2,2-Dimethyl-1,3-dioxane-4,6-dione → 2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyridin-4-yl)benzoic acid

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A mixture of 1-(1-methyl-1H-pyrazol-4-yl)-2-(thiophen-3-yl)ethanone (Intermediate 3) (300 mg, 1.5 mmol), methyl 4-formyl-2-hydroxybenzoate (Intermediate 5) (315 mg, 1.7 mmol), meldrum's acid (245 mg, 1.7 mmol) and AcONH4 (130 mg, 1.7 mmol) in AcOH (3 mL) was refluxed under N2 atmosphere overnight. The mixture was concentrated under reduced pressure and taken up in MeOH (10 mL) and aq. NaOH (2 M, 10 mL). The reaction was stirred at 40° C. for 5 hours. The resulting mixture was cooled to room temperature, and then acidified with aq. HCl (2 M, 12 mL) to pH=5, followed by a standard aqueous/EtOAc workup. The residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound 9 as a gray solid (45 mg, 2-steps yield 8%). 1H NMR (DMSO-d6 400 MHz): δ 11.24 (brs, 1H), 9.41 (brs, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.38 (dd, J=4.8, 2.8 Hz, 1H), 7.08 (s, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.90-6.82 (m, 2H), 6.67 (d, J=5.2 Hz, 1H), 3.94 (d, J=6.4 Hz, 1H), 3.77 (s, 3H), 3.12 (dd, J=16.0, 7.6 Hz, 1H), 2.48-2.38 (m, 1H). MS (ESI): m/z 395.9 [M+1]+.

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