPh(OH)2 (6) (Figure25A); isolated ProPhos 9 (Figure 25B); and the reaction of 9 with 6 (2 equiv) at rt (Figure 25C).

[0043] Figures 26A-26C show 31P{1H} NMR (162.04 MHz, C6D6) spectra of: isolated ProPhos9 (Figure 26A); the reaction of ProPhos 9 with 6 (2 equiv) (Figure 26B); and the reaction mixture from (b) reacts with KOH (2.0 equiv) and H2O (1 ^L) (Figure 26C).

[0044] Figure 27 shows SMC catalyzed by Ni(ProPhos) precatalyst 21.

[0045] Figure 28A shows time-courses of Ni-SMC that reflects the effect of the ligand. Reactionconditions: [4]0= 0.50 M, [5]0or [6]0= 0.55 M, reactions were monitored by GC with calibrations of the product. Figure 28B shows rate laws of Ni-SMC catalyzed by (Ph2MeP)Ni and (ProPhos)Ni catalysts.

[0046] Figures 29A-29B show mechanisms of Ni(PPh2Me) and Ni(ProPhos)-catalyzed SMC.

[0047] Figure 30 shows scope of Ni(ProPhos)-Catalyzed SMC. aConditions: Ni(cod)2 (x mol%),ProPhos (4x mol%), K3PO4 (2.5 equiv), 2-MeTHF / H2O (5:1), 16 hours.bNiCl2•6H2O (x mol%), ProPhos (4x mol%), K3PO4 (2.5 equiv), i-PrOH, 16 hours. %Yield determined by GC with calibrations and isolated %yield in the parenthesis.

[0048] Figure 31 shows synthesis and X-ray crystal structure of (ProPhos)Ni(cod) (atomicdisplacement parameters at the 50% probability level). Hydrogen atoms bound to carbon are omitted for clarity.

[0049] Figure 32 shows 31P{1H} NMR (162.04 MHz, C6D6:2-MeTHF = 1:4) spectrum of thecatalytic cross-coupling of 2-bromotoluene and B(p-Tol)Pin (5) using 10 mol % Ni(cod)2 and 40 mol% PPh2Me at 70oC, showing the observed Ni species overtime.

[0050] Figures 33A-33C show organometallic studies of transmetalation in Ni-SMC.

[0051] Figure 34 shows 31P{1H} NMR (162.04 MHz, C6D6:2-MeTHF = 1:4) spectrum of thecatalytic cross-coupling of 2-chlorotoluene and B(p-Tol)Pin (5) using 10 mol % Ni(cod)2 and 40 mol% ProPhos at rt for 15 min.

[0052] Figure 35 shows 31P{1H} NMR (162.04 MHz, C6D6:2-MeTHF = 1:4) spectrum of thecatalytic cross-coupling of 2-chlorotoluene and B(p-Tol)Pin (5) using 10 mol % Ni(cod)2 and 40mol% ProPhos at 70oC, showing the observed Ni species overtime. The broad signal due to the Ni boron adduct (e.g. green dot) could be attributed to the reversible chelation of the phosphine ligands to the cationic Ni center.

[0053] Figure 36 shows stoichiometric transmetalation of complexNi(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with B(p-Tol)Pin (5), BPh(OH)2(6) and KB[(p- Tol)Pin(OH)] (15). %Yields of products 19 and 20 determined by GC.

[0054] Figure 37 shows partial 1H NOESY (400.30 MHz, C6D6) spectrum for the reaction ofcomplex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with 22 (5.0 equiv) at rt, showing a weak NOE (orange ^) between CH2protons in the phosphine ligand and the OH proton in the boronic acid, as well as a strong EXSY (purple ^) between the OH proton in the boronic acid and H2O. The 2D EXSY technique is the same as the 2D NOESY technique. To differentiate between them, a straightforward approach is to observe the phase: in EXSY, off-diagonal peaks share the same phase as the diagonal peaks, whereas in NOESY, the off-diagonal peaks exhibit a different phase from the diagonal ones.

[0055] Figure 38 shows molecular structure of Ni(PPh2CH2CH2CH2OH)2(cod) (11). Thethermal ellipsoids are shown at 50% probability. Hydrogen atoms at carbons and THF have been omitted for clarity. Selected distances (Å) and bond angles (°): Ni1-C1 2.106(4), Ni1-C2 2.093(4); Ni1-C5 2.100(4); Ni1-C6 2.107(4); Ni1-P2 2.1679(10); Ni1-P1 2.1811(10); C1-C2 1.392(5); O1-H10.8400; O2-H20.8400; P2-Ni1-P1106.48(4).

[0056] Figure 39 shows molecular structure of Ni(PPh2Me)2Cl(o-Tol) (13). The thermalellipsoids are shown at 50% probability. Hydrogen atoms at carbons have been omitted for clarity. Selected distances (Å) and bond angles (°): Ni1-C1 1.8967(14); Ni1-P2 2.1998(4); Ni1-P1 2.2035(4); Ni1-Cl12.2221(4); C1-Ni1-P286.21(4); C1-Ni1-P187.89(4); P2-Ni1-P1172.495(16); C1-Ni1-Cl1176.38(5); P2-Ni1-Cl191.760(14); P1-Ni1-Cl193.882(14).

[0057] Figure 40 shows molecular structure of Ni(PPh2Me)2(O-o-Tol)(o-Tol) (17). The thermalellipsoids are shown at 50% probability. Hydrogen atoms at carbons have been omitted for clarity. Selected distances (Å) and bond angles (°): Ni1-O1 1.8928(12); Ni1-C11 1.9086(16); Ni1-P1 2.1894(5); Ni1-P22.2055(5); O1-C11.321(2); O1-Ni1-C11176.97(6); O1-Ni1-P190.80(4); C11- Ni1-P186.47(5); O1-Ni1-P294.73(4); C11-Ni1-P287.50(5); P1-Ni1-P2162.06(2); C1-O1-Ni1 122.39(11).

[0058] Figure 41 shows GC response factor (Rf, navy) of products against n-decane as theinternal standard, determined by calibration curves using corresponding isolated compounds.

[0059] Figure 42 shows Variable Time Normalization Analysis (VTNA) results for the reactionrate dependence on [Ni] for the cross-coupling of 4-bromoacetophenone (4) and B(p-Tol)Pin (5)using Ni(cod)2 and PPh2Me. Original plot is top-left, time normalization plots show that there is a first-order dependence on [Ni] (bottom-left plot encompassed by red square). Condition: [4] = 0.5 M, [5] = 0.55 M, 60oC.

[0060] Figure 43 shows VTNA for the reaction rate dependence on [4-bromoacetophenone] forthe cross-coupling of 4-bromoacetophenone (4) and B(p-Tol)Pin (5) using 1.5 mol% Ni(cod)2and 6 mol% PPh2Me. Original plot is top-left, time normalization plots show that there is a zero-order dependence on [4] (top-right plot encompassed by red square). Condition: [5] = 0.55 M, 60oC.

[0061] Figure 44 shows VTNA for the reaction rate dependence on [B(p-Tol)Pin] for the cross-coupling of 4-bromoacetophenone (4) and B(p-Tol)Pin (5) using 1 mol% Ni(cod)2and 4 mol% PPh2Me. Original plot is top-left, time normalization plots show that there is a zero-order dependence on [5] (top-right plot encompassed by red square). Condition: [4] = 0.5 M, 60oC.

[0062] Figure 45 shows VTNA for the reaction rate dependence on [Ni] for the cross-couplingof 4-bromoacetophenone (4) and B(p-Tol)Pin (5) using Ni(cod)2 and ProPhos. Original plot is top- left, time normalization plots show that there is a first-order dependence on [Ni] (bottom-left plot encompassed by red square). Condition: [4] = 0.5 M, [5] = 0.55 M, 60oC.

[0063] Figure 46 shows VTNA for the reaction rate dependence on [4-bromoacetophenone] forthe cross-coupling of 4-bromoacetophenone (4) and B(p-Tol)Pin (5) using 0.5 mol% Ni(cod)2 and 2 mol% ProPhos. Original plot is top-left, time normalization plots show that there is a zero-order dependence on [4] (top-right plot encompassed by red square). Condition: [5] = 0.55 M, 60oC.

[0064] Figure 47 shows VTNA for the reaction rate dependence on [B(p-Tol)Pin] for the cross-coupling of 4-bromoacetophenone (4) and B(p-Tol)Pin (5) using 0.5 mol% Ni(cod)2 and 2 mol%ProPhos. Original plot is top-left, time normalization plots show that there is a first-order dependence on [5] (bottom-left plot encompassed by red square). Condition: [4] = 0.5 M, 60oC.

[0065] Figure 48 shows VTNA for the reaction rate dependence on [phenylboronic acid] for thecross-coupling of 4-bromoacetophenone (4) and BPh(OH)2(6) using 0.2 mol% Ni(cod)2and 0.8 mol% ProPhos. Original plot is top-left, time normalization plots show that there is a first-order dependence on [6] (bottom-left plot encompassed by red square). Condition: [4] = 0.5 M, 60oC.

[0066] Figure 49 shows 31P{1H} NMR (162.04 MHz, C6D6:2-MeTHF = 1:4) spectrum of thecatalytic cross-coupling of 2-bromotoluene and BPh(OH)2(6) using 10 mol % Ni(cod)2and 40 mol% PPh2Me at 70oC, showing the observed Ni species overtime.

[0067] Figure 50 shows 31P{1H} NMR (162.04 MHz, C6D6:2-MeTHF = 1:4) spectrum of thecatalytic cross-coupling of 2-bromotoluene and B(p-Tol)Pin (5) using 10 mol % Ni(cod)2and 40 mol% ProPhos, showing the observed Ni species overtime at rt and heating at 70oC. The assigned complex Ni(PPh2CH2CH2CH2OH)2Br(o-Tol) showed an identical31P shift to its analogue 21.

[0068] Figure 51 shows 31P{1H} NMR (162.04 MHz, C6D6:2-MeTHF = 1:4) spectrum of thecatalytic cross-coupling of 2-bromotoluene and BPh(OH)2(6) using 10 mol % Ni(cod)2and 40 mol% ProPhos at 70oC, showing the observed Ni species overtime. A noticeable broadening was observed in most signals due to Ni species (e.g.11).

[0069] Figure 52 shows known monomeric and dimeric Ni-OH Complexes. Ni-OH monomers:Cámpora et al., “CO Insertion Reactions into the M−OH Bonds of Monomeric Nickel and Palladium Hydroxides. Reversible Decarbonylation of a Hydroxycarbonyl Palladium Complex,” Organometallics 23(8):1652–1655 (2004); Heimann et al., “Effect of Nucleophilicity on the Kinetics of CO2 Insertion into Pincer-Supported Nickel Complexes,” Organometallics 37(21):3649–3653 (2018); Eberhardt et al., “Dehydrogenative Coupling of Aldehydes with Alcohols Catalyzed by a Nickel Hydride Complex,” Organometallics 38(7):1468–1478 (2019); Olding et al., “Pretransmetalation Intermediates in Suzuki–Miyaura C–C and Carbonylative Cross-Couplings: Synthesis and Structural Authentication of Aryl- and Aroylnickel(II) Boronates,” ACS Catal.13(5):3153–3157 (2023), which are hereby incorporated by reference in their entirety. Ni- OH dimers: Malapit et al., “Base-Free Nickel-Catalysed Decarbonylative Suzuki–Miyaura Coupling of Acid Fluorides.” Nature 563(7729):100–104 (2018); Newman-Stonebraker et al., “Structure–Reactivity Relationships of Buchwald-Type Phosphines in Nickel-Catalyzed Cross- Couplings,” J. Am. Chem. Soc.144(42):19635–19648 (2022); Carmona et al., “Pyrrolyl, Hydroxo, and Carbonate Organometallic Derivatives of Nickel(II). Crystal and Molecular Structure of [Ni(CH2C6H4-o-Me)(PMe3)(μ-OH)]2•2,5-HNC4H2Me2,” Inorg. Chem. 28(10):1895–1900 (1989); So et al., “4-Hydroxyaryl Complexes of Group 10 Metals,” J. Organomet. Chem.853:1– 4 (2017), which are hereby incorporated by reference in their entirety.

[0070] Figure 53 shows representative 31P{1H} NMR (162.04 MHz, THF / C6D6) spectra ofcomplex [Ni(PPh2Me)(m-OH)(o-Tol)]2 (16) with BPh(OH)2 (6) overtime, showing the formation of the Ni(0) species throughout the reaction and product distribution analyzed by GC.

[0071] Figure 54 shows representative 31P{1H} NMR (162.04 MHz, THF / C6D6) spectra of[Ni(PPh2Me)(m-OH)(o-Tol)]2 (16) with B(p-Tol)Pin (5) overtime, showing the decrease of the Ni- OH complexes and increase of the Ni(PPh2Me)4 (18) throughout the reaction. Internal standard (IS): P(O)Ph3in a small capillary.

[0072] Figure 55 shows 31P{1H} NMR (162.04 MHz, THF / C7D8) spectra of Ni(PPh2Me)2Cl(o-Tol) (13) with BPh(OH)2 (6) in the presence of excess KOH overtime. Internal standard (IS): PPh3 in a small capillary.

[0073] Figure 56 shows 31P{1H} NMR (162.04 MHz, THF / C6D6) spectra of Ni(PPh2Me)2Cl(o-Tol) (13) with BPh(OH)2 (6) in the presence of excess K3PO4 overtime. Internal standard (IS): PPh3 in a small capillary.

[0074] Figure 57 shows product distribution of the NMR Monitoring Reactions after 24 hours(analyzed by GC).

[0075] Figure 58 shows stoichiometric transmetalation of complex 13, 16 or 21 with KB[(p-Tol)Pin(OH)] (15) in the presence of 18-crown-6. %Yields of products 19 determined by GC.

[0076] Figure 59 shows comparison of stoichiometric transmetalation activity between[complex 13 + 15] and [complex 16 and 5]. %Yields of product 19 determined by GC.

[0077] Figure 60 shows 31P{1H} NMR (162.04 MHz, THF / C6D6) spectra of Ni(PPh2Me)2Cl(o-Tol) (13) with excess K3PO4 (15 equiv) at 24 hours. Internal standard (IS): PPh3 in a small capillary. The broad signal around 5 ppm is due to unidentified species.

[0078] Figure 61 shows relative rates of relevant reactions in the Ni-PPh2Me transmetalation.

[0079] Figure 62 shows comparison of stoichiometric transmetalation activity between complex13 and 21 using 5 and 15. %Yields of product 20 determined by GC.

[0080] Figure 63 shows comparison of stoichiometric transmetalation activity between complex13 and complex 21 using 6. %Yields of product 19 determined by GC.

[0081] Figure 64 shows 31P{1H} NMR (162.04 MHz, THF / C7D8) spectra of complexNi(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with BPh(OH)2(6) in the presence of excess KOH overtime. Internal standard (IS): PPh3in a small capillary. Ni(^2-PPh2CH2CH2CH2O)(o- Tol)(ProPhos) (24, ^).33% of 19 was detected by GC at 30 min and remains unchanged throughout the reaction.

[0082] Figures 65A-65C show 31P{1H} NMR (162.04 MHz, THF / C6D6) spectra of:Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with BPh(OH)2 (6) in the presence of excess K3PO4 at 15 min (Figure 65A); the catalytic reaction mixture of 2-chlorotoluene and B(p-Tol)Pin (5) using 10 mol % Ni(cod)2 and 40 mol% ProPhos after 16 h at 70oC (2-MeTHF instead of THF) (Figure 65B); the reaction of complex 21 with 6 after 15 min at rt (Figure 65C). Internal standard (IS): PPh3in a small capillary

[0083] Figure 66 shows 31P{1H} NMR (162.04 MHz, THF / C6D6) spectra ofNi(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with BPh(OH)2 (6) in the presence of excess K3PO4 overtime. Internal standard (IS): PPh3 in a small capillary. The broad31P signal at ~3 ppm is tentatively assigned to Ni( PPh2CH2CH2CH2OH)2(L)2.

[0084] Figure 67 shows product distribution analyzed by GC.

[0085] Figure 68 shows VTNA for the reaction rate dependence on [Ni] for the cross-couplingof 4-bromoacetophenone and B(3-Py)(OH)2using NiCl₂•6H₂O and ProPhos. Original plot is top- left, time normalization plots show that there is a first-order dependence on [Ni] (red square). Condition: [ArBr] = 0.500 M; [B(3-Py)(OH)2] = 0.750 M; [Ni] = 0.000325 M, 0.0006 M, 0.00125 M, 0.0025 M; [ProPhos] = 0.0013 M; 0.0024 M; 0.006 M; 0.01 M; K3PO4= 106 mg.

[0086] Figure 69 shows VTNA for the reaction rate dependence on [B(3-Py)(OH)2] for thecross-coupling of 4-bromoacetophenone and [B(3-Py)(OH)2] using 0.05 mol% NiCl₂•6H₂O and0.20 mol% ProPhos. Original plot is top-left, time normalization plots show that there is a zero- order dependence on [B(3-Py)(OH)2] (red square). Condition: [ArBr] = 0.500 M; [B(3-Py)(OH)2] = 0.750 M; 0.900 M, 1.00 M, 1.15 M; [Ni] = 0.000250 M; [ProPhos] = 0.001 M; K3PO4 = 106 mg. DETAILED DESCRIPTION

[0087] Detailed embodiments of the present invention are disclosed herein; however, it is to beunderstood that the disclosed embodiments are merely illustrative of the invention that may be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the invention is intended to be illustrative, and not restrictive. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.

[0088] Nickel-catalyzed Suzuki-Miyaura Coupling (Ni-SMC) offers the potential to reduce thecost of pharmaceutical process synthesis. However, its application has been restricted by challenges such as slow reaction rates, high catalyst loading, and a limited scope of heterocycles. Despite recent investigations, the mechanism of transmetalation in Ni-SMC, often viewed as the turnover-limiting step, remains insufficiently understood. The "Ni-oxo" transmetalation pathway was elucidated, applying PPh2Me as the ligand, and the formation of a nickel-oxo intermediate was identified as the turnover-limiting step. Building on this insight, a scaffolding ligand, ProPhos, featuring a pendant hydroxyl group connected to the phosphine via a linker was developed. The design pre-organized both the nucleophile and the nickel catalyst, thereby facilitating transmetalation. This catalyst exhibited fast kinetics and robust activity across a wide range of heteroarenes, with a catalyst loading of 0.5-3 mol%. For arene substrates, the catalyst loading can be further reduced to 0.1 mol%.

[0089] The optimization of transition-metal catalyzed reactions pivots crucially on liganddesign. Recent efforts aimed at improving Ni-SMC have revealed that a monodentate phosphine ligand can facilitate oxidative addition and transmetalation, while a bidentate phosphine ligand can stabilize the catalyst against deactivation (Borowski et al., “Comparison of Monophosphine and Bisphosphine Precatalysts for Ni-Catalyzed Suzuki–Miyaura Cross-Coupling: Understanding the Role of the Ligation State in Catalysis,” ACS Catal.13(12):7966–7977 (2023), which is hereby incorporated by reference in its entirety). This insight resonates with the recent application of Ph2MeP (Haibach et al., “Enabling Suzuki–Miyaura Coupling of Lewis-Basic Arylboronic Esterswith a Nonprecious Metal Catalyst,” Chem. Sci. 13(43):12906–12912 (2022), which is hereby incorporated by reference in its entirety), Buchwald-type ligands (Newman-Stonebraker et al., “Structure–Reactivity Relationships of Buchwald-Type Phosphines in Nickel-Catalyzed Cross- Couplings,” J. Am. Chem. Soc. 144(42):19635–19648 (2022), which is hereby incorporated by reference in its entirety), and dppb (dppb = 1,4-bis(diphenylphosphino)butane) (Guo et al., “Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling Facilitated by a Weak Amine Base with Water as a Cosolvent,” Organometallics 41(11):1269–1274 (2022), which is hereby incorporatedby reference in its entirety) in Ni-SMC. While data analysis and machine learning models emergeas powerful tools for identifying new ligands (Newman-Stonebraker et al., “Univariate Classification of Phosphine Ligation State and Reactivity in Cross-Coupling Catalysis,” Science 374(6565):301–308 (2021), which is hereby incorporated by reference in its entirety), a complementary strategy involves design based on mechanistic understanding. The latter approach lead to novel ligand frameworks described in the present disclosure that might otherwise evaded the discovery through the former method.

[0090] Prior mechanistic investigations determined that Ni-SMC operates through a Ni(0) / Ni(II)cycle (Guard et al., “Comparison of Dppf-Supported Nickel Precatalysts for the Suzuki–Miyaura Reaction: The Observation and Activity of Nickel(I),” Angew. Chem. Int. Ed.54(45):13352–13356 (2015); Beromi et al., “Mechanistic Study of an Improved Ni Precatalyst for Suzuki–Miyaura Reactions of Aryl Sulfamates: Understanding the Role of Ni(I) Species,” J. Am. Chem. Soc. 139(2):922–936 (2017), which are hereby incorporated by reference in their entirety), with transmetalation of arylboronic acid or ester nucleophiles to nickel identified as the turnover- limiting step, typically facilitated by a base (Quasdorf et al., “Suzuki−Miyaura Cross-Coupling of Aryl Carbamates and Sulfamates: Experimental and Computational Studies,” J. Am. Chem. Soc. 133(16):6352–6363 (2011); Christian et al., “Nickel Hydroxo Complexes as Intermediates in Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling,” Organometallics 33(9):2134–2137 (2014); Payard et al., “Taming Nickel-Catalyzed Suzuki-Miyaura Coupling: A Mechanistic Focus on Boron-to-Nickel Transmetalation,” ACS Catal. 8(6):4812–4823 (2018), which are herebyincorporated by reference in their entirety). Generally, transmetalation can follow one of twopossible pathways, distinguished by the role the base plays (Paths A and B, Figure 1C) (Lennox et al., “Transmetalation in the Suzuki–Miyaura Coupling: The Fork in the Trail,” Angew. Chem. Int. Ed. 52(29):7362–7370 (2013), which is hereby incorporated by reference in its entirety). InPath A, the "boronate" mechanism, the base initially activates the boronic acid or ester by forming a boronate, which subsequently substitutes the halide on the nickel intermediate 1, generating Ni- O-B intermediate 2. In Path B, the "nickel-oxo" mechanism, the base first displaces the halide of 1, resulting in the nickel-oxo intermediate 3. Intermediate 3 is then associated with arylboronic acid or ester to generate intermediate 2. Studies on Pd-SMC have established Path B to be kinetically viable (Carrow, B. P. and Hartwig, J. F., “Distinguishing Between Pathways for Transmetalation in Suzuki−Miyaura Reactions,” J. Am. Chem. Soc. 133(7):2116–2119 (2011), which is hereby incorporated by reference in its entirety), and NMR characterization has verified the formation of a Pd-O-B intermediate as the pre-transmetalation species (Thomas, A. A. and Denmark, S. E., “Pre-Transmetalation Intermediates in the Suzuki-Miyaura Reaction Revealed: The Missing Link,” Science 352(6283):329–332 (2016); Thomas et al., “Structural, Kinetic, and Computational Characterization of the Elusive Arylpalladium(II)boronate Complexes in the Suzuki–Miyaura Reaction,” J. Am. Chem. Soc. 139(10):3805–3821 (2017); Thomas et al., “Elucidating the Role of the Boronic Esters in the Suzuki–Miyaura Reaction: Structural, Kinetic, and Computational Investigations,” J. Am. Chem. Soc. 140(12):4401–4416 (2018), which arehereby incorporated by reference in their entirety). Regarding Ni-SMC, there remains ambiguityregarding the transmetalation pathway, particularly concerning the reactivity of nickel-oxo intermediates 3 (Olding et al., “Pretransmetalation Intermediates in Suzuki–Miyaura C–C and Carbonylative Cross-Couplings: Synthesis and Structural Authentication of Aryl- and Aroylnickel(II) Boronates,” ACS Catal.13(5):3153–3157 (2023), which is hereby incorporated by reference in its entirety). An investigation of the (PCy3)Ni catalyst supported Path B, suggesting that the formation of a nickel-oxo species before transmetalation represented the turnover-limiting step (Christian et al., “Nickel Hydroxo Complexes as Intermediates in Nickel-Catalyzed Suzuki– Miyaura Cross-Coupling,” Organometallics 33(9):2134–2137 (2014), which is hereby incorporated by reference in its entirety). Another study with a (PPh3)Ni catalyst implied the formation of a nickel-oxo dimer as an off-cycle species, suggesting that the catalytic reaction might be limited by the slow dissociation of the dimer prior to transmetalation (Payard et al., “Taming Nickel-Catalyzed Suzuki-Miyaura Coupling: A Mechanistic Focus on Boron-to-Nickel Transmetalation,” ACS Catal.8(6):4812–4823 (2018), which is hereby incorporated by reference in its entirety). These varying proposals highlighted the complexity of the transmetalation step in Ni-SMC, whose mechanisms may diverge depending on the specific catalysts and bases used.

[0091] The present disclosure provides comprehensive insights into the transmetalation pathwayusing a Ni(PPh2Me) catalyst through kinetic and organometallic studies. The formation of nickel- oxo intermediates was identified as the turnover-limiting step and their fast reactivity in transmetalation was verified. These findings led to development of a phosphine scaffolding ligand, featuring a tethered Lewis basic group designed to promote transmetalation (Figure 1D). This ligand framework enabled the colocation and pre-organization of the catalyst and nucleophile, thus facilitating transmetalation in an intramolecular fashion (Tan et al., “Scaffolding Catalysis: Expanding the Repertoire of Bifunctional Catalysts,” Synlett 2012(03):321-325 (2012), which is hereby incorporated by reference in its entirety). Moreover, the basic group could function as a hemi-labile ligand, offering protection against catalyst poisoning through heteroatom coordination, while still readily dissociating to maintain high catalytic activity. The work described in the present disclosure not only unveils a highly reactive catalyst informed by a mechanistic hypothesis, but also sets a course for ligand optimization, paving the way for the application of Ni- SMC in pharmaceutical process synthesis. Definitions

[0092] To facilitate an understanding of the principles and features of the various embodimentsof the invention, various illustrative embodiments are explained below. Although exemplary embodiments of the invention are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the invention is limited in its scope to the details of construction and arrangement of components set forth in the following description or examples. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, in describing the exemplary embodiments, specific terminology will be resorted to for the sake of clarity.

[0093] As used in this specification and the appended claims, the singular forms “a”, “an”, and“the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those persons skilled in the art upon reading this disclosure.

[0094] The term “about” or “approximately” means within a statistically meaningful range of avalue. Such a range can be within an order of magnitude, preferably within 50%, more preferably within 20%, still more preferably within 10%, and even more preferably within 5% of a given value or range. The allowable variation encompassed by the term “about” or “approximately”depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art.

[0095] By “comprising” or “containing” or “including” is meant that at least the namedcompound, element, particle, or method step is present in the composition or article or method, but does not exclude the presence of other compounds, materials, particles, or method steps, even if the other such compounds, material, particles, or method steps have the same function as what is named.

[0096] Compounds of the present invention include those described generally herein, and arefurther illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001 , the entire contents of which are hereby incorporated by reference.

