849217-45-4

929252-65-3

Step 4. Synthesis of tert-butyl 4-(((4-(4-(4-amino-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate (81): to a mixture of ethanol (8 mL) and water (4 mL) of Compound 80 (0.50 g, 0.95 mmol) was added iron powder (0.254 g, 4.55 mmol) and ammonium chloride ( 0.123 g, 2.26 mmol). The reaction mixture was heated to reflux for 2 hours. After completion of the reaction, the reaction mixture was diluted with methanol and filtered to remove the solid suspension. The filtrate was concentrated and the resulting residue was purified by a Gilson automated purification system (eluent gradient: 35% to 57% methanol/dichloromethane) to afford the target product 4-(((4-(4-(4-amino-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester 81 (0.25 g, 52% yield).