60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (194 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate M1) (200 mg, 0.81 mmol) as suspension in dry THF (4 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric acid (2 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography with ethyl acetate to give the product (300 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 1.17 (3H, d), 1.19 (3H, d), 2.29 (3H, s), 2.34 (3H, s), 3.69-3.76 (1H, m), 4.09 (2H, d), 6.01 (1H, t), 7.51 (1H, d), 7.53 (1H, dd), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.43 (1H, s), 8.60 (1H, s), 8.62 (1H, dd), 8.67 (1H, s), 8.68 (1H, s); m/z (ESI+) (M+H)+=448; HPLC tR=1.78 min.
