acetic acid;ethanimidamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Reaction of tert-butyl 4-oxo-3-(dimethylaminomethylidene)-1-piperidinecarboxylate (1.15 g) from Intermediate 28, Step A with acetamidine acetate (0.54 g) according to the procedure described for Intermediate 28, Step B, and purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant) afforded the title compound as a viscous orange oil. described for Intermediate 28, Step B, and purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Reaction of tert-butyl 4-oxo-3-(dimethylaminomethylidene)-1-piperidinecarboxylate (1.15 g) from Intermediate 28, Step A with acetamidine acetate (0.54 g) according to the procedure described for Intermediate 28, Step B, and purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant) afforded the title compound as a viscous orange oil. described for Intermediate 28, Step B, and purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetamidine acetate (37.21 g, 0.31 mole) and diethyl ethoxymethylenemalonate (63 mL, 0.31 mole) were refluxed for 4 h in ethanol (60 mL). The reaction mixture was allowed to cool for 15 min., then acetamidine acetate (37.21 g, 0.31 mole) was added. The reaction mixture was refluxed for 22 hours, allowed to cool to room temperature, and diluted with water (200 mL) and dichloromethane (200 mL). The aqueous layer was extracted with 10% isopropanol/dichloromethane (2×200 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered and the solvent was removed. The residue was recrystallized from chloroform/hexanes in two crops to afford the title compound (24.92 g) in 46% yield as yellowish crystals. Rf =0.27 (silica gel, 10% isopropanol in dichloromethane). m.p. 187°-188° C. to cool for 15 min. The reaction mixture was refluxed for 22 hours The aqueous layer was extracted with 10% isopropanol/dichloromethane (2×200 mL) The combined organic extracts were washed with water (50 mL), brine (50 mL) dried over magnesium sulfate filtered the solvent was removed The residue was recrystallized from chloroform/hexanes in two crops

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetamidine acetate (37.21 g, 0.31 mole) and diethyl ethoxymethylenemalonate (63 mL, 0.31 mole) were refluxed for 4 h in ethanol (60 mL). The reaction mixture was allowed to cool for 15 min., then acetamidine acetate (37.21 g, 0.31 mole) was added. The reaction mixture was refluxed for 22 hours, allowed to cool to room temperature, and diluted with water (200 mL) and dichloromethane (200 mL). The aqueous layer was extracted with 10% isopropanol/dichloromethane (2×200 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered and the solvent was removed. The residue was recrystallized from chloroform/hexanes in two crops to afford the title compound (24.92 g) in 46% yield as yellowish crystals. Rf =0.27 (silica gel, 10% isopropanol in dichloromethane). m.p. 187°-188° C. to cool for 15 min. The reaction mixture was refluxed for 22 hours The aqueous layer was extracted with 10% isopropanol/dichloromethane (2×200 mL) The combined organic extracts were washed with water (50 mL), brine (50 mL) dried over magnesium sulfate filtered the solvent was removed The residue was recrystallized from chloroform/hexanes in two crops

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetamidine acetate (37.21 g, 0.31 mole) and diethyl ethoxymethylenemalonate (63 mL, 0.31 mole) were refluxed for 4 h in ethanol (60 mL). The reaction mixture was allowed to cool for 15 minutes, then acetamidine acetate (37.21 g, 0.31 mole) was added. The reaction mixture was refluxed for 22 hours, allowed to cool to room temperature, and diluted with water (200 mL) and dichloromethane (200 mL). The aqueous layer was extracted with 10% isopropanol/dichloromethane (2×200 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered and the solvent was removed. The residue was recrystallized from chloroform/hexanes in two crops to afford the title compound (24.92 g) in 46% yield as yellowish crystals. Rf=0.27 (silica gel, 10% isopropanol in dichloromethane); m.p. 187 to 188° C. to cool for 15 minutes The reaction mixture was refluxed for 22 hours The aqueous layer was extracted with 10% isopropanol/dichloromethane (2×200 mL) The combined organic extracts were washed with water (50 mL), brine (50 mL) dried over magnesium sulfate filtered the solvent was removed The residue was recrystallized from chloroform/hexanes in two crops

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Reaction of tert-butyl 4-oxo-3-(dimethylaminomethylidene)-1-piperidinecarboxylate (1.15 g) from Intermediate 28, Step A with acetamidine acetate (0.54 g) according to the procedure described for Intermediate 28, Step B, and purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant) afforded the title compound as a viscous orange oil. described for Intermediate 28, Step B, and purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant)