(E)-but-2-enenitrile

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 10.0 g of 2-(3,4-dimethoxyphenyl)ethylamine with 14 ml of crotononitrile was stirred at 100° C. for 30 h.

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

Procedure: A solution of 8.0 parts of crotononitrile in 20 parts by volume of tetrahydrofuran is added to a stirred mixture of 16.5 parts of α-morpholino-α(4-morpholino-3-nitrophenyl)-acetonitrile in 150 parts by volume of tetrahydrofuran and 1.5 parts of potassium hydroxide in 5 parts by volume of methanol at room temperature under an atmosphere of nitrogen. The reaction mixture is stirred for a further 6 hours, diluted with 500 parts by volume of water and extracted with 4×250 parts by volume of ethyl acetate. The combined organic extracts are dried over magnesium sulphate and concentrated under vacuum. The resulting crude product is triturated with a mixture of 50 parts by volume of ethyl acetate and hexane. The solid product is collected, washed with ethyl acetate and dried at 80° under vacuum to give 4-(4-morpholino-3-nitrophenyl)-4-(cyano)-4-(morpholino)-3-methylbutyronitrile having melting point 175°-177° C. extracted with 4×250 parts by volume of ethyl acetate The combined organic extracts are dried over magnesium sulphate concentrated under vacuum The resulting crude product is triturated with a mixture of 50 parts by volume of ethyl acetate and hexane The solid product is collected washed with ethyl acetate dried at 80° under vacuum

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

Procedure: A solution of 8.0 parts of crotononitrile in 20 parts by volume of tetrahydrofuran is added to a stirred mixture of 16.5 parts of α-morpholino-α(4-morpholino-3-nitrophenyl)-acetonitrile in 150 parts by volume of tetrahydrofuran and 1.5 parts of potassium hydroxide in 5 parts by volume of methanol at room temperature under an atmosphere of nitrogen. The reaction mixture is stirred for a further 6 hours, diluted with 500 parts by volume of water and extracted with 4×250 parts by volume of ethyl acetate. The combined organic extracts are dried over magnesium sulphate and concentrated under vacuum. The resulting crude product is triturated with a mixture of 50 parts by volume of ethyl acetate and hexane. The solid product is collected, washed with ethyl acetate and dried at 80° under vacuum to give 4-(4-morpholino-3-nitrophenyl)-4-(cyano)-4-(morpholino)-3-methylbutyronitrile having melting point 175°-177° C. extracted with 4×250 parts by volume of ethyl acetate The combined organic extracts are dried over magnesium sulphate concentrated under vacuum The resulting crude product is triturated with a mixture of 50 parts by volume of ethyl acetate and hexane The solid product is collected washed with ethyl acetate dried at 80° under vacuum

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

Procedure: The starting material may be prepared as follows: A solution of 23.5 g of ethyl (diethoxymethyl)phosphonite and 6.7 g of crotononitrile in 30 ml of dry ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 2-cyano-1-methylethyl(diethoxymethyl)phosphinate, b.p. 116° C./0.01 mbar, 31P=+42.2 and +42.0 ppm (CDCl3). The starting material may be prepared the mixture concentrated under reduced pressure The resulting crude product is dissolved in 50 ml of ethyl acetate washed twice with 25 ml of water the organic extract is dried over magnesium sulphate concentrated under reduced pressure The crude product is distilled under reduced pressure

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

Procedure: The starting material may be prepared as follows: A solution of 23.5 g of ethyl (diethoxymethyl)phosphonite and 6.7 g of crotononitrile in 30 ml of dry ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 2-cyano-1-methylethyl(diethoxymethyl)phosphinate, b.p. 116° C./0.01 mbar, 31P=+42.2 and +42.0 ppm (CDCl3). The starting material may be prepared the mixture concentrated under reduced pressure The resulting crude product is dissolved in 50 ml of ethyl acetate washed twice with 25 ml of water the organic extract is dried over magnesium sulphate concentrated under reduced pressure The crude product is distilled under reduced pressure

