To racemic trans 4-(2,5-dimethylpiperazine-1-yl)-1-phenylpyrido[3,4-d]pyridazine 44 (360 mg, 1127 μmol) dissolved in 4 mL of DMF was added EDCI (259 mg, 1.35 mmol), 4,4-difluorocyclohexanecarboxylic acid (204 mg, 1.24 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (184 mg, 1.35 mmol) (HOAT), and sodium carbonate (239 mg, 2.25 mmol). The reaction was stirred at RT for 4 h, and the solvent was removed in vacuo. The crude reaction mixture was dissolved in 100 mL of ethyl acetate and washed with 1×25 mL of water, 1×25 mL of sat. NaHCO3, and 1×25 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purified by column chromatography to isolate racemic (4,4-difluorocyclohexyl)(trans-2,5-dimethyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 45. MS 465.2 (calc'd) 466.1 (M+H, found).
