N,N-Dimethylcyanoacetamide

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

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

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A reaction mixture was prepared from 22.4 g. of N,N-dimethylcyanoacetamide, 21 ml. of liquid hydrogen sulfide and 1 ml. of triethylamine. The reaction mixture was placed in an autoclave and the autoclave shaken at about 55° C. for about 12 hours. The reaction mixture was taken from the autoclave and the volatile constituents removed by evaporation. Ethanol was added to the residue, thus producing a crystalline solid. The solid was filtered and the filter cake washed with cold ethanol. Twenty-one grams of 3-amino-3-thioxo-N,N-dimethylpropanamide were obtained melting at 111°-114° C. The compound had the following nmr (CDCl3 +DMSOd6):δ3.07 (doublet, 6H); 3.82 (singlet, 2H); 9.1 (very broad, 1H). A reaction mixture was prepared from 22.4 g the volatile constituents removed by evaporation Ethanol was added to the residue thus producing a crystalline solid The solid was filtered the filter cake washed with cold ethanol

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

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

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

Procedure: A solution containing 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 1.2 g of N,N-dimethylcyanoacetamide and catalytic amount of piperidine acetate in 40 ml of dry ethanol was refluxed over night. Yield 1.1 g (40%), m.p. 183°-185° C. was refluxed over night

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

Procedure: To a 250 ml 3-necked R.B. flask was charged 50 g malonodialdehyde bis(dimethylacetal), 22.5 g N,N-dimethyl-2-cyanoacetamide, 60 g acetic anhydride, 0.5 g zinc chloride and 100 ml acetic acid. It was heated to reflux to distill off low boilers until the pot temperature reached 125° C. and head reached 110° C. and a total of 60 ml distillate was collected. GC analysis of the pot content showed disappearance of N,N-dimethyl-2-cyanoacetamide. The reaction mixture was filtered to remove zinc catalyst and then rotovapped. The pot residue was crystallized from a methanol in dry ice-acetone bath to afford 16 g (44.3%) of the title compound. It was heated to reflux to distill off low boilers until the pot temperature reached 125° C. reached 110° C. a total of 60 ml distillate was collected The reaction mixture was filtered to remove zinc catalyst The pot residue was crystallized from a methanol in dry ice-acetone bath

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

Procedure: To a 250 ml 3-necked R.B. flask was charged 50 g malonodialdehyde bis(dimethylacetal), 22.5 g N,N-dimethyl-2-cyanoacetamide, 60 g acetic anhydride, 0.5 g zinc chloride and 100 ml acetic acid. It was heated to reflux to distill off low boilers until the pot temperature reached 125° C. and head reached 110° C. and a total of 60 ml distillate was collected. GC analysis of the pot content showed disappearance of N,N-dimethyl-2-cyanoacetamide. The reaction mixture was filtered to remove zinc catalyst and then rotovapped. The pot residue was crystallized from a methanol in dry ice-acetone bath to afford 16 g (44.3%) of the title compound. It was heated to reflux to distill off low boilers until the pot temperature reached 125° C. reached 110° C. a total of 60 ml distillate was collected The reaction mixture was filtered to remove zinc catalyst The pot residue was crystallized from a methanol in dry ice-acetone bath

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (186.2 mg, 4.65 mmol, 60% dispersion in oil) was added to a solution of 2-cyano-N,N-dimethyl-acetamide (373.7 mg, 3.33 mmol) in dimethylformamide (10 mL) at 0° C. The mixture was removed from the ice bath for 20 min, and a solution of 2,4-dibromopyridine (300 mg, 1.33 mmol) in dimethylformamide (3 mL) was quickly added. The mixture was heated at 60° C. for 16 h. The reaction was cooled to room temperature, quenched by addition of 200 μL saturated ammonium chloride and concentrated to a residue. The compound was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 2-(4-bromo-pyridin-2-yl)-2-cyano-N,N-dimethyl-acetamide and 2-(3-bromo-pyridin-4-yl)-2-cyano-N,N-dimethyl-acetamide. The mixture was removed from the ice bath for 20 min The reaction was cooled to room temperature quenched by addition of 200 μL saturated ammonium chloride concentrated to a residue The compound was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (186.2 mg, 4.65 mmol, 60% dispersion in oil) was added to a solution of 2-cyano-N,N-dimethyl-acetamide (373.7 mg, 3.33 mmol) in dimethylformamide (10 mL) at 0° C. The mixture was removed from the ice bath for 20 min, and a solution of 2,4-dibromopyridine (300 mg, 1.33 mmol) in dimethylformamide (3 mL) was quickly added. The mixture was heated at 60° C. for 16 h. The reaction was cooled to room temperature, quenched by addition of 200 μL saturated ammonium chloride and concentrated to a residue. The compound was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 2-(4-bromo-pyridin-2-yl)-2-cyano-N,N-dimethyl-acetamide and 2-(3-bromo-pyridin-4-yl)-2-cyano-N,N-dimethyl-acetamide. The mixture was removed from the ice bath for 20 min The reaction was cooled to room temperature quenched by addition of 200 μL saturated ammonium chloride concentrated to a residue The compound was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A reaction mixture was prepared from 22.4 g. of N,N-dimethylcyanoacetamide, 21 ml. of liquid hydrogen sulfide and 1 ml. of triethylamine. The reaction mixture was placed in an autoclave and the autoclave shaken at about 55° C. for about 12 hours. The reaction mixture was taken from the autoclave and the volatile constituents removed by evaporation. Ethanol was added to the residue, thus producing a crystalline solid. The solid was filtered and the filter cake washed with cold ethanol. Twenty-one grams of 3-amino-3-thioxo-N,N-dimethylpropanamide were obtained melting at 111°-114° C. The compound had the following nmr (CDCl3 +DMSOd6)δ: 3.07 (doublet, 6H); 3.82 (singlet, 2H); 9.1 (very broad, 1H). A reaction mixture was prepared from 22.4 g the volatile constituents removed by evaporation Ethanol was added to the residue thus producing a crystalline solid The solid was filtered the filter cake washed with cold ethanol

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

Procedure: To a 25 ml three necked round bottom flask, N-tert-butyl-2-(4-formylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.022 g, 0.000047 mol) and 2-cyano-N,N-dimethylacetamide (0.021 g, 0.000187 mol) was taken in ethanol (2 ml). Piperidine acetate (3.3 M solution in water) (0.2 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed overnight. After completion of the reaction, the ethanol was distilled out and water was added to the residue. Aqueous was extracted with ethyl acetate, organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product which was purified by triturated with n-pentane. The solid was filtered and dried under vacuum to yield 0.015 g of N-tert-butyl-2-(4-(2-cyano-3-(dimethylamino)-3-oxoprop-1-enyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. After completion of the addition, reaction mixture was refluxed overnight After completion of the reaction the ethanol was distilled out and water was added to the residue Aqueous was extracted with ethyl acetate, organic layers dried over Na2SO4 filtered concentrated to afford crude product which was purified by triturated with n-pentane The solid was filtered dried under vacuum