4-Bromo-2-methoxypyridine

A heterogeneous reaction mixture of 4-bromo-2- fluoropyridine (2.64 mL, 25.6 mmol) and NaOMe (8.29 g, 153 mmol) in MeOH (36.5 mL) was reacted in a pressure tube at 155 °C for 5 h. The reaction mixture was cooled to rt and the solids were filtered and washed with EtOAc. The filtrate was concentrated to a pale yellow oil with some white solids. The oil yellow was decanted and diluted with water and the solution was extracted with EtOAc (2x). The combined organic layers were washed with water and brine, dried over MgS0General procedure: A mixture of 4-bromo-2-ethoxypyridine (150 mg, 0.742 mmol), £>/s(pinacolato)diboron (754 mg, 2.97 mmol), PdCI2(dppf) (54.3 mg, 0.074 mmol) and potassium acetate (291 mg, 2.97 mmol) in 1 , 4- dioxane (3 ml.) was heated in a microwave at 1 10 C for 2 x 30 min. The reaction was diluted with EtOAc and filtered through a Celite column. The filtrate was evaporated to give a brown residue. This crude material was used in subsequent steps without further purification and the yield was assumed to be 100% (0.742 mmol, 185 mg).To a solution of diisopropylamine (2.9 g, 28.7 mmol) in dry THF (30 ml.) at -78 C under nitrogen was added n-BuLi (2.5 M solution in hexanes, 12.5 ml_, 31.1 mmol) dropwise and the mixture was stirred at -78 C for 45 min. The resulting LDA solution was then added slowly to a solution of Example 31a was synthesized starting from Example la following Representative procedure for N-arylation (Pd - catalyzed Buchwald coupling) described in synthesis of Example 26a (yield: 11%). LC-MS: m/z [M+H]+ = 467.1 (exact mass calc. = 466.18). 1HNMR (400 MHz, DMSO-General procedure: To degassed tetrahydrofuran (5 mL) was added chloro-(2-dicyclohexylphosphino-2', 6'-diisopropoxy-1 , 1 '-biphenyl)[2-(2-aminoethyl)phenyl]palladium(ll)-methyl-f-butyl ether adduct (PdRuPhos G1 ) (0.017 g, 0.024 mmol), 2-dicyclohexylphosphino-2?, 6'-diisopropoxybiphenyl (RuPho) (0.011 g, 0.024 mmol), the title compound from Preparative (0.05 g, 0.024 mmol), and the commercially available 4-(6-bromobenzo[d]thiazol-2-yl)morpholine (0.073 g, 0.029 mmol). Then, a 1 M solution of lithium bis(trimethylsilyl)amide (LiHMDS) in tetrahydrofuran (1 mL, 1 mmol) was added. The resulting reaction mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, dissolved in dichloromethane (100 mL). The organic phase was washed with water and brine and dried over Na2S04. The solvent was removed under reduced pressure. The crude product was purified on a silica gel column using a Biotage Isolera One purification system employing an ethyl acetate/n-heptane gradient (80/20 => 100/0) to afford the title compound (0.070 g, 69 %).A mixture of