2-chloroprop-2-enenitrile

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

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 600 ml of ethanol were added 59.94 g of tert-butylhydrazine hydrochloride, 79.3 g of sodium acetate and 2-chloroacrylonitrile followed by stirring at 80° C. for 12 hours. After removal of the solvent, water was added and then was neutralized with sodium hydrogen carbonate followed by extracting with ethyl acetate. The resulting organic layer was washed with saturated brine, and then dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1 to 1/2) to give the title compound. After removal of the solvent, water was added by extracting with ethyl acetate The resulting organic layer was washed with saturated brine dried over magnesium sulfate The organic layer was filtered concentrated in vacuo The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1 to 1/2)

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

Procedure: A solution of N-(2,2,2-trifluoroethyl)-3,5-dichlorobenzimidoyl chloride (8.72 g, 0.03 mol) in N,N-dimethylformamide is treated with 2-chloroacrylonitrile (3.0 g, 0.0345 mol) under a nitrogen atmosphere. Triethylamine (9.56 g, 0.0945 mol) is added slowly at 50° C. over two hours and the reaction mixture is stirred at 58°-60° C. for 18 hours. Bromine (4.8 g, 0.03 mol) is then added over 20 minutes as the temperature rises from 25° C. to 36° C. The resultant reaction mixture is diluted with water and extracted with methylene chloride. Evaporation and flash column chromatography using silica gel and a 20% ethyl acetate in heptane solution gives the title product as a white crystalline solid (5.4 g, 46.9% yield) which is identified by 19F and 1H NMR. rises from 25° C. to 36° C The resultant reaction mixture extracted with methylene chloride Evaporation and flash column chromatography

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

Procedure: 1.45 g (15.5 mmol) of 2-chloroacrylonitrile and 6 g (43.5 mmol) of dry potassium carbonate are added in succession to 6.6 g (60 mmol) of catechol dissolved in 80 ml of anhydrous acetone. The operation is repeated 4 times within one hour; the mixture is then heated to boiling. After 18 hours at reflux under argon, the reaction mixture is cooled and then filtered over Celite. After evaporation of the solvent, the residue is taken up in a water/ethyl acetate mixture (50:50) and then the aqueous phase is extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is evaporated under reduced pressure. The title nitrile is obtained pure in the form of a white solid after purification on a silica column (eluant: AcOEt/PE 30/70). within one hour the mixture is then heated to boiling After 18 hours at reflux under argon the reaction mixture is cooled filtered over Celite After evaporation of the solvent the aqueous phase is extracted with ethyl acetate The organic phase, dried over magnesium sulphate filtered is evaporated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250 mL RBF containing a solution of 1-(2,4-difluorophenyl)hydrazine hydrochloride (10.33 g, 57 mmol), Et3N (8.0 mL, 57 mmol), EDTA disodium salt dihydrate (50 mg, 0.13 mmol) in 100 mL of MeOH was fitted with a reflux condenser, and heated to 70° C. To the refluxing solution was added 2-chloroacrylonitrile (5.0 mL, 57 mmol) slowly. The solution was heated at reflux for an additional 7.5 h. It was cooled to RT then concentrate sulfuric acid (5.2 mL, 97 mmol) was added slowly and the reaction mixture again heated to reflux for 18 h. The reaction mixture was cooled to 0° C. and treated with Na2CO3 monohydrate (21.00 g) and stirred at RT for 8 h. The reaction mixture was concentrated on the rotovap to remove the MeOH. The resulting rust colored solid was then treated with 100 mL of water and extracted with EtOAc (2×100 mL). The combined EtOAc layers were washed with brine, dried and concentrated. Purification of the crude material on an ISCO 120 g column (20-80% EtOAc in hexanes) afforded 1-(2,4-difluorophenyl)-1H-pyrazol-5-amine as an orange-brown viscous oil. MS (ES+): 196.1 (M+H)+. A further general description of this procedure can be found in U.S. Pat. No. 4,803,215. was fitted with a reflux condenser The solution was heated at reflux for an additional 7.5 h It was cooled to RT the reaction mixture again heated to reflux for 18 h The reaction mixture was cooled to 0° C. The reaction mixture was concentrated on the rotovap to remove the MeOH The resulting rust colored solid was then treated with 100 mL of water extracted with EtOAc (2×100 mL) The combined EtOAc layers were washed with brine dried concentrated Purification of the crude material on an ISCO 120 g column (20-80% EtOAc in hexanes)

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

Procedure: Under a nitrogen purge, a solution of trifluoromethyl-1-chloro-N-(p-chlorobenzyl)thioformimidate (1.1 g, 0.004 mol) and 2-chloroacrylonitrile (0.4 mL, 0.005 mol) is treated with a solution of triethylamine (1.3 mL, 0.009 mol) in toluene. After an induction period, solids begin to form as the reaction mixture exotherms slightly. When the exotherm subsides, the reaction mixture is heated at reflux temperature for 16 hours, cooled and filtered. The filter cake is washed with ehtyl acetate and the filtrate is concentrated in vacuo to obtain a semi-solid. The semi-solid is dissolved in ethyl acetate and the organic solution is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. The solid is twice recrystallized from 1,2-dichloroethane to give the title product as a beige solid (0.7 g, mp 203°-205° C.) which is identified by 1HNMR spectral analysis. Under a nitrogen purge to form as the reaction mixture When the exotherm subsides, the reaction mixture is heated at reflux temperature for 16 hours cooled filtered The filter cake is washed with ehtyl acetate the filtrate is concentrated in vacuo to obtain a semi-solid the organic solution is washed with water and brine dried over anhydrous magnesium sulfate concentrated in vacuo to obtain a solid The solid is twice recrystallized from 1,2-dichloroethane

