(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester → 3-[[N-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-methoxybenzyloxy)ethyl]-1-piperidinyl]pyridine

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To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (112 mg, 0.31 mmol) and 4-[2-(4-methoxybenzyloxy)ethyl]piperidine (86 mg, 0.34 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (45 mg, 0.47 mmol, 1.5 equiv.), Pd2dba3 (5.7 mg, 6.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 10.8 mg, 19 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 3:2, then 1:2. The product (137 mg, 84%) was obtained as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.23-7.30 (m, 3H), 7.24 (d, 2H, J=8.4 Hz), 6.86 (d, 2H, J=8.4 Hz), 4.41 (s, 2H), 4.10 (m, 2H), 3.90-3.80 (m, 1H), 3.78 (s, 3H), 3.65 (m, 2H), 3.49 (t, 2H, J=6.0 Hz), 3.39 (m, 2H), 2.72 (m, 2H), 2.02 (m, 3H), 1.84 (m, 1H), 1.75 (d, 2H, J=12.4 Hz), 1.55 (m, 3H), 1.45 (s, 9H), 1.31 (m, 2H).

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