In a dry three-neck flask, 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]oxazole (9.61 g, 27.8 mmol, Preparation #C.1) was dissolved in THF (75 mL) under an atmosphere of nitrogen. The reaction mixture was cooled to about −30° C. and then i-PrMgCl (2.0 M in THF, 15.3 mL, 30.5 mmol) was added dropwise. The reaction mixture was stirred at about −30° C. for about 15 min. In a separate dry flask, zinc chloride (4.92 g, 36.1 mmol) was dissolved in THF (75 mL) and cooled to about 0° C. The zinc chloride solution was added dropwise to the heteroaryl Grignard mixture. The reaction mixture was stirred at about −15° C. for about 30 min. A flask containing 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (8.00 g, 27.8 mmol; Preparation #H.1) and Pd(Ph3P)4 (Strem, 1.28 g, 1.11 mmol) in DMF (75 mL) was stirred at about 80° C. until all of the solids were in solution. This solution was poured into the reaction mixture and the mixture was immediately heated to about 50° C. in an oil bath. After heating at about 50° C. for about 15 min, the mixture was cooled to ambient temperature. DMF was removed in vacuo and the residue was dissolved in DCM (50 mL) and was washed with 1N HCl (3×50 mL). The combined organic layers were washed with 6N HCl (1×50 mL) followed by a back extraction with DCM (50 mL). The aqueous layer was basified with solid Na2CO3 until the pH was about 9 and then extracted with DCM (3×70 mL). The combined organic layers were then washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ACN. The resulting solid was filtered and then dissolved in 6N HCl (40 mL). The aqueous solution was extracted with DCM (2×40 mL). The product was recovered after basifying the aqueous portion with 1M aqueous Na2CO3 and a final extraction with DCM (3×40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (2.34 g, 22%). The mother liquor from the initial trituration was purified by silica gel flash chromatography using DCM/MeOH (gradient, 0-3% MeOH). A final recrystallization of the recovered material with ACN afforded an additional amount of the title compound (2.65 g, 25%) for a total recovered amount of 6-(2,4-difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)imidazo[2,1-b]oxazole (4.99 g, 47%) as a white solid: LC/MS (Table 1, Method a) Rt=2.16 min; MS m/z: 381.2 (M+H)+; 1H NMR (DMSO-d6) δ 8.26 (m, 3H), 7.74 (m, 1H), 7.44 (m, 1H), 7.29 (m, 1H), 6.97 (m, 1H), 3.71 (m, 1H), 1.44 (m, 6H), Anal. calcd. for C19H14F2N6O: C, 60.00; H, 3.71; N, 22.09. found C, 59.76; H, 3.38; N, 22.08.
