[H-].[Na+].CO[C:5]([C:7]1[S:8][CH:9]=[C:10](C)[C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:6].C([CH:25]([C:29](Cl)=[O:30])[C:26](Cl)=[O:27])C.[O-:32][CH2:33][CH3:34].[Na+]>CN(C=O)C>[CH2:33]([O:32][C:29]([C:25]1[C:26](=[O:27])[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:5]=1[OH:6])=[O:30])[CH3:34]Solid NaH (60% in min. oil, 4.62 g, 135 mmol) was added in portions to a stirred solution of 3-(4-methoxybenzylamino)-thiophene-2-carboxylic acid methyl ester (53) (26.69 g, 96 mmol) in dry DMF. The solution was stirred for 10 min. at room temperature and cooled to 0° C. Ethyl malonyl chloride was added slowly and the solution was further stirred at room temperature for 15 min. Sodium ethoxide (13.1 g, 192 mmol) was added to the solution and the solution was heated to 110° C. for 2 h. The solution was cooled and excess solvent was distilled off The residue was dissolved in a mixture of water (350 mL) and 4 M NaOH (50 mL), and the insoluble impurities were filtered off The filtrate was washed by diisopropyl ether and then acidified to pH 4 by cold diluted HCl solution. The solids formed were filtered, washed by water, and dried under vacuum at room temperature to yield 27 g (79%) of 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester as off-white solids. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 3.70 (s, 3H), 4.32 (q, J=7.2 Hz, 2H), 5.27 (s, 2H), 6.86 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.34 (d, J=5.6 Hz, 1H), 8.14 (d, J=5.6 Hz, 1H), 13.31 (br, 1H) ppm; MS m/z=360 amu (M++1).
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