[NH2:1]/[C:2](=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.O.[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32](=[CH2:35])[CH:33]=O)=[CH:29][CH:28]=1>CCCCO>[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32]2[CH:35]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:1][CH:33]=2)=[CH:29][CH:28]=1To a solution of diethyl 2-aminofumarate (153 g, 0.81 mol) and p-TsOH.H2O (1.5 g, 8.1 mmol) in n-BuOH (325 mL) was added 2-(4-fluorobenzyl)propenal (162 g, 0.98 mol) dropwise at 120° C. The mixture was stirred for 17 h at 120° C. and at rt for ca. 24 h. The mixture was filtered and concentrated under vacuum to yield the crude diethyl 5-(4-fluorobenzyl)-2,3-pyridinedicarboxylate. This material was dissolved in EtOH (400 mL) and an ice-cold solution of NaOH (88 g, 2.2 mol) in water (300 mL) was added. The mixture was stirred for 2 h at rt. After removal of EtOH in vacuo, water (400 mL) and 6N HCl (200 mL) were added and the mixture was extracted with EtOAc. The EtOAc layer was washed with water and the combined aqueous layers adjusted to pH 2 with 6N HCl (175 mL). The mixture was stirred for 1 h at ice-bath temperature and the product was collected by filtration: 1H NMR (d6-DMSO) δ 8.64 (1H, d, J=2 Hz), 8.01 (1H, d, J=2 Hz), 7.32 (2H, dd, J˜9, 6 Hz), 7.12 (2H, t, J˜9 Hz), 4.05 (2H, s); ES+ MS: 276 (M+H+, 100).
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