[0097] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or“aryloxyalkyl,” refers to an aromatic monocyclic or polycyclic ring system containing from 6 to 19 (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 6–7, 6–8, 6–9, 6–10, 6–11, 6–12, 6–13, 6–14, 6–15, 6–16, 1–17, 6–18, 7–8, 7–9, 7–10, 7–11, 7–12, 7–13, 7–14, 7–15, 7–16, 7–18, 7–19, 8–9, 8–10, 8–11, 8–12, 8–13, 8–14, 8–15, 8–16, 8–17, 8–18, 8–19, 9–10, 9–11, 9–12, 9–13, 9–14, 9– 15, 9–16, 9–17, 9–18, 9–19, 10–11, 10–12, 10–13, 10–14, 10–15, 10–16, 10–17, 10–18, 10–19, 11–12, 11–13, 11–14, 11–15, 11–16, 11–17, 11–18, 11–19, 12–13, 12–14, 12–15, 12–16, 12–17, 12–18, 12–19, 13–14, 13–15, 13–16, 13–17, 13–18, 13–19, 14–15, 14–16, 14–17, 14–18, 14–19, 15–16, 15–17, 15–18, 15–19, 16–17, 16–18, 16–19, 17–18, 17–19, 18–19) carbon atoms, where the ring system may be optionally substituted. Aryl groups of the present invention include, but are not limited to, groups such as phenyl, naphthyl, azulenyl, phenanthrenyl, anthracenyl, fluorenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl.

[0098] As used herein, the term “alkyl” means an aliphatic hydrocarbon group which may bestraight or branched having about 1 to about 8 (e.g., 1–2, 1–3, 1–4, 1–5, 1–6, 1–7, 1–8) carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, orpropyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl.

[0099] As used herein, the term “cycloalkyl” refers to a non-aromatic saturated or unsaturatedmono- or polycyclic ring system which may contain 3 to 8 (3, 4, 5, 6, 7, 8, 3–4, 3–5, 3–6, 3–7, 4– 5, 4–6, 4–7, 4–8, 5–6, 5–7, 5–8, 6–7, 6–8, 7–8) carbon atoms, and which may include at least one double bond. Exemplary cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, anti- bicyclopropane, or syn-bicyclopropane.

[0100] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and“heterocyclic ring” are used interchangeably and refer to a stable 3- to 18-membered (3-, 4-, 5-, 6- , 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, or 18-membered) ring system that consists of carbon atoms and from one to five (1, 2, 3, 4, 5, 1–2, 1–3, 1–4, 2–3, 2–4, 2–5, 3–4, 3–5, 4–5) heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocyclyl may be a monocyclic or a polycyclic ring system, which may include fused, bridged, or spiro ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the ring may be partially or fully saturated. Representative monocyclic heterocyclyls include piperidine, piperazine, pyrimidine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, pyran, tetrahydropyran, oxetane, and the like. Representative polycyclic heterocyclyls include indole, isoindole, indolizine, quinoline, isoquinoline, purine, carbazole, dibenzofuran, chromene, xanthene, and the like.

[0101] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic, bicyclic, tricyclic, tetracyclic, and / or otherwise polycyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0102] As used herein, “heteroaryl” refers to an aromatic ring radical which consists of carbonatoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, without limitation, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienopyrrolyl, furopyrrolyl, indolyl, azaindolyl, isoindolyl, indolinyl, indolizinyl, indazolyl, benzimidazolyl, imidazopyridinyl, benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, pyrazolopyridinyl, triazolopyridinyl, thienopyridinyl, benzothiadiazolyl, benzofuyl, benzothiophenyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, cinnolinyl, quinazolinyl, quinolizilinyl, phthalazinyl, benzotriazinyl, chromenyl, naphthyridinyl, acrydinyl, phenanzinyl, phenothiazinyl, phenoxazinyl, pteridinyl, and purinyl. Additional heteroaryls are described in Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds (Katritzky et al. eds., 1984), which is hereby incorporated by reference in its entirety.

[0103] As used herein, the term “partially unsaturated” refers to a ring moiety that includes atleast one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0104] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring.

[0105] As used herein, the term “radical” means an atom, molecule, compound, or ion that hasat least one unpaired valence electron or an open electron shell.

[0106] The term “monocyclic” used herein indicates a molecular structure having one ring.

[0107] The term “polycyclic” or “multi-cyclic” used herein indicates a molecular structurehaving two or more rings, including, but not limited to, fused, bridged, or spiro rings.

[0108] As described herein, compounds of the invention may contain “optionally substituted”moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0109] The term “halogen” means fluorine, chlorine, bromine, or iodine.

[0110] Unless otherwise stated, structures depicted herein are also meant to include all isomeric(e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

[0111] Unless otherwise stated, all tautomeric forms of the compounds of the invention arewithin the scope of the invention.

[0112] Additionally, unless otherwise stated, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a11C- or13C- or14C -enriched carbon are within the scope of this invention.

[0113] It is also to be understood that the mention of one or more method steps does not precludethe presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more components in a device or system does not preclude the presence of additional components or intervening components between those components expressly identified.

[0114] Also, in describing the exemplary embodiments, terminology will be resorted to for thesake of clarity. It is intended that each term contemplates its broadest meaning as understood bythose skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose. Nickel-Based Catalysts

[0115] In one aspect, provided herein is a process for making a compound of Formula (I):wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12 alkyl, PPh2C1-6 alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6alkyl, -C(O)C1-6alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6alkyl; R5is independently at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; andc is 1, 2, 3, or 4. This process comprises: providing a nickel salt comprising NiX2; providing a phosphorus containing compound of Formula (II):and reacting the nickel salt with the phosphorus containing compound in a solvent in a presence of a base under conditions effective to form a compound of Formula (I).

[00116] Compounds described herein may contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. This technology is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[00117] The present invention also includes salts of the compounds described herein. As usedherein, “salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of salts include, but are not limited to, mineral acid (such as HC1, HBr, H2SO4) or organic acid (such as acetic acid, benzoic acid, trifluoroacetic acid salts of basic residues such as amines; alkali (such as Li, Na, K, Mg, Ca) or organic (such as trialkylammonium) salts of acidic residues such as carboxylic acids; and the like. The salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety via conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) are preferred.

[00118] In some embodiments, X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituentsselected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2.

[00119] In some embodiments, the compound of Formula (I) has a Formula (Ia):

[00120] In some embodiments, the compound of Formula (Ia) is selected from the groupconsisting of:

[00121] In some embodiments, the compound of Formula (Ia) is selected from the groupconsisting of:

[0122] According to the present disclosure, the nickel salt comprised NiCl2, NiBr2, Ni(OAc)2,Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4, Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o-Tol)]2. In some embodiments, the nickel salt comprises NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, or Ni(o-totyl)Cl. In some embodiments, the nickel salt is selected from the group consisting of NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4, Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o-Tol)]2 or hydrate or solvate thereof. In some embodiments, the nickel salt is selected from the group consisting of NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, and Ni(o- totyl)Cl, or hydrate or solvate thereof. In some embodiments, the nickel salt is selected from the group consisting of NiCl2*6H2O, nickel(II) chloride ethylene glycol dimethyl ether complex, and nickel(II) bromide ethylene glycol dimethyl ether complex.

[0123] According to the present disclosure, any suitable base can be used, such as monomericphosphazene bases, dimeric phosphazene bases, tetrameric phosphazene bases, Verkade’s bases, amine based traditional bases, lithium based traditional bases, and potassium based traditional bases. For example, N’-tert-Butyl-N,N,N’,N’,N’’,N’’-hexamethylphosphorimidic triamide, tert- butylimino-tri(pyrrolidino)phosphorane (BTPP), tert-octylimino- tris(dimethylamino)phosphorane, 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2diazaphosphorine (BEMP), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2Λ5,4Λ5- catenadi(phosphazene), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2Λ5,4Λ5- catenadi(phosphazene), 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)- phosphoranylidenamino]-2Λ5,4Λ5-catenadi(phosphazene), 1-tert-octyl-4,4,4- tris(dimethylamino)-2,2-bis[tris(dimethylamino) phosphoranylidenamino]-2Λ5,4Λ5- catenadi(phosphazene), 2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane, and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane.

[0124] In some embodiments, the base is selected from the group consisting of 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3- tetramethylguanidine (TMG), quinuclidine, 2,2,6,6-tetramethylpiperidine (TMP), pempidine (PMP), tributylamine, triethylamine, 1,4-diazabicyclo[2.2.2]octan (TED), collidine, 2,6-lutidine (2,6-dimethylpyridine), 2-tert-butyl-1,1,3,3-tetramethyl-guanidine, N,N- dicyclohexylmethylamine, N,N-diethylaniline, N,N-diisopropyl-2-ethylbutylamine, N,N- diisopropylmethylamine, N,N-diisopropyl-3-pentylamine, N,N-dimethylaniline, 2,6-di-tert-butyl- 4-methylpyridine, N-ethyldiisopropylamine, 3,3,6,9,9-pentamethyl-2,10-diazabicyclo-(4.4.0)dec- 1-ene (PMDBD), 2,4,6-tri-tert-butylpyridine, tris(trimethylsilyl)amine, Butyllithium (n-BuLi), sec-butyllithium (sec-BuLi), tert-butyllithium (t-BuLi), lithium diisopropylamide (LDA), methyllithium (MeLi), potassium tert-butoxide, and sodium tert-butoxide.

[0125] In some embodiments, the base is selected from the group consisting of NaOH, KOH,Ba(OH)2, dimethylamine, triethylamine, diethylamine, ammonia, tetraethylammonium hydroxide, choline hydroxide, 2,2,6,6-tetramethylpiperidine, sodium bicarbonate, lithium bis(trimethylsilyl)amide, Mg(OH)2, tert-butylmagnesium chloride, diethylamine, Dabco®, copper(II) carbonate, hydrazine, barium carbonate, lithium tert-butoxide, ethylamine, lithium carbonate, sodium carbonate, potassium carbonate, methyllithium, hexyllithium, cesium hydroxide, sodium bicarbonate, rubidium carbonate, sodium bis(trimethylsilyl)amide, ammonium bicarbonate, 2-tert-butyl-1,1,3,3-tetramethylguanidine, ammonium hydroxide, calcium carbonate, 2,6-lutidine, tetramethylammonium hydroxide, tetrapropylammonium hydroxide, piperidine, strontium carbonate, potassium bis(trimethylsilyl)amide, methylamine, sodium ethoxide, zinc carbonate, KCl, potassium trimethylsilanolate, sodium tert-butoxide, lithium bis(trimethylsilyl)amide, tetrabutylammonium hydroxide, ethylmagnesium bromide, sodiumtrimethylsilanolate, potassium methoxide, tetramethylammonium hydroxide, butylmagnesium chloride, lithium 2,2,6,6-tetramethylpiperidide, ethylmagnesium chloride, 5- diazabicyclo[4.3.0]non-5-ene, potassium hydroxide, sodium tert-pentoxide, lithium amide, lithium methoxide, methylmagnesium iodide, isopropylmagnesium chloride, lithium dimethylamide, 2- tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, pentylmagnesium bromide, isobutylmagnesium bromide, hexylmagnesium bromide, tetrahexylammonium hydroxide, sodium ethoxide, ethyllithium, isopropyllithium, potassium tert-pentoxide, 2,8,9- triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane, N-ethyldiisopropylamine, 4- (dimethylamino)pyridine, lithium ethoxide, lithium methoxide, sodium tert-pentoxide, 1,5- diazabicyclo[4.3.0]non-5-ene, piperazine, 2,8,9-trimethyl-2,5,8,9-tetraaza-1- phosphabicyclo[3.3.3]undecane, tert-butyllithium, 2,8,9-triisopropyl-2,5,8,9-tetraaza-1- phosphabicyclo[3,3,3]undecane, N,N-diisopropylmethylamine, imino- tris(dimethylamino)phosphorane, lithium dicyclohexylamide, isobutyllithium, magnesium di-tert- butoxide, 4-piperidinopyridine, hexylmagnesium chloride, and morpholine.

[00126] In some embodiments, the base is selected from the group consisting of K3PO4, KOH,K2CO3, Na2CO3, Li2CO3, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2-tert-butyl-1,1,3,3- tetramethylguanidine, triethylamine, piperidine, and DMAP.

[00127] According to the present disclosure, any suitable solvent or a mixture of two or moresolvents can be used. In some embodiments, the solvent is a mixture of 2-methyltetrahydrofuran (2-Me-THF) and water. In some embodiments, the solvent is an alcohol. Suitable alcohols that can be used as a solvent include, but are not limited to, MeOH, EtOH, and i-PrOH.

[00128] In some embodiments, the phosphorus containing compound has a Formula (IIa):

[00129] In some embodiments, the phosphorus containing compound has a Formula (IIb):where Z1is independently at each occurrence selected from the group consisting of -OH, -NH2, - C(O)OMe, -OC(O)Me, -C(O)Me, -O-Si(Me)2(t-Bu), and pyridinyl.

[0130] In some embodiments, the phosphorus containing compound is selected from the groupconsisting of: , , , ,

[0131] According to the present disclosure, the step of reacting the nickel salt with thephosphorus containing compound in a presence of a base can be carried out at a temperature from about 20°C to about 150°C, from about 30°C to about 140°C, from about 40°C to about 130°C, from about 50°C to about 120°C, from about 50°C to about 110°C, from about 50°C to about 100°C, from about 50°C to about 90°C, from about 50°C to about 80°C, from about 55°C to about 75°C, from about 60°C to about 75°C, or from about 65°C to about 75°C.

[0132] According to the present disclosure, the step of reacting the nickel salt with thephosphorus containing compound in a presence of a base can be carried out for from about 15 min to about 60 min, from about 25 min to about 50 min, for from about 35 min to about 60 min, or from about 25 min to about 45 min.

[0133] In a further aspect, provided herein is a composition comprising:a nickel salt comprising NiX2, whereinX is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2;and a phosphorus containing compound of Formula (II):wherein Y is absent or, if present, is –C(R3)(R4)- or -O-; Z is selected from the group consisting of -OH, -OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O- Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R3is H or C1-6 alkyl; R4is H or C1-6 alkyl; R5is independently at each occurrence C1-6alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4.

[00134] In some embodiments, the composition can further comprise a base.

[0135] In some embodiments, the composition can further comprise a solvent.

[0136] In some embodiments, X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituentsselected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2.

[0137] Any of the above-described nickel salts, phosphorus containing compound of Formula(II), bases, and salts can be used according to the above aspect of the present disclosure.

[0138] In another aspect, provided herein is a compound of Formula (I):wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently at each occurrence C1-6 alkyl; a is 0, 1, or 2;b is 1 or 2; and c is 1, 2, 3, or 4.

[00139] In some embodiments, X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2. Methods of Use

[00140] The compounds and compositions can be used to prepare a compound of Formula (III):as described herein.

[00141] In one aspect, provided herein is a process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5. This process comprises: providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formproviding a compound of Formula (I):wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6alkyl, and N(C1-6alkyl)2;Y is independently at each occurrence absent or, if present, is – C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 timeswith one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the compound of Formula (I) under conditions effective to produce the compound of Formula (III).

[00142] In some embodiments, X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2.

[00143] In some embodiments, the compound of Formula (I) has a Formula (Ia):

[00144] In some embodiments, the compound of Formula (Ia) is selected from the groupconsisting of:

[00145] In some embodiments, the compound of Formula (Ia) is selected from the groupconsisting of:

[00146] According to the present disclosure, the step of reacting the compound of Formula (IV)with the compound of Formula (V) in the presence of the compound of Formula (I) can be carriedout at a temperature from about 60°C to about 100°C, from about 65°C to about 100°C, from about 65°C to about 95°C, from about 65°C to about 90°C, from about 70°C to about 90°C, or from about 75°C to about 85°C.

[00147] According to the present disclosure, the step of reacting the compound of Formula (IV)with the compound of Formula (V) in the presence of the compound of Formula (I) can be carried out for from about 0.5 hours to about 16 hours, for from about 1 hour to about 14 hours, for from about 2 hours to about 12 hours, for from about 3 hours to about 10 hours, or for from about 5 hours to about 8 hours.

[00148] In some embodiments, the step of providing a compound of Formula (I) comprises:providing a nickel salt comprising NiX2; providing a phosphorus containing compound of Formula (II):reacting the nickel salt and the phosphorus containing compound in a solvent in the presence of a base under conditions effective to form a compound of Formula (I).

[00149] In another aspect, provided herein is a process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3;m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5. This process comprises: providing a compound of Formula (VI)wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6 alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1-6alkyl, -C(O)C1-6alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6alkyl; R5is independently selected at each occurrence C1-6alkyl; a is 0, 1, or 2;b is 1 or 2; and c is 1, 2, 3, or 4, providing a compound of Formula (IV)wherein Hal is halogen; and reacting the compound of Formula (VI) with the compound of Formula (IV) under conditions effective to produce the compound of Formula (III).

[00150] In some embodiments, X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2.

[00151] In some embodiments, the step of providing a compound of Formula (VI) comprises:providing a compound of Formula (Ia)providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formreacting the compound of Formula (Ia) with the compound of Formula (V) under conditions effective to produce the compound of Formula (VI).

[0152] In some embodiments, the compound of Formula (Ia) is selected from the groupconsisting of:

[00153] In some embodiments, the compound of Formula (Ia) is selected from the groupconsisting of:

[0154] According to the present disclosure, the step of reacting the compound of Formula (VI)with the compound of Formula (IV) can be carried out at a temperature from about 60°C to about 100°C, from about 65°C to about 100°C, from about 65°C to about 95°C, from about 65°C to about 90°C, from about 70°C to about 90°C, or from about 75°C to about 85°C.

[00155] According to the present disclosure, the step of reacting the compound of Formula (VI)with the compound of Formula (IV) can be carried out for from about 0.5 hours to about 16 hours, for from about 1 hour to about 14 hours, for from about 2 hours to about 12 hours, for from about 3 hours to about 10 hours, or for from about 5 hours to about 8 hours.

[00156] In some embodiments, the step of providing a compound of Formula (Ia) comprises:providing a nickel salt comprising NiX2; providing a phosphorus containing compound of Formula (II): andreacting the nickel salt and the phosphorus containing compound in a solvent in the presence of a base under conditions effective to form a compound of Formula (Ia).

[00157] In a further aspect, provided herein is a process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3;m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5. This process comprises: providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formproviding a nickel salt comprising NiX2, wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6 alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; providing a phosphorus containing compound of Formula (II):whereinY is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, - C(O)NC1-6 alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the nickel salt and the compound of Formula (II) under conditions effective to produce the compound of Formula (III).

[0158] The exemplary embodiments provided below may be applied to any of the above-mentioned processes for making the compound of Formula (III).

[0159] In some embodiments, X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2.

[0160] In some embodiments,is selected from a group consisting of phenyl, pyridinyl,pyrimidinyl, pyrazolyl, quinolinyl, benzofuranyl, and indolyl. For example,is selected from a group consisting of phenyl, pyridinyl, pyrimidinyl, 1H-pyrazolyl, quinolinyl, benzofuranyl, and 1H-indolyl.

[0161] In some embodiments,is selected from a group consisting of phenyl, pyridinyl,pyrimidinyl, pyrazolyl, quinolinyl, benzofuranyl, and indolyl. For example,is selected from a group consisting of phenyl, pyridinyl, pyrimidinyl, 1H-pyrazolyl, quinolinyl, benzofuranyl, and 1H-indolyl.

[0162] In some embodiments, the compound of Formula (IV) is selected from a group consistingof: , ,

[0163] In some embodiments, the compound of Formula (V) is selected from a group consistingof:

[00164] In some embodiments, the compound of Formula (III) is selected from a group consistingof:

[0165] According to the present disclosure, the nickel salt comprises NiCl2, NiBr2, Ni(OAc)2,Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4, Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o-Tol)]2. In some embodiments, the nickel salt comprises NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, or Ni(o-totyl)Cl. In some embodiments, the nickel salt is selected from the group consisting of NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4, Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o-Tol)]2 or hydrate or solvate thereof. In some embodiments, the nickel salt is selected from the group consisting of NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, and Ni(o- totyl)Cl, or hydrate or solvate thereof. In some embodiments, the nickel salt is selected from the group consisting of NiCl2*6H2O, nickel(II) chloride ethylene glycol dimethyl ether complex, and nickel(II) bromide ethylene glycol dimethyl ether complex.

[0166] According to the present disclosure, any suitable base can be used, such as monomericphosphazene bases, dimeric phosphazene bases, tetrameric phosphazene bases, Verkade’s bases, amine based traditional bases, lithium based traditional bases, and potassium based traditional bases. For example, N’-tert-Butyl-N,N,N’,N’,N’’,N’’-hexamethylphosphorimidic triamide, tert- butylimino-tri(pyrrolidino)phosphorane (BTPP), tert-octylimino- tris(dimethylamino)phosphorane, 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2 diazaphosphorine (BEMP), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2Λ5,4Λ5- catenadi(phosphazene), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2Λ5,4Λ5- catenadi(phosphazene), 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)- phosphoranylidenamino]-2Λ5,4Λ5-catenadi(phosphazene), 1-tert-octyl-4,4,4- tris(dimethylamino)-2,2-bis[tris(dimethylamino) phosphoranylidenamino]-2Λ5,4Λ5-catenadi(phosphazene), 2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane, and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane.

[0167] In some embodiments, the base is selected from the group consisting of 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3- tetramethylguanidine (TMG), quinuclidine, 2,2,6,6-tetramethylpiperidine (TMP), pempidine (PMP), tributylamine, triethylamine, 1,4-diazabicyclo[2.2.2]octan (TED), collidine, 2,6-lutidine (2,6-dimethylpyridine), 2-tert-butyl-1,1,3,3-tetramethyl-guanidine, N,N- dicyclohexylmethylamine, N,N-diethylaniline, N,N-diisopropyl-2-ethylbutylamine, N,N- diisopropylmethylamine, N,N-diisopropyl-3-pentylamine, N,N-dimethylaniline, 2,6-di-tert-butyl- 4-methylpyridine, N-ethyldiisopropylamine, 3,3,6,9,9-pentamethyl-2,10-diazabicyclo-(4.4.0)dec- 1-ene (PMDBD), 2,4,6-tri-tert-butylpyridine, tris(trimethylsilyl)amine, Butyllithium (n-BuLi), sec-butyllithium (sec-BuLi), tert-butyllithium (t-BuLi), lithium diisopropylamide (LDA), methyllithium (MeLi), potassium tert-butoxide, and sodium tert-butoxide.

[0168] In some embodiments, the base is selected from the group consisting of NaOH, KOH,Ba(OH)2, dimethylamine, triethylamine, diethylamine, ammonia, tetraethylammonium hydroxide, choline hydroxide, 2,2,6,6-tetramethylpiperidine, sodium bicarbonate, lithium bis(trimethylsilyl)amide, Mg(OH)2, tert-butylmagnesium chloride, diethylamine, Dabco®, copper(II) carbonate, hydrazine, barium carbonate, lithium tert-butoxide, ethylamine, lithium carbonate, sodium carbonate, potassium carbonate, methyllithium, hexyllithium, cesium hydroxide, sodium bicarbonate, rubidium carbonate, sodium bis(trimethylsilyl)amide, ammonium bicarbonate, 2-tert-butyl-1,1,3,3-tetramethylguanidine, ammonium hydroxide, calcium carbonate, 2,6-lutidine, tetramethylammonium hydroxide, tetrapropylammonium hydroxide, piperidine, strontium carbonate, potassium bis(trimethylsilyl)amide, methylamine, sodium ethoxide, zinc carbonate, KCl, potassium trimethylsilanolate, sodium tert-butoxide, lithium bis(trimethylsilyl)amide, tetrabutylammonium hydroxide, ethylmagnesium bromide, sodium trimethylsilanolate, potassium methoxide, tetramethylammonium hydroxide, butylmagnesium chloride, lithium 2,2,6,6-tetramethylpiperidide, ethylmagnesium chloride, 5- diazabicyclo[4.3.0]non-5-ene, potassium hydroxide, sodium tert-pentoxide, lithium amide, lithium methoxide, methylmagnesium iodide, isopropylmagnesium chloride, lithium dimethylamide, 2- tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, pentylmagnesiumbromide, isobutylmagnesium bromide, hexylmagnesium bromide, tetrahexylammonium hydroxide, sodium ethoxide, ethyllithium, isopropyllithium, potassium tert-pentoxide, 2,8,9- triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane, N-ethyldiisopropylamine, 4- (dimethylamino)pyridine, lithium ethoxide, lithium methoxide, sodium tert-pentoxide, 1,5- diazabicyclo[4.3.0]non-5-ene, piperazine, 2,8,9-trimethyl-2,5,8,9-tetraaza-1- phosphabicyclo[3.3.3]undecane, tert-butyllithium, 2,8,9-triisopropyl-2,5,8,9-tetraaza-1- phosphabicyclo[3,3,3]undecane, N,N-diisopropylmethylamine, imino- tris(dimethylamino)phosphorane, lithium dicyclohexylamide, isobutyllithium, magnesium di-tert- butoxide, 4-piperidinopyridine, hexylmagnesium chloride, and morpholine.

[00169] In some embodiments, the base is selected from the group consisting of K3PO4, KOH,K2CO3, Na2CO3, Li2CO3, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2-tert-butyl-1,1,3,3- tetramethylguanidine, triethylamine, piperidine, and DMAP.

[00170] According to the present disclosure, any suitable solvent or a mixture of two or moresolvents can be used. In some embodiments, the solvent is a mixture of 2-methyltetrahydrofuran (2-Me-THF) and water. In some embodiments, the solvent is an alcohol. Suitable alcohols that can be used as a solvent include, but are not limited to, MeOH, EtOH, and i-PrOH.

[00171] In some embodiments, the phosphorus containing compound has a Formula (IIa):

[00172] In some embodiments, the phosphorus containing compound has a Formula (IIb):where Z1is independently at each occurrence selected from the group consisting of -OH, -NH2, - C(O)OMe, -OC(O)Me, -C(O)Me, -O-Si(Me)2(t-Bu), and pyridinyl.

[00173] In some embodiments, the phosphorus containing compound is selected from the groupconsisting of:, ,

[0174] According to the present disclosure, the step of reacting the nickel salt with the compoundof Formula (II) can be carried out at a temperature from about 20°C to about 150°C, from about 30°C to about 140°C, from about 40°C to about 130°C, from about 50°C to about 120°C, from about 50°C to about 110°C, from about 50°C to about 100°C, from about 50°C to about 90°C, from about 50°C to about 80°C, from about 55°C to about 75°C, from about 60°C to about 75°C, or from about 65°C to about 75°C.

[0175] According to the present disclosure, the step of reacting the nickel salt with the compoundof Formula (II) can be carried out for from about 15 min to about 60 min, from about 25 min to about 50 min, for from about 35 min to about 60 min, or from about 25 min to about 45 min.

[0176] According to the present disclosure, the step of reacting the compound of Formula (IV)with the compound of Formula (V) in the presence of the nickel salt and the compound of Formula (II) can be carried out at a temperature from about 20°C to about 150°C, from about 30°C to about 140°C, from about 40°C to about 130°C, from about 50°C to about 120°C, from about 50°C to about 110°C, from about 50°C to about 100°C, from about 50°C to about 90°C, from about 50°C to about 80°C, from about 55°C to about 75°C, from about 60°C to about 75°C, or from about 65°C to about 75°C.

[0177] According to the present disclosure, the step of reacting the compound of Formula (IV)with the compound of Formula (V) in the presence of the nickel salt and the compound of Formula(II) can be carried out for from about 15 min to about 60 min, from about 25 min to about 50 min, for from about 35 min to about 60 min, or from about 25 min to about 45 min.

[0178] According to the present disclosure, the amount of nickel salt that can be used from about0.01 mol% to about 5 mol%, from about 0.01 mol% to about 4 mol%, from about 0.01 mol% to about 3 mol%, from about 0.01 mol% to about 2 mol%, from about 0.02 mol% to about 2 mol%, from about 0.03 mol% to about 2 mol%, or from about 0.03 mol% to about 1 mol%.

