Ethyl Acetoacetate → Ethyl 4-amino-6-methyl-3-(3-methylphenyl)thieno[2,3-b]pyridine-5-carboxylate

To a stirred solution of 2-amino-4-(3-methylphenyl)-3-thiophenecarbonitrile (Description 56) (2.98 g, 13.91 mmol) in toluene (75 mL) at RT was added ethyl acetoacetate (1.76 mL, 13.91 mmol) and SnCl4 (3.26 mL, 27.8 mmol). The reaction mixture was refluxed under a nitrogen atmosphere for ca. 4 h and was then cooled to RT and concentrated in vacuo. The residue was re-partitioned between ethyl acetate and water (ca. 80 mL each) and the aqueous layer separated and re-extracted with ethyl acetate (ca. 50 mL×2). The combined organic layer was then passed though a phase separator and the solvent removed in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (880 mg). LCMS (A) m/z: 327 [M+1]+, Rt 1.23 min (acidic).