Azetidine → 4-(azetidin-1-yl)-5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazine

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A mixture of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (5.02 g, 16.2 mmol) and toluene (100 mL) was treated with phosphorus oxychloride (7.50 mL, 80.5 mmol) and heated to 45° C. N,N-Diisopropylethylamine (17.0 mL, 97.6 mmol) was added in four equal portions, waiting for the exotherm to subside before adding another portion. The reaction mixture was heated to 95° C. for 42 hours, cooled to 35° C. and added to an aqueous solution of potassium phosphate (2.5 M, 45.0 mL), also at 35° C., in four portions; during this addition the temperature rose to 63° C. The resulting mixture was filtered through Celite, which was then rinsed with additional toluene. The organic layer of the filtrate was washed with aqueous citric acid solution (0.57 M, 30 mL), then washed with saturated aqueous sodium chloride solution (25 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo to a volume of approximately 100 mL. This was added to a solution of azetidine (2.34 g, 41.0 mmol) in tetrahydrofuran (20 mL), and the reaction mixture was stirred for 1 hour at room temperature, at which time it was poured in four portions into an aqueous sodium bicarbonate solution (0.65 M, 125 mL) with vigorous stirring. The aqueous layer was extracted with toluene (3×50 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a volume of approximately 75 mL. Heptane (100 mL) was added with vigorous stirring, and the mixture was granulated at room temperature for 2 hours, then cooled in an ice bath for 15 minutes. The resulting solid was collected by vacuum filtration to provide C7. Yield: 4.45 g, 12.8 mmol, 79%. 1H NMR (400 MHz, CDCl3) δ 2.24-2.33 (m, 2H), 2.68 (s, 3H), 3.5-4.5 (v br m, 4H), 3.96 (s, 3H), 7.65 (s, 1H), 7.88 (s, 1H).

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