Reaction Steps
To a degassed solution of 4-(5-bromo-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.250 g, 0.6 mmol, Example D.27) in anhydrous DMF (3 mL) was added zinc cyanide (0.0511 g, 0.43 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.0346 g, 0.03 mmol). The resulting mixture was heated, in a sealed microwave vessel, for about 1 h, at about 120° C. in a microwave. After cooling to rt, ethyl acetate (50 mL) and water (50 mL) were added, and the mixture was filtered through a pad of Celite®. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate 1:1) followed by trituration with diethyl ether to give 4-methyl-3-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzonitrile (0.042 g, 0.117 mmol, 20%). LC-MS (Table 1, Method e) Rt=8.10 min, m/z 362 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 2.57-2.66 (1 H, m) 2.63 (3 H, s) 2.70 (1 H, dd, J=14.7, 4.4 Hz) 3.04 (1 H, ddt, J=13.1, 10.6, 1.6 Hz) 3.68-3.77 (1 H, m) 3.79 (3 H, s) 5.87 (1 H, d, J=5.5 Hz) 6.87 (1 H, s) 7.17 (1 H, ddd, J=7.4, 4.9, 1.3 Hz) 7.34 (1 H, d, J=8.0 Hz) 7.46 (1 H, dd, J=7.8, 1.8 Hz) 7.54 (1 H, d, J=1.8 Hz) 7.70 (1 H, ddd, J=9.4, 7.3, 1.8 Hz) 7.86 (1 H, dt, J=8.0, 1.0 Hz) 8.46 (1 H, ddd, J=4.9, 1.9, 0.9 Hz).
