In a dry three-neck flask, 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]oxazole (15.0 g, 43.3 mmol, Preparation #C.1) was dissolved in THF (113 mL) under an atmosphere of nitrogen. The reaction mixture was cooled to about −50° 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 −50° C. for about 15 min. In a separate dry flask, zinc chloride (7.98 g, 58.5 mmol) was dissolved in THF (88 mL). The zinc chloride solution was added dropwise to the heteroaryl Grignard and formed a light yellow suspension. The reaction mixture was stirred while warming to about 0° C. over about 30 min. In a separate flask, a mixture of 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (11.9 g, 41.2 mmol; Preparation #H.1) and DMF (120 mL) was heated at about 80° C. until all of the solids were in solution then Pd(Ph3P)4 (Strem, 2.00 g, 1.73 mmol) was added. This solution was poured into the reaction flask and the mixture was immediately heated to about 80° C. in an oil bath. After heating at about 80° C. for about 30 min, the mixture was cooled to ambient temperature. The reaction was concentrated in vacuo and the residue was partitioned between in DCM (200 mL) and 1N HCl (50 mL). The layers were separated, the aqueous layer was discarded, and the organic layer was washed with additional 1N HCl (total of 400 mL). An orange solid was filtered from the organic layer and discarded (inorganic materials). The organic layer was extracted with 5N HCl (160 mL) and then discarded. The acidic aqueous layer was basified with solid Na2CO3 (about 40 g) and extracted with DCM. The emulsion that formed during extraction was filtered through Florisil® and washed with DCM (1 L) to give a yellow solution that was concentrated under reduced pressure, dissolved in DCM (200 mL), and washed with water (500 mL). The organic layer was then dried over MgSO4, filtered, and concentrated under reduced pressure under reduced pressure to give a yellow solid that was triturated with ACN and filtered to give the title compound as white solid (3.89 g). The mother liquor was concentrated and further purified by flash silica gel chromatography using DCM/MeOH (gradient, 1:0 to 19:1). The product-containing fractions were combined and concentrated under reduced pressure to give additional title compound as white solid (0.80 g). The Florisil® from the emulsion filtration was eluted with DCM/MeOH 9:1 (1 L) and then MeOH (1 L). These filtrates were combined and concentrated under reduced pressure. The residue was then dissolved in DCM (300 mL), and the organic solution washed with water (500 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give a reddish-brown solid that was triturated with ACN and filtered to give a slightly pink solid. This solid was then triturated with MeOH and washed with ACN to give additional title compound as a cream colored solid (3.84 g). The mother liquor was concentrated and the resulting solid was triturated with ACN then filtered to give additional title compound as a light yellow solid (1.17 g). The final mother liquor was concentrated and then further purified by flash silica gel chromatography using DCM/MeOH (gradient, 1:0 to 19:1). The product-containing fractions were combined and concentrated under reduced pressure to give additional title compound as light yellow product (1.3 g). In total the reaction yielded 11 g (66%) of the title compound: LC/MS (Table 1, Method a) Rt=2.36 min; MS m/z: 381.2 (M+H)+.
