Potassium Phosphate, Tribasic → (R)-4-(4-(4-(4,4-difluorocyclohexanecarbonyl)-2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)benzonitrile

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A 15 ml Schlenk tube was charged with (R)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone 60 (123 mg, 300 μmol), 4-cyanophenylboronic acid (66 mg, 450 μmol), tris(dibenzylideneacetone)-dipalladium (o) (5.5 mg, 6.0 μmol), dicyclohexyl(2,6-dimethoxyphenyl)phosphine (4.0 mg, 12 μmol), and potassium phosphate tribasic (127 mg, 600 μmol). The tube was evacuated and backfilled with argon 5 times and previously degassed n-butanol (1 ml) was added. The reaction was heated at 100° C. for 21 hours, then cooled and added to 30 ml aqueous K2CO3. This was extracted three times with dichloromethane (30 ml) and the combined extracts were dried (MgSO4) and evaporated to give an orange oil. The residue was chromatographed over silica with a gradient of hexane with 2.5% triethylamine and 0-100% ethyl acetate with 2.5% triethylamine to give (R)-4-(4-(4-(4,4-difluorocyclohexanecarbonyl)-2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)benzonitrile 65 as a yellow solid. LC/MS m/z=477 (M+H+).

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