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

Procedure: (see, e.g., Misra, R. N., et al., Bioorg Med Chem Lett 2003, 13, 1133-6). To a solution of hydrazine monohydrate (hydrazine 78-82%) (0.80 ml, 16.5 mmol) in THF (3 mL), crotononitrile (mixture of cis and trans) (1.1 ml, 13.5 mmol) was added dropwise. The mixture was stirred at 40° C. for 2 h. The mixture was allowed to cool to room temperature and 3-phenoxybenzaldehyde (2.14 ml, 12 mmol) was added dropwise. The mixture was stirred at 40° C. for 2 h. The mixture was concentrated under reduced pressure. To the resulting intermediate was added nPrOH (10 mL) and the suspension was transferred to a pressure vessel. t-BuONa (1.41 g, 14.7 mmol) was added and the mixture was stirred at 110° C. for 2 h 30 min. The mixture was allowed to cool to room temperature and diluted with water (50 mL). The mixture was extracted with Et2O (50 mL×2). The combined organic layers were extracted with 1N aq. HCl (2×30 mL). The combined aqueous phases were basified to pH 14 with 50% aq. NaOH and extracted with Et2O (50 mL×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound (670 mg, 20% over three steps) as an orange oil. Crude was used in the next reaction without further purification. 1H NMR (500 MHz, CDCl3) δ 7.32 (t, J=7.0 Hz, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.10 (t, J=6.9 Hz, 1H), 6.98 (d, J=7.8 Hz, 2H), 6.85 (t, J=7.6 Hz, 2H), 6.80 (s, 1H), 5.37 (d, J=2.6 Hz, 1H), 5.10 (s, 2H), 2.17 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 157.81, 156.75, 147.74, 145.05, 139.08, 130.19, 129.75, 123.46, 121.22, 119.04, 117.63, 116.99, 91.65, 50.86, 13.92. to cool to room temperature The mixture was stirred at 40° C. for 2 h The mixture was concentrated under reduced pressure To the resulting intermediate was added nPrOH (10 mL) the suspension was transferred to a pressure vessel the mixture was stirred at 110° C. for 2 h 30 min to cool to room temperature The mixture was extracted with Et2O (50 mL×2) The combined organic layers were extracted with 1N aq. HCl (2×30 mL) extracted with Et2O (50 mL×2) The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: (see, e.g., WO2009150614A1). To a solution of hydrazine monohydrate (hydrazine 78-82%) (0.51 ml, 10.5 mmol) in THF (2 mL), crotononitrile (mixture of cis and trans) (0.82 ml, 10.1 mmol) was added dropwise. The mixture was stirred at 40° C. for 2 h. The mixture was allowed to cool to room temperature and biphenyl-4-carboxaldehyde (1.82 g, 10.0 mmol) was added. The mixture was stirred at 40° C. for 2 h. The mixture was concentrated under reduced pressure. To the resulting yellow solid was added iPrOH (15 mL) and the suspension was transferred to a pressure vessel. t-BuONa (993 mg, 10.3 mmol) was added and the mixture was stirred at 100° C. for 2 h 30 min. The mixture was allowed to cool to room temperature and diluted with water (50 mL). The mixture was extracted with Et2O (50 mL×2). The combined organic layers were extracted with IN aq. HCl (2×30 mL). The combined aqueous phases were basified to pH 14 with 50% aq. NaOH and extracted with Et2O (50 mL×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound (885 mg, 34% over three steps) as a yellow solid. Crude was used in the next reaction without further purification. 1H NMR (500 MHz, DMSO-d6) δ 7.68-7.61 (m, 4H), 7.45 (t, J=7.5 Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 7.37-7.33 (m, 1H), 5.59 (s, 1H), 5.38 (s, 2H), 2.20 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 151.46, 146.77, 140.52, 139.98, 134.32, 129.40, 128.62, 128.09, 127.51, 127.14, 91.23, 48.92, 11.54. to cool to room temperature The mixture was stirred at 40° C. for 2 h The mixture was concentrated under reduced pressure To the resulting yellow solid was added iPrOH (15 mL) the suspension was transferred to a pressure vessel the mixture was stirred at 100° C. for 2 h 30 min to cool to room temperature The mixture was extracted with Et2O (50 mL×2) The combined organic layers were extracted with IN aq. HCl (2×30 mL) extracted with Et2O (50 mL×2) The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: (see, e.g., WO2009150614A1). To a solution of hydrazine monohydrate (hydrazine 78-82%) (0.51 ml, 10.5 mmol) in THF (2 mL), crotononitrile (mixture of cis and trans) (0.82 ml, 10.1 mmol) was added dropwise. The mixture was stirred at 40° C. for 2 h. The mixture was allowed to cool to room temperature and biphenyl-4-carboxaldehyde (1.82 g, 10.0 mmol) was added. The mixture was stirred at 40° C. for 2 h. The mixture was concentrated under reduced pressure. To the resulting yellow solid was added iPrOH (15 mL) and the suspension was transferred to a pressure vessel. t-BuONa (993 mg, 10.3 mmol) was added and the mixture was stirred at 100° C. for 2 h 30 min. The mixture was allowed to cool to room temperature and diluted with water (50 mL). The mixture was extracted with Et2O (50 mL×2). The combined organic layers were extracted with IN aq. HCl (2×30 mL). The combined aqueous phases were basified to pH 14 with 50% aq. NaOH and extracted with Et2O (50 mL×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound (885 mg, 34% over three steps) as a yellow solid. Crude was used in the next reaction without further purification. 1H NMR (500 MHz, DMSO-d6) δ 7.68-7.61 (m, 4H), 7.45 (t, J=7.5 Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 7.37-7.33 (m, 1H), 5.59 (s, 1H), 5.38 (s, 2H), 2.20 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 151.46, 146.77, 140.52, 139.98, 134.32, 129.40, 128.62, 128.09, 127.51, 127.14, 91.23, 48.92, 11.54. to cool to room temperature The mixture was stirred at 40° C. for 2 h The mixture was concentrated under reduced pressure To the resulting yellow solid was added iPrOH (15 mL) the suspension was transferred to a pressure vessel the mixture was stirred at 100° C. for 2 h 30 min to cool to room temperature The mixture was extracted with Et2O (50 mL×2) The combined organic layers were extracted with IN aq. HCl (2×30 mL) extracted with Et2O (50 mL×2) The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 49.85 g (0.38 mol) of 3-[1,3]-dioxolan-2-yl-propylamine and 43.34 g (0.646 mol) of crotono-nitrile are combined in a 200 ml round-bottomed flask and heated at 100° C. for 72 hours. After cooling, the brown mass is diluted with ethyl acetate and washed with water. The organic phase is dried over calcium carbonate and purified by filtration on silica gel (eluent: ethyl acetate). Evaporation of the solvent gives 69.8 g of 3-(3-[1,3]-dioxolan-2-yl-propylamino)butyronitrile as a reddish liquid which is used without further purification in the next stage. After cooling washed with water The organic phase is dried over calcium carbonate purified by filtration on silica gel (eluent: ethyl acetate) Evaporation of the solvent