[0179] Preparation of compounds can involve the protection and deprotection of variouschemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Greene Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons: New York, 2006. EXAMPLES

[0180] The following examples are provided to further describe some of the embodimentsdisclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments. General Methods

[0181] All air- and moisture-sensitive reactions and manipulations were performed undernitrogen in a glovebox or using conventional Schlenk techniques. Common solvents (e.g., THF) were dried and deoxygenated by passing through alumina in a solvent purification system. Deuterated solvents were purchased from commercial sources. Deuterated solvents used in the glovebox (C6D6and C7D8) were degassed using three freeze-pump-thaw cycles and stored over activated molecular sieve for 3 days before use. Unless otherwise specified, reagents were purchased from commercial sources. Ni(acac)2, Ni(cod)2, NiCl2•6H2O, and PPh2Me (neat, 97%) were purchased from commercial sources. Other phosphine ligands and organometallic compounds were synthesized following the procedures described below.

[0182] NMR spectra were recorded on a Bruker Avance 400 spectrometer (400.30 MHz for 1H,162.04 MHz for31P and 100.67 MHz for13C), and a Bruker Avance 500 spectrometer (500.20 MHz for1H and 202.49 MHz for31P). Unless otherwise noted, chemical shifts are reported in ppm at RT.1H chemical shifts are referenced to residual proteo-solvent peak at 7.26 ppm (CHCl3), 7.16 ppm (C6D5H), 4.79 ppm (DHO), 2.50 ppm ((CD2H)S(O)(CD3)) and 2.08 ppm (C7D7H);13C chemical shifts are referenced to 128.1 ppm (C6D6),77.1 ppm (CDCl3), 29.8 ppm ((CD3)2SO) and20.4 ppm (C7D8).1H and13C chemical shifts are reported relative to tetramethylsilane (TMS), and 31P chemical shifts are reported relative to 85% H3PO4 (aq).

[00183] High resolution mass spectra (HRMS) were recorded on an Agilent 6224 TOF LC / MS(APCI source). GC data were obtained using a Shimadzu GC-2010 with a Shimadzu SH-Rxi-5Sil MS column. GC data for kinetic experiments and %yield determination was obtained using a Shimadzu GC-2010 Plus with a Restek Rxi-5MS column (L 15 m, ID 0.25, DF 0.25). Example 1. Synthesis and Catalytic Activity of Phosphine Ligands

[00184] All phosphine syntheses were conducted using conventional Schlenk techniques.Characterization details for new phosphine ligands PPh2CH2CH2CH2OC(O)Me (S6) and PPh2CH2CH2CH2CH2OSiMe2But(S8) are provided below. All phosphines were dried under vacuum before use.

[00185] To a solution of diphenylphosphine (2.00 g, 10.7 mmol, 1.0 equiv) and 3-chloropropanol(1.02 g, 10.7 mmol, 1.0 equiv) in THF (20 mL) was added n-butyl lithium (10.7 mL, 2.00 M in hexanes, 21.5 mmol, 2.0 equiv) dropwise at 0 °C. The mixture was stirred for 1 hour at room temperature (rt). Water (10 mL) was added, and the mixture was evaporated, and the residue was extracted in CH2Cl2 (2 x 10 mL). The suspension was filtered, and the solution evaporated. The remaining residue was further purified via column chromatography (hexane:CH2Cl21:1→CH2Cl2:EtOAc 7:3) to yield the product (2.06 g, 8.43 mmol, 78%) as a white solid. The NMR data was consistent with literature reports (Grasset et al., “Titanium Complexes with Functional Alkoxido Ligands for Selective Ethylene Dimerization – A High Throughput Experimentation Approach,” ChemCatChem 13(9):2167–2178 (2021), which is hereby incorporated by reference in its entirety).

[00186] 1H NMR (400.30 MHz, CDCl3) δ: 7.44 (ddt, J = 7.5, 5.4, 2.6 Hz, 4H, Ho), 7.37 – 7.31(m, 6H, Hm&Hp), 3.72 (t, J = 6.4 Hz, 2H, CH2O), 2.18 – 2.11 (m, 2H, PCH2), 1.79 – 1.60 (m, 3H, CH2 & OH, OH signal is broad and overlapped with CH2 signals).31P{1H} NMR (162.04 MHz, CDCl3) δ: -15.5 (s).13C{1H} NMR (100.67 MHz, CDCl3) δ: 138.1 (d, J = 11Hz, Cipso), 132.9 (d, J = 18 Hz, Co), 128.9 (s, Cp), 128.6 (d, J = 7 Hz, Cm), 63.7 (d, J = 13 Hz, CH2O), 29.1 (d, J = 15Hz, PCH2), 24.3 (d, J = 10 Hz, CH2). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C15H18OP 245.11, found 245.11.

[00187] To a solution of diphenylphosphine (1.00 g, 5.37 mmol, 1.0 equiv) and 2-chloroethanol(0.432 g, 5.37 mmol, 1.0 equiv) in THF (20 mL) was added n-butyl lithium (5.91 mL, 2.00 M in hexanes, 11.8 mmol, 2.2 equiv). The mixture was stirred for 3 hours at 0 °C. The THF was evaporated, and the residue was extracted in CH2Cl2(2 x 20 mL). The resulting solution was treated with an excess of solid NH4Cl in CH2Cl2. The suspension was filtered, and the solution was evaporated. The remaining residue was extracted with Et2O (2 x 15 mL), and the volatiles were removed. The crude residue was further purified via column chromatography (hexane:CH2Cl21:1→CH2Cl2:EtOAc 7:3) to yield the product (0.605 g, 2.63 mmol, 24%) as a colorless oil. The NMR data was consistent with literature reports (Grasset et al., “Titanium Complexes with Functional Alkoxido Ligands for Selective Ethylene Dimerization – A High Throughput Experimentation Approach,” ChemCatChem 13(9):2167–2178 (2021), which is hereby incorporated by reference in its entirety).

[00188] 1H NMR (400.30 MHz, CDCl3) δ: 7.44 (ddt, J = 7.5, 5.3, 2.4 Hz, 4H, Ho), 7.37 – 7.30(m, 6H, Hm&Hp), 3.80 (dtd, J = 9.6, 7.2, 5.5 Hz, 2H, CH2O), 2.40 (t, J = 7.2 Hz, 2H, PCH2), 1.54 (s, 1H, OH).31P{1H} NMR (162.04 MHz, CDCl3) δ: -24.1 (s).13C{1H} NMR (100.67 MHz, CDCl3) δ: 138.1 (d, J = 12 Hz, Cipso), 132.9 (d, J = 19 Hz, Co), 128.9 (s, Cp), 128.7 (d, J = 7 Hz, Cm), 60.4 (d, J = 22 Hz, CH2O), 32.4 (d, J = 13 Hz, PCH2). MS (ESI-TOF, CH3OH) m / z: [M + H]+calculated for C14H15OP 231.09, found 231.09.

[00189] To a solution of diphenylphosphine (0.943 g, 5.07 mmol, 1.0 equiv) and 4-chlorobutanol(0.550 g, 5.07 mmol, 85% mixed with HCl, 1.0 equiv) in THF (20 mL) was added n-butyl lithium (5.57 mL, 2.00 M in hexanes, 11.1 mmol, 2.2 equiv) dropwise at 0 °C. The mixture was stirred for 3 hours at rt. Water (10 mL) was added, and the mixture was evaporated, and the residue was extracted in CH2Cl2(2 x 10 mL). The suspension was filtered, and the solution evaporated. Theremaining residue was further purified via column chromatography (hexane:CH2Cl21:1→CH2Cl2:EtOAc 7:3) to yield the product (0.811 g, 3.14 mmol, 62%) as a colourless oil. The NMR data was consistent with literature reports (Grasset et al., “Titanium Complexes with Functional Alkoxido Ligands for Selective Ethylene Dimerization – A High Throughput Experimentation Approach,” ChemCatChem 13(9):2167–2178 (2021), which is hereby incorporated by reference in its entirety).

[00190] 1H NMR (400.30 MHz, CDCl3) δ: 7.43 (tt, J = 7.2, 2.0 Hz, 4H, Ho), 7.37 – 7.28 (m, 6H,Hm&Hp), 3.61 (t, J = 6.5 Hz, 2H, H4), 2.11 – 2.05 (m, 2H, H1), 1.79 – 1.65 (m, 3H, H3&OH, OH signal is broad and overlapped with CH2 signals), 1.58 – 1.47 (m, 2H, H2).31P{1H} NMR (162.04 MHz, CDCl3) δ: -16.3 (s).13C{1H} NMR (100.67 MHz, CDCl3) δ: 138.8 (d, J = 13 Hz, Cipso), 132.8 (d, J = 18 Hz, Co), 128.6 (s, Cp), 128.5 (d, J = 7 Hz, Cm), 62.4 (s, C4), 34.2 (d, J = 12 Hz, C1), 27.9 (d, J = 11 Hz, C2), 22.4 (d, J = 17 Hz, C3). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C16H20OP 259.12, found 259.12.

[00191] To a mixture of neat diphenylphosphine (0.833 g, 4.48 mmol, 1.0 equiv) and but-3-en-2-one (0.377 g, 5.37 mmol, 1.2 equiv), 2-MeTHF (1.81 mL, 17.9 mmol, 4.0 equiv) was added. The mixture was stirred for 16 hours at rt. The mixture was evaporated, and the residue was extracted in EtOAc (2 x 2 mL). The suspension was filtered, and the solution evaporated. The remaining residue was then purified by flash silica gel chromatography using a gradient from hexane to hexane:EtOAc 8:2 to obtain the product (0.850 g, 3.32 mmol, 74%) as a colorless oil. The NMR data was consistent with literature reports (Bissessar et al., “Catalyst-Free Hydrophosphination of Alkenes in Presence of 2-Methyltetrahydrofuran: A Green and Easy Access to a Wide Range of Tertiary Phosphines,” RSC Adv. 9(47):27250–27256 (2019), which is hereby incorporated by reference in its entirety).

[00192] 1H NMR (400.30 MHz, C6D6) δ: 7.46 – 7.32 (m, 4H, Ho), 7.13 – 6.98 (m, 6H, Hm&Hp),2.32 – 2.23 (m, 2H, CH2CO), 2.19 – 2.07 (m, 2H, PCH2), 1.50 (s, 3H, COCH3).31P{1H} NMR (162.04 MHz, C6D6) δ: -15.7 (s).13C{1H} NMR (100.67 MHz, C6D6) δ: 205.2 (d, J = 12 Hz, C=O), 139.2 (d, J = 14 Hz, Cipso), 133.1 (d, J = 19 Hz, Co), 128.9 (s, Cp), 128.8 (d, J = 7 Hz, Cm), 39.6 (d,J = 18 Hz, CH2CO), 29.1 (s, COCH3), 21.8 (d, J = 12 Hz, PCH2). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C16H18OP 257.11, found 257.11.

[00193] To neat diphenylphosphine (0.909 g, 4.88 mmol, 1.0 equiv) 2-methyltetrahydrofuran(0.403 mL, 4.0 equiv) and methyl acrylate (0.462 g, 5.37 mmol, 1.1 equiv) were added. The mixture was stirred for 16 hours at rt. The mixture was evaporated under vacuum to remove extra methyl acrylate. The crude product was obtained (1.12 g, 4.08 mmol, 84%) as a colorless oil, with 94% purity determined by NMR (6% consisting of the branched product S3’). It was used without further purification. The crude product could be purified by flash silica gel chromatography using a gradient from hexane to hexane:EtOAc 8:2, yielding the pure linear product. The NMR data was consistent with literature reports (Bissessar et al., “Catalyst-Free Hydrophosphination of Alkenes in Presence of 2-Methyltetrahydrofuran: A Green and Easy Access to a Wide Range of Tertiary Phosphines,” RSC Adv.9(47):27250–27256 (2019), which is hereby incorporated by reference in its entirety).

[00194] 1H NMR (400.30 MHz, C6D6) δ: 7.40 – 7.31 (m, 4H, Ho), 7.08 – 6.99 (m, 6H, Hm&Hp),3.27 (s, 3H, CH3), 2.34 – 2.26 (m, 4H, CH2).31P{1H} NMR (162.04 MHz, C6D6) δ: -15.9 (s). 13C{1H} NMR (100.67 MHz, C6D6) δ: 172.9 (d, J = 15 Hz, C=O), 138.8 (d, J = 14 Hz, Cipso), 133.1 (d, J = 19 Hz, Co), 128.9 (s, Cp), 128.8 (d, J = 7 Hz, Cm), 51.2 (s, CH3), 30.8 (d, J = 20 Hz, CH2CO), 23.6 (d, J = 13 Hz, PCH2). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C16H18O2P 273.10, found 273.11.

[00195] To a solution of diphenylphosphine (1.20 g, 6.46 mmol, 1.0 equiv) and 3-chloropropanol(0.520 g, 6.46 mmol, 1.0 equiv) in THF (20 mL) was added n-butyl lithium (6.5 mL, 2.0 M in hexanes, 12.9 mmol, 2.0 equiv). The mixture was stirred for 3 hours at 0 °C. The THF was evaporated, and the residue was treated with EtOAc and stirred for 1 hour. The suspension was extracted with water. The organic layer was evaporated. The crude residue was further purified viacolumn chromatography (hexane:EtOAc 9:1→ hexane:EtOAc 7 / 3) to yield the product (0.628 g, 2.31 mmol, 36%) as a colorless oil.

[00196] 1H NMR (400.30 MHz, CDCl3) δ: 7.45 (tt, J = 7.5, 2.2 Hz, 4H, Ho), 7.38 – 7.30 (m, 6H,Hm&Hp), 4.27 – 4.16 (m, 2H, CH2O), 2.44 (dd, J = 8.0, 7.1 Hz, 2H, PCH2), 1.95 (s, 3H, CH3). 31P{1H} NMR (162.04 MHz, CDCl3) δ: -22.4 (s).13C{1H} NMR (100.67 MHz, CDCl3) δ: 171.0 (s, C=O), 137.7 (d, J = 12 Hz, Cipso), 132.8 (d, J = 19 Hz, Co), 129.0 (s, Cp), 128.7 (d, J = 7 Hz, Cm), 62.2 (d, J = 24 Hz, CH2O), 28.0 (d, J = 14 Hz, PCH2), 21.0 (s, CH3). MS (ESI-TOF, CH3CN) m / z: [M + H]+calcd for C16H18O2P 273.10, found 273.10.

[00197] This compound can be synthesized using another literature procedure, and the NMR datafor S4 was consistent with the literature reports (Turner et al., “The Thermal Stability of (2- Substituted Ethyl)Diphenylphosphines. The Potent Neighboring Group Effect of the Trivalent Phosphorus Atom1,” J. Org. Chem. 30(12):4031–4034 (1965), which is hereby incorporated by reference in its entirety). The literature also reports the thermal decomposition of this phosphine to produce s-ethylenebis(diphenylphosphine). A proposed mechanism suggests that these decompositions occur through the initial formation of a 1,1-diphenylphosphoniacyclopropane salt intermediate, which formed due to the anchimeric effect of the trivalent phosphorus atom. The rapid formation of a brown solid from a large amount of neat phosphine at rt was observed. Thus, a small amount of phosphine was placed in a small vial and stored in the freezer, which slowed the thermal decomposition.

[00198] This compound was isolated from the reaction mixture of synthesis S4. The crude residuewas further purified via column chromatography (hexane:EtOAc 3:1) to yield the product (50.0 mg) as a colorless oil. The NMR data was consistent with the literature reports (Ipaktschi et al., “Synthese Und Charakterisierung von Hydridotrispyrazolylborat-Heterobimetall-Komplexen Mit Titan Und Molybdän,” J. Organomet. Chem. 434(3):287–302 (1992), which is hereby incorporated by reference in its entirety).

[00199] 1H NMR (400.30 MHz, CDCl3) δ: 7.44 (ddt, J = 7.6, 5.5, 2.8 Hz, 4H, Ho), 7.34 (ddt, J =5.6, 2.3, 1.4 Hz, 6H, Hm&Hp), 3.89 – 3.84 (m, 2H, H3), 3.80 (dt, J = 9.7, 7.2 Hz, 2H, H2), 3.69 – 3.64 (m, 2H, H4), 2.41 (t, J = 7.2 Hz, 2H, H1), 2.02 (br s, 1H, OH).31P{1H} NMR (162.04 MHz,CDCl3) δ: -23.6 (s).13C{1H} NMR (100.67 MHz, CDCl3) δ: 137.6 (d, J = 12 Hz, Cipso), 132.9 (d, J = 19 Hz, Co), 129.0 (s, Cp), 128.7 (d, J = 7 Hz, Cm), 63.1 (s, C3), 60.2 (d, J = 21.6 Hz, C2), 47.1 (s, C4), 32.3 (d, J = 12 Hz, C1). MS (ESI-TOF, CH3OH) m / z: [M + H]+calcd for C16H20O2P 275.12, found 275.11.

[00200] To a solution of diphenylphosphine (2.00 g, 10.7 mmol, 1.0 equiv) and 3-chloropropanol(1.02 g, 10.7 mmol, 1.0 equiv) in THF (20 mL) was added n-butyl lithium (10.7 mL, 2.0 M in hexanes, 21.5 mmol, 2.0 equiv). The mixture was stirred for 3 hours at 0 °C. The THF was evaporated, and the residue was treated with EtOAc and then stirred for 1 hour. The suspension was extracted by H2O. The organic layer was evaporated. The crude residue was further purified via column chromatography (hexane:EtOAc 9:1→ hexane:EtOAc 7:3) to yield the product (1.80 g, 6.30 mmol, 59%) as a colorless oil.

[00201] 1H NMR (400.30 MHz, CDCl3) δ: 7.46 – 7.40 (m, 4H, Ho), 7.39 – 7.29 (m, 6H, Hm&Hp),4.12 (t, J = 6.5 Hz, 2H, CH2O), 2.13 – 2.07 (m, 2H, PCH2), 2.04 (s, 3H, CH3), 1.82 – 1.70 (m, 2H, CH2).31P{1H} NMR (162.04 MHz, CDCl3) δ: -16.5 (s).13C{1H} NMR (100.67 MHz, CDCl3) δ: 171.1 (s, C=O), 138.4 (d, J = 13 Hz, Cipso), 132.8 (d, J = 19 Hz, Co), 128.8 (s, Cp), 128.6 (d, J = 7 Hz, Cm), 65.0 (d, J = 14 Hz, CH2O), 25.4 (d, J = 17 Hz, PCH2), 24.5 (d, J = 12 Hz, CH2), 21.1 (s, CH3). HRMS (ESI-TOF, CH3CN) m / z: [M + H]+calcd for C17H19O2P 287.1195, found 287.1171.

[00202] In a round-bottomed flask, solid tert-butyldimethylsilyl chloride (2.15 g, 14.3 mmol, 1.0equiv) was dissolved in dry CH2Cl2(50 mL) at 0 °C using an ice bath.4-Chlorobutanol (1.55 g, 14.3 mmol, 85% mixed with HCl, 1.0 equiv) was added dropwise to the reaction mixture, and stirred at 0 °C for 30 min. After that, solid imidazole (1.12 g, 16.4 mmol, 1.2 equiv) was added to the flask and further stirred at 0 °C for 1.5 h. The reaction mixture was filtered through a frit, and the filtrate was concentrated under vacuum, and the resulting translucent oil was stored at -35oCovernight. Hexanes (30 mL) was then added, and the suspension was passed through a Celite / MgSO4 plug over a fine frit. The filtrate was concentrated under reduced pressure to give a colorless, transparent oil (2.65 g, 11.9 mmol, 83%). This compound is commercially available, and can be prepared by the literature procedure (Roach et al., “ Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent κ-OR Agonist,” ACS Cent. Sci. 3(12):1329–1336 (2017), which is hereby incorporated by reference in its entirety).

[00203] 1H NMR (400.30 MHz, CDCl3) δ: 3.64 (t, J = 6.1 Hz, 2H, OCH2), 3.57 (t, J = 6.7 Hz,2H, ClCH2), 1.85 (ddt, J = 9.0, 8.2, 6.5 Hz, 2H, CH2), 1.70 – 1.62 (m, 2H, CH2), 0.89 (s, 9H, But), 0.05 (s, 6H, CH3). The1H data was comparable with the literature report (Roach et al., “ Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent κ-OR Agonist,” ACS Cent. Sci. 3(12):1329–1336 (2017), which is hereby incorporated by reference in its entirety). Synthesis of PPh2CH2CH2CH2CH2OSiMe2But(S8)

[00204] To a solution of diphenylphosphine (2.03 g, 10.9 mmol, 1.0 equiv) and (4-chlorobutoxy)(1,1-dimethylethyl)dimethyl-silane (S7, 2.42 g, 10.9 mmol, 1.0 equiv) in THF (20 mL) was added n-butyl lithium (5.5 mL, 2.00 M in hexanes, 11.0 mmol, 1 equiv) dropwise at 0 °C. The mixture was stirred for 3 hours at rt. Water (10 mL) was added, and the mixture was evaporated, and the residue was extracted in CH2Cl2 (2 x 10 mL). The suspension was filtered, and the solution was evaporated. The remaining residue was further purified via column chromatography (hexane:CH2Cl21:1→CH2Cl2:EtOAc 7:3) to yield the product (1.81 g, 4.83 mmol, 45%) as a colorless oil.

[00205] 1H NMR (400.30 MHz, CDCl3) δ: 7.43 (ddt, J = 7.3, 5.2, 2.8 Hz, 4H, Ho), 7.38 – 7.29(m, 6H, Hm&Hp), 3.60 (t, J = 6.3 Hz, 2H, H4), 2.12 – 2.01 (m, 2H, H1), 1.65 (p, J = 6.6 Hz, 2H, H3), 1.56 – 1.45 (m, 2H, H2), 0.86 (s, 9H, But), 0.02 (s, 6H, CH3).31P{1H} NMR (162.04 MHz, CDCl3) δ: -16.0 (s).13C{1H} NMR (100.67 MHz, CDCl3) δ: 139.1 (d, J = 13 Hz, Cipso), 132.9 (d, J = 18 Hz, Co), 128.6 (s, Cp), 128.5 (d, J = 7 Hz, Cm), 62.8 (s, C4), 34.4 (d, J = 13 Hz, d, C1), 28.0 (d, J = 11 Hz, C2), 26.1 (s, SiC(CH3)3), 22.5 (d, J = 17 Hz, C3), 18.4 (s, SiC(CH3)3), -5.2 (s,SiCH3). HRMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C22H34OPSi 373.2111, found 373.2134.

[0206] 1-(Diphenylphosphino)-1-methanol: Diphenylphosphine (2.00 g, 10.7 mmol, 1.0 equiv)and paraformaldehyde (0.323 g, 10.7 mmol, 1.0 equiv) were heated to 110°C with stirring for 30 min until the paraformaldehyde completely dissolved, forming a clear liquid. The mixture was then allowed to cool to rt and stored at -35oC for 2 days. Crystals is formed in the colorless oil (2.30 g, 10.6 mmol, 99%). The synthesis was carried out according to the established literature procedure, and the NMR data matched with the reported values (Kühl et al., “Metallatriphos Complexes: Synthesis and Molecular Structure of [TpZr(OCH2PPh2)3] (Tp=tris(pyrazolyl)hydroborate) and Formation of the Heterodinuclear Complex [TpZr(μ- OCH2PPh2)3Mo(CO)3] With Bridging Phosphinoalkoxide Ligands” Polyhedron 20:2171–2177 (2001), which is hereby incorporated by reference in its entirety). Note: The thermal hydrophosphination reaction produces P-capped oligomers, such as PPh2(CH2O)n-H, as byproducts. Due to the thermal instability of PPh2CH2OH (Hope et al., “A Nickel Complex Containing an Extremely Long Nickel-Phosphorus Bond. Syntheses and X-ray Structures of [Ni(CN)2[P(CH2OH)Ph2]3](C6H6)0.5and trans-[Ni(CN)2[P(CH2-OH)Ph2]2],” Inorg. Chem. 23:326-330 (1984); Hellmann et al., “Hydroxymethyl-Phosphine, Hydroxymethyl- Phosphoniumsalze und Chlormethyl-Phosphoniumsalze,” Liebigs Ann. Chem.659:49-63 (1962); Kühl et al., “Metallatriphos Complexes: Synthesis and Molecular Structure of [TpZr(OCH2PPh2)3] (Tp=tris(pyrazolyl)hydroborate) and Formation of the Heterodinuclear Complex [TpZr(μ- OCH2PPh2)3Mo(CO)3] With Bridging Phosphinoalkoxide Ligands” Polyhedron 20:2171–2177 (2001), which are hereby incorporated by reference in their entirety), distillation cannot be used for further purification. Its purity, determined to be 91% by31P{1H} NMR analysis, is considered adequate for use in catalytic reactions.

[00207] 1H NMR (400.30 MHz, CDCl3) δ: 7.53 – 7.45 (m, 4H, Ho), 7.37 (dtd, J = 6.1, 3.6, 1.5Hz, 6H, Hm&Hp), 4.46 – 4.38 (m, 2H, CH2), 1.51 (h, J = 3.1 Hz, 1H, OH).31P{1H} NMR (162.04 MHz, CDCl3) δ: -9.8 (s).13C{1H} NMR (100.67 MHz, CDCl3) δ: 135.4 (d, J = 12 Hz, Cipso), 133.3 (d, J = 18 Hz, Co), 129.1 (s, Cp), 128.8 (d, J = 7 Hz, Cm), 62.7 (d, J = 16 Hz, CH2).

[00208] 3-(Di-p-Tolylphosphino)-1-propanol: To a solution of diphenylphosphine (0.700 g, 3.27mmol, 1.0 equiv) and 3-chloropropanol (0.309 g, 3.27 mmol, 1.0 equiv) in THF (20 mL), n-butyllithium (3.3 mL, 2.20 M in hexanes, 21.5 mmol, 2.2 equivalents) was added dropwise at 0 °C. The mixture was stirred for 1 h at room temperature (rt). Afterward, deoxygenate water (10 mL) was added, and the mixture was evaporated. The residue was then extracted with CH2Cl2 (2 x 10 mL). The resulting suspension was filtered, and the solution was evaporated. The remaining residue was purified further by column chromatography using a solvent system of hexane / CH2Cl2 (1:1) initially, followed by CH2Cl2 / EtOAc (7:3), yielding the product (0.342 g, 1.26 mmol, 38%) as a colorless oil.

[0209] 1H NMR (500.20 MHz, CD3Cl) δ: 7.32 (t, J = 7.7 Hz, 4H, Ho), 7.14 (d, J = 7.6 Hz, 4H,Hm), 3.70 (td, J = 6.4, 1.6 Hz, 2H, OCH2), 2.34 (s, 6H, CH3), 2.08 (ddd, J = 7.9, 6.4, 1.7 Hz, 2H, PCH2), 1.73 – 1.64 (m, 2H, CH2), 1.42 (s, 1H, OH).31P{1H} NMR (202.47 MHz, CD3Cl) δ: -18.3 (s).13C{1H} NMR (125.79 MHz, CD3Cl) δ: 138.7 (s, Cp), 135.3 (d, J = 11 Hz, Cipso), 132.8 (d, J = 19 Hz, Co), 129.4 (d, J = 7 Hz, Cm), 63.8 (d, J = 14 Hz, OCH2), 29.3 (d, J = 15 Hz, PCH2), 24.6 (d, J = 11 Hz, CH2), 21.4 (s, CH3). HRMS (ESI-TOF, CH3OH) m / z: [M + Na]+calculated for C17H21PONa 295.1222, found 295.1223.

