DIAD (5.20 mL, 26.39 mmol) was added dropwise to benzyl 4-(4-hydroxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (6.80 g, 21.99 mmol), tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (5.91 g, 24.19 mmol) and triphenylphosphine (6.92 g, 26.39 mmol) in THF (100 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated to dryness then the residues were dissolved in ether (50 mL) and stirred for 10 minutes at ambient temperature. The resulting precipitate was removed by filtration. The filtrate was washed with water (50 mL) and saturated brine (50 mL), then dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM (50 mL) and the solution was washed with 2M NaOH (50 mL), followed by saturated brine (50 mL), then dried over MgSO4, filtered, evaporated and purified by flash silica chromatography, elution gradient 30 to 70% ethyl acetate in isohexane. Fractions were evaporated to a gum, which was dissolved in MeOH (150 mL) and stirred with 5% palladium on carbon (50% wet, 1.907 g, 0.45 mmol) under an atmosphere of hydrogen at 5 bar and 25° C. for 16 hours. The catalyst was removed by filtration, washed with MeOH and the solvents were evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 2M ammonia in methanol in DCM. Fractions containing the desired product were evaporated to dryness to give tert-butyl 4-[3-[4-(piperidin-4-yl)phenoxy]propyl]piperazine-1-carboxylate (4.95 g, 56%) as a solid.
