Methanesulfonyl chloride (0.165 mL, 2.12 mmol) was added dropwise to (R)-2-(4-acetyl-3-methylpiperazin-1-yl)ethanol (360 mg, 1.94 mmol) and triethylamine (0.404 mL, 2.90 mmol) in DCM (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes, warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (15 mL). The organic layer was passed through a phase separating cartridge and concentrated in vacuo. The residual orange gum was dissolved in DMF (5 mL) and added to 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (obtained as described in Example 46, preparation of starting materials) (235 mg, 0.64 mmol) and potassium carbonate (445 mg, 3.22 mmol) in DMF (10 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 100° C. for 3 hours and the solvent was removed in vacuo. The residue was partitioned between DCM (100 mL) and water (100 mL) and the organic phase was separated. The aqueous phase was re-extracted with DCM (100 mL), and the is combined organic phases were washed with brine (100 mL), passed through phase separating cartridge and concentrated under reduced pressure to give an orange gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford a pale yellow gum, which was triturated with ether to give 6-[4-(4-{2-[(3R)-4-acetyl-3-methylpiperazin-1-yl]ethoxy}phenyl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (101 mg, 29.4%) as a white solid.