[0210] 3-(Diphenylphosphino)-2,2-dimethyl-1-propanol: To a solution of diphenylphosphine(1.86 g, 10.0 mmol, 1.0 equiv) and 3-chloro-2,2-dimethylpropanol (1.23 g, 10.0 mmol, 1.0 equiv) in THF (20 mL), n-butyl lithium (13.6 mL, 2.20 M in hexanes, 30.0 mmol, 3.0 equiv) was added dropwise at 0 °C. The yellow reaction mixture was heated to reflux for 18 h, during which the color gradually changed from orange to dark red. The reaction was quenched with deoxygenated water (20 mL), and the solvents were removed under vacuum. The combined organic layers were concentrated and the residue was further purified via column chromatography (hexane:CH2Cl21:1→CH2Cl2:EtOAc 7:3) to yield a viscous oil. This oil was dissolved in a small amount of THF, layered with Et2O, resulting in an off-white crystal (1.54 g, 5.65 mmol, 56%). The synthesis was slightly modified according to the establish literature procedure, and the NMR data matched with the reported values (Jacobi et al., “Tripod Ligands Containing a Mixed P / N / S Doner Set: Synthesis and Coordination Chemistry,” Chemische Berichte 130:1279-1294 (1997), which is hereby incorporated by reference in its entirety).

[0211] 1H NMR (400.30 MHz, C6D6) δ: 7.49 (ddt, J = 8.8, 5.6, 1.6 Hz, 4H, Ho), 7.11 – 6.99 (m,6H, Hm&Hp), 3.22 (s, 2H, OCH2), 2.16 (d, J = 3.4 Hz, 2H, PCH2), 0.95 (s, 6H, CH3), 0.85 (s, 1H, OH).31P{1H} NMR (162.04 MHz, C6D6) δ: -24.7 (s).13C{1H} NMR (100.67 MHz, C6D6) δ:140.8 (d, J = 13 Hz, Cipso), 133.4 (d, J = 20 Hz, Co), 128.7 (d, J = 7 Hz, Cm), 128.6 (s), 72.1 (d, J = 9 Hz, CH2O), 39.5 (d, J = 17 Hz, PCH2), 36.4 (d, J = 13 Hz, C(Me)2), 25.96 (d, J = 9 Hz, CH3). Example 2. Evaluation of Phosphine Ligands on Ni-SMC General Procedure for the Optimized Ligand and Catalyst Screening

[0212] In a nitrogen-filled glove box, Ni(cod)2 (with 4.0 equiv of phosphine ligand) or a Ni-PPh2Me catalyst (with 2.0-3.0 equiv of PPh2Me), 4-bromoacetophenone (4), and p-tolylboronic acid pinacol ester (B(p-Tol)Pin 5) were separately dissolved in 2-MeTHF to prepare stock solutions. Solid K3PO4(2.5 equiv) was weighed into a 2 mL crimp-top vial. The catalyst solution (0.2 mL, 0.5-3 mol%), 4 (0.1 mL, 0.2 mmol, 1.0 equiv), and 5 (0.1 mL, 1.1 equiv) were sequentially added to the vial. The vial was then sealed, removed from the glove box, and added with deionized water (80 mL). The vial was placed in a shaker and heated to 60-80 °C with an agitation speed of 800 rpm. To the reaction mixture, n-decane (0.1 mmol) was added as the internal standard. Samples were extracted at specific time intervals and extracted with ethyl acetate. The resultant organic layer was separated, and subsequently washed with water. An aliquot of the organic layer was analyzed by GC (Tables 1-5). %Yields in duplicate runs displayed an error of ^2%.Table 1. Evaluation of Ligands with Various Catalyst Loading.aa%Yields determined by GC after 24 hours and %yields at 2 hours in the parentheses.Table 2. Evaluation of Temperature EffectaTable 3. Evaluation of Base and Boronate Effect for Ni-PPh2Me CatalysisaaCondition: [4] = 0.5 M, %yields determined by GC after 16 h.Table 4. Evaluation of Base Effect for Ni-ProPhos CatalysisaaCondition: [4] = 0.5 M, %yields determined by GC after 2 hours. Table 5. Evaluation of Activity for Ni-PPh2Me CatalystsaaCondition: [4] = 0.5 M, %yields determined by GC after 16 hours.Example 3. Kinetics Experiments General Procedure for Kinetic Experiments

[00213] In a nitrogen-filled glove box, Ni(cod)2 (with 4.0 equiv of PPh2Me or ProPhos 9), 4-bromoacetophenone (4) and a boronic substrate (B(p-Tol)Pin 5 or BPh(OH)26) were separately dissolved in 2-MeTHF to form stock solutions in various concentrations, respectively. In most cases, solid K3PO4 (2.5 equiv) was weighed into a 2 mL crimp-top vial. The solutions of Ni phosphine (0.20 mL, 0.4^6.0 ^mol), the aryl bromide (0.10 mL, 0.20 mmol, 1.0 equiv) and the boronic substrate (0.10 mL, 0.22 mmol, 1.1 equiv) were then added to the vial. After that, the vial was sealed and removed from the glove box, then deionized water (80 ^L) was added to the vial via a syringe. The reaction was placed in a shaker and heated to 60 °C. The agitation speed was set to 800 rpm. The reaction progress was monitored by preparing a series of identical samples (#s = 10). At the specific time point, a sample was removed from the shaker. Each sample was extracted by ethyl acetate, the resulting organic layer was collected, washed with water. An aliquot of the organic layer was analyzed by GC. Reactions were conducted in duplicates, and determined concentrations have a ^2% error bar in replicate runs. Figures 41-48 demonstrate the results of the kinetic experiments. Effect of Potential Hydrolysis of B(p-Tol)Pin (5) During Catalysis

[00214] The rate of hydrolysis of B(p-Tol)Pin (5) was compared with the catalytic conversion of5 (Figure 2). The hydrolysis of B(p-Tol)Pin (5) in the catalytic solvents and temperature was slower (e.g. 40% at 24 hours) than the catalytic conversion. At the 24-hour mark, the boron speciation in both the organic (2-MeTHF) and aqueous phases were examined. In the organic phase, toluene was identified via GCMS. Boron species isolated from the organic phase revealed only the presence of 5, with no detection of B(p-Tol)(OH)2 by NMR. Isolation of the boron product in the aqueous phase indicated a trace amount of KB[(p-Tol)Pin(OH)] (15). Overall, the hydrolysis of the boronic ester under basic conditions appeared to be complex, involving protodeboronation,aligning with recent findings by Hayes et al., “Protodeboronation of (Hetero)Arylboronic Esters: Direct versus Prehydrolytic Pathways and Self- / Auto-Catalysis,” J. Am. Chem. Soc. 143(36):14814–14826 (2021), which is hereby incorporated by reference in its entirety). While the potential transient formation of B(p-Tol)(OH)2under catalytic conditions cannot be ruled out, the major boron species in the organic phase remained the boronic ester 5. Variable Time Normalization Analysis (VTNA) results

[0215] VTNA for the reaction rate dependence on [Ni] for the cross-coupling of 4-bromoacetophenone and B(3-Py)(OH)2using NiCl₂•6H₂O and ProPhos is shown in Figure 68. Original plot is top-left, time normalization plots show that there is a first-order dependence on [Ni] (red square). Condition: [ArBr] = 0.500 M; [B(3-Py)(OH)2] = 0.750 M; [Ni] = 0.000325 M, 0.0006 M, 0.00125 M, 0.0025 M; [ProPhos] = 0.0013 M; 0.0024 M; 0.006 M; 0.01 M; K3PO4 = 106 mg.

[0216] VTNA for the reaction rate dependence on [B(3-Py)(OH)2] for the cross-coupling of 4-bromoacetophenone and [B(3-Py)(OH)2] using 0.05 mol% NiCl₂•6H₂O and 0.20 mol% ProPhos is shown in Figure 69. Original plot is top-left, time normalization plots show that there is a zero- order dependence on [B(3-Py)(OH)2] (red square). Condition: [ArBr] = 0.500 M; [B(3-Py)(OH)2] = 0.750 M; 0.900 M, 1.00 M, 1.15 M; [Ni] = 0.000250 M; [ProPhos] = 0.001 M; K3PO4 = 106 mg.Example 4. Synthesis of Ni Complexes

[00217] A vial was charged with Ni(cod)2 (50.0 mg, 0.182 mmol, 1.0 equiv),PPh2CH2CH2CH2OH (88.8 mg, 0.364 mmol, 2.0 equiv), and THF (4 mL). The mixture was stirred at 20oC overnight. The red solution was filtered through a Celite. The filtrate was concentrated under vacuum, layered with pentane (5 mL), and stored at -35oC overnight to give an orange crystal (74.0 mg, 0.113 mmol, 62%). The complex contained two equivalents of co-crystallized THF, as detected by both X-ray and NMR analyses.

[00218] 1H NMR (400.30 MHz, C6D6) δ: 7.44 (ddt, J = 7.9, 5.2, 2.3 Hz, 8H, Ho), 7.07 (qd, J =4.3, 2.0 Hz, 12H, Hm& Hp), 4.57 – 4.45 (m, 4H, CH at cod), 3.13 (t, J = 6.2 Hz, 4H, H1), 2.23 (dt, J = 12.0, 3.0 Hz, 4H, H3), 2.03 – 1.80 (m, 8H, CH2at cod), 1.48 – 1.42 (m, 4H, H2 overlapping with THF signals), 0.92 (br s, 2H, OH overlapping with pentane signals).31P{1H} NMR (162.04 MHz, C6D6) δ: 31.7 (s).13C{1H} NMR (100.67 MHz, C6D6) δ: 140.1 (dd, J = 23, 4 Hz, Cipso), 133.7 (d, J = 12 Hz, Co), 128.6 (s, Cp, overlapping with C6D6signals and detected by13C DEPT 135), 128.5 (d, J = 8 Hz, Cm, overlapping with C6D6 signals and detected by13C DEPT 135), 83.4 (t, J = 6 Hz, CH at cod), 83.3 (t, J = 6 Hz, CH at cod), 64.2 (d, J = 11 Hz, C1), 31.1 – 30.9 (m, CH2at cod), 30.2 – 29.9 (m, C2), 29.6 (s, C3). HRMS (ESI-TOF, CH3CN) m / z: [M + K]+calculated for C38H46NiO2P2K 693.1958, found 693.1989.

[00219] A vial was charged with Ni(cod)2 (40.0 mg, 0.145 mmol, 1.0 equiv),PPh2CH2CH2CH2OH (142 mg, 0.582 mmol, 4.0 equiv), THF (4 mL). The mixture was stirred at 20oC overnight. The red suspension was filtered through a Celite. To the filtrate, pentane (5 mL)was added to precipitate a dark orange solid. The solid was washed with pentane (3 x 3 mL) and further dried under vacuum for 2 hours to afford an orange solid (65 mg), which contained a mixture of Ni(PPh2CH2CH2CH2OH)4 (12, 80%) and Ni(PPh2CH2CH2CH2OH)2(cod) (11, 20%), as determined by31P{1H} NMR (Figure 3).31P{1H} NMR (162.04 MHz, C6D6) δ: 12.7 (br s, ^1 / 2= 724 Hz).31P{1H} NMR (162.04 MHz, C6D6:THF = 1:4) δ: 13.2 (br s, ^1 / 2= 410 Hz).

[00220] HRMS (ESI-TOF, CH3OH) m / z:[M + O + 2K]2+calculated for C60H68NiO5P4K2564.1317, found 564.1284; [M – 1 ligand + O + Na]+calculated for C45H51NaNiO4P3829.2246, found 829.2248; [M – 2 ligands + O + NH4]+calculated for C30H38NniO3P2580.1675, found 580.1671; [M – 3 ligands + O + Na]+calculated for C15H17NaNiO2P 341.0212, found 340.0242. Only Ni complex containing one phosphine oxide was detected by HRMS due to the highly air- sensitive nature of this complex.

[00221] The NMR signals of 1H, 31P{1H}, and 1 1associated with complex 12 exhibitedsignificant broadening. Thus, only31P{1H} NMR data is reported. Plausible rationales include the limited solubility of this complex in C6D6 and / or the occurrence of dynamic processes in solution, such as ligand dissociation and re-coordination. To address the solubility concern, 0.4 mL of THF and 0.1 mL of C6D6 (locking purposes) were employed for dissolve this complex (Figure 4), but the broad signal attributed to 12 persisted.

[00222] Furthermore, when complex 12 was in the presence of excess THF (close to catalyticconditions), a new Ni species emerged. This species was tentatively identified as the bipyramidal complex Ni(PPh2CH2CH2CH2OH)4(THF). The basis for this assignment lied in the diagnostic multiplicity observed in the31P{1H} signals (δ: 124.1 ppm (q, J = 31 Hz, integration = 1), 20.8 ppm (d, J = 31 Hz, integration = 3)), providing further support for the proposed characterization.

[00223] A Schlenk flask was charged with Ni(cod)2 (100 mg, 0.364 mmol, 1.0 equiv), THF (5mL), 2-chlorotoluene (460 mg, 3.64 mmol, 10 equiv), and PPh2Me (291 mg, 1.45 mmol, 4.0 equiv). The reaction mixture was stirred at 60 °C for 5 days, then cooled to rt and concentrated under vacuum to give an orange oil. The orange oil was dissolved in a minimal MeOH and layeredwith hexane to give a dark red crystal (102 mg, 0.174 mmol, 48%). Spectroscopic data was consistent with the literature reports (Standley et al., “A Broadly Applicable Strategy for Entry into Homogeneous Nickel(0) Catalysts from Air-Stable Nickel(II) Complexes,” Organometallics 33(8):2012–2018 (2014), which is hereby incorporated by reference in its entirety).

[00224] 1H NMR (400.30 MHz, C6D6) δ: 7.84 (ddt, J = 7.4, 5.4, 3.4 Hz, 4H, Ho at Ph), 7.62 (qd,J = 4.9, 2.5 Hz, 4H, Ho at Ph), 7.13 – 6.92 (m, 13H, Hm, Hp at Ph & o-Tol), 6.75 – 6.64 (m, 1H, o- Tol), 6.59 (d, J = 7.8 Hz, 2H, o-Tol), 2.75 (s, 3H, CH3at o-Tol), 1.08 (t, J = 3.6 Hz, 6H, CH3at PPh2Me).31P{1H} NMR (162.04 MHz, C6D6) δ: 7.6 (s).13C{1H} NMR (100.67 MHz, C6D6) δ: 153.1 (t, J = 34 Hz, o-Tol), 143.3 (d, J = 7 Hz, o-Tol), 136.1, (t, J = 5 Hz, o-Tol), 135.01 (t, J = 20 Hz, Cipsoat Ph), 133.9 (t, J = 6 Hz, Coat Ph), 133.5 (t, J = 21 Hz, Cipsoat Ph), 133.3 (t, J = 5 Hz, Coat Ph), 129.9 (s, Cpat Ph), 129.5 (s, Cpat Ph), 128.3 (t, J = 5 Hz, Cmat Ph), 128.1 (t, J = 5 Hz, Cm at Ph), 124.0 (t, J = 3 Hz, o-Tol), 122.6 (t, J = 3 Hz, o-Tol), 26.6 (CH3 at o-Tol), 12.9 (t, J = 16 Hz, CH3 at PPh2Me). HRMS (ESI-TOF, CH3CN) m / z: [M - Cl]+calculated for C33H33NiP2 549.1405, found 549.1414. No HRMS was reported in literature.

[00225] A Schlenk flask was charged with Ni(acac)2 (400 mg, 1.56 mmol, 1.0 equiv), THF (10mL), and PPh2Me (686 mg, 3.42 mmol, 2.2 equiv). The suspension was cooled to 0 °C with an ice bath and o-tolylmagnesium bromide (1.56 mmol, 0.68 M in THF, 2.3 mL) was added dropwise with vigorous stirring. The solution began to turn orange at the end of the addition. The solution was stirred for 30 min at 0 °C. After that, the solvent was removed under vacuum and MeOH (5 mL) was added. The mixture was sonicated and stored at -35oC for 2 hours to give a yellow suspension. The yellow precipitate was collected by vacuum filtration, washed with cold MeOH (3 x 10 mL), and dried under vacuum to give an orange-yellow solid (447 mg, 0.709 mmol, 46%). Spectroscopic data was consistent with the literature reports (Haibach et al., “Enabling Suzuki– Miyaura Coupling of Lewis-Basic Arylboronic Esters with a Nonprecious Metal Catalyst,” Chem. Sci.13(43):12906–12912 (2022), which is hereby incorporated by reference in its entirety).

[00226] MeOH is important to remove Mg(acac)2 and precipitate out the complex. However, thecomplex is partially soluble in MeOH, leading to the low yield.

[0227] 1H NMR (400.30 MHz, C6D6) δ: 7.81 (qt, J = 5.3, 2.4 Hz, 4H, Ho at Ph), 7.63 (ddt, J =9.5, 4.8, 2.5 Hz, 4H, Ho at Ph), 7.13 – 6.96 (m, 13H, Hm, Hp at Ph & o-Tol), 6.67 (td, J = 7.2, 1.6 Hz, 1H, o-Tol), 6.62 – 6.54 (m, 2H, o-Tol), 2.76 (s, 3H, CH3 at o-Tol), 1.13 (t, J = 3.7 Hz, 6H, CH3at PPh2Me).31P{1H} NMR (162.04 MHz, C6D6) δ: 8.6 (s). HRMS (ESI-TOF, CH3CN) m / z: [M - Br]+calculated for C33H33NiP2 549.1405, found 549.1397. No HRMS was reported in literature. Synthesis of [Ni(PPh2Me)(^-OH)(o-Tol)]2 (16)

[0228] A vial was charged with Ni(PPh2Me)2X(o-Tol) (13, X = Cl: 50.0 mg or 14, X = Br: 53.8mg, 0.0854 mmol, 1.0 equiv), KOH (95.8 mg, 1.71 mmol, 20 equiv), THF (4 mL), and deionized H2O (20 mL). The mixture was stirred at 20oC overnight, then solvent was removed under vacuum to give a yellow oil containing a white solid. The mixture was extracted with pentane (3 x 5 mL), and further filtered through a Celite. The resulting yellow solution was concentrated under vacuum (~2 mL), and stored at -35oC overnight to give a yellow solid. The solid was collected by filtration, and further dried under vacuum to afford a yellow solid (21.8 mg, 0.0297 mmol, 70%). This compound was extremely soluble in pentane, which made it difficult to isolate it free of the PPh2Me. A trace amount of free PPh2Me and its oxide were detected by31P NMR in the isolated mixture. Characterization of the Isomeric Ni Hydroxo-Bridged Dinuclear Complexes

[0229] The identity of the isolated mixture containing four isomeric Ni bridging OH complexeswas supported by the correlations in the1H / 31P{1H} HMBC spectrum (Figures 5A-C). Two most intense signals at 17.2 and 17.9 ppm were assigned to two trans-isomers, which showed the correlations with the bridging OH signals at -3.34 and -3.35 ppm (Figure 5A). These1H shifts were consistent with the literature reported for trans-analogues (Christian et al., “Nickel Hydroxo Complexes as Intermediates in Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling,” Organometallics 33(9):2134–2137 (2014), which is hereby incorporated by reference in its entirety). For two cis-isomers, two sets of the bridging OH signals (four signals total) were observed due to the symmetry. Two upfield signals at -5.31 and -5.51 ppm were assigned to the two OH cis to the PPh2Me (Figure 5B). According to the1H / 31P{1H} HMBC, the31P signals at 17.9 and 16.8 ppm were assigned due to the two cis-isomers. The two most downfield bridging OH signals at -1.75 and -1.87 ppm were assigned to the signals due to the OH trans to the PPh2Me ligand for the cis-Ni complexes (syn- and anti-). In addition, four signals between 3.20 and 3.59ppm were assigned to four CH3signals at the Ni-Tol fragment based on the1H / 31P{1H} HMBC correlations (Figure 5C). However, the spectroscopic evidence to distinguish the syn- and anti- isomers was lacking. Nevertheless, the trans-isomers were major species, which was consistent with the reported DFT calculation for their high stability (Payard et al., “Taming Nickel-Catalyzed Suzuki-Miyaura Coupling: A Mechanistic Focus on Boron-to-Nickel Transmetalation,’ ACS Catal.8(6):4812–4823 (2018), which is hereby incorporated by reference in its entirety). Since the resting signals in these four isomers were close, not every1H and13C NMR signals were assigned.

[00230] 1H NMR (500.20 MHz, C6D6) δ: 8.06 – 7.19 (m, Ar at PPh2Me), 7.16 – 6.64 (m, Ar atPPh2Me & Ar at o-Tol), 3.59 (s, CH3at cis-isomer), 3.35 (s, CH3at cis-isomer), 3.26 (s, CH3at trans-isomer), 3.20 (s, CH3at trans-isomer), 0.81 – 0.69 (m, CH3at PPh2Me), -1.75 (s, OH at cis- isomer), -1.87 (s, OH at cis-isomer), -3.34 (s, OH at trans-isomer), -3.35 (s, trans-isomer), -5.31 (s, cis-isomer), -5.51 (s, cis-isomer).31P{1H} NMR (202.50 MHz, C6D6) δ: 17.9 (s, cis-isomer), 17.4 (s, trans-isomer), 17.2 (s, trans-isomer), 16.8 (s, cis-isomer).13C{1H} NMR spectrum was obtained but not assigned (Figure 6). HRMS (ESI-TOF, CH3CN) m / z: [M + O + H]+calculated for C40H43Ni2O3P2749.1389, found 749.1410; presumably, one of the PPh2Me ligands at the Ni complex is oxidized during the MS analysis. [M - 1 ligand + H]+calculated for C27H30Ni2O2P 533.0685, found 533.0716.

[00231] A vial was charged with Ni(cod)2 (50.0 mg, 0.181 mmol, 1.0 equiv), PPh2Me (145 mg,0.727 mmol, 4.0 equiv) and THF (4 mL). The mixture was stirred at 20oC overnight, then solvent was removed under vacuum to give an orange solid. The solid was washed with pentane (3 x 5 mL), and further dried under vacuum for 2 hours to afford an orange solid (121 mg, 0.141 mmol, 77%). Spectroscopic data was consistent with the literature reports (Haibach et al., “EnablingSuzuki–Miyaura Coupling of Lewis-Basic Arylboronic Esters with a Nonprecious Metal Catalyst,” Chem. Sci.13(43):12906–12912 (2022), which is hereby incorporated by reference in its entirety).1H NMR (500.20 MHz, C6D6) δ: 7.28 – 7.20 (m, 16H, Ho), 7.04 (d, J = 7.3 Hz, 8H, Hp), 6.97 (t, J = 7.4 Hz, 16H, Hm), 1.71 (s, 12H, CH3).31P{1H} NMR (202.50 MHz, C6D6) δ: 3.9 (s).

[00232] The synthesis was slightly modified from the literature (Magano et al., “Development ofan Air-Stable, Broadly Applicable Nickel Source for Nickel-Catalyzed Cross-Coupling,” ACS Catal. 5(5):3120–3123 (2015), which is hereby incorporated by reference in its entirety). A vial was charged with Ni(cod)2(300 mg, 1.09 mmol, 1.0 equiv), N,N,N’,N’- tetramethylethylenediamine (152 mg, 1.31 mmol, 1.2 equiv) and 2-chlorotoluene (4 mL). The mixture was stirred at 20oC for 3 days. To the dark orange suspension, pentane (5 mL) was added, and the resulting suspension was stirred for 30 min at 20oC. The solid was vacuum-filtered and washed with pentane (3 x 3 mL). The resulting solid was further dried under vacuum for 2 h to afford an orange solid (300 mg, 0.995 mmol, 91%). NMR data was consistent with the literature (Magano et al., “Development of an Air-Stable, Broadly Applicable Nickel Source for Nickel- Catalyzed Cross-Coupling,” ACS Catal.5(5):3120–3123 (2015), which is hereby incorporated by reference in its entirety). The crude of this compound was directly used for the further synthesis of the corresponding Ni phosphine complex without purification. The purification of S9 was reported in the literature (Magano et al., “Development of an Air-Stable, Broadly Applicable Nickel Source for Nickel-Catalyzed Cross-Coupling,” ACS Catal.5(5):3120–3123 (2015), which is hereby incorporated by reference in its entirety).

[00233] 1H NMR (400 MHz, C6D6) δ: 7.69 (dd, J = 7.4, 1.3 Hz, 1H, Ho at o-Tol), 7.04 – 6.89 (m,3H, Hs at o-Tol), 3.67 (s, 3H, CH3at o-Tol), 2.22 (s, 3H, N-CH3), 2.10 – 2.01 (m, 4H, N-CH3& N-CH2), 1.82 (s, 3H,N-CH3), 1.55 – 1.40 (m, 1H, N-CH2), 1.32 – 1.15 (m, 4H, N-CH3 & N-CH2), 1.06 – 0.93 (m, 1H, N-CH2).

[00234] A vial was charged with Ni(TMEDA)Cl(o-Tol) (S9, 100 mg, 0.332 mmol, 1.0 equiv),PPh2CH2CH2CH2OH (172 mg, 0.730 mmol, 2.2 equiv) and THF (4 mL). The mixture was stirred at 20oC for 2 days, then solvent was removed under vacuum to give an orange oil. To the orange oil, toluene (2 mL) was added, and the suspension was filtrated through a celite. The resulting orange solution was concentrated under vacuum, layered with pentane (5 mL), and stored at -35 oC overnight to give a yellow solid. The solid was further dried under vacuum for 2 hours to afford an orange solid (197 mg, 0.292 mmol, 88%).

[00235] 1H NMR (400.30 MHz, C6D6) δ: 7.83 (tdd, J = 7.1, 5.4, 3.6 Hz, 4H, Ho at Ph), 7.45 (dtd,J = 8.5, 4.5, 2.4 Hz, 4H, Hoat Ph), 7.10 – 6.97 (m, 13H, Hm, Hpat Ph & o-Tol), 6.63 – 6.48 (m, 2H, o-Tol), 6.39 (dd, J = 7.3, 1.7 Hz, 1H, o-Tol), 3.16 (q, J = 5.9 Hz, 4H, H1), 2.75 (s, 3H, CH3at o-Tol), 2.10 – 1.90 (m, 4H, H3), 1.56 – 1.36 (m, 4H, H2), 0.79 (t, J = 5.6 Hz, 2H, OH).31P{1H} NMR (162.04 MHz, C6D6) δ: 13.4 (s).13C{1H} NMR (100.67 MHz, C6D6) δ: 150.0 (t, J = 33 Hz, o-Tol), 143.8 (t, J = 3 Hz, o-Tol), 137.0 (t, J = 5 Hz, o-Tol), 134.6 (t, J = 6 Hz, Coat Ph), 133.5 (t, J = 5 Hz, Co at Ph), 132.7 (t, J = 20 Hz, Cipso at Ph), 132.4 (t, J = 20 Hz, Cipso at Ph), 129.9 (s, Cp at Ph), 129.3 (s, Cpat Ph), 124.0 (t, J = 3 Hz, o-Tol), 122.6 (t, J = 3 Hz, o-Tol), 63.0 (t, J = 7 Hz, C1), 28.3 (s, C3), 26.5 (s, CH3at o-Tol), 23.0 (t, J = 14 Hz, C2). Signals due to Cmat Ph are not observed because of their overlapping with the signal due to C6D6. HRMS (ESI-TOF, CH3CN) m / z: [M - Cl]+calculated for C37H41NiO2P2637.1935, found 637.1929. Example 5. Organometallic Study of Ni Phosphine Complexes Resting State Analysis of the Catalytic Systems Using Pph2me or Prophos as a Ligand General Procedure for Detecting the Catalyst Resting State

[00236] Ni(cod)2 (3.0 mg, 0.011 mmol, 1.0 equiv) and a phosphine ligand (ProPhos 9: 11 mg,0.044 mmol, 4.0 equiv; PPh2Me: 8.1 mL, 0.044 mmol, 4.0 equiv) were dissolved in 2-MeTHF (0.4 mL) for 30 min. An electrophile (2-chlorotoluene: 13 mL, 0.109 mmol, 10 equiv; 2-bromotoluene: 13 mL, 0.109 mmol, 10 equiv) and B(p-Tol)Pin 5 (26 mg, 0.120 mmol, 11 equiv) / BPh(OH)36 (15 mg, 0.120 mmol, 11 equiv) were separately added to the Ni solution. The solution was transferredto a J. Young tube. After that, the K3PO4(23 mg, 0.109 mmol, 10 equiv) and C6D6(0.1 mL, for locking purpose) were added to the NMR tube and removed from the glove box, then deionized water (2 mL) was added to the tube via a syringe. The sample was initially monitored by31P{1H} NMR prior to the heating (obtained at 15 min), and then placed in an oil bath and heated to 70 °C. The reaction progress was monitored by31P{1H} NMR (run at rt).

