60% Sodium hydride (95 mg, 2.38 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide (Intermediate AU3) (540 mg, 1.08 mmol) in anhydrous THF (15 mL), at 0° C., under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (314 mg, 1.08 mmol) was added. The reaction mixture was allowed to warm to room temperature and was then stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in isohexane. Fractions were evaporated to dryness to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)propanamide (466 mg, 57.2%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, d), 3.83-3.66 (4H, m), 4.11-4.04 (1H, m), 4.20-4.12 (1H, m), 6.00 (1H, s), 7.44-7.31 (6H, m), 7.60 (4H, m), 7.87 (2H, m), 8.03 (1H, t), 8.22-8.13 (2H, m), 8.39 (1H, d), 8.62 (1H, d), 8.68 (1H, d), 11.23 (1H, s). m/z (ES+) (M+H)+=752; HPLC tR=3.89 min.
