Phosphorus oxychloride (1.864 ml, 20.00 mmol) was added to 1-(2-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate N1) (0.290 g, 1 mmol), at ambient temperature. The resulting mixture was stirred at 100° C. for 4 hours. The solution was allowed to cool to ambient temperature. The reaction mixture was evaporated. The residue was dissolved in DCM (30 mL). MP-Carbonate was added and the mixture stirred for 30 minutes then evaporated. The residue was dissolved in THF (5 mL). Sodium hydride (55.9 mg, 1.40 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (238 mg, 1.00 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes and then the THF solution prepared above was added. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was concentrated, diluted with water (10 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (25 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluent to afford (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(2-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (242 mg, 47.5%, 81% ee). 1H NMR (400 MHz, DMSO-d6) δ 1.12 (6H, dd), 2.24 (3H, s), 3.38 (3H, s), 3.72-3.80 (1H, m), 3.96-4.05 (2H, m), 5.87-5.91 (1H, m), 7.58 (1H, dd), 7.77 (1H, dd), 7.86-7.92 (2H, m), 7.94-7.99 (1H, m), 8.16-8.21 (2H, m), 8.53 (1H, s), 8.60 (1H, s), 10.82 (1H, s); m/z (ESI+) (M+H)+=511; HPLC tR=2.07 min.
