Reagents and conditions: (i)
(COCl)2 (1.5 to 2.0 equiv), cat. DMF (10 μL), toluene,
0 °C to room temperature, 89–96%; (ii) N,O-dimethylhydroxylamine hydrochloride (1.2 to 1.5
equiv), K2CO3 (2.0 equiv), EtOAc–H2O (2:1), 0 °C to room temperature, 16–18 h, 86–98%;
(iii) 4-picoline (1.2 to 1.5 equiv), LDA (1.0 M in THF/hexane (1.0–4.0
equiv), THF, −78 °C to room temperature, 2 to 3 h, 58–71%;
(iv) Br2 (1.0 equiv), AcOH, 4 h, 80 °C, 43–90%;
(v) methylthiourea (1.1 equiv), Et3N (2.1 to 3.0 equiv),
ACN, reflux, 3 h, 38–87%; (vi) nicotinoyl chloride hydrochloride
or 5-bromonicotinoyl chloride (1.5 equiv), DMAP (0.3 equiv) in DMA
or NMP, 80 °C, 16 h; sat. NaHCO3, 39–87%; (vii)
Pd/C, tritum gas.