4-(4-chlorophenyl)-3-oxobutanenitrile

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 4-(4-chlorophenyl)-3-oxo-butyronitrile (Preparation 96, 2.2 g, 11 mmol) and N-methylhydrazine (1.94 mL, 36.5 mmol) in EtOH (40 mL, 800 mmol) was heated at 100° C. in a 40 mL vial (the reaction was split into 2 equal batches). After 20 h, the reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified on the Isco (40 g SiO2, hexanes to ethyl acetate) to afford the title compound as an off-white solid (1.83 g, 69%). was split into 2 equal batches) concentrated in vacuo The residue was purified on the Isco (40 g SiO2, hexanes to ethyl acetate)

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

Procedure: 2 M of isopropylmagnesium chloride in THF (300 mL) was added to a −78° C. solution of cyanoacetic acid (28.3 g, 333 mmol) in anhydrous THF (600 mL, 7000 mmol). After 1 h, a solution of 4-chlorophenylacetic acid (20 g, 100 mmol) and N,N-carbonyldiimidazole (21.7 g, 134 mmol) in anhydrous THF (200 mL, 2000 mmol) was added. The reaction mixture was warmed to rt. After 16 h, the reaction mixture was poured into water (1 L, 60000 mmol). The mixture was adjusted to pH 4 with glacial AcOH. Gas evolution was evident during addition of the AcOH. The mixture was concentrated in vacuo to remove the THF (in 1 L portions). The product crystallized from the aqueous portions. The solid was collected by filtration, washing with water. Dried under vacuum to afford the product as a fluffy light orange-yellow solid (15.89 g, 60%). After 16 h The mixture was concentrated in vacuo to remove the THF (in 1 L portions) The product crystallized from the aqueous portions The solid was collected by filtration washing with water Dried under vacuum

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

Procedure: A solution of 4-(4-chlorophenyl)-3-oxo-butyronitrile (Preparation 96, 2.2 g, 11 mmol) and N-methylhydrazine (1.94 mL, 36.5 mmol) in EtOH (40 mL, 800 mmol) was heated at 100° C. in a 40 mL vial (the reaction was split into 2 equal batches). After 20 h, the reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified on the Isco (40 g SiO2, hexanes to ethyl acetate) to afford the title compound as an off-white solid (1.83 g, 69%). was split into 2 equal batches) concentrated in vacuo The residue was purified on the Isco (40 g SiO2, hexanes to ethyl acetate)

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

Procedure: 2 M of isopropylmagnesium chloride in THF (300 mL) was added to a −78° C. solution of cyanoacetic acid (28.3 g, 333 mmol) in anhydrous THF (600 mL, 7000 mmol). After 1 h, a solution of 4-chlorophenylacetic acid (20 g, 100 mmol) and N,N-carbonyldiimidazole (21.7 g, 134 mmol) in anhydrous THF (200 mL, 2000 mmol) was added. The reaction mixture was warmed to rt. After 16 h, the reaction mixture was poured into water (1 L, 60000 mmol). The mixture was adjusted to pH 4 with glacial AcOH. Gas evolution was evident during addition of the AcOH. The mixture was concentrated in vacuo to remove the THF (in 1 L portions). The product crystallized from the aqueous portions. The solid was collected by filtration, washing with water. Dried under vacuum to afford the product as a fluffy light orange-yellow solid (15.89 g, 60%). After 16 h The mixture was concentrated in vacuo to remove the THF (in 1 L portions) The product crystallized from the aqueous portions The solid was collected by filtration washing with water Dried under vacuum

