(2-METHYLPYRIMIDIN-5-YL)BORONIC ACID

To a mixture of Example 73a (200 mg, 0.43mmol), Example 73b (66 mg, 0.47 mmol), Na2C03 (138 mg, 1.3 mmol) in dioxane (4 mL) and H20 (2 mL) was added Pd(dppf)Cl2(32 mg, 0.04 mmol). Then the mixture was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 95°C for 16 h. The mixture was directly purified by silica gel chromatography(DCM/MeOH = 20/1) and prep-TLC (DCM/MeOH = 15/1) to give the desired product ( Example 73 , 8 mg, yield 4percent) as a white solid.LCMS [M+l]+ = 214.6/418.0. NMR (400 MHz, Chloroform-) delta 11.44 (s, 1H), 8.89 (s, 2H), 8.52 (d, J= 2.5 Hz, 1H), 8.23 (s, 1H), 8.09-8.03 (m, 2H), 7.94 (t, J= 7.9 Hz, 1H), 7.75-7.71 (m, 1H), 7.19 (d, J= 8.6 Hz, 1H), 4.43-4.26 (m, 4H), 2.80 (s, 3H), 2.75 (br, 2H), 2.12 (br, 2H).A solution of To the stirred solution of compound 4 (210 mg, 0.57 mmol) in 1, 4- dioxane (2 mL) and water (0.5 mL) was added A round-bottom flask was charged with compound 220-S9 (30mg, 0.075 mmol), To a solution of 146-S3 (494 mg, 1.384 mol) in 1, 4-dioxane/H20 (28mL, 6:1) was added To a solution of 145-S4 (41 mg, 0.11 mmol) and To a mixture of 133-S6 (86 mg, 0.2 mmol), (2-methylpyrimidin- 5-yl)boronic acid (42 mg, 0.31 mmol), and K2C03 (70 mg, 0.51 mmol)in 1, 4-dioxane (5 mL) and H20 (1 mL) was added Pd(PPh3)4 (23 mg, 0.02 mmol). The reaction mixture was stirred at 90 °Cunder an atmosphere of nitrogen overnight. The mixture was filtered and the filtrate was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The remaining residue was purified by chromatography on silica gel (PE/EtOAc = 3:1 to 1:1) to afford 133-S7 (67 mg, 75.5percent yield) as a yellow solid. LC/MS (ESI) m/z: 435 (M+H)tA round-bottom flask was charged with 51-S5 (2.63 g, 7.18 mmol), 2- methylpyrimidin-5-ylboronic acid (0.99 g, 7.18 mmol), K2C03 (2.48 g, 17.96 mmol), and dioxane/H20 (20 mL, v/v = 9:1) under an atmosphere of nitrogen. To this mixture was added tetrakis(triphenylphosphine) palladium(0) (0.42 g, 0.36 mmol) and the resulting mixture wasstirred at 90 °C overnight under an atmosphere of nitrogen. The mixture was diluted with EtOAc and filtered. The filtrate was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The remaining crude product was purified by column chromatography on silica gel (eluted with PE/EtOAc = 100:1 to 3:1) to afford 51-S6 (1.93 g, 70.7percent yield) as light a yellow solid.