3-methylbut-2-enenitrile

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methylbut-2-enenitrile (179 mg, 1.57 mmol) and DBU (143 mg, 0.94 mmol) were added to a stirred solution of N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (250 mg, 0.73 mmol) in acetonitrile (3.9 mL). The mixture was heated to 75° C. overnight and concentrated under reduced pressure The residue was purified by column chromatography on silica gel to afford 3-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]butanenitrile. MS ESI calcd. for C20H20F3N6 [M+H]+ 401. found 401. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.27 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 7.26 (d, J=4.9 Hz, 1H), 7.15 (s, 1H), 3.24 (s, 2H), 2.31 (s, 3H), 1.67 (s, 6H). concentrated under reduced pressure The residue was purified by column chromatography on silica gel

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

Procedure: 3.81 ml of a cyclohexane solution of 1.75M of butyllithium were added at -30° to -40° C. to a mixture of 1.05 ml of diisopropylamine and 4 ml of tetrahydrofuran and the mixture was stirred for 10 minutes and was then cooled to -60° to -70° C. Then 1.22 g of p-tolyl isopropylsulfone were added to the mixture which after 15 minutes of contact was poured over 10 minutes under an inert atmosphere into a solution of 0.5 g of dimethylacrylonitrile and 4 ml of tetrahydrofuran at -60° to -70° C. The mixture was stirred for 30 minutes at -60° to -70° C. and was then poured into an aqueous saturated monosodium phosphate solution. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness. The residue was crystallized from isopropyl ether to obtain 0.740 g of 4-p-tolylsulfonyl-4,3,3,-trimethyl-pentanenitrile melting at 126° C. was then cooled to -60° to -70° C The mixture was stirred for 30 minutes at -60° to -70° C. The mixture was extracted with benzene the organic phase was dried evaporated to dryness The residue was crystallized from isopropyl ether

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

Procedure: 3.81 ml of a cyclohexane solution of 1.75M of butyllithium were added at -30° to -40° C. to a mixture of 1.05 ml of diisopropylamine and 4 ml of tetrahydrofuran and the mixture was stirred for 10 minutes and was then cooled to -60° to -70° C. Then 1.22 g of p-tolyl isopropylsulfone were added to the mixture which after 15 minutes of contact was poured over 10 minutes under an inert atmosphere into a solution of 0.5 g of dimethylacrylonitrile and 4 ml of tetrahydrofuran at -60° to -70° C. The mixture was stirred for 30 minutes at -60° to -70° C. and was then poured into an aqueous saturated monosodium phosphate solution. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness. The residue was crystallized from isopropyl ether to obtain 0.740 g of 4-p-tolylsulfonyl-4,3,3,-trimethyl-pentanenitrile melting at 126° C. was then cooled to -60° to -70° C The mixture was stirred for 30 minutes at -60° to -70° C. The mixture was extracted with benzene the organic phase was dried evaporated to dryness The residue was crystallized from isopropyl ether

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

Procedure: To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol) and the resulting mixture was heated to 60° C. for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. The mixture was cooled to room temperature the ACN was evaporated The mixture was diluted with ethyl acetate washed with dilute HCl and brine The organic solution was dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (ethyl acetate/hexanes)

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

Procedure: To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol) and the resulting mixture was heated to 60° C. for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. The mixture was cooled to room temperature the ACN was evaporated The mixture was diluted with ethyl acetate washed with dilute HCl and brine The organic solution was dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (ethyl acetate/hexanes)

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

Procedure: To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol) and the resulting mixture was heated to 60° C. for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. The mixture was cooled to room temperature the ACN was evaporated The mixture was diluted with ethyl acetate washed with dilute HCl and brine The organic solution was dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (ethyl acetate/hexanes)

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

Procedure: To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol) and the resulting mixture was heated to 60° C. for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. The mixture was cooled to room temperature the ACN was evaporated The mixture was diluted with ethyl acetate washed with dilute HCl and brine The organic solution was dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (ethyl acetate/hexanes)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 4.7 g of sodium amide and 400 ml of liquid ammonia is cooled to -40° C., then the solution of 24.5 g of 4-diisopropylamino 2-(2-pyridyl) butane nitrile (Example 1a) in 30 ml of anhydrous ether is added, the temperature being maintained between -40° C. and -33° C. The mixture is stirred for 15 mins. at this temperature then the solution of 9 g of 3,3-dimethyl acrylonitrile in 40 ml of ether is added, still at the same temperature. The temperature is allowed to rise slowly up to ambient temperature (duration: about 5 hrs.). 200 ml of ether are added then water is added drop by drop. The ethereal phase is separated and the aqueous phase is re-extracted with ether. The ethereal extracts are collected and dried over sodium sulfate. The solvent is evaporated to dryness and the residue is chromatographed over a column of alumina with the eluting ethyl acetate-pentane (2.5-100) vol/vol mixture. the temperature being maintained between -40° C. and -33° C to rise slowly up to ambient temperature (duration: about 5 hrs.) The ethereal phase is separated the aqueous phase is re-extracted with ether The ethereal extracts are collected dried over sodium sulfate The solvent is evaporated to dryness the residue is chromatographed over a column of alumina with the eluting ethyl acetate-pentane (2.5-100) vol/vol mixture

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 4.7 g of sodium amide and 400 ml of liquid ammonia is cooled to -40° C., then the solution of 24.5 g of 4-diisopropylamino 2-(2-pyridyl) butane nitrile (Example 1a) in 30 ml of anhydrous ether is added, the temperature being maintained between -40° C. and -33° C. The mixture is stirred for 15 mins. at this temperature then the solution of 9 g of 3,3-dimethyl acrylonitrile in 40 ml of ether is added, still at the same temperature. The temperature is allowed to rise slowly up to ambient temperature (duration: about 5 hrs.). 200 ml of ether are added then water is added drop by drop. The ethereal phase is separated and the aqueous phase is re-extracted with ether. The ethereal extracts are collected and dried over sodium sulfate. The solvent is evaporated to dryness and the residue is chromatographed over a column of alumina with the eluting ethyl acetate-pentane (2.5-100) vol/vol mixture. the temperature being maintained between -40° C. and -33° C to rise slowly up to ambient temperature (duration: about 5 hrs.) The ethereal phase is separated the aqueous phase is re-extracted with ether The ethereal extracts are collected dried over sodium sulfate The solvent is evaporated to dryness the residue is chromatographed over a column of alumina with the eluting ethyl acetate-pentane (2.5-100) vol/vol mixture

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

Procedure: To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol) and the resulting mixture was heated to 60° C. for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. The mixture was cooled to room temperature the ACN was evaporated The mixture was diluted with ethyl acetate washed with dilute HCl and brine The organic solution was dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (ethyl acetate/hexanes)

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

Procedure: To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol) and the resulting mixture was heated to 60° C. for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. The mixture was cooled to room temperature the ACN was evaporated The mixture was diluted with ethyl acetate washed with dilute HCl and brine The organic solution was dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (ethyl acetate/hexanes)

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

Procedure: To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol) and the resulting mixture was heated to 60° C. for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. The mixture was cooled to room temperature the ACN was evaporated The mixture was diluted with ethyl acetate washed with dilute HCl and brine The organic solution was dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (ethyl acetate/hexanes)