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

Procedure: 2 M of isopropylmagnesium chloride in THF (300 mL) was added to a −78° C. solution of cyanoacetic acid (28.3 g, 333 mmol) in anhydrous THF (600 mL, 7000 mmol). After 1 h, a solution of 4-chlorophenylacetic acid (20 g, 100 mmol) and N,N-carbonyldiimidazole (21.7 g, 134 mmol) in anhydrous THF (200 mL, 2000 mmol) was added. The reaction mixture was warmed to rt. After 16 h, the reaction mixture was poured into water (1 L, 60000 mmol). The mixture was adjusted to pH 4 with glacial AcOH. Gas evolution was evident during addition of the AcOH. The mixture was concentrated in vacuo to remove the THF (in 1 L portions). The product crystallized from the aqueous portions. The solid was collected by filtration, washing with water. Dried under vacuum to afford the product as a fluffy light orange-yellow solid (15.89 g, 60%). After 16 h The mixture was concentrated in vacuo to remove the THF (in 1 L portions) The product crystallized from the aqueous portions The solid was collected by filtration washing with water Dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 4-(4-chlorophenyl)-3-oxo-butyronitrile (Preparation 96, 2.2 g, 11 mmol) and N-methylhydrazine (1.94 mL, 36.5 mmol) in EtOH (40 mL, 800 mmol) was heated at 100° C. in a 40 mL vial (the reaction was split into 2 equal batches). After 20 h, the reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified on the Isco (40 g SiO2, hexanes to ethyl acetate) to afford the title compound as an off-white solid (1.83 g, 69%). was split into 2 equal batches) concentrated in vacuo The residue was purified on the Isco (40 g SiO2, hexanes to ethyl acetate)

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

Procedure: 2 M of isopropylmagnesium chloride in THF (300 mL) was added to a −78° C. solution of cyanoacetic acid (28.3 g, 333 mmol) in anhydrous THF (600 mL, 7000 mmol). After 1 h, a solution of 4-chlorophenylacetic acid (20 g, 100 mmol) and N,N-carbonyldiimidazole (21.7 g, 134 mmol) in anhydrous THF (200 mL, 2000 mmol) was added. The reaction mixture was warmed to rt. After 16 h, the reaction mixture was poured into water (1 L, 60000 mmol). The mixture was adjusted to pH 4 with glacial AcOH. Gas evolution was evident during addition of the AcOH. The mixture was concentrated in vacuo to remove the THF (in 1 L portions). The product crystallized from the aqueous portions. The solid was collected by filtration, washing with water. Dried under vacuum to afford the product as a fluffy light orange-yellow solid (15.89 g, 60%). After 16 h The mixture was concentrated in vacuo to remove the THF (in 1 L portions) The product crystallized from the aqueous portions The solid was collected by filtration washing with water Dried under vacuum

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

Procedure: A solution of 4-(4-chloro-phenyl)-3-oxo-butyronitrile (200 mg, 1 mmol, 1.0 equiv) and N-methylhydrazine (153 mg, 3.32 mmol, 3.2 equiv) in 4 mL of ethanol was heated at 100° C. in a sealed tube. After 4 d, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, gradient from hexanes to ethyl acetate) to afford the product as a yellow solid (188 mg, 80%). concentrated in vacuo The residue was purified

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

Procedure: A solution of 4-(4-chloro-phenyl)-3-oxo-butyronitrile (500 mg, 2 mmol, 1.0 equiv), triethylamine (1.16 mL, 8.3 mmol, 3.2 equiv), and tert-butylhydrazine hydrochloride (1.03 g, 8.3 mmol, 3.2 equiv) in 10 mL of ethanol was heated at 100° C. in a sealed tube. After 4 d, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, gradient from hexanes to ethyl acetate) to afford the product as a yellow oil (610 mg, 70%). concentrated in vacuo The residue was purified

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

Procedure: Isopropylmagnesium chloride (24.6 mL, 2 M solution in THF, 50 mmol, 5 equiv) was added to a −78° C. solution of cyanoacetic acid (2.52 g, 29.6 mmol, 2.96 equiv) in 80 mL of anhydrous tetrahydrofuran. After 1 h, a solution of 4-chlorophenylacetic acid (1.7 g, 10 mmol, 1.0 equiv) and N,N-carbonyldiimidazole (1.93 g, 11.9 mmol, 1.19 equiv) in 20 mL of anhydrous tetrahydrofuran was added to the reaction mixture, and the reaction mixture was warmed to ambient temperature. After 16 h, the reaction mixture was poured into 300 mL of water. The mixture was adjusted to pH 4 with glacial acetic acid. Gas evolution was evident during addition of the acetic acid. The mixture was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via automated flash chromatography (80 g SiO2, gradient from hexanes to ethyl acetate) to afford the product as a white solid (1.17 g, 57%). After 16 h The mixture was extracted with ethyl acetate (4×100 mL) The combined organic layers were washed with brine dried over sodium sulfate filtered concentrated in vacuo The residue was purified