Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=1.[CH:15](=[O:17])[CH3:16].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:6][O:7][C:8]1[N:9]=[C:10]([CH2:14][CH:15]([OH:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CC=O
Reactant: COc1cccc(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CC(C)O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 2-hydroxy-6-methylpyridine (164 g, 1.47 mol), iodomethane (1.35 kg, 9.53 mol), Ag2CO3 (526 g, 1.91 mol) in THF (10 ml) was strirred overnight at ambient temperature while protecting from light. The mixture was filtered through Celite and the filter cake was washed with THF. The filtrate was concentrated in vacuo until all methyl iodide was removed by HPLC analysis to yield 145.6 g (80%) of 2-methoxy-6-methylpyridine. BuLi (2.5 M, 49.0 ml, 122 mmol) was added to a solution of 2-methoxy-6-methylpyridine in THF (300 ml) at −78° C. over a period of 30 min. After warming the mixture to 0° C. over a period of 1 h, the reaction was re-cooled to −78° C. and acetaldehyde (22.3 ml, 407 mmol) was slowly added. The mixture was stirred for 1 h at −78° C. and allowed to warm to ambient temperature. Addition of sat. aq. NH4Cl and extraction with EtOAc was followed by a wash of the organic layer with sat. aq. NaHCO3 and brine. Concentration of the organic layer in vacuo and chromatographic purification of the resulting residue gave 8.96 g (66%) of 1-(6-methoxypyridin-2-yl)propan-2-ol. 1H-NMR (CDCl3) δ 7.51 (dd, 1H), 6.71 (d, 1H), 6.63 (d, 1H), 5.18 (br s, 1H), 4.21 (qdd, 1H), 3.91 (s, 3H), 2.84 (dd, 1H), 2.77 (dd, 1H), 1.28 (d, 3H) ppm. Br2 (8.41 g, 52.6 mmol) was added dropwise to a mixture of 1-(6-methoxypyridin-2-yl)propan-2-ol (5.00 g, 32.6 mmol), Na2HPO4 buffer (0.15 M, 1.20 1) and MeOH (15 ml). After stirring for 16 h at ambient temperature, the reaction mixture was parted between EtOAc and NaHCO3. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatographic purification rendered 8.29 g (63%) of 1-(3-bromo-6-methoxypyridin-2-yl)propan-2-ol. 1H-NMR (CDCl3) δ 7.70 (dd, 1H), 6.56 (d, 1H), 4.65 (br s, 1H), 4.36 (qdd, 1H), 3.91 (s, 3H), 3.10 (dd, 1H), 2.83 (dd, 1H), 1.34 (d, 3H) ppm. To a mixtrue of pyridine (2.17 ml, 26.8 mmol) and TFA (1.08 ml) in toluene (40 ml) was added a solution of 1-(3-bromo-6-methoxypyridin-2-yl)propan-2-ol (6.60 g, 26.8 mmol) in DMF (27 ml). The mixture was stirred for 5 h and, after addition of DCC (5.53 g, 26.8 mmol), an extra 2 h at ambient temperature. The mixture was diluted with Et2O (400 ml) and a solution of oxalic acid (18.0 g, 112 mmol) in MeOH (67 ml) was added which resulted in formation of CO2. After filtration of the precipitate, the filter cake was washed with Et2O and the filtrate was extracted with sat. aq. NaHCO3, washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo and chromatographic purification of the resulting residue gave 6.70 g (99%) of 1-(3-bromo-6-methoxypyridin-2-yl)acetone. 1H-NMR (CDCl3) δ 7.66 (dd, 1H), 6.55 (d, 1H), 3.98 (s, 2H), 3.86 (s, 3H), 2.23 (s, 3H) ppm. A mixture of 1-(3-bromo-6-methoxypyridin-2-yl)acetone (267 mg, 1.09 mmol), allylamine (90.0 μl, 1.20 mmol), AcOH (314 μl), and DCE (10 ml) was stirred for 5 min at room temperature, then NaBH(OAc)3 (700 mg, 3.27 mmol) was added and it was stirred for another 3 h at ambient temperature. The mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over Na2SO4, and concentrated in vacuo. The crude residue was dissolved in DCM (3 ml) and Et3N (310 ml, 2.20 μmol) and TFAA (154 ml, 1.1 μmol) were added. After stirring for 5 min, the mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over Na2SO4, concentrated in vacuo and chromatographically purified to give 282 mg (68%) of N-allyl-N-[2-(3-bromo-6-methoxypyridin-2-yl)-1-methylethyl]-2,2,2-trifluoroacetamide. 1H-NMR of rotamers (CDCl3) δ 7.65 (d, 0.5H), 7.63 (d, 0.5H), 6.53 (d, 0.5H), 6.51 (d, 0.5H), 5.94 (dddd, 0.5H), 5.66 (dddd, 0.5H), 5.32-5.16 (m, 2H), 4.78 (qd, 0.5H), 4.51 (qd, 0.5H), 4.20 (dd, 0.5H), 4.04 (dd, 0.5H), 3.95 (dd, 0.5H), 3.88 (s, 1.5H), 3.99 (s, 1.5H), 3.79 (dd, 0.5H), 3.39 (dd, 0.5H), 3.25 (dd, 0.5H), 3.19 (dd, 0.5H), 3.02 (dd, 0.5H), 1.43 (d, 1.5H), 1.31 (d, 1.5H) ppm. A mixture of N-allyl-N-[2-(3-bromo-6-methoxypyridin-2-yl)-1-methylethyl]-2,2,2-trifluoroacetamide (265 mg, 696 μmol), NaOAc (171 mg, 2.09 mmol), (Ph3P)2PdCl2 (244 mg, 348 μmol), and DMA (5 ml) was heated at 130° C. for 1 h. The reaction mixture was diluted with EtOAc, filtered through Celite and concentrated in vacuo. Chromatographic purification rendered 169 mg (81%) of 2-methoxy-8-methyl-5-methylene-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. Hydrogenation of the resulting olefin (142 mg, 473 μmol) was carried out with 5% Pd/C (100 mg) in MeOH (3 ml) under H2 (1 atm). Filtration and concentration of the reaction mixture yielded 142 mg (99%) of the desired alkane. The resulting 2-methoxy-5,8-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine was brominated in Na2HPO4 buffer (0.15 M, 17 ml) and MeOH (6 ml) by slow addition of Br2 (144 μl, 2.81 mmol). After stirring for 16 h at ambient temperature, the reaction mixture was parted between EtOAc and NaHCO3. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatographic purification rendered 120 mg (81%) of 3-bromo-2-methoxy-5,8-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. A mixture of 3-bromo-2-methoxy-5,8-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (109 mg, 286 μmol), K2CO3 (200 mg, 1.45 mmol), and MeOH (10 ml) was refluxed for 8 h. Evaporation of the solvent was followed by addition of aq. sat. NaHCO3 and subsequent extraction with EtOAc. The organic layer was dried, concentrated in vacuo and purified by column chromatography to furnish 64 mg (79%) of 3-bromo-2-methoxy-5,8-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.58 (s, 1H), 4.00 (s, 3H), 3.13-2.88 (m, 5H), 2.61 (dd, 1H), 1.31 (d, 3H), 1.27 (d, 3H) ppm.