[0237] 2-Chlorotoluene or 2-bromotoluene were selected since the corresponding Ni aryl halidecomplexes (e.g. Ni(PPh2Me)2Br(o-Tol) 14) were isolated. Using established31P chemical shift values for these complexes helped assign reaction intermediates. Less K3PO4 and water were added to the sample in order to decelerate the reaction to facilitate kinetic measurements and improve shimming. Parallel experiments were performed in the NMR tubes to ensure the catalytic conversion. The reaction mixture after 1 hour heating was extracted with ethyl acetate and washed with water. An aliquot of organic layer was analyzed by GCMS, revealing the formation of the product. The reaction with 6 resulted in a heterogeneous solution with poor shimming. Thus, the reaction mixtures at the specific time point were filtrated in the glovebox, and the filtrates were analyzed by31P{1H} NMR. Study of B,O-Coordination Between Complex Ni(PPh2CH2CH2CH2OH)2Cl(o- Tol) (21) with Boronic Acids and Esters Reaction of Complex 21 with 4-OMe-PhB(OH)2 (22)

[0238] 4-Methoxyphenylboronic acid (4-OMe-PhB(OH)222, 3.4 mg, 22 ^mol, 5.0 equiv) wasadded to a C6D6 solution of the isolated complex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21, 3.0 mg, 4.5 ^mol, 1.0 equiv) at rt. Over a 15-minute period, there was no observable change in color. The31P{1H} NMR spectrum shows three new major signals at 14.9, 14.2 and 13.8 ppm, along with other trace signals (Figure 7).1H / 31P{1H}-HMBC NMR experiments on these31P signals were performed (Figure 8), revealing that both31P signals at 13.8 and 14.2 ppm (green dots) exhibited a correlation with the1H signals ranging from 2.08 to 1.91 ppm (green). Despite the overlap of all three resonances (21 and 23) corresponding to the methylene group (green) attached to P at approximately 2.0 ppm, the suggested coordination involving B and O resulted in a minor shift in the other methylene protons (blue and orange) tentatively assigned as 23, as depicted in the1H- COSY spectrum of this blend (Figure 9). The1H signals falling within 2.08 and 1.91 ppm (green) showed a1H-COSY correlation with thesignals from 1.91 to 1.58 ppm (blue), and the later (blue) shows a correlation with a1H multiplet signal around 3.75 ppm (orange). Additionally, the11B NMR spectrum of this reaction mixture showed a broad singlet at 29.3 ppm, closely resembling the signal observed for boronic acid 22 (Figure 10). Both11B chemical shifts are characteristic of three-coordinated boronic acids and esters (11B δ: 25-33 ppm) (Lennox et al., “Selection of Boron Reagents for Suzuki–Miyaura Coupling,” Chem. Soc. Rev.43(1):412–443 (2014), which is hereby incorporated by reference in its entirety). Reaction of Complex 21 with BPh(OH)2 (6)

[0239] The addition of BPh(OH)2 (6, 4.3 mg, 36 ^mol, 5.0 equiv) to a C6D6 solution of complex21 (4.8 mg, 7.1 ^mol, 1.0 equiv) at rt produced a series of new complexes, analogous to the reaction observed with 4-methoxyphenylboronic acid. In the31P{1H} NMR spectrum (Figure 11), three major new signals at 14.9, 14.2 and 13.8 ppm were observed, which showed identical chemical shifts to that observed in the reaction using 4-OMe-PhB(OH)222 (forming the analogous complex S10) However, the reaction with 6 shows more other unidentified product than that with 22, as detected by31P{1H} NMR (Figures 11 vs 7).

[0240] In Figure 12A, the 1H NMR spectrum of BPh(OH)2 (6) showed an OH signal atapproximately 3.99 ppm and aromatic1H signals at 7.65 and 7.21 ppm (Ha and Hb,c). However, in the1H NMR spectrum of the mixture containing complex S10 (Figure 12B), the OH signal due to 6 was shifted further downfield to 5.05 ppm (blue). The aromatic1H signals of 6 were shifted in the1H NMR spectrum (Figure 12B) compared to that of free 6, but these shifted signals were heavily overlapped with the signals due to the Ph at the phosphine ligand. Thus, they were not located in the1H spectrum. By comparing the spectrum (Figure 12B) to the1H NMR spectrum of the isolated 21 (Figure 12C), it was found that: 1) the CH2 signal at 3.16 ppm (Hd’, Figure 12C) shifted downfield to 3.72 ppm (Hd); 2) a signal due to CH3 in the o-Tol group emerged at 2.71 ppm (He), which was slightly shifted more upfield compared to that in the isolated 21 (He’at 2.74ppm). Reactions of Complex 21 with B(p-Tol)Pin (5)

[0241] Similar reactions of complex 21 (3.0 mg, 4.5 ^mol, 1.0 equiv) with p-Tol boronic acidpinacol esters (5, 1.2 mg, 5.3 ^mol, 1.2 equiv) were performed. Both reactions show no new species even after 24 hours (Figures 13A-13C). Reactions of Complex Ni(PPh2Me)2Cl(o-Tol) (13) with Boronic Acids and Esters

[0242] Control experiments with Ni(PPh2Me)2Cl(o-Tol) (13, 4.0 mg, 6.8 ^mol, 1.0 equiv) andtwo boronic acids, 4-methoxyphenylboronic acid (22, 5.2 mg, 34 ^mol, 5.0 equiv) and BPh(OH)2(6, 4.2 mg, 34 ^mol, 5.0 equiv) were performed, respectively. Beside some unknowndecomposition of the Ni starting material, both reactions showed no significant change after 3 days (Figures 14-15). A similar reaction with B(p-Tol)Pin (5, 1.8 mg, 8.2 ^mol, 1.2 equiv) also showed no significant change after several days. Variable Temperature NMR Study of ProPhos (9) with 4-OMe-PhB(OH)2 (22)

[0243] NMR experiments were conducted at various temperatures for the reaction mixture offree ligand 9 and boronic acid 22 to explore possible equilibria involving the B,O-coordination. It is important to highlight that: 1) high-temperature NMR studies with complex 21 and 22 were not carried out due to the rapid "base-free" transmetalation between 21 and 22 (vide infra); 2) analyzing the resulting B,O-adduct from the reaction mixture of 9 and 22 was considerably less intricate compared to that of 21 and 22.

[0244] Room temperature experiments. Addition of 4-OMe-PhB(OH)2 (22, 12 mg, 0.082 mmol,4.0 equiv) to the isolated PPh2CH2CH2CH2OH (9, 5.0 mg, 0.020 mmol, 1.0 equiv) in C6D6led to an immediate formation of the phosphine-borane adduct PPh2CH2CH2CH2OB(4-OMe-Ph)(OH), as detected by1H (Figure 16B) and31P{1H} NMR (Figure 17). All1H shifts for this phosphine- borane adduct were downfield shift compared to PPh2CH2CH2CH2OH (Figures 16B-16C), which was consistent with previously identified Ni-P-O-B adducts 23. The31P{1H} NMR spectrum (Figure 17) also showed a new signal at -16.3 ppm due to PPh2CH2CH2CH2OBPh(OH)2 , which is slightly shifted compared to that due to 9 (-16.1 ppm). ESI-MS analysis of this mixture showed a signal at m / z = 379.15, presumably matching the calculated m / z for C22H24BO3P (379.16, i.e. PPh2CH2CH2CH2OB(4-OMe-Ph)(OH) + H+). Furthermore, the11B NMR spectrum of this reaction mixture showed a broad singlet at 29.2 ppm.

[0245] High temperature experiments. Heating the reaction mixture of ProPhos 9 and 22gradually caused both31P signals due to 9 and its B,O-adduct shifted more downfield (Figure 18 right). Notably, the signal intensity of the B,O-adduct diminished compared to that of 9, suggesting a shift in equilibrium toward the side of 9 and boronic acid at higher temperatures. The VT-1H NMR (Figure 18 left) spectra revealed the gradual merging of Ha (22) and Hc (B,O-adduct) signals with the temperature increasing, accompanied by a reduction in their intensities compared to the boroxine signal (Hb). These findings indicated an overall shift in equilibrium toward the boroxine at elevated temperatures, consistent with computational studies predicting the endothermic nature of boronic acid dehydration (Bhat et al., “Thermodynamics of Boroxine Formation from the Aliphatic Boronic Acid Monomers R–B(OH)2(R = H, H3C, H2N, HO, and F):A Computational Investigation,” J. Phys. Chem. A 115(26):7785–7793 (2011), which is hereby incorporated by reference in its entirety). Cooling the sample back to 25°C restored the original spectrum, providing evidence for the reversibility of the B,O-coordination between ligand 9 and boronic acid 22. Such equilibrium dynamics could be more intricate under catalytic conditions involving the presence of H2O and a base. Reactivity Studies of Complex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) with KOH Reaction of Complex 21 with KOH in THF / H2O

[00246] A vial was loaded with Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21, 22 mg, 0.032 mmol, 1.0equiv) and KOH (26 mg, 0.64 mmol, 20 equiv). A mixture of THF:H2O (20:1, 2 mL) was then added and the yellow solution was stirred at rt overnight. After that, the solvent was removed under vacuum and the residue was redissolved in pentane (2 mL), filtered through a Celite and the filtrate was stored was stored at -35oC for 3 hours. The yellow solid was suspended in pentane, collected by filtration to afford a yellow solid (12 mg, %yield is not determined due to the mixture, Scheme 1). Scheme 1. Reaction of Complex 21 with KOH in THF / H2O, Showing the Products 24

[00247] 31P{1H} NMR showed the mixture contains three signals (Figure 19C). The two signalsat 21.8 and 22.4 ppm were assigned to the trans- and cis-isomers of Ni(^2-PPh2CH2CH2CH2O)(o- Tol)(L) (24, L = PPh2CH2CH2CH2OH), based on analogous P,O-coordinated Ni complexes observed during the preparation of complex 21 (Figure 19B). The other signal at -16.3 ppm was raised by the coordination of PPh2CH2CH2CH2OH through the OH group, supported by the comparison of1H signals of the OH group (Ha) and the Hband that of free PPh2CH2CH2CH2OH (Figures 20A-20B). The1H NMR spectrum shows no signals corresponding to Ni-OH or Ni- PPh2CH2CH2CH2OH (Figure 21). Although full assignment was difficult due to peak overlap in the alkyl region, two new1H signals were observed due to the CH3groups at the Ni-Tol fragments(3.41 and 3.23 ppm), which were more downfield compared to that in the isolated Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21) (2.75 ppm). Reactivity of the Mixture Containing Ni(^2-PPh2CH2CH2CH2O)(o-Tol)(ProPhos) (24) with B(p-Tol)Pin (5) or BPh(OH)2 (6)

[0248] When Ni(^2-PPh2CH2CH2CH2O)(o-Tol)(ProPhos) (24, 5.0 mg, 7.8 ^mol, 1.0 equiv) andBPh(OH)2(6, 2.0 mg, 16 ^mol, 2.0 equiv) were mixed, a new Ni species formed within 15 min along with the disappearance of the two Ni isomers in the31P{1H} NMR spectrum. This new species at 21.6 ppm was assigned to a B,O-coordinated adduct (Figure 22), based on the downfield shift and broadening of the1H signal due to boronic acid coordination. The transmetalation products after 1 hour were analyzed by GC, showing 22% of the desired product 19 and 22% of biphenyl (homocoupling product). Transmetalation Studies of Ni-PPh2Me Complexes (13 and 16) and Ni-ProPhos Complex (21)

[0249] General Experimental Procedure for the Product Analysis Using GC. Ni(PPh2Me)2Cl(o-Tol) (13, 6.8^10 ^mol, 1.0 equiv) or [Ni(PPh2Me)(^-OH)(o-Tol)]2 (16, 3.0-4.1 ^mol, 1.0 equiv)or Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21, 5.2-10 ^mol, 1.0 equiv) and PPh2Me (if applicable, 2.0 equiv), were dissolved in THF (1 mL) for 30 min in a 4 mL vial with a stir bar. p-Tolylboronic acid pinacol ester (5, 2 equiv) or phenylboronic acid (6, 2^5.0 equiv) or the corresponding potassium aryl boronate (K[B(p-Tol)Pin(OH)] 15, 2.0 equiv) was added to the Ni solution. For the reactions with boronate 15, 18-crown-6 (1 equiv, if applicable) was added for facilitate its solubility in THF. Dry K3PO4(10 equiv) and H2O (10 mL) were added (if applicable). An aliquot (50 mL) was analyzed by GC with an internal standard (n-decane).

[0250] General Experimental Procedure for the Ni Speciation Analysis by NMR. Subsequent tothe general protocol above for product analysis, a minor adjustment was implemented to enhance shimming. The sample was then meticulously prepared in an NMR tube. Dry K3PO4 or KOH (10 equiv) and H2O (1 mL) were used. Additionally, C6D6 or C7D8 (0.1 mL, for locking purpose) were added. After preparation, the sample was placed in an NMR tube shaker. Monitoring was carried out using31P{1H} NMR. Synthesis of K[B(p-Tol)Pin(OH)] (15)

[0251] The synthesis was slightly modified from the literature procedure (Mills et al.,“Mechanistic Investigations of Phenoxyimine–Cobalt(II)-Catalyzed C(Sp2)–C(Sp3) Suzuki–Miyaura Cross-Coupling,” J. Am. Chem. Soc. 145(31):17029–17041 (2023), which is hereby incorporated by reference in its entirety). To a 20 mL vial with a stir bar, 5 (400 mg, 1.83 mmol, 1.0 equiv), potassium hydroxide (103 mg, 1.83 mmol, 1.0 equiv), and MeCN (5 mL) were sequentially added. The reaction was rigorously stirred at 70oC for 16 hours. The solution was filtered by a frit, and the precipitate was washed with hexane (5 x 5 mL). The precipitate was dried under vacuum to yield the product as a white solid (355 mg, 1.29 mmol, 71%).

[0252] 1H NMR (400.30 MHz, D2O) δ: 7.46 (d, J = 7.5 Hz, 2H, Ho), 7.11 (d, J = 7.5 Hz, 2H,Hm), 2.28 (s, 3H, CH3 at o-Tol), 1.91 (s, 1H, OH), 1.22 (s, 6H, CH3), 1.04 (s, 6H, CH3).13C{1H} NMR (100.67 MHz, D2O) δ: 135.3 (s, Ar at o-Tol), 131.4 (s, Co at o-Tol), 127.8 (s, Cm at o-Tol), 75.6 (BOC(CH3)2), 23.7 (s, CH3at BPin), 20.1 (s, CH3at o-Tol). One quaternary13C signal at Tol group is not observed. HRMS (ESI-TOF, CH3OH) m / z: [M -KOH + Cl]- calculated for C13H19BClO2253.1175, found 253.1188. The boronic ester 5 is barely soluble in D2O, suggesting that NMR data we obtained is from the boronate 15. Reactions of Complex Ni(PPh2Me)2Cl(o-Tol) (13) with B(p-Tol)Pin (5), BPh(OH)2(6) and K[B(p-Tol)Pin(OH)] (15)

[0253] The reactions of Ni(PPh2Me)2Cl(o-Tol) (13) with B(p-Tol)Pin (5) with or without K3PO4showed nearly no formation of the desired biaryl product even after 24 hours (orange and pink) (Figure 23). The reaction of 13 with K[B(p-Tol)Pin(OH)] (15) showed a gradient product formation up to 29% over 24 hours (cyan). Additionally, transmetalation of 13 using boronic acid 6 (blue and red) was faster than those using boronic esters.

[0254] The faster transmetalation rate using boronate 15 was attributed to the boronate's bettersolubility in THF. Boronate served as a base to facilitate the formation of Ni-OH. The pH of K3PO4 and boronate solutions in THF were measured. Under these transmetalation conditions, the pH for the boronate reaction was found to be around 9. In contrast, with an excess of K3PO4, even upon the addition of water, the concentration of OH anion remained too low to be detected by pH paper. Under catalytic conditions, the discernible difference in pH values between the phases affects the speciation of boron species, resulting in a higher concentration of boronic acid or ester in the bulk phase. Reactions of Complex [Ni(PPh2Me)(^-OH)(o-Tol)]2 (16) with B(p-Tol)Pin (5), BPh(OH)2 (6), and K[B(p-Tol)Pin(OH)] (15)

[0255] The reactivity of Ni-OH complex 16 towards both boronic acid 6 and ester 5 was higherthan that of complex 13 (Figure 24). Notably, the transmetalation reaction of complex 16 with boronate 15 exhibited low reactivity, potentially attributable to the competition between Ni-OH and free OH anion for boron coordination. In summary, the fast transmetalation of dimeric Ni-OH complex 16 with a boronic acid and ester, leading to the liberation of biaryl product and the regeneration of highly active monomeric Ni(0) species, suggested a plausible pathway for 16 to re-enter the catalytic cycle. Reactions of Complexes 13 and 16 with K[B(p-Tol)Pin(OH)] (B) in the Presence of 18-Crown-6

[00256] In the cases of complexes 13, the reactions exhibited a slightly enhanced productconversion over 24 hours compared to reactions without 18-crown-6 (vide supra). This improvement was likely ascribed to the ability of 18-crown-6 to enhance the solubility of boronate in THF (Scheme 2). Noteworthy was the transmetalation reaction between 16 and boronate 15, which displayed the lower reactivity than that without 18-crown-6. This could be attributed to the competitive binding between Ni-OH and free OH anion for boron coordination (Scheme 2). Scheme 2. Proposed Mechanisms of Boronate 15 Reacting with Complexes 13 and 16Role of the Base in the Ni-ProPhos Catalytic System

[00257] Addition of BPh(OH)2 (6, 4.9 mg, 0.040 mmol, 2.0 equiv) to the isolatedPPh2CH2CH2CH2OH (9, 5.0 mg, 0.020 mmol, 1.0 equiv) in C6D6 led to an immediate formation of the phosphine-borane adduct PPh2CH2CH2CH2OB(OH)Ph, as detected by1H (Figures 25A-C) and31P{1H} NMR (Figure 26B). The result was similar to the observation in the analogousreaction using 9 and 22 (vide supra). KOH (2.3 mg, 0.040 mmol, 2.0 equiv) was added along with a trace amount H2O (1 ^L) into this reaction mixture, resulting in a rapid regeneration of PPh2CH2CH2CH2OH in situ as detected by1H and31P{1H} NMR (Figure 26C). These results indicated that deboronation of the phosphine-borane adduct by base was feasible and rapid. This OH regeneration in the ligand will be a fast and important step in this catalytic system.

[0258] Next, a catalytic investigation involving a "base-free" reaction was carried out.Specifically, the cross-coupling reaction between 4-bromoacetophenone 4 and phenylboronic acid 6 was explored, employing the well-established kinetic experimental approach with a 0.5 mol% Ni loading. Notably, this reaction yielded an only 1% of the desired cross-coupled product (corresponding to a turnover number, TON, of 2). This result implied that a single phosphine ligand attached to the nickel center facilitated one transmetallation event, with the catalyst resting state featuring two phosphine ligands. Collectively, these studies revealed that while the Ni-ProPhos complex demonstrated significant stoichiometric "base-free" transmetalation reactivity, the presence of a base proved imperative to achieve catalytic transmetalation. Example 6. Substrate Study Using ProPhos 9 General Procedure for Determining the Yield of the Biaryl Compounds 2-MeTHF / H2O System

[0259] A vial was charged with Ni(cod)2 (0.0002–0.006 mmol, 0.10–3.0 mol%), 2-MeTHF (4mL), and PPh2CH2CH2CH2OH (9, 0.0008–0.024 mmol, 0.40–12.0 mol%) and the resulting deep red stock solution was stirred for 0.5 hour. This solution (0.4 mL) was transferred to a vial containing the aryl boronic ester or acid (0.22–0.30 mmol), aryl halide (if solid, 0.20 mmol), and K3PO4(0.50 mmol). After that, aryl halide (if liquid, 0.20 mmol) and H2O (80 mL) were added. The reaction was placed in a shaker, the agitation speed was set to 800 rpm, and heated to 70 °C for 16 hours, then cooled to rt. The n-decane (internal standard, 0.1 mmol) was added to the reaction mixture. Then, the reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (2 x 5 mL). The combined aqueous layers were extracted with EtOAc (5 mL). An aliquot of the combined organic layer was analyzed by gas chromatography to obtain the GC yield (Rf values for each compounds determined, vide infra). The combined organic layers were concentrated in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc).i-PrOH System

[00260] A vial was charged with NiCl2^6H2O (0.002–0.006 mmol, 1.0–3.0 mol%), i-PrOH (4mL), and PPh2CH2CH2CH2OH (9, 0.008–0.024 mmol, 4.0–12.0 mol %) and the resulting deep red stock solution was stirred for overnight. (Poor solubility of the Ni(II) precursor in the i-PrOH was observed. For expedited procedures, direct weighing of Ni and ligand precursors was feasible for 3 mol% catalysis. However, the stock solution was required for the 1 mol% catalysis.) This solution (0.4 mL) was transferred to a vial containing the aryl boronic acid (0.24–0.30 mmol), aryl halide (if solid, 0.20 mmol), and K3PO4(0.50 mmol). After that, aryl halide (if liquid, 0.20 mmol) was added. The reaction was placed in a shaker, the agitation speed was set to 800 rpm, and heated to 70 °C for 16 hours, then cooled to rt. The n-decane (internal standard, 0.1 mmol) was added to the reaction mixture. Then, the reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (2 x 5 mL). The combined aqueous layers were extracted with EtOAc (5 mL). An aliquot of the combined organic layer was analyzed by gas chromatography to obtain the GC yield (Rf values for each compounds determined, vide infra). The combined organic layers were concentrated in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc).

[00261] Air-stable complex Ni(PPh2CH2CH2CH2OH)2Cl(o-Tol) (21, 0.006 mmol, 3.0 mol%) canalso be used as a precatalyst without adding 9 and a reducing reagent in i-PrOH (Figure 27). Characterization Data for Ni-SMC Products

[00262] Multiple scales (0.2–1 mmol) were conducted for synthesizing this compound (Peter etal., “A Green Direct Preparation of a Magnetic Ordered Mesoporous Carbon Catalyst Containing Fe–Pd Alloys: Application to Suzuki–Miyaura Reactions in Propane-1,2-Diol,” New J. Chem. 41(12):4931–4936 (2017), which is hereby incorporated by reference in its entirety). For example, 4-bromophenylethanone (40 mg, 0.20 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2- dioxaborolane (48 mg, 0.22 mmol, 1.1 equiv) were used to give a white solid (41 mg, 0.19 mmol, 97%).1H NMR (400.30 MHz, CDCl3) δ: 8.06 – 7.99 (m, 2H), 7.71 – 7.65 (m, 2H), 7.57 – 7.51 (m, 2H), 7.31 – 7.27 (m, 2H), 2.64 (s, 3H, COCH3), 2.41 (s, 3H, CH3).13C{1H} NMR (100.67MHz, CDCl3) δ: 197.9 (s, C=O), 145.9 (s), 138.4 (s), 137.1 (s), 135.8 (s), 129.8 (s), 129.1 (s), 127.3 (s), 127.1 (s), 26.8 (s, COCH3), 21.3 (s, CH3). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C15H15O 211.11, found 211.11.

[00263] Multiple scales (0.2–1 mmol) were conducted for synthesizing this compound (Wang etal., “Entangled Pd Complexes over Fe3O4@SiO2 as Supported Catalysts for Hydrogenation and Suzuki Reactions,” Catal. Sci. Technol.4(5):1333–1339 (2014), which is hereby incorporated by reference in its entirety). For an example using 0.1 mol% Ni, 4-bromophenylethanone (40 mg, 0.20 mmol, 1.0 equiv) and phenylboronic acid (37 mg, 0.30 mmol, 1.5 equiv) were used. The reaction was repeated 5 times. The combined mixture gave a white solid (180 mg, 0.93 mmol, 93%).1H NMR (400.30 MHz, CDCl3) δ:8.07 – 7.99 (m, 2H), 7.73 – 7.66 (m, 2H), 7.65 – 7.60 (m, 2H), 7.48 (tt, J = 6.7, 0.9 Hz, 2H), 7.43 – 7.38 (m, 1H), 2.64 (s, 3H, CH3).13C{1H} NMR (100.67 MHz, CDCl3) δ: 197.9 (s, C=O), 145.9 (s), 140.0 (s), 136.0 (s), 129.1 (s), 129.1 (s), 128.4 (s), 127.4 (s), 127.4 (s), 26.8 (s, CH3). MS (ESI-TOF, CH3CN) m / z: [M + Na]+calculated for C15H11NaO 218.07, found 218.07.

[00264] 6-Chloroquinoline (33 mg, 0.20 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane (52 mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (41 mg, 0.19 mmol, 93%) (Wilson et al., “Cyrene as a Bio-Based Solvent for the Suzuki–Miyaura Cross- Coupling,” Synlett 29(05):650–654 (2018), which is hereby incorporated by reference in its entirety).1H NMR (400.30 MHz, CDCl3) δ: 8.91 (dd, J = 4.3, 1.7 Hz, 1H), 8.23 – 8.13 (m, 2H), 8.01 – 7.94 (m, 2H), 7.65 – 7.61 (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 7.35 – 7.29 (m, 2H), 2.43 (s, 3H, CH3).13C{1H} NMR (100.67 MHz, CDCl3) δ: 150.2 (s), 147.6 (s), 139.3 (s), 137.7 (s),137.4 (s), 136.2 (s), 129.8 (s), 129.7 (s), 129.2 (s), 128.5 (s), 127.3 (s), 125.1 (s), 121.4 (s), 21.2 (s, CH3). MS (ESI-TOF, CH3CN) m / z: [M + K]+calculated for C16H13NK 258.06, found 258.06.

[00265] 4-Bromophenylethanone (40 mg, 0.20 mmol, 1.0 equiv) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (49 mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (37 mg, 0.19 mmol, 94%) (Chen et al., “Nickel-Catalyzed Cross-Coupling of Phenols and Arylboronic Acids Through an In Situ Phenol Activation Mediated by PyBroP,” Chem. – A Eur. J.17(14):4038–4042 (2011), which is hereby incorporated by reference in its entirety).1H NMR (400.30 MHz, CDCl3) δ: 8.89 (dd, J = 2.4, 0.9 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.12 – 8.03 (m, 2H), 7.92 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.75 – 7.63 (m, 2H), 7.41 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 2.65 (s, 3H, CH3).13C{1H} NMR (100.67 MHz, CDCl3) δ: 197.7 (s, C=O), 149.5 (s), 148.5 (s), 142.5 (s), 136.7 (s), 135.6 (s), 134.6 (s), 129.3 (s), 127.5 (s), 123.8 (s), 26.9 (s, CH3). MS (ESI- TOF, CH3OH) m / z: [M + H]+calculated for C13H12NO 198.09, found 198.09.