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

Procedure: Solutions of 2-chloroacrylonitrile (15.7 g.) in acetonitrile (20 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (27 g.) in acetonitrile (20 ml.) were added simultaneously over 30 minutes to a stirred, ice-cooled solution of 2-chloroacetamidine hydrochloride (19.2 g.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (22.5 g.) in acetonitrile (200 ml.), keeping the temperature below 30° and the mixture stirred a further 4 hours at room temperature after the addition was complete. The resulting mixture was stirred with a mixture of water (100 ml.) and ethyl acetate (200 ml.) and then filtered through a pad of diatomaceous earth and the ethyl acetate phase separated. The aqueous phase was further extracted with ethyl acetate (2×100 ml.) and the combined ethyl acetate extracts dried and evaporated to dryness to give 4-amino-2-chloromethylpyrimidine (14.5 g.) which was used without further purification. the temperature below 30° after the addition filtered through a pad of diatomaceous earth the ethyl acetate phase separated The aqueous phase was further extracted with ethyl acetate (2×100 ml.) the combined ethyl acetate extracts dried evaporated to dryness

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

Procedure: A solution of 2-chloroacrylonitrile (1.75 g.) in acetonitrile (10 ml.) was added over 15 minutes to an ice-cooled mixture of 1-amidino-4-phthalimidobutane hydrochloride (5.64 g.), acetonitrile (50 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (6.08 g.). The mixture was stirred for a further two hours and then evaporated to dryness. The residue was treated with water (50 ml.) and the mixture extracted with ethyl acetate (2×50 ml.). The combined ethyl acetate extracts were extracted with N hydrochloric acid (3×30 ml.) and the combined aqueous extracts neutralised with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extracts were evaporated to dryness and the residue recrystallised from acetonitrile to give 4-amino-2-(4-phthalimidobutyl)pyrimidine (2.5 g.), m.p. 139°-140°. cooled evaporated to dryness The residue was treated with water (50 ml.) the mixture extracted with ethyl acetate (2×50 ml.) The combined ethyl acetate extracts were extracted with N hydrochloric acid (3×30 ml.) extracted with ethyl acetate The ethyl acetate extracts were evaporated to dryness the residue recrystallised from acetonitrile

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

Procedure: Part A: A magnetically stirred mixture of N-(4-chlorophenyl)-2,4-dichlorobenzenecarboxamidine (10.0 gram, 0.033 mol), 2-chloroacrylonitrile (5.7 gram, 0.065 mol) and N,N-diisopropylethylamine (DIPEA) (12.5 ml, 0.069 mol) in tetrahydrofuran (150 ml) is heated at reflux temperature for 40 hours (N2 atmosphere). After cooling to room temperature the mixture is concentrated in vacuo. The residue is dissolved in a mixture of dichloromethane and water (200 ml/200 ml). The dichloromethane layer is collected, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallised from ethanol/water to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carbonitrile (11.23 gram, 97% yield). 1H-NMR (400 MHz, CDCl3): δ 4.28 (dd, J=10 and 8 Hz, 1H), 4.36 (t, J=10 Hz, 1H), 5.07 (dd, J=10 and 8 Hz, 1H), 6.68 (br d, J=8 Hz, 2H), 7.16 (br d, J=8 Hz, 2H), 7.32–7.36 (m, 2H), 7.45 (d, J=8 Hz, 1H). is heated is concentrated in vacuo The residue is dissolved in a mixture of dichloromethane and water (200 ml/200 ml) The dichloromethane layer is collected dried over MgSO4 filtered concentrated in vacuo The residue is recrystallised from ethanol/water

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 2-formylamino-2-(4-methylphenyl)acetic acid (4.00 g) in acetic anhydride (45 ml) was added 2-chloroacrylonitrile (16.5 ml) at room temperature and the resulting suspension was heated at 90° C. for 2.5 hours. After cooling, the solvent was evaporated and the residue was washed with isopropyl ether. The mixture was filtered and the resulting solid was dissolved into ethyl acetate and the solution was washed with aqueous saturated sodium bicarbonate and water successively. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with n-hexane/methylene chloride 1:3 (V/V) to give 2-(4-methylphenyl)pyrrole-3-carbonitrile (0.73 g) as a colorless viscous oil. After cooling the solvent was evaporated the residue was washed with isopropyl ether The mixture was filtered the resulting solid was dissolved into ethyl acetate the solution was washed with aqueous saturated sodium bicarbonate and water successively The organic layer was dried with magnesium sulfate filtered concentrated in vacuo The residue was purified by silica gel column chromatography eluted with n-hexane/methylene chloride 1:3 (V/V)