60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H3) (199 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) added portionwise 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 organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc to afford (2S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-[1-(3-methylpyridin-4-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanamide (370 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 1.23 (3H, t), 2.34 (3H, s), 3.61-3.69 (2H, m), 4.06-4.14 (2H, m), 6.05 (1H, t), 7.49 (1H, d), 7.68 (1H, dd), 8.22 (1H, dd), 8.23-8.25 (1H, m), 8.44 (1H, s), 8.61 (1H, s), 8.63 (1H, dd), 8.69 (1H, s), 8.76 (1H, s); m/z (ESI+) (M+H)+=454; HPLC tR=1.93 min.