[00266] 6-Chloroquinoline (33 mg, 0.20 mmol, 1.0 equiv) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (49 mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (35 mg, 0.18 mmol, 85%).1H NMR (400.30 MHz, (CD3)2S=O) δ: 9.10 – 9.04 (m, 1H), 8.94 (dt, J = 4.5, 2.1 Hz, 1H), 8.63 (dt, J = 5.0, 1.3 Hz, 1H), 8.48 – 8.42 (m, 1H), 8.39 (d, J = 4.0 Hz, 1H), 8.26 (ddd, J = 8.3, 3.5, 2.0 Hz, 1H), 8.15 (p, J = 2.0 Hz, 2H), 7.66 – 7.51 (m, 2H).13C{1H} NMR (100.67 MHz, (CD3)2S=O) δ: 151.1 (s), 148.9 (s), 148.0 (s), 147.3 (s), 136.5 (s), 135.0 (s), 134.9 (s), 134.6 (s), 129.8 (s), 128.5 (s), 128.2 (s), 126.1 (s), 124.0 (s), 122.1 (s). MS (ESI-TOF, CH3OH) m / z: [M + H]+calculated for C14H11N2207.09, found 207.09.

[00267] 4-Bromophenylethanone (40 mg, 0.20 mmol, 1.0 equiv) and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (68 mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (51 mg, 0.18 mmol, 92%).1H NMR (400.30 MHz, CDCl3) δ: 7.94 (dq, J = 8.2, 1.5 Hz, 2H), 7.89 (q, J = 1.1 Hz, 1H), 7.70 (q, J = 1.1 Hz, 1H), 7.54 (dq, J = 8.3, 1.6 Hz, 2H), 7.37 (tdd, J = 8.1, 6.5, 3.5 Hz, 3H), 7.28 (d, J = 7.6 Hz, 2H), 5.36 (s, 2H, CH2 in Bn), 2.65 – 2.55 (2, 3H, CH3).13C{1H} NMR (100.67 MHz, CDCl3) δ: 197.6 (s, C=O), 137.5 (s), 137.4 (s), 136.2 (s), 135.2 (s), 129.3 (s), 129.1 (s), 128.5 (s), 128.0 (s), 127.0 (s), 125.4 (s), 122.6 (s), 56.6 (s, CH2 in Bn), 26.7 (s, CH3). HRMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C18H17N2O 277.1335, found 277.1328.

[00268] 3-Bromopyridin-2-amine (33 mg, 0.20 mmol, 1.0 equiv) and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (68 mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (43 mg, 0.17 mmol, 87%).1H NMR (400.30 MHz, (CD3)2S=O) δ: 8.18 (d, J = 0.8 Hz, 1H), 7.87 (dd, J = 4.9, 1.8 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 7.49 (dd, J = 7.4, 1.8 Hz, 1H), 7.39 – 7.24 (m, 5H, Ph in Bn), 6.61 (dd, J = 7.4, 4.9 Hz, 1H), 5.59 (s, 2H, NH2), 5.35 (s, 2H, CH2in Bn).13C{1H} NMR (100.67 MHz, (CD3)2S=O) δ: 156.2 (s), 145.9 (s), 138.0 (s), 137.4 (s), 135.9 (s), 128.6 (s), 128.5 (s), 127.8 (s), 127.7 (s), 118.0 (s), 113.2 (s), 112.2 (s), 55.0 (s, CH2 in Bn). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C15H14N4251.13, found 251.13.

[00269] 5-Bromopyrimidine (32 mg, 0.20 mmol, 1.0 equiv) and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (68 mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (41 mg, 0.18 mmol, 91%) (Handa et al., “Sustainable Fe–Ppm Pd Nanoparticle Catalysis of Suzuki-Miyaura Cross-Couplings in Water,” Science 349(6252):1087–1091 (2015), which is hereby incorporated by reference in its entirety).1H NMR (400.30 MHz, CDCl3) δ: 9.06 (s, 1H), 8.82 (s, 2H), 7.87 (d, J = 0.8 Hz, 1H), 7.71 (d, J = 0.8 Hz, 1H), 7.43 – 7.33 (m, 3H), 7.31 – 7.27 (m, 2H), 5.37 (s, 2H, CH2 in Bn).13C{1H} NMR (100.67 MHz, CDCl3) δ: 156.8 (s), 153.5 (s), 137.0 (s), 135.8 (s), 129.2 (s), 128.6 (s), 128.0 (s), 127.0 (s), 126.9 (s), 116.6 (s), 56.7 (s, CH2 in Bn). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C14H13N4237.11, found 237.11.

[00270] 5-Bromopyrimidine (32 mg, 0.20 mmol, 1.0 equiv) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (58 mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (36 mg, 0.18 mmol, 92%). This compound (Lou et al., “Palladium / Tris(Tert-Butyl)Phosphine- Catalyzed Suzuki Cross-Couplings in the Presence of Water,” Adv. Synth. Catal. 352(11– 12):2081–2084, (2010), which is hereby incorporated by reference in its entirety) can be synthesized by one other literature procedure (no HRMS data reported). The NMR data was reported using CDCl3, but we found its low solubility in CDCl3. Thus, (CD3)2S=O was used as the solvent.1H NMR (400.30 MHz, (CD3)2S=O) δ: 11.28 (s, 1H, NH), 9.13 (s, 2H), 9.11 (s, 1H), 8.01 – 7.96 (m, 1H), 7.58 – 7.48 (m, 2H), 7.43 (t, J = 2.8 Hz, 1H), 6.53 (ddd, J = 3.0, 2.0, 0.8 Hz, 1H). 13C{1H} NMR (100.67 MHz, (CD3)2S=O) δ: 156.2 (s), 154.4 (s), 136.2 (s), 134.8 (s), 128.4 (s), 126.7 (s), 124.5 (s), 120.0 (s), 118.8 (s), 112.4 (s), 101.8 (s). HRMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C12H10N3196.0869, found 196.0889.

[00271] 5-Bromopyrimidine (32 mg, 0.20 mmol, 1.0 equiv) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (49 mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (18 mg, 0.11 mmol, 57%). Isolated mixture contains a small amount of 5,5'-bipyrimidine byproduct (15%), which was very difficult to be removed due to the similar polarity (Ye et al., “Ligand-Promoted C3-Selective Arylation of Pyridines with Pd Catalysts: Gram-Scale Synthesis of (±)-Preclamol,” J. Am. Chem. Soc.133(47):19090–19093, (2011), which is hereby incorporated by reference in its entirety).

[00272] 1H NMR (400.30 MHz, CDCl3) δ: 9.28 (s, 1H), 8.98 (s, 2H), 8.87 (dd, J = 2.4, 0.9 Hz,1H), 8.74 (dd, J = 4.9, 1.6 Hz, 1H), 7.91 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.47 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H).13C{1H} NMR (100.67 MHz, CDCl3) δ: 158.3 (s), 155.0 (s), 150.3 (s), 148.0 (s), 134.4 (s), 131.5 (s), 130.2 (s), 124.1 (s). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C9H8N3158.07, found 158.07.

[00273] 6-Chloroquinoline (33 mg, 0.20 mmol, 1.0 equiv) and phenylboronic acid (29 mg, 0.24mmol, 1.2 equiv) were used to give a white solid (38 mg, 0.19 mmol, 93%) (Xu et al., “Nickel- Catalyzed Efficient and Practical Suzuki−Miyaura Coupling of Alkenyl and Aryl Carbamates with Aryl Boroxines,” Org. Lett.12(4):884–887 (2010), which is hereby incorporated by reference in its entirety).1H NMR (400.30 MHz, CDCl3) δ: 8.92 (dd, J = 4.3, 1.7 Hz, 1H), 8.24 – 8.15 (m, 2H), 8.03 – 7.97 (m, 2H), 7.77 – 7.69 (m, 2H), 7.54 – 7.47 (m, 2H), 7.45 – 7.38 (m, 2H).13C{1H} NMR (100.67 MHz, CDCl3) δ: 150.5 (s), 147.9 (s), 140.5 (s), 139.5 (s), 136.4 (s), 130.1 (s), 129.4 (s), 129.1 (s), 128.6 (s), 127.9 (s), 127.6 (s), 125.6 (s), 121.6 (s). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C15H12N 206.09, found 206.09.

[00274] 6-Chloroquinoline (33 mg, 0.20 mmol, 1.0 equiv) and (4-methoxyphenyl)boronic acid(37mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (44 mg, 0.19 mmol, 94%) (Beromi et al., “Mechanistic Study of an Improved Ni Precatalyst for Suzuki–Miyaura Reactions of Aryl Sulfamates: Understanding the Role of Ni(I) Species,” J. Am. Chem. Soc.139(2):922–936 (2017), which is hereby incorporated by reference in its entirety).1H NMR (400.30 MHz, CDCl3) δ: 8.90 (dd, J = 4.2, 1.7 Hz, 1H), 8.25 – 8.11 (m, 2H), 7.99 – 7.94 (m, 2H), 7.71 – 7.63 (m, 2H), 7.44 – 7.38 (m, 1H), 7.08 – 7.01 (m, 2H), 3.88 (s, 3H, OMe).13C{1H} NMR (100.67 MHz, CDCl3) δ: 159.7 (s), 150.3 (s), 147.6 (s), 139.1 (s), 136.2 (s), 132.9 (s), 123.0 (s), 129.2 (s), 128.7 (s), 128.7 (s), 124.8 (s), 121.6 (s), 114.6 (s), 55.6 (s, OMe). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C16H14NO 236.10, found 236.10.

[00275] 6-Chloroquinoline (33 mg, 0.20 mmol, 1.0 equiv) and (4-fluorophenyl)boronic acid (34mg, 0.24 mmol, 1.2 equiv) were used to give a white solid (41 mg, 0.18 mmol, 90%) (Sahoo et al., “A Robust Iron Catalyst for the Selective Hydrogenation of Substituted (Iso)Quinolones,” Chem. Sci.9(42):8134–8141 (2018), which is hereby incorporated by reference in its entirety).1H NMR (400.30 MHz, CDCl3) δ: 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.25 – 8.13 (m, 2H), 7.99 – 7.90 (m, 2H), 7.72 – 7.63 (m, 2H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.23 – 7.16 (m, 2H).13C{1H} NMR (100.67 MHz, CDCl3) δ: 164.1 (s), 161.7 (s), 150.6 (s), 147.8 (s), 138.5 (s), 136.6 (d, J = 3 Hz), 136.3 (s), 130.2 (s), 129.2 (d, J = 8 Hz), 128.6 (s), 125.5 (s), 121.7 (s), 116.0 (d, J = 22 Hz).19F{1H} NMR (470.61 MHz, CDCl3) δ: -114.88 (s). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C15H11NF 224.08, found 224.08.

[00276] 3-Bromopyridin-2-amine (33 mg, 0.20 mmol, 1.0 equiv) and pyridin-3-ylboronic acid(37 mg, 0.30 mmol, 1.5 equiv) were used to give a white solid (20 mg, 0.12 mmol, 58%) (Kearney et al., “Synthesis of Nitrogen Heterocycles by the Ring Opening of Pyridinium Salts,” Angew. Chem. Int. Ed. 45(46):7803–7806 (2006), which is hereby incorporated by reference in its entirety).1H NMR (400.30 MHz, (CD3)2S=O) δ: 8.61 (dd, J = 2.4, 0.9 Hz, 1H), 8.56 (dd, J = 4.8, 1.6 Hz, 1H), 7.99 (dd, J = 5.0, 1.9 Hz, 1H), 7.86 (dt, J = 7.8, 2.0 Hz, 1H), 7.46 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.36 (dd, J = 7.3, 1.9 Hz, 1H), 6.68 (dd, J = 7.3, 4.9 Hz, 1H), 5.70 (s, 2H, NH2). 13C{1H} NMR (100.67 MHz, (CD3)2S=O) δ: 156.8 (s), 149.2 (s), 148.3 (s), 147.8 (s), 138.0 (s), 136.1 (s), 134.1 (s), 123.8 (s), 117.1 (s), 113.1 (s). MS (ESI-TOF, CH3OH) m / z: [M + H]+calculated for C10H10N3172.09, found 172.09.

[00277] 3-Chloropicolinonitrile (28 mg, 0.20 mmol, 1.0 equiv) and pyridin-3-ylboronic acid (37mg, 0.30 mmol, 1.5 equiv) were used to give a white solid (30 mg, 0.17 mmol, 83%).1H NMR (400.30 MHz, CDCl3) δ: 8.81 – 8.74 (m, 3H), 7.98 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.89 (dd, J = 8.0, 1.6 Hz, 1H), 7.65 (dd, J = 8.0, 4.7 Hz, 1H), 7.49 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H).13C{1H} NMR (100.67 MHz, CDCl3) δ: 150.8 (s), 150.4 (s), 149.4 (s), 138.9 (s), 137.7 (s), 136.2 (s), 132.7 (s), 131.5 (s), 127.0 (s), 123.8 (s), 116.6 (s, CN). HRMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C11H8N3182.0713, found 182.0698.

[00278] 6-Chloroquinoline (33 mg, 0.20 mmol, 1.0 equiv) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (55 mg, 0.30 mmol, 1.5 equiv) were used to give a white solid (51 mg, 0.19 mmol, 95%).1H NMR (400.30 MHz, CDCl3) δ: 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.38 (s, 1H), 8.22 – 8.12 (m, 2H), 7.94 – 7.82 (m, 2H), 7.47 – 7.40 (m, 1H), 4.07 (s, 3H, OCH3), 4.07 (s, 3H, OCH3). 13C{1H} NMR (100.67 MHz, CDCl3) δ: 168.4 (s), 165.0 (s), 158.1 (s), 150.9 (s), 147.8 (s), 136.3 (s), 131.9 (s), 130.7 (s), 129.7 (s), 128.4 (s), 127.6 (s), 121.6 (s), 115.7 (s), 55.1 (s, OCH3), 54.4 (s, OCH3). HRMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C15H13N3O2268.1081, found 268.1061.

[00279] 2-Chloropyridine (19 mL, 0.20 mmol, 1.0 equiv) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (55 mg, 0.30 mmol, 1.5 equiv) were used to give a white solid (41 mg, 0.19 mmol, 94%) (Noël et al., “Suzuki–Miyaura Cross-Coupling of Heteroaryl Halides and Arylboronic Acids in Continuous Flow,” Org. Lett. 13(19):5180–5183 (2011), which is hereby incorporated by reference in its entirety).1H NMR (400.30 MHz, CDCl3) δ: 8.90 (s, 1H), 8.67 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H), 7.83 (dt, J = 8.1, 1.1 Hz, 1H), 7.72 (ddd, J = 8.1, 7.4, 1.8 Hz, 1H), 7.22 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 4.09 (s, 3H, OCH3), 4.06 (s, 3H, OCH3).13C{1H} NMR (100.67 MHz, CDCl3) δ: 168.4 (s), 165.2 (s), 160.0 (s), 152.0 (s), 149.8 (s), 136.4 (s), 124.1 (s), 122.3 (s), 114.8 (s), 55.2 (s), 54.3 (s). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C11H12N3O2218.09, found 218.09. Example 7. Crystallographic Data

[0280] X-ray diffraction data were collected on a Bruker D8 VENTURE diffractometer usingCu K^ radiation (for 11 and 17) or Mo K^ radiation (13) (Figures 38-40). Crystal data, datacollection and refinement parameters are summarized in Table 6. The structures were solved using a dual-space method and standard difference map techniques, and were refined by full-matrix least-squares procedures on F2with SHELXTL (Version 2019 / 1) (Sheldrick, G. M. “Crystal Structure Refinement with SHELXL,” Acta. Cryst. C71:3–8 (2015); Sheldrick, G. M. “SHELXTL, An Integrated System for Solving, Refining, and Displaying Crystal Structures from Diffraction Data,” University of Göttingen, Göttingen, Federal Republic of Germany (1981), which is hereby incorporated by reference in its entirety). All hydrogen atoms bound to carbon were placed in calculated positions and refined with a riding model [Uiso(H) = 1.2–1.5Ueq(C)] (For 11, hydrogen atoms bound to oxygen were located on the difference map and refined with a riding model [Uiso(H) = 1.2Ueq(O)]).Table 6. Crystal, Intensity Collection, and Refinement Data for Complexes 11, 13 and 17Example 8. Results and Discussion of Examples 1-7

[0281] Ligand Design. Diphenylmethylphosphine (Ph2MeP) is currently recognized as one ofthe most effective catalysts in Ni-SMC (Haibach et al., “Enabling Suzuki–Miyaura Coupling ofLewis-Basic Arylboronic Esters with a Nonprecious Metal Catalyst,” Chem. Sci.13(43):12906–12912 (2022), which is hereby incorporated by reference in its entirety). To develop a scaffoldingligand, a series of ligands featuring hydroxyl, ester, and silyl ether groups tethered to diphenylphosphine through linkages of various lengths were synthesized (Figure 28A). The studies began with testing these ligands in a model SMC of 4 and 5 to afford 7 using a catalyst loading of 0.5 mol% at 60 ºC. A comparison of their performances against Ph2MeP (entry 1, Figure 28A) after 24 hours revealed that the ethanol-tethered phosphine ligand 10, 2- (diphenylphosphino)ethanol, led to a reduced reactivity (entry 2). In contrast, ligands with longer linkae tethered basic groups generally enhanced reactivity (entries 3-6), with the propanol-tethered phosphine ligand (ProPhos) 9, 3-(diphenylphosphino)propanol, being the most effective (entry 3). Protecting the hydroxyl group with a tert-butyldimethylsilyl (TBS) group resulted in decreased reactivity (entry 7). An analysis at the 3-hour time point indicated that ProPhos's enhanced performance was attributed to an acceleration in reaction rate.

[0282] The kinetic analysis of the SMC further demonstrated the higher reactivity of ProPhos incomparison to Ph2MeP (Figure 28A). Fitting the time-course data to a first-order kinetic modelresulted in kobs for SMC of 4 and 5 catalyzed by 9, 10, and Ph2MeP. The rate with ProPhos 9 (k2)was higher than that with PPh2Me (k3) or 2-(diphenylphosphino)ethanol 10 (k4) by several folds. Applying ProPhos to SMC of 4 with 6 resulted in complete conversion to 8 within 3 hours (k1).

[0283] The excellent performance of ProPhos prompted the investigation of its coordination tonickel (Figure 31). Combining Ni(cod)2with two equivalents of ProPhos at room temperature afforded an orange crystal 11. Analysis of 11 through single crystal X-ray diffraction and NMR spectroscopy revealed that ProPhos coordinates to nickel via the phosphine, while the hydroxyl group remained pendent, not interacting with nickel. In the presence of four equivalents of ProPhos, the reaction afforded a mixture of 11 and Ni(ProPhos)412.

[0284] Kinetics. To probe the mechanistic attributes for the faster rate with ProPhos 9, thekinetic orders of the substrates and the catalysts were determined and compared using Variable Time Normalization Analysis (VTNA) (Nielsen et al., “Visual Kinetic Analysis,” Chem. Sci. 10(2):348–353 (2019), which is hereby incorporated by reference in its entirety). With PPh2Me as the ligand, the reaction exhibited first-order dependence on the nickel catalyst and was independentof both [4] and [5] (Figure 28B). In contrast, with ProPhos 9, the rate displayed first-orderdependence on both the catalyst and the nucleophile, [5] or [6].

[0285] Catalyst Resting State. Subsequently, the catalyst resting state in (PPh2Me)Ni-catalyzedSMC of o-tolyl bromide and 5 was determined by monitoring the reaction using31P NMR spectroscopy. During the reaction, a31P NMR resonance at 8.6 ppm was observed (Figure 32). Independently, complexes (PPh2Me)2Ni(o-Tol)Cl 13 and (PPh2Me)2Ni(o-Tol)Br 14 were prepared through oxidative addition of Ni(PPh2Me)418 to o-Tol chloride and bromide, respectively. By comparing the31P NMR signals, the catalyst resting state in (PPh2Me)Ni-catalyzed SMC was inferred to likely be (PPh2Me)2Ni(o-Tol)Br 14 (Figures 32 and 33A).

[0286] Synergistically, (ProPhos)Ni-catalyzed SMC of o-Tol chloride with 5 was monitoredusing31P NMR spectroscopy for a direct comparison. The reaction mixture displayed a31P NMR signal at 13.4 ppm, representing the major catalyst species in the resting state (Figure 34). Ni(ProPhos)2(o-Tol)Cl 21 was synthesized through ligand exchange of Ni(TMEDA)Cl(o-Tol) (TMEDA = tetramethylethylenediamine) (Magano et al., “Development of an Air-Stable, Broadly Applicable Nickel Source for Nickel-Catalyzed Cross-Coupling,” ACS Catal. 5(5):3120–3123 (2015); Shields et al., “A Modular, Air-Stable Nickel Precatalyst,” Org. Lett. 17(9):2166–2169 (2015), which are hereby incorporated by reference in their entirety) with ProPhos 9. Ni(ProPhos)2(o-Tol)Cl 21 displayed a characteristic31P NMR resonance at 13.4 ppm, consistent with the major signal observed during the catalytic reaction. Thus, the resting state in (ProPhos)Ni- catalyzed SMC was attributed to 21 (Figures 33B and 35).

[0287] Organometallic Studies. The transmetalation reactivity of 13 and 21 with boronic acid6, ester 5, and boronate 15 was investigated (Figure 33) (Lennox et al., “Selection of Boron Reagents for Suzuki–Miyaura Coupling,” Chem. Soc. Rev.43(1):412–443 (2014), which is hereby incorporated by reference in its entirety). The formation of boronate 15 from 5 and KOH was a slow process, requiring heating at 70 ºC for 16 hours. No reaction occurred between 13 and 5, regardless of whether K3PO4was present. Additionally, the reactions of 13 with both PhB(OH)26 and boronate 15 were slow, forming 19 and 20, respectively, but in low yields (Figure 33A).

[0288] Subjecting 13 to KOH resulted in the formation of 16, appearing as a mixture of fourdiastereomers (Figures 5 A-C). The1H signals of the OH groups were identified at -1.75, -1.87, - 3.34, 3.35, -5.31, and -5.51 ppm, diagnostic for cis- and trans-m-O-dimers, respectively, as previously observed experimentally (Christian et al., “Nickel Hydroxo Complexes as Intermediates in Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling,” Organometallics 33(9):2134–2137 (2014), which is hereby incorporated by reference in its entirety) and verifiedcomputationally (Payard et al., “Taming Nickel-Catalyzed Suzuki-Miyaura Coupling: A Mechanistic Focus on Boron-to-Nickel Transmetalation,” ACS Catal. 8(6):4812–4823 (2018), which is hereby incorporated by reference in its entirety). The identity of 16 was further confirmed by HRMS. An analysis of the1H / 31P{1H}-HMBC spectra allowed the assignment of the resonances for each diastereomer (Figure 5A-C). Although the co-existence of diastereomers has complicated the attempts to obtain single-crystal structural characterization, 16 underwent C–O bond-forming reductive elimination to form 17, whose structure was elucidated via X-ray crystallography. In contrast to nickel(di-hydroxide) (Inada et al., “Synthesis of Biaryls via Cross- Coupling Reaction of Arylboronic Acids with Aryl Chlorides Catalyzed by NiCl2 / Triphenylphosphine Complexes,” Tetrahedron 56(44):8657–8660 (2000), which is hereby incorporated by reference in its entirety) or nickel(di-alkoxide) (Day et al., “Elucidating Electron- Transfer Events in Polypyridine Nickel Complexes for Reductive Coupling Reactions,” Nat. Catal.6(3):244–253 (2023), which is hereby incorporated by reference in its entirety), which have been reported to exhibit no reactivity towards nucleophiles, complex 16 reacted rapidly with 5 and6, to produce 19 and 20, respectively (Figure 24). The reaction of 16 with 15 was slightly slowercompared to the reaction of 13 with 15. The modest yields were attributed to complications arising from the comproportionation of 16 with the in-situ generated 18. In comparing the relative rates of stoichiometric reactions, the steps were labeled in kinetically slow pathways as "slow", the rate- limiting step in the productive pathway as "rate-determining", and the rapid processes within the productive pathway as "fast" (Figure 33).

[0289] The transmetalation reactivity of 21 was investigated (Figure 33B). Subjecting 21 toeither 5 or 15 led to no significant change in the1H and31P NMR spectra. Over 16 hours at room temperature, the reaction mixture yielded only trace amounts of 20, regardless the presence or absence of K3PO4. However, combining 21 with PhB(OH)26 resulted in the rapid formation of19, even without K3PO4 (Figure 36); K3PO4 further accelerated the reaction. Upon treating 21 with4-OMe-C6H4B(OH)222, the formation of a new species 23 was observed. The1H NMR spectrum of 22 displayed a resonance at 3.81 ppm, attributed to the OH (Ha), and AA'XX' aromatic resonances at 7.63 and 6.79 ppm (Hband Hc) (Figure 33C). In 23, Hashifts downfield to 4.74 ppm, accompanied by minor downfield shifts of Hband Hcsignals to 7.73 and 6.85 ppm, respectively. A new methyl signal emerges at 3.30 ppm (Hd), which is slightly more upfield compared to the methoxy signal in 22.

[0290] In comparing the spectra of 23 with that of 21 (Figure 33C), the OH signal of ProPhos(He) was observed to undergo a slight downfield shift from 0.79 to 0.84 ppm. Moreover, the resonance at 3.20 ppm, corresponding to the a-H of the alcohol (Hf'), split into two signals at 3.75 (Hf) and 3.20 (Hg) ppm. Additionally, the signal at 2.72 ppm, corresponding to the methyl group on the o-Tol ligand, shifted upfield to 2.71 ppm (Hh).

[0291] Analysis of the 1H NMR spectra led to assignment of the series of new resonances toboronic ester 23 formed from the association of 21 with 22 followed by elimination of a water molecule. The connectivity of the H signals of 23 was further verified by1H COSY and1H / 31P{1H}-HMBC (Figures 8-9). To further substantiate the spatial correlation between the nickel catalyst and 22,1H-NOESY experiments was conducted (Figure 37). The spectra unambiguously established a correlation between Haat 4.74 ppm and Hfat 3.75 ppm, supporting the bonding connectivity between ProPhos and the boronic acid. The loss of a water molecule and the formation of a three-coordinate boronic ester was substantiated by the11B NMR signal at 29.3 ppm (Figure 10) (Thomas et al., “Structural, Kinetic, and Computational Characterization of the Elusive Arylpalladium(II)boronate Complexes in the Suzuki–Miyaura Reaction,” J. Am. Chem. Soc.139(10):3805–3821 (2017); Lennox et al., “Selection of Boron Reagents for Suzuki–Miyaura Coupling,” Chem. Soc. Rev.43(1):412–443 (2014), which are hereby incorporated by reference in their entirety). At a higher temperature, the equilibrium favored the formation of aryl boroxine 22', which drove the hydrolysis of 23 (Figure 18). Integration of peaks assigned to 21 and 23 allowed the estimation of the equilibrium constant (K) for the association of 21 with 22 to be approximately 1 at room temperature.