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

Procedure: A solution of 50.0 g of isobutyl P-methylphosphonite and 22.8 g of crotononitrile in 50 ml of dry ethanol is added to a stirred mixture of 0.8 g of sodium hydride (50% dispersion in oil) in 25 ml of ethanol at 0° C., under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled to give isobutyl P-(3-cyanoprop-2-yl)-P-(methyl)-phosphinate, b.p. 110°/0.125 mbar, 31P-NMR spectrum: δ=+55.9 and +55.5 ppm (CDCl3). the mixture is concentrated under reduced pressure The resulting crude product is dissolved in 50 ml of ethyl acetate washed twice with 25 ml of water the organic extract is dried over magnesium sulphate concentrated under reduced pressure The crude product is distilled

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

Procedure: 20 g of 2-hydrazino-4,5,6,7-tetrahyro-benzothiazole hydrochloride are added to a sodium ethylate solution of 5.7 g of sodium and 250 ml of ethanol and the mixture is stirred at room temperature for 10 minutes. 5.5 g of crotononitrile are then added dropwise and the mixture is boiled under reflux for 5 hours. After cooling, the ethanol is stripped off in vacuo and the residue is taken up in water. The insoluble material is filtered off and washed thoroughly with water, acetone and ether in succession. After drying, 11.8 g of beige crystals of 3-amino-5-methyl-1-(4,5,6,7-tetrahydro-benzothiazolyl)-2-pyrazoline of melting point 247°-249° C. are obtained. under reflux for 5 hours After cooling The insoluble material is filtered off washed thoroughly with water, acetone and ether in succession After drying

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

Procedure: 20 g of 2-hydrazino-4,5,6,7-tetrahyro-benzothiazole hydrochloride are added to a sodium ethylate solution of 5.7 g of sodium and 250 ml of ethanol and the mixture is stirred at room temperature for 10 minutes. 5.5 g of crotononitrile are then added dropwise and the mixture is boiled under reflux for 5 hours. After cooling, the ethanol is stripped off in vacuo and the residue is taken up in water. The insoluble material is filtered off and washed thoroughly with water, acetone and ether in succession. After drying, 11.8 g of beige crystals of 3-amino-5-methyl-1-(4,5,6,7-tetrahydro-benