[CH3:1]C(S)C([O-])=O.COC(=O)C(Cl)=C.[OH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].IC>C[O-].[Na+]>[OH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].[CH3:1][O:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([OH:22])=[O:21]Methyl 3-aminothiophene-2-carboxylate was Boc-protected and the resulting ester was saponified to yield 3-[(tert-butoxy)carbonylamino]-2-thiophene-carboxylic acid (11). Methyl 3-hydroxythiophene-2-carboxylate (12) was prepared by cyclization of methylthioglycolate and methyl-2-chloroacrylate in methanolic sodium methoxide (Huddleston et al., Synth. Commun. 1979, 9, 731). Alkylation of (12) with iodomethane and subsequent hydrolysis of the methyl ester yielded 3-methoxy-2-thiophenecarboxylic acid (13). 3-Fluorothiophene-2-carboxylic acid (14) was synthesized as described by Taylor et al. (Org. Prep. Proc. Int. 1997, 29, 221) (FIG. 3A, 3B, 3C). The remaining 3-substituted-thiophene-2-carboxylic acids were obtained from commercial sources.
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