To ethyl 5-ethoxycarbonylmethyl-3-methylisoxazole-4-carboxylate (1.00 g, 4.15 mmol) was added an excess of conc. aqueous ammonia (d = 0.88 kg·dm -3 , 5.0 cm 3 ) and EtOH (3.0 cm 3 ), and the suspension was stirred vigorously at room temperature for 14 h. After this period a white solid had precipitated which was filtered and recrystallized (EtOAc) to yield the desired product as a white solid (0.81 g, 92%).

    Prepared as described above for ethyl 5-carbamoylmethyl-3-methylisoxazole-4-carboxylate but using methyl-5-ethoxycarbonyl- 3-methylisoxazole-4-carboxylate (1.00 g, 4.15 mmol) and methylamine in toluene (30% w/v, 10.0 cm 3 ), to yield the desired product as a white solid(0.93 g, 99%).

     The ester (4.11 g, 14 mmol) was dissolved in absol. methanolic ammonia (100 ml, 20 % NH 3 ), and the solution was allowed to stand at temperature for 3 days, the solvent was then evaporated, and the resulting crystalline was purified by recrystallization.

      To an autoclave, was added methyl 6-methylniconate (500 g, 3.31 mol), sat. aq. NH 4 OH (500ml) and ethanol (500 ml). After sealing, the reaction was heated to 80 ℃ for 2 days. The cooled reaction mixture was filtrated, and the filter cake was recrystallized to afford white solid (247 g, 54.8%)。

     tert-Butyl 4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate (0.60 g, 2.0 mmol, the product of Production example 43-1) and formamide (0.27 ml, 6.7 mmol) were dissolved in N,N-dimethylformamide (1.0 ml); sodium ethoxide (0.095 g, 1.4 mmol) was added thereto while stirred and heated at 100 .deg.C; the reaction mixture was stirred for 2 hours under nitrogen atmosphere.After cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane-ethyl acetate = 95:5 to 85:15). The title compound was obtained as a colorless oil (0.38 g, 1.4 mmol, 70percent).

      A stirred suspension of ammonium chloride (963 mg, 3 equiv. ) in toluene at 5.deg.C is treated with trimethylaluminium (9 mL of 2 M solution in toluene, 3 equiv.), stirred at room temperature for 2 h, treated with a solution of ethyl 1-(thieno[2,3- b]pyrrol-4-yl) acetate (1.25g, 6 MMOL, 1 equiv.) in toluene, heated at 50.deg.C for 16 h, cooled to room temperature, quenched with water and extracted with EtOAc. The extracts are combined, dried over MgS04 and concentrated in vacuo to give the title product as a tan oil, 1. 1g (quantitative yield), identified by liquid chromatography and mass spectral analyses.

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