A mixture of tert-butyl 4-((3-amino-2-chloro-5-cyanophenyl)amino)piperidine-1-carboxylate (57 mg, 0.16 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(58 mg, 0.16 mmol), Cs2CO3 (106 mg, 0.325 mmol), DPPF (9 mg, 0.016 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (9 mg, 0.016 mmol), and Pd(OAc)2 (11 mg, 0.049 mmol) in a microwave vial was flushed with nitrogen. Dioxane (3 mL) was added and the vial was sealed and heated at 100° C. for 3 hr. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed from the filtrate and radial silica gel chromatography with DCM containing 0 to 10% EtOAc afforded tert-butyl 4-((2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)piperidine-1-carboxylate (74 mg, 68% yield) as a white solid. This was dissolved in DCM (1 mL) and anisole (0.238 mL, 2.18 mmol) and TFA (1 mL) were added. After stirring at room temperature overnight, the solvent were removed and the residue was applied onto a SCX column. This was washed with MeOH and the crude product was eluted with 2 N NH3 in MeOH. Removal solvents followed by silica gel radial chromatography eluting with DCM containing 0 to 5% 2N NH3 in MeOH) afforded 2-((2-chloro-5-cyano-3-(piperidin-4-ylamino)phenyl)amino)-4-(-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38 mg, 0.085 mmol, 78% yield) as a white solid. This was suspended in a mixture of MeOH (0.5 mL) and DCM (0.5 mL). Oxetan-3-one (117 mg, 1.62 mmol), triethylorthoformate (0.448 mL, 4.05 mmol), and acetic acid (0.046 mL, 0.811 mmol) were added with stirring. After 15 min. sodium cyanoborohydride (1 M in THF, 0.811 mL, 0.811 mmol) was added and the reaction was left stirring for 4 hrs. It was partitioned between EtOAc and sat. aq. NaHCO3 solution. After stirring for 15 min, the aqueous phase was separated and washed with EtOAc. The combined organic phases were washed with brine and dried with sodium sulfate. Preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 20-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to give the title compound (7.3 mg). This was converted to the mono HCl salt.