[0292] Subsequently, the effect of strong bases on the speciation of the nickel catalyst andtransmetalation was probed. Addition of KOH to 21 led to dissociation of chloride and formation of 24 as a mixture of two diastereomers, in which the deprotonated alcohol reached around to chelate on nickel. However, 24 was inactive with 5, and it reacted with PhB(OH)2 6 slowly compared to 21, giving 19 in 22% yield over 1 hour.

[0293] Proposed Mechanisms. Collectively, the data suggested two distinct scenarios for SMCcatalyzed by Ni(PPh2Me) and Ni(ProPhos), respectively (Figures 29A-B). The mechanism of reactions facilitated by PPh2Me followed a classic "nickel-oxo" pathway (Figure 29A). The rate law (eq 1), with a first-order dependence on [Ni] and no dependence on either substrate, aligned with a turnover-limiting step involving the formation of the Ni-OH species 25, consistent withprevious proposals (Christian et al., “Nickel Hydroxo Complexes as Intermediates in Nickel- Catalyzed Suzuki–Miyaura Cross-Coupling,” Organometallics 33(9):2134–2137 (2014), which is hereby incorporated by reference in its entirety). This was further supported by the observation of 14 as the catalyst resting state. The stoichiometric studies revealed that the nickel-oxo intermediate 25 was stabilized by forming the m-oxo dimer 16 (Nelson et al., “Hydroxide Complexes of the Late Transition Metals: Organometallic Chemistry and Catalysis,” Coord. Chem. Rev.353:278– 294 (2017); Martínez-Prieto et al., “Nickel and Palladium Complexes with Reactive σ-Metal- Oxygen Covalent Bonds,” Isr. J. Chem.60(3–4):373–393 (2020), which are hereby incorporated by reference in their entirety). In these experiments, a rapid transmetelation of 16 with boronic acids and esters was observed leading to reductive elimination product via formation of intermediate 26 (Figure 33A). The fast conversion of 16 suggested that the dissociation of 16 to 25 was rapid. In contrast, the slow reaction of 13 with boronate 15, coupled with the even slower formation of boronate 15 from 5 and a base, suggested that the "boronate pathway" was not kinetically competent. Without wishing to be bound by theory, it has been hypothesized that the hydroxide from 15 might displace the halide on nickel, leading to the formation of the nickel- hydroxide intermediate 25 prior to transmetalation (Butters et al., “Aryl Trifluoroborates in Suzuki–Miyaura Coupling: The Roles of Endogenous Aryl Boronic Acid and Fluoride,” Angew. Chem. Int. Ed. 49(30):5156–5160 (2010), which is hereby incorporated by reference in its entirety).

[0294] The application of ProPhos led to a different pathway (Figure 29B). The rate laws (eqs2-3) indicate that the boron nucleophile was involved during or before the turnover-limiting step. Characterization of the catalyst resting species and organometallic studies suggested that the coordination of the boron nucleophile to the pendant hydroxyl group of ProPhos in 21 to form 23 was indeed a critical pre-equilibrium prior to transmetalation. When ArBPin was used as the nucleophile, the equilibrium predominantly favored dissociation (K << 1). In comparison, when ArB(OH)2 served as the nucleophile, it exhibited a more favorable coordination to ProPhos (K ≈ 1), resulting in the faster catalytic rate of 6 relative to 5 (Figure 28A). The Lewis acidity of ArBPin was greater than that of ArB(OH)2, due to the tendency of boron to rehybridization from sp2to sp3to reduce the angle strain (Hayes et al., “Protodeboronation of (Hetero)Arylboronic Esters: Direct Versus Prehydrolytic Pathways and Self- / Auto-Catalysis,” J. Am. Chem. Soc. 143(36):14814- 14826 (2021), which is hereby incorporated by reference in its entirety). The difference inequilibrium can be attributed to the steric hindrance of ArBPin and the ability of ArB(OH)2to lose a molecule of water to form boronic ester 23 upon ProPhos coordination. NMR experiments characterized the formation of a nickel intermediate, assigned to the adduct 23 formed between 21 and ArB(OH)2. The Nuclear Overhauser Effect (NOE) between ProPhos and the boronic acid substantiates the association between these two species. In Ni(ProPhos)-catalyzed SMC, the formation of a nickel-oxo intermediate 25 was not necessary. It is noteworthy that strong bases, such as KOH, can inhibit the reaction by fully deprotonating ProPhos, leading to the formation of cyclized species 24. In this context, the formation of the nickel-alkoxy species was detrimental. The transmetalation of 23 to form 28 was expected to be the turnover-limiting step, proceeding via the formation of the intramolecular transition state 27.

[0295] Comparing the mechanisms of SMC catalyzed by Ni(PPh2Me) and Ni(ProPhos) shedlight on the mechanistic attributes for the rate acceleration observed with Ni(ProPhos) compared to Ni(PPh2Me). With PPh2Me as the ligand, the turnover rate depended on the formation of the nickel-oxo intermediate through ligand exchange of nickel halide with hydroxide, a step enhanced by a stronger base. In contrast, with PhoPhos, the formation of a nickel-oxo intermediate was not essential for transmetalation. The pendant hydroxyl group in ProPhos can coordinate to boronic acids and esters, directing the approach of the nucleophile and facilitating transmetalation without the need for a base. While a weak base was necessary for catalytic turnover, a strong base could inhibit the reaction by deprotonating ProPhos and forming 24. This ligand-based mechanism alteration and the consequent change in turnover-limiting steps present a strategic alternative to the empirical ligand screening approach. The nucleophilicity of the tethered directing group determines the turnover rate and unveils avenues for further optimization.

[0296] Synthetic Application of ProPhos. Lastly, the performance of ProPhos in Ni-SMC wasevaluated with respect to its compatibility with heterocycles, which are typically challenging substrates (Figure 30) (Haibach et al., “Enabling Suzuki–Miyaura Coupling of Lewis-Basic Arylboronic Esters with a Nonprecious Metal Catalyst,” Chem. Sci.13(43):12906–12912 (2022); Goldfogel et al., “Advancing Base-Metal Catalysis: Development of a Screening Method for Nickel-Catalyzed Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heterocycles,” Org. Process Res. Dev. 26(3):785–794 (2022), which are hereby incorporated by reference in their entirety). Without an extensive catalyst optimization, a mixed solvent system consisting of 2- MeTHF / H2O for ArBPin and iPrOH for ArB(OH)2were employed. Notably, NiCl2·6H2O provedeffective in iPrOH with a range of boronic acids, yielding the desired products. In pharmaceutical process synthesis, replacing Ni(cod)2 with an air-stable and cost-effective nickel precursor, such as NiCl2·6H2O, is highly desirable for large-scale applications.

[0297] With a catalyst loading of 0.5-1 mol%, a variety of substrates containing pyridine,quinoline, pyrazole, pyrimidine, and 2-aminopyridine underwent SMC, forming products in high yields. In cases of lower yields, increasing the catalyst loading to 3 mol% was sufficient to improve the performance. Five-membered heterocycles are uncommon examples in Ni-SMC. Pyrazole derivatives 33-35 proved compatible with the (ProPhos)Ni catalyst. Moreover, 34 and 41, featuring the typically challenging unprotected 2-amino pyridine, were synthesized with excellent yields using (ProPhos)Ni. Compound 41 was previously unattainable with nickel catalysts and requiring a 6 mol% loading of palladium (Kearneyet al., “Synthesis of Nitrogen Heterocycles by the Ring Opening of Pyridinium Salts,” Angew. Chem. Int. Ed.45(46):7803–7806 (2006), which is herebyincorporated by reference in its entirety). Additionally, indole products, such as 35, required noprotection using the (ProPhos)Ni catalyst. Finally, ProPhos was challenged with a catalyst loading as low as 0.1 mol%. Under this condition, the SMC of 4 with 6 proceeded to give a quantitative yield of 8 in 16 hours.

[0298] Transmetalation plays a vital role in determining the turnover rate and the scope of Ni-SMC. The formation of a nickel-oxo intermediate was elucidated to be the turnover-limiting step for (PPh2Me)Ni-catalyzed SMC. These insights helped to design the ProPhos scaffolding ligand, which altered the turnover-limiting step to transmetalation from a pre-coordinated intermediate formed between the ligand's pendant hydroxyl group and boronic acids and esters. This ligand- substrate interaction allowed for faster catalytic turnover rates by directing the nucleophile towards the nickel center. The (ProPhos)Ni catalyst has demonstrated efficiency in SMC across a broad range of heteroarenes with a catalyst loading of 0.5-3 mol%. In the case of arene substrates, the Ni-SMC can operate at catalyst loadings as low as 0.1 mol%. The strategy of introducing scaffolding ligands to pre-organize the nucleophile and catalyst represents a novel avenue for optimizing Ni-SMC towards pharmaceutical process production. Example 9. Phosphine Ligand Screenings on Ni-SMC General procedure for the ligand screening

[00299] In a nitrogen-filled glove box, NiCl₂•6H₂O (7.5 µmol, 1.8 mg, 1.0 equiv) was combinedwith either monodentate / hemi-labile phosphines (30 µmol, 4.0 equiv) or bidentate phosphines (15 µmol, 2.0 equiv) in a 2 mL glass vial containing i-PrOH (1.5 mL). The vial was then removed from the glove box, placed in a shaker, and heated to 70 °C with agitation at 800 rpm for 30 minutes. The resulting stock solution or suspension was brought back into the glove box for further use. Separately, an aryl halide (0.2 mmol, 1.0 equiv) and a boronic acid (0.3 mmol, 1.5 equiv) were weighed or measured (for liquid) into a 2 mL glass vial, along with solid K₃PO₄ (2.5 equiv). The precatalyst solution / suspension (0.4 mL) was added to the vial. For suspensions, an aliquot was taken while vigorously shaking the vial to ensure even distribution of the catalyst. The vial was then sealed, removed from the glove box, and placed in a shaker, heated to 80 °C with agitation at 800 rpm for 6 to 12 hours. After cooling to room temperature, n-decane (0.1 mmol) was added as an internal standard. The samples were quenched with water and extracted with ethyl acetate. The organic layer was combined, and an aliquot was analyzed by GC (Calibration curves for three isolated biaryl products were created to determine their Rf values for quantitively analysis). The % yields from duplicate runs had an error margin of ±2%.Scheme 3. Structures of Monodentate and Bidentate Phosphine Ligands in the ScreeningExperimentsScheme 4. Structures of Hemi-labile Phosphine Ligands in the Screening ExperimentsTable 2 Evaluation of Ligands with Various Catalyst Loadingawith a tethered functional group. Example 10. Substrate Scope Studies Using Ni-ProPhos Catalysts General Procedure for Synthesizing Biaryl Compounds

[00300] A 2 mL vial was charged with NiCl2^6H2O (0.002–0.006 mmol), i-PrOH (2 mL) and aphosphine ligand (0.008–0.024 mmol). The vial was sealed, removed from the glove box, and placed in a shaker. It was then heated to 70°C with agitation at 800 rpm for 30 minutes, resulting in a red stock solution. This solution was returned to the glove box for subsequent use.

[00301] A separate vial was prepared with the aryl boronic acid or ester (0.30 mmol), aryl halide(0.20 mmol if solid), and K3PO4(0.50 mmol). If the aryl halide was liquid, it was added afterward (0.20 mmol). The Ni phosphine stock solution and deoxygenated i-PrOH were then added to the vial to reach a total volume of 0.4 mL. The vial was sealed and removed from the glove box, then placed in a shaker. The reaction mixture was heated to 80°C with agitation at 800 rpm and then cooled to room temperature. The mixture was diluted with 10 mL of ethyl acetate (EtOAc) and washed with water (2 x 5 mL). The combined aqueous layers were further extracted with 5 mL of EtOAc. An aliquot of the combined organic layers was analyzed by gas chromatography (GC) or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) to monitor the reaction progress. The combined organic layers were then concentrated in vacuo, and the crude product was purified by flash chromatography. Synthesis and characterization of Ni-SMC products

[00302] Multiple Ni catalyst loadings (0.03–1 mol%) with three phosphine ligands were used forsynthesizing this compound. For the lowest Ni loading (0.03 mol%) with tri-ProPhos, 4- bromophenylethanone (40 mg, 0.20 mmol, 1.0 equiv) and pyridin-3-ylboronic acid (37 mg, 0.30mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 40 % EtOAc in hexane), to give a white solid (35 mg, 0.18 mmol, 89%). The NMR data is consistent with the literature reports (see Chen, G.-J.; Huang, J.; Gao, L.-X.; Han, F.-S. Nickel-Catalyzed Cross-Coupling of Phenols and Arylboronic Acids Through an In Situ Phenol Activation Mediated by PyBroP. Chem. – A Eur. J. 2011, 17 (14), 4038–4042, which is incorporated by reference herein in its entirety).

[0303] 1H NMR (400 MHz, CDCl3) δ 8.89 (dd, J = 2.4, 0.9 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz,1H), 8.12 – 8.03 (m, 2H), 7.92 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.75 – 7.63 (m, 2H), 7.41 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 2.65 (s, 3H, CH3).13C{1H} NMR (100 MHz, CDCl3) δ 197.7 (s, C=O), 149.5 (s), 148.5 (s), 142.5 (s), 136.7 (s), 135.6 (s), 134.6 (s), 129.3 (s), 127.5 (s), 123.8 (s), 26.9 (s, CH3). LCMS (ESI-TOF, CH3OH) m / z: [M + H]+calculated for C13H12NO 198.09, found 198.09. For Ni, this simple “pyridine-like” substrate is challenging. For example, Chem. Eur. J.2011, 17, 4038 – 4042.5 mol% of NiCl2(dppp) + additive -> 82%. 3-(4-Fluorophenyl)pyridine

[00304] Multiple Ni catalyst loadings (0.05–1 mol%) with three phosphine ligands were used forsynthesizing this compound. For the lowest Ni loading (0.05 mol%) with p-Tol-ProPhos, 3- chloropyridine (19 ^L mg, 0.20 mmol, 1.0 equiv) and (4-fluorophenyl)boronic acid (42 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 20 % EtOAc in hexane), to give a brown liquid (32 mg, 0.18 mmol, 90%). The NMR data is consistent with the literature report (see J. Am. Chem. Soc.2018, 140, 51, 17851–17856, which is incorporated by reference herein in its entirety).

[00305] 1H NMR (500 MHz, CDCl3) δ 8.80 (d, J = 2.5 Hz, 1H), 8.60 – 8.56 (m, 1H), 7.84 – 7.80(m, 1H), 7.53 (ddt, J = 8.9, 5.3, 2.8 Hz, 2H), 7.34 (dd, J = 7.8, 4.7 Hz, 1H), 7.16 (td, J = 8.7, 2.1 Hz, 2H).19F{1H} NMR (471 MHz, CDCl3) δ -114.18.13C{1H} NMR (101 MHz, CDCl3) δ 163.0 (d, J = 248 Hz), 148.6 (s), 148.3 (s), 135.8 (s), 134.3 (s), 134.1 (d, J = 3 Hz), 128.9 (d, J = 8 Hz), 123.7, 116.2 (d, J = 22 Hz). MS (ESI-TOF, CH3CN) m / z: [M + H]+calculated C11H9FN 174.07, found 174.07.

[00306] Multiple Ni catalyst loadings (0.05–1 mol%) with three phosphine ligands were used forsynthesizing this compound. For the lowest Ni loading (0.05 mol%) with p-Tol-ProPhos, 3- chloropyridine (19 ^L mg, 0.20 mmol, 1.0 equiv) and 2,4-dimethoxypyrimidin-5-yl)boronic acid (55 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 100 % EtOAc in hexane), to give a white solid (38 mg, 0.17 mmol, 87%).

[00307] 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 2.2 Hz, 1H), 8.59 (dd, J = 4.9, 1.6 Hz, 1H),8.29 (s, 1H), 7.87 – 7.79 (m, 1H), 7.36 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 4.05 (s, 3H, OMe), 4.04 (s, 3H, OMe).13C{1H} NMR (101 MHz, CDCl3) δ 168.4 (s), 165.3 (s), 157.8 (s), 149.6 (s), 148.9 (s), 136.3 (s), 129.5 (s), 123.4 (s), 113.1 (s), 55.2 (s, OMe), 54.4 (s, OMe). HRMS (ESI-TOF, CH3CN) m / z: [M + Na]+calculated for C11H11N3O2Na 240.0743, found 240.0745.

[00308] Multiple Ni catalyst loadings (0.05–1 mol%) with three phosphine ligands were used forsynthesizing this compound. For the lowest Ni loading (0.05 mol%) with p-Tol-ProPhos, 4- bromophenylethanone (40 mg, 0.20 mmol, 1.0 equiv) and 2,4-dimethoxypyrimidin-5-yl)boronic acid (55 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 60 % EtOAc in hexane), to give a white solid (49 mg, 0.19 mmol, 95%).

[00309] 1H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H), 8.05 – 7.98 (m, 2H), 7.64 – 7.58 (m,2H), 4.05 (s, 3H, OMe), 4.04 (s, 3H, OMe), 2.63 (s, 3H, Me).13C{1H} NMR (101 MHz, Chloroform-d) δ 197.7 (s), 168.3 (s), 165.1 (s), 158.0 (s), 138.4 (s), 136.3 (s), 129.0 (s), 128.6 (s),115.3 (s), 55.2 (s, OMe), 54.4 (s, OMe), 26.8 (s, Me). HRMS (ESI-TOF, CH3CN) m / z: [M + Na]+calculated for C14H15N2O3259.1077, found 259.1067.

[00310] For the lowest Ni loading (0.05 mol%) with p-Tol-ProPhos, 4-bromophenylethanone (40mg, 0.20 mmol, 1.0 equiv) and (1-methyl-1H-pyrazol-4-yl)boronic acid (38 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 60 % EtOAc in hexane), to give a white solid (36 mg, 0.18 mmol, 90%). The NMR data is consistent with the literature report (H. Cheng et al. Chinese Chemical Letters 25:705–709 (2014), which is hereby incorporated by reference in its entirety).

[00311] 1H NMR (400.30 MHz, CDCl3) δ 7.95 (d, J = 8.5 Hz, 2H), 7.83 (s, 1H), 7.70 (s, 1H),7.54 (d, J = 8.5 Hz, 2H), 3.96 (s, 3H, Me), 2.60 (s, 3H, Me).13C{1H} NMR (100.67 MHz, CDCl3) δ 197.6 (s), 137.6 (s), 137.3 (s), 135.1 (s), 129.3 (s), 127.9 (s), 125.3 (s), 122.4 (s), 39.4 (s, Me), 26.7 (s, Me). LCMS (ESI-TOF, CH3CN) m / z: [M + NH4]+calculated C12H16N3O 218.13, found 218.13.

[00312] For the lowest Ni loading (0.1 mol%) with p-Tol-ProPhos, 6-chloroisoquinoline (33 mg,0.20 mmol, 1.0 equiv) and isoquinolin-4-ylboronic acid (52 mg, 0.30 mmol, 1.5 equiv) were used,purified by flash chromatography (0%→ 40 % EtOAc in hexane), to give a white solid (46 mg, 0.18 mmol, 90%).

[00313] 1H NMR (400.30 MHz, CDCl3) δ 9.31 (d, J = 2.3 Hz, 1H), 8.97 (dd, J = 4.3, 1.7 Hz, 1H),8.43 (d, J = 2.3 Hz, 1H), 8.27 (dd, J = 8.1, 1.6 Hz, 2H), 8.20 – 8.12 (m, 2H), 8.08 (dd, J = 8.7, 2.1 Hz, 1H), 7.92 (dd, J = 8.3, 1.5 Hz, 1H), 7.76 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.66 – 7.55 (m, 1H), 7.47 (dd, J = 8.3, 4.2 Hz, 1H).13C{1H} NMR (100.67 MHz, CDCl3) δ 151.0 (s), 145.0 (s), 148.0 (s), 147.7 (s), 136.5 (s), 136.1 (s), 133.9 (s), 133.1 (s), 130.7 (s), 129.9 (s), 129.5 (s), 129.1 (s), 128.7 (s), 128.2 (s), 128.1 (s), 127.4 (s), 126.3 (s), 122.0 (s). HRMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated C18H13N2258.1105, 258.1117.

[00314] For the lowest Ni loading (0.1 mol%) with p-Tol-ProPhos, 5-bromobenzofuran (25 ^L,0.20 mmol, 1.0 equiv) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (79 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→10 % MeOH in DCM), to give a white solid (mixed with unreacted boronic ester). The mixture was further purified by HPLC (36 mg, 0.14 mmol, 71%).

[00315] 1H NMR (400.30 MHz, CDCl3) δ 8.06 – 7.97 (m, 2H), 7.68 (d, J = 2.2 Hz, 1H), 7.59 –7.53 (m, 2H), 7.38 (dt, J = 7.8, 0.7 Hz, 1H), 7.26 – 7.23 (m, 1H), 6.81 (dd, J = 2.2, 1.0 Hz, 1H), 2.35 (s, 3H, Me). Although the proton of -CO2H was not detected, we noticed that a broad signal around 4.66 ppm, which could be due to the H2O affected by the CO2H.13C{1H} NMR (100.67 MHz, CDCl3) δ 171.3 (s), 154.4 (s), 145.8 (s), 142.6 (s), 142.5 (s), 135.7 (s), 132.0 (s), 130.7 (s), 129.0 (s), 127.6 (s), 126.9 (s), 125.7 (s), 121.8 (s), 111.2 (s), 106.8 (s), 21.1 (s, Me). HRMS (ESI- TOF, CH3CN) m / z: [M + H]+calculated for C16H13O3253.0859, found 253.0856.

[00316] For the lowest Ni loading (0.1 mol%) with p-Tol-ProPhos, 4-chloropyrimidin-2-amine(26 mg, 0.20 mmol, 1.0 equiv) and p-tolylboronic acid (41 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 100 % EtOAc in hexane), to give a white solid (34 mg, 0.18 mmol, 92%). This is a known compound, (Chen et al., “Design, Synthesis and SAR Study of Novel Sulfonylurea Derivatives Containing Arylpyrimidine Moieties as Potential Anti- Phytopathogenic Fungal Agents,” Chinese Chemical Letters 30(12):2160-2162. (2019), which is hereby incorporated by reference in its entirety) but no SMC method has been employed for its synthesis.

[00317] 1H NMR (400.30 MHz, CDCl3) δ 8.32 (d, J = 5.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.27(d, J = 8.1 Hz, 2H), 7.02 (d, J = 5.3 Hz, 1H), 5.14 (s, 2H, NH2), 2.41 (s, 3H, Me).13C{1H} NMR (100.67 MHz, CDCl3) δ 165.6 (s), 163.3 (s), 158.7 (s), 141.1 (s), 134.5 (s), 129.7 (s), 127.1 (s), 107.6 (s), 21.6 (s, Me). LCMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C11H12N3186.10, found 186.10.

[00318] For the lowest Ni loading (0.5 mol%) with p-Tol-ProPhos / ProPhos, 4-chloropyrimidin-2-amine (26 mg, 0.20 mmol, 1.0 equiv) and (S)-3-(4-boronophenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (93 mg, 0.30 mmol, 1.5 equiv) were used. Purification of the product is difficulty. Initial purification by silica column is not effective. Crystallization of the crude in iPrOH / heptane give a sufficiently pure product as off-white solid (26 mg, purity > 77% by1H NMR). The mixture was further purified by HPLC for obtaining characterization data. NMR assignments are based on 2D NMR experiments.

[0319] The low yield was due to the difficulty of isolation. The product conversion for thisreaction was sufficiently high because LCMS showed it as the major product and GC showed the full consumption of the ArCl.

[00320] 1H NMR (500.20 MHz, (CD3)2S=O) δ 8.26 (d, J = 5.2 Hz, 1H, H2), 7.93 (d, J = 7.9 Hz,2H, H6), 7.27 (d, J = 8.0 Hz, 2H, H7), 7.08 (d, J = 5.2 Hz, 1H, H3), 6.59 (s, 2H, NH2), 6.28 (s, 1H, NHBoc), 3.93 – 3.87 (m, 1H, H10), 3.10 (dd, J = 13.4, 5.0 Hz, 2H, H9), 2.93 (dd, J = 13.4, 7.2 Hz, 1H, H9), 1.33 (s, 9H, t-Bu).1H signal due to COOH was not observed.13C{1H} NMR (100.67 MHz, (CD3)2S=O) δ 164.9 (s, C1), 163.8 (s, C4), 158.5 (s, C2), 141.7 (s, C8), 134.1 (s, C5), 129.7 (s, C7), 126.2 (s, C6), 105.6 (s, C3), 77.5 (s, C(CH3)4), 55.7 (s, C10), 37.0 (s, C9), 28.2 (s, CH3).13C signals due to C=O no were not observed. HRMS (ESI-TOF, CH3OH) m / z: [M + H]+calculated for C18H23N4O4359.1714, found 359.1703.

[00321] For the lowest Ni loading (0.1 mol%) with ProPhos, (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (51 mg, 0.20 mmol, 1.0 equiv) and (3-methoxyphenyl)boronic acid (46 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 20 % EtOAc in hexane), to give a white solid (37 mg, 0.13 mmol, 66%). The NMR data is consistent with the literature report (Zhao et al., “Process Development of Tryptophan Hydroxylase Inhibitor LX1031, a Drug Candidate for the Treatment of Irritable Bowel Syndrome, Org. Process Res. Dev.24(2):261–273 (2020), which is hereby incorporated by reference in its entirety)

[00322] 1H NMR (500.20 MHz, CDCl3) δ 7.63 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.37(t, J = 7.9 Hz, 1H), 7.18 (dt, J = 7.7, 1.2 Hz, 1H), 7.12 (t, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.2, 2.5 Hz, 1H), 5.08 (q, J = 6.8 Hz, 1H, CH), 3.87 (s, 3H, OMe), 2.63 (s, 1H, OH).19F{1H} NMR (470.61 MHz, CDCl3) δ -78.25 (s).13C{1H} NMR (125.79 MHz, CDCl3) δ 160.1 (s), 142.5 (s), 142.0 (s),133.1 (s), 130.0 (s), 128.0 (s), 127.6 (s), 125.5 (s), 123.3 (s), 119.8 (s), 113.2 (s), 113.1 (s), 72.8 (q, J = 32 Hz), 55.5 (s, OMe). LCMS (ESI-TOF, CH3CN) m / z: [M + K]+calculated C15H13F3O2K 321.05, found 321.05.

[00323] For the lowest Ni loading (0.1 mol%) with p-Tol-ProPhos, 2-chloro-5-fluoropyrimidine(19 ^L, 0.20 mmol, 1.0 equiv) and (2-methoxyphenyl)boronic acid (46 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 40 % EtOAc in hexane), to give a white solid (37 mg, 0.18 mmol, 91%).

[00324] 1H NMR (400.30 MHz, CDCl3) δ 8.71 (s, 2H), 7.68 (dd, J = 7.6, 1.8 Hz, 1H), 7.51 – 7.38(m, 1H), 7.14 – 6.96 (m, 2H), 3.87 (s, 3H, OMe).19F{1H} NMR (470.61 MHz, CDCl3) δ -140.68 (s).13C{1H} NMR (100.67 MHz, CDCl3) δ 162.2 (d, J = 6 Hz), 157.6 (s), 155.0 (s), 144.9 (d, J = 20 Hz), 131.8 (s), 131.3 (s), 127.5 (d, J = 2 Hz), 120.8 (s), 112.1 (s), 56.2 (s, OMe). HRMS (ESI- TOF, CH3CN) m / z: [M + H]+calculated for C11H10FN2O 205.0772, found 205.0772.

