A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (Example 357A) (300 mg, 0.624 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (162 mg, 0.811 mmol), Pd2(dba)3 (28.6 mg, 0.031 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (36.1 mg, 0.062 mmol), and Cs2CO3 (610 mg, 1.872 mmol) in a dried microwave vial was flushed with nitrogen. Dioxane (6 mL) was added and the vial was sealed and heated at 95° C. overnight. The reaction was diluted with EtOAc and filtered through celite. Removed solvent from the filtrate followed by radial silica gel chromatography eluting with hexane containing 0 to 40% EtOAc to give tert-butyl 4-((3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)amino)piperidine-1-carboxylate (211 mg, 56% yield) as a foam. This was dissolved in DCM (3 mL) and anisole (0.202 ml, 1.847 mmol) and TFA (2 ml) were added. After 4 hr, the solvents were removed and the residue was taken up in MeOH and applied onto an SCX column. This was washed with MeOH, and then eluted with 2N NH3 in MeOH. Removal of the solvents followed by silica gel radial chromatography with DCM containing 0 to 12% 2 N NH3 in MeOH gave 3-amino-4-chloro-5-(piperidin-4-ylamino)benzonitrile (84 mg).
