5-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-N,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-amine (13.26 g, 41.16 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (98%, 9.72 g, 50.2 mmol) were combined in ethanol (126 mL), and the resulting slurry was treated with a solution of potassium phosphate (98%, 11.13 g, 51.39 mmol) in water (42 mL) and warmed to 70° C. over 40 minutes while a vigorous nitrogen flow was applied through a bubbler. After addition of tetrakis(triphenylphosphine)palladium(0) (482 mg, 0.417 mmol), the reaction mixture was heated at reflux for 3.5 hours, then cooled to room temperature and stirred for an additional 16 hours. The mixture was filtered through a plug of cotton, and the filtrate was concentrated in vacuo, then reconcentrated with 2-methyltetrahydrofuran (2×200 mL). The residue was reconstituted in 2-methyltetrahydrofuran (150 mL) and extracted with aqueous hydrochloric acid (1 M, 70 mL, stirred for 20 minutes). The aqueous layer (pH ˜2-3) was discarded. [This step removes most of the debrominated starting material; it is important that the pH of the HCl wash is ≧2.] The organic layer was then extracted twice with 1 M aqueous hydrochloric acid: first with 100 mL (stirring for 40 minutes), then with 75 mL (stirring for 20 minutes). The 100 mL aqueous layer was back-extracted with 2-methyltetrahydrofuran (80 mL, stirred for 30 minutes) to remove some color. The two hydrochloric acid layers were combined and treated with aqueous sodium hydroxide solution (5 M, 35.5 mL), which adjusted the pH to 6. The resulting mixture was extracted with 2-methyltetrahydrofuran (130 mL); the organic layer was passed through a plug of sodium sulfate (74 g) and concentrated in vacuo to a volume of roughly 150 mL. This was treated with Darco® G-60 activated carbon (5.03 g), and spun on a rotary evaporator in a 50° C. water bath for 1 hour. The warm solution was filtered through a pad of Celite, rinsing with 2-methyltetrahydrofuran, and the filtrate was concentrated under reduced pressure. The resulting pale yellow foam was treated with tert-butyl methyl ether (150 mL) and swirled in a 50° C. water bath for 5 minutes, then was cooled to room temperature with stirring over 1 hour. The resulting slurry was cooled in an ice bath and held for an additional 30 minutes. The solids were collected by filtration and rinsed with chilled tert-butyl methyl ether (cooled with a bath of ice-saturated aqueous sodium chloride solution; 79 mL), then slurried in heptane (150 mL). This mixture was concentrated in vacuo to a small volume and reconcentrated with heptane (2×150 mL), to a final volume of approximately 50 mL. Filtration provided the product as a white solid. Yield: 11.91 g, 30.75 mmol, 75%. LCMS m/z 388.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.65 (br s, 3H), 3.00 (d, J=5.0 Hz, 3H), 3.95 (s, 3H), 5.49-5.57 (m, 1H), 7.61 (br AB quartet, JAB=8.2 Hz, ΔvAB=41.4 Hz, 4H), 7.73 (s, 1H), 7.91 (br s, 1H).