[00325] For the lowest Ni loading (0.1 mol%) with p-Tol-ProPhos, 2-chloro-5-fluoropyrimidine(19 ^L, 0.20 mmol, 1.0 equiv) and (2-methoxypyrimidin-5-yl)boronic acid (46 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 40 % EtOAc in hexane), to give a white solid (40 mg, 0.19 mmol, 97%).

[0326] 1H NMR (500.20 MHz, CDCl3) δ 9.44 (s, 2H), 8.66 (s, 2H), 4.11 (s, 3H, OMe). 19F{1H}NMR (470.61 MHz, CDCl3) δ -138.91 (s).13C{1H} NMR (125.79 MHz, CDCl3) δ 166.7 (s), 159.6 (s), 157.7 (d, J = 6 Hz), 157.0 (d, J = 266 Hz), 145.4 (d, J = 20 Hz), 124.5 (s), 55.5 (s, OMe). HRMS (ESI-TOF, CH3OH) m / z: [M + H]+calculated for C9H8FN4O 207.0677, found 207.0685.

[00327] For the lowest Ni loading (0.1 mol%) with p-Tol-ProPhos, 4-bromophenylethanone (40mg, 0.20 mmol, 1.0 equiv) and (1H-indol-6-yl)boronic acid (48 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 40 % EtOAc in hexane), to give a brown solid (44 mg, 0.19 mmol, 94%).

[00328] 1H NMR (400.30 MHz, CDCl3) δ 8.29 (s, 1H), 8.07 – 8.02 (m, 2H), 7.78 – 7.66 (m, 4H),7.43 (dd, J = 8.3, 1.6 Hz, 1H), 7.29 (dd, J = 3.2, 2.4 Hz, 1H), 6.60 (ddd, J = 3.1, 2.0, 1.0 Hz, 1H), 2.65 (s, 3H, Me).13C{1H} NMR (100.79 MHz, CDCl3) δ 198.0 (s, C=O), 147.1 (s), 136.5 (s), 135.4 (s), 134.2 (s), 129.1 (s), 128.2 (s), 127.4 (s), 125.6 (s), 121.3 (s), 119.8 (s), 110.0 (s), 102.9 (s), 26.8 (s, Me). HRMS (ESI-TOF, CH3CN) m / z: [M + K]+calculated for C16H13NOK 274.0629, found 274.0617.

[00329] For the lowest Ni loading (0.5 mol%) with ProPhos, 1-bromo-4-(methylsulfonyl)benzene(47 mg, 0.20 mmol, 1.0 equiv) and pyridin-3-ylboronic acid (37 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 40 % EtOAc in hexane), to give a white solid (30 mg, 0.13 mmol, 64%). The NMR data is consistent with the literature reports (Cervantes-Reyes et al., “Decarbonylative Pd-Catalyzed Suzuki Cross-Coupling for the Synthesis of StructurallyDiverse Heterobiaryls,” Org. Lett. 24:1678–1683 (2022), which is hereby incorporated by reference in its entirety).

[00330] The low yield of this reaction was attributed to the instability of 1-bromo-4-(methylsulfonyl)benzene.

[00331] 1H NMR (400.30 MHz, CDCl3) δ 8.88 (s, 1H), 8.69 (s, 1H), 8.08 – 8.03 (m, 2H), 7.91(ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.78 (dq, J = 8.7, 2.2 Hz, 2H), 7.43 (dd, J = 7.9, 4.8 Hz, 1H), 3.10 (s, 3H).13C{1H} NMR (100.79 MHz, CDCl3) δ 149.9 (s), 148.4 (s), 143.5 (s), 140.2 (s), 135.0 (s), 134.8 (s), 128.4 (s), 128.2 (s), 124.0 (s), 44.7 (s, Me). LCMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated C12H12NO2S 234.06, found 234.05.

[00332] For the lowest Ni loading (0.5 mol%) with ProPhos, 1-bromo-3-(methylsulfonyl)benzene(47 mg, 0.20 mmol, 1.0 equiv) and pyridin-3-ylboronic acid (37 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 40 % EtOAc in hexane), to give a light yellow oily solid (40 mg, 0.17 mmol, 86%). The NMR data is consistent with the literature reports (Takale et al., “Mild and Robust Stille Reactions in Water using Parts Per Million Levels of a Triphenylphosphine-Based Palladacycle,” Angew. Chem. Int. Ed.60:4158–4163 (2021), which is hereby incorporated by reference in its entirety).

[00333] 1H NMR (400.30 MHz, CDCl3) δ 8.88 (dd, J = 2.4, 0.9 Hz, 1H), 8.67 (dd, J = 4.8, 1.6Hz, 1H), 8.16 (t, J = 1.8 Hz, 1H), 7.99 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.93 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.88 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.71 (td, J = 7.8, 0.5 Hz, 1H), 7.43 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 3.11 (s, 3H, Me).13C{1H} NMR (100.79 MHz, CDCl3) δ 149.7 (s), 148.3 (s), 141.8 (s), 139.6 (s), 134.9 (s), 134.7 (s), 132.4 (s), 130.4 (s), 127.0 (s), 126.1 (s), 124.0 (s), 44.7 (s, Me). LCMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C12H12NO2S 235.06, found 235.06.

[0334] For the lowest Ni loading (0.5 mol%) with ProPhos, 1-chloro-2-methylbenzene (24 ^L,0.20 mmol, 1.0 equiv) and pyridin-3-ylboronic acid (37 mg, 0.30 mmol, 1.5 equiv) were used, purified by flash chromatography (0%→ 40 % EtOAc in hexane), to give a colorless oil (31 mg, 0.18 mmol, 92%). The NMR data is consistent with the literature reports (Haibach et al., “Enabling Suzuki–Miyaura Coupling of Lewis-Basic Arylboronic Esters with a Nonprecious Metal Catalyst,” Chem. Sci. 13:12906-12912 (2022), which is hereby incorporated by reference in its entirety).

[0335] 1H NMR (400.30 MHz, CDCl3) δ 8.62 – 8.56 (m, 2H), 7.68 – 7.61 (m, 1H), 7.34 (ddd, J= 7.9, 4.9, 0.9 Hz, 1H), 7.32 – 7.25 (m, 3H), 7.21 (dt, J = 6.8, 1.4 Hz, 1H), 2.27 (s, 3H, Me).13C{1H} NMR (100.79 MHz, CDCl3) δ 150.0 (s), 148.2 (s), 138.2 (s), 137.6 (s), 136.6 (s), 135.7 (s), 130.7 (s), 130.0 (s), 128.2 (s), 126.2 (s), 123.1 (s), 20.5 (s, Me). LCMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated C12H12N 171.10, found 171.10.

[0336] For the lowest Ni loading (0.5 mol%) with P(p-Tol)2CH2CH2CH2OH (S10), 4-chloropyrimidin-2-amine (2.00 g, 15.4 mmol, 1.0 equiv) and pyridin-3-ylboronic acid (2.85 g, 23.2 mmol, 1.5 equiv) were used, purified by flash chromatography (MeOH:DCM), to give a white solid (2.42 g, 14.1 mmol, 91%). The NMR data is consistent with the literature reports (Heo et al., “Preparation of Copper(II) Oxide Bound on Polystyrene Beads and Its Application in the Aryl Aminations: Synthesis of Imatinib,” Tetrahedron Lett. 53:6657-6661 (2012), which is hereby incorporated by reference in its entirety).

[0337] 1H NMR (400.30 MHz, DMSO-d6) δ: 9.23 (dd, J = 2.3, 0.9 Hz, 1H), 8.68 (dd, J = 4.8,1.7 Hz, 1H), 8.39 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 8.36 (s, 1H), 7.53 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.20 (d, J = 5.1 Hz, 1H), 6.77 (s, 2H, NH2).13C{1H} NMR (100.79 MHz, DMSO-d6) δ: 163.8 (s), 161.6 (s), 159.4 (s), 151.2 (s), 148.0 (s), 134.2 (s), 132.5 (s), 123.8 (s), 106.0 (s). HRMS (ESI- TOF, CH3OH) m / z: [M + H]+calculated for C9H9N4173.0822, found 173.0827.

[00338] The i loading (3 mol%) with ProPhos was not optimized, 6-chloroisoquinoline (33 mg,0.20 mmol, 1.0 equiv) and 2-(2,6-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg, 0.24 mmol, 1.2 equiv) were used, purified by flash chromatography (hexane:EtOAc), to give a white solid (41 mg, 0.16 mmol, 82%). The NMR data is consistent with the literature reports (Liu et al., “Synthesis of Biaryls via Decarbonylative Palladium-Catalyzed Suzuki-Miyaura Cross- Coupling of Carboxylic Acids,” iScience 19:749-759 (2019), which is hereby incorporated by reference in its entirety).

[00339] 1H NMR (400.30 MHz, CDCl3) δ: 8.90 (dd, J = 4.3, 1.7 Hz, 1H), 8.19 – 8.10 (m, 2H),7.82 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 8.7, 1.9 Hz, 1H), 7.40 – 7.31 (m, 2H), 6.70 (d, J = 8.4 Hz, 2H), 3.75 (s, 6H, OCH3).13C{1H} NMR (100.79 MHz, CDCl3) δ: 157.8 (s), 150.2 (s), 147.5 (s), 136.3 (s), 133.3 (s), 132.8 (s), 129.7 (s), 129.3 (s), 128.5 (s), 128.2 (s), 120.9 (s), 118.7 (s), 104.3 (s), 56.0 (s, OCH3). LCMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C17H16NO2266.12, found 266.12.

[00340] The Ni loading (3 mol%) with ProPhos was not optimized, 5-bromopyrimidine (32 mg,0.20 mmol, 1.0 equiv) and 2-(2,6-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg, 0.24 mmol, 1.2 equiv) were used, purified by flash chromatography (hexane:EtOAc), to give a white solid (38 mg, 0.18 mmol, 88%).

[00341] 1H NMR (400.30 MHz, CDCl3) δ: 9.11 (s, 1H), 8.74 (s, 2H), 7.35 (t, J = 8.4 Hz, 1H),6.67 (d, J = 8.4 Hz, 2H), 3.77 (s, 6H, OCH3).13C{1H} NMR (100.79 MHz, CDCl3) δ: 158.7 (s), 157.7 (s), 156.7 (s), 130.6 (s), 128.4 (s), 112.1 (s), 104.2 (s), 56.0 (s, OCH3). HRMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C12H13N2O2217.0972, found 217.0977.

[00342] The Ni loading (3 mol%) with ProPhos was not optimized, 4-bromophenylethanone (40mg, 0.20 mmol, 1.0 equiv) and 2-(2,6-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg, 0.24 mmol, 1.2 equiv) were used, purified by flash chromatography (hexane:EtOAc), to give a white solid (43 mg, 0.17 mmol, 84%). The NMR data is consistent with the literature reports (Xu et al., “Abnormal N-Heterocyclic Carbene Promoted Suzuki-Miyaura Coupling Reaction: A Comparative Study,” Organometallics 29:6343-6349 (2010), which is hereby incorporated by reference in its entirety).

[00343] 1H NMR (400.30 MHz, CDCl3) δ: 8.05 – 7.96 (m, 2H), 7.49 – 7.43 (m, 2H), 7.31 (t, J =8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 3.74 (s, 6H, OCH3), 2.63 (s, 3H, CH3).13C{1H} NMR (100.79 MHz, CDCl3) δ: 198.1 (s), 157.6 (s), 139.9 (s), 135.6 (s), 131.4 (s), 129.5 (s), 127.9 (s), 118.5 (s), 104.3 (s), 56.0 (s, OCH3), 26.8 (s, CH3). LCMS (ESI-TOF, CH3CN) m / z: [M + H]+calculated for C16H17O3257.12, found 257.12. * * *

[00344] The present invention is not to be limited in scope by the specific embodiments describedherein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[00345] All patents, applications, publications, test methods, literature, and other materials citedherein are hereby incorporated by reference in their entirety as if physically present in this specification.

Claims

WHAT IS CLAIMED IS:

1. A process for making a compound of Formula (I):wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently at each occurrence C1-6alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, said process comprising:providing a nickel salt comprising NiX2; providing a phosphorus containing compound of Formula (II):reacting the nickel salt with the phosphorus containing compound in a solvent in a presence of a base under conditions effective to form a compound of Formula (I).

2. A process for making a compound of Formula (I):wherein X is independently at each occurrence a halogen, -OC(O)C1-12 alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1- 6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1- 6 alkyl, -C(O)C1-6alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6alkyl;R5is independently at each occurrence C1-6alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, said process comprising: providing a nickel salt comprising NiX2; providing a phosphorus containing compound of Formula (II):reacting the nickel salt with the phosphorus containing compound in a solvent in a presence of a base under conditions effective to form a compound of Formula (I).

3. The process of claim 1 or 2, wherein the compound of Formula (I) has a Formula(Ia):

4. The process of any one of claims 1-3, wherein the nickel salt comprises NiCl2,NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, or Ni(o-totyl)Cl.

5. The process of any one of claims 1-3, wherein the nickel salt comprises NiCl2,NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4, Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o-Tol)]2.

6. The process of any one of claims 1-3, wherein the nickel salt is selected from thegroup consisting of NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, and Ni(o-totyl)Cl, or hydrate or solvate thereof.

7. The process of any one of claims 1-3, wherein the nickel salt is selected from thegroup consisting of NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4,Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o- Tol)]2or hydrate or solvate thereof.

8. The process of any one of claims 1-6, wherein the nickel salt is selected from thegroup consisting of NiCl2*6H2O, nickel(II) chloride ethylene glycol dimethyl ether complex, and nickel(II) bromide ethylene glycol dimethyl ether complex.

9. The process of any one of claims 1-8, wherein the base is selected from the groupconsisting of K3PO4, KOH, K2CO3, Na2CO3, Li2CO3, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2-tert-butyl-1,1,3,3-tetramethylguanidine, triethylamine, piperidine, and DMAP.

10. The process of any one of claims 1-9, wherein the solvent is a mixture of 2-methyltetrahydrofuran (2-Me-THF) and water.

11. The process of any one of claims 1-9, wherein the solvent is an alcohol.

12. The process of claim 11, wherein the alcohol is i-PrOH.

13. The process of claims 1-12, wherein the phosphorus containing compound has aFormula (IIa):

14. The process of claims 1-12, wherein the phosphorus containing compound has aFormula (IIb):where Z1is independently at each occurrence selected from the group consisting of -OH, -NH2, - C(O)OMe, -OC(O)Me, -C(O)Me, -O-Si(Me)2(t-Bu), and pyridinyl.

15. The process of any one of claims 1-13, wherein the phosphorus containingcompound is selected from the group consisting of: , , , ,16. The process of any one of claims 1-14, wherein said reacting is carried out at atemperature from about 20°C to about 150°C.

17. The process of claim 16, wherein said reacting is carried out at a temperature fromabout 65°C to about 75°C.

18. The process of any one of claims 1-17, wherein said reacting is carried out for fromabout 15 min to about 60 min.

19. The process of claim 18, wherein said reacting is carried out for from about 25 minto about 45 min.

20. A composition comprising:a nickel salt comprising NiX2, wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12 alkyl, PPh2C1-6 alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1- 6 alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; and a phosphorus containing compound of Formula (II):wherein Y is absent or, if present, is –C(R3)(R4)- or -O-; Z is selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6alkyl, -C(O)C1-6alkyl, -O- Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is H or C1-6alkyl; R4is H or C1-6alkyl; R5is independently at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4.

21. A composition comprising:a nickel salt comprising NiX2, wherein X is independently at each occurrence a halogen, -OC(O)C1-12 alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2; and a phosphorus containing compound of Formula (II):wherein Y is absent or, if present, is –C(R3)(R4)- or -O-; Z is selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6alkyl, -C(O)C1-6alkyl, -O- Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is H or C1-6alkyl; R4is H or C1-6alkyl; R5is independently at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4.

22. The composition of claim 20, further comprising a base.

23. The composition of any one of claims 20-22, further comprising a solvent.

24. The composition of any one of claims 20-23, wherein the nickel salt comprisesNiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, or Ni(o-totyl)Cl.

25. The composition of any one of claims 20-23, wherein the nickel salt comprisesNiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4, Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o-Tol)]2.

26. The composition of any one of claims 20-24, wherein the nickel salt is selectedfrom the group consisting of NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, and Ni(o-totyl)Cl, or hydrate or solvate thereof.

27. The composition of any one of claims 20-23, wherein the nickel salt is selectedfrom the group consisting of NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4, Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o-Tol)]2or hydrate or solvate thereof.

28. The composition of claims 20-27, wherein the nickel salt is selected from the groupconsisting of NiCl2*6H2O, nickel(II) chloride ethylene glycol dimethyl ether complex, and nickel(II) bromide ethylene glycol dimethyl ether complex.

29. The composition of any one of claims 20-28, wherein the base is selected from thegroup consisting of K3PO4, KOH, K2CO3, Na2CO3, Li2CO3, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2-tert-butyl-1,1,3,3-tetramethylguanidine, triethylamine, piperidine, and DMAP.

30. The composition of any one of claims 20-29, wherein the solvent is an alcohol.

31. The composition of claim 30, wherein the alcohol is i-PrOH.

32. The composition of any one of claims 20-31, wherein the phosphorus containingcompound has a Formula (IIa):

33. The composition of any one of claims 20-31, wherein the phosphorus containingcompound has a Formula (IIb):where Z1is independently at each occurrence selected from the group consisting of -OH, -NH2, - C(O)OMe, -OC(O)Me, -C(O)Me, -O-Si(Me)2(t-Bu), and pyridinyl.

34. The composition of any one of claims 20-31 or 33, wherein the phosphorus containingcompound is selected from the group consisting of:

35. A process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6 alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5; said process comprising: providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; orR´´ and R´´´ combine with the boron atom to which they are attached to formproviding a compound of Formula (I):wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6 alkyl; a is 0, 1, or 2;b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the compound of Formula (I) under conditions effective to produce the compound of Formula (III).

36. A process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6alkyl, -OC1-6alkyl, -C(O)C1-6alkyl, C(O)OH, and -S(O)2C1-6alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6alkyl, -OC1-6alkyl, -C(O)C1-6alkyl, C(O)OH, and -S(O)2C1-6alkyl, wherein C1-6 alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5; said process comprising: providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formproviding a compound of Formula (I):wherein X is independently at each occurrence a halogen, -OC(O)C1-12alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, - OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1-6alkyl, -C(O)C1-6alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or –(CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl;R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the compound of Formula (I) under conditions effective to produce the compound of Formula (III).

37. The process of claim 35, wherein the compound of Formula (I) has a Formula (Ia):

38. The process of any one of claims 35-37, wherein said reacting is carried out at atemperature from about 60°C to about 100°C.

39. The process of claim 38, wherein said reacting is carried out at a temperature from about70°C to about 90°C.

40. The process of any one of claims 35-39, wherein said reacting is carried out for from about0.5 hours to about 16 hours.

41. The process of claim 40, wherein said reacting is carried out for from about 5 hours toabout 8 hours.

42. The process of any one of claims 35-41, wherein said providing a compound of Formula(I) comprises: providing a nickel salt comprising NiX2;providing a phosphorus containing compound of Formula (II):reacting the nickel salt and the phosphorus containing compound in a solvent in the presence of a base under conditions effective to form a compound of Formula (I).

43. A process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6alkyl, -OC1-6alkyl, -C(O)C1-6alkyl, C(O)OH, and -S(O)2C1-6alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6alkyl, -OC1-6alkyl, -C(O)C1-6alkyl, C(O)OH, and -S(O)2C1-6alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5, said process comprising: providing a compound of Formula (VI)whereinX is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6 alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2; Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, -C(O)NC1-6 alkyl, -OC(O)C1-6alkyl, -C(O)C1-6alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6alkyl; R5is independently selected at each occurrence C1-6alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, providing a compound of Formula (IV)wherein Hal is halogen; and reacting the compound of Formula (VI) with the compound of Formula (IV) under conditions effective to produce the compound of Formula (III).

44. A process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6 alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5, said process comprising: providing a compound of Formula (VI)wherein X is independently at each occurrence a halogen, -OC(O)C1-12 alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6 alkyl)2;Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6alkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2, -C(O)OC1-6alkyl, -C(O)NC1-6alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6 alkyl and -OC1-6 alkyl; R3is independently at each occurrence H or C1-6alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6 alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, providing a compound of Formula (IV)wherein Hal is halogen; and reacting the compound of Formula (VI) with the compound of Formula (IV) under conditions effective to produce the compound of Formula (III).

45. The process according to claim 43, wherein said providing a compound of Formula (VI)comprises: providing a compound of Formula (Ia)providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formreacting the compound of Formula (Ia) with the compound of Formula (V) under conditions effective to produce the compound of Formula (VI).

46. The process of any one of claims 43-45, wherein said reacting is carried out at atemperature from about 60°C to about 100°C.

47. The process of claim 46, wherein said reacting is carried out at a temperature from about70°C to about 90°C.

48. The process of any one of claims 43-47, wherein said reacting is carried out for from about0.5 hours to about 16 hours.

49. The process of claim 48, wherein said reacting is carried out for from about 5 hours toabout 8 hours.

50. The process of claim 45, wherein said providing a compound of Formula (Ia) comprises:providing a nickel salt comprising NiX2;providing a phosphorus containing compound of Formula (II):and reacting the nickel salt and the phosphorus containing compound in a solvent in the presence of a base under conditions effective to form a compound of Formula (Ia).

51. A process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6alkyl, -OC1-6alkyl, -C(O)C1-6alkyl, C(O)OH, and -S(O)2C1-6alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6alkyl, -OC1-6alkyl, -C(O)C1-6alkyl, C(O)OH, and -S(O)2C1-6alkyl, wherein C1-6alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, 4, or 5; said process comprising: providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formproviding a nickel salt comprising NiX2, wherein X is independently at each occurrence a OH, halogen, -OC(O)C1-12alkyl, PPh2C1-6alkyl, PPh3, phenyl, or naphthyl, wherein phenyl and naphthyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6alkyl, CF3, OC1-6alkyl, SC1-6alkyl, SOC1-6alkyl, SO2C1-6alkyl, NHC1-6alkyl, and N(C1-6alkyl)2; providing a phosphorus containing compound of Formula (II):wherein Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-; Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, - C(O)NC1-6 alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl;R2is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the nickel salt and the compound of Formula (II) under conditions effective to produce the compound of Formula (III).

52. A process for making a compound of Formula (III):wherein is aryl or heteroaryl;is aryl or heteroaryl; R is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6 alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; R´ is independently at each occurrence selected from the group consisting of halogen, CN, NH2, C1-6 alkyl, -OC1-6 alkyl, -C(O)C1-6 alkyl, C(O)OH, and -S(O)2C1-6 alkyl, wherein C1-6 alkyl can be substituted from 1 to 3 times with a substituent selected independently at each occurrence from OH, Ph, NHBoc, C(O)OH, or CF3; m is 0, 1, 2, 3, 4, or 5; andn is 0, 1, 2, 3, 4, or 5; said process comprising: providing a compound of Formula (IV):wherein Hal is halogen; providing a compound of Formula (V):wherein R´´ is OH; R´´´ is OH; or R´´ and R´´´ combine with the boron atom to which they are attached to formproviding a nickel salt comprising NiX2, wherein X is independently at each occurrence a halogen, -OC(O)C1-12 alkyl, or phenyl, wherein phenyl can be optionally substituted with one or more substituents selected independently at each occurrence thereof from the group consisting of OH, CN, C1-6 alkyl, CF3, OC1-6 alkyl, SC1-6 alkyl, SOC1-6 alkyl, SO2C1-6 alkyl, NHC1-6 alkyl, and N(C1-6alkyl)2; providing a phosphorus containing compound of Formula (II):wherein Y is independently at each occurrence absent or, if present, is –C(R3)(R4)- or -O-;Z is independently at each occurrence selected from the group consisting of -OH, -OC1-6 alkyl, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(O)OC1-6 alkyl, - C(O)NC1-6 alkyl, -OC(O)C1-6 alkyl, -C(O)C1-6 alkyl, -O-Si(R5)3, and pyridinyl; R1is independently at each occurrence C1-6alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R2is independently at each occurrence C1-6 alkyl, aryl, cycloalkyl, or – (CH2)c-OH, wherein the aryl, cycloalkyl, and the –(CH2)c-OH can be optionally substituted from 1 to 3 times with one or more substituents selected independently at each occurrence thereof from the group consisting of C1-6alkyl and -OC1-6alkyl; R3is independently at each occurrence H or C1-6 alkyl; R4is independently at each occurrence H or C1-6 alkyl; R5is independently selected at each occurrence C1-6alkyl; a is 0, 1, or 2; b is 1 or 2; and c is 1, 2, 3, or 4, and reacting the compound of Formula (IV) with the compound of Formula (V) in the presence of the nickel salt and the compound of Formula (II) under conditions effective to produce the compound of Formula (III).

53. The process of any one of claims 50-52, wherein the nickel salt comprises NiCl2, NiBr2,Ni(OAc)2, Ni(OC(O)C7H15)2, or Ni(o-totyl)Cl.

54. The process of any one of claims 42 or 50-52, wherein the nickel salt comprises NiCl2,NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4, Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o-Tol)]2.

55. The process of any one of claims 42 or 50-52, wherein the nickel salt is NiCl2, NiBr2,Ni(OAc)2, Ni(OC(O)C7H15)2, or Ni(o-totyl)Cl, or hydrate or solvate thereof.

56. The process of any one of claims 42 or 50-52, wherein the nickel salt is selected from thegroup consisting of NiCl2, NiBr2, Ni(OAc)2, Ni(OC(O)C7H15)2, Ni(o-totyl)Cl, Ni(PPh2Me)4, Ni(PPh2Me)2Cl(o-Tol), Ni(PPh2Me)2Br(o-Tol), Ni(PPh3)2(Naph)Cl, and [Ni(PPh2Me)(^-OH)(o-Tol)]2or hydrate or solvate thereof.

57. The process of any one of claims 42 or 50-56, wherein the nickel salt is NiCl2*6H2O,nickel(II) chloride ethylene glycol dimethyl ether complex, or nickel(II) bromide ethylene glycol dimethyl ether complex.

58. The process of any one of claims 42 or 50, wherein the base is selected from the groupconsisting of K3PO4, KOH, K2CO3, Na2CO3, Li2CO3, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2-tert-butyl-1,1,3,3-tetramethylguanidine, triethylamine, piperidine, and DMAP.

59. The process of any one of claims 42 or 50, wherein the solvent is an alcohol.

60. The process of claim 59, wherein the alcohol is i-PrOH.

61. The process of any one of claims 42 or 50-52, wherein the phosphorus containingcompound has a Formula (IIa):

62. The process of any one of claims 42 or 50-52, wherein the phosphorus containingcompound has a Formula (IIb):where Z1is independently at each occurrence selected from the group consisting of -OH, -NH2, - C(O)OMe, -OC(O)Me, -C(O)Me, -O-Si(Me)2(t-Bu), and pyridinyl.

63. The process of any one of claims 42, wherein the phosphorus containing compound isselected from the group consisting of:

64. The process of any one of claims 42 or 50, wherein said reacting is carried out at atemperature from about 20°C to about 150°C.

65. The process of claim 64, wherein said reacting is carried out at a temperature from about65°C to about 75°C.

66. The process of any one of claims 42 or 50-65, wherein said reacting is carried out for fromabout 15 min to about 60 min.

67. The process of claim 66, wherein said reacting is carried out for from about 25 min to about45 min.

68. The process of any one of claims 42 or 50-57, wherein the nickel salt is provided in theamount of from about 0.01 mol% to about 5 mol%.

69. The process of claim 68, wherein the nickel salt is provided in the amount of from about0.03 mol% to about 1 mol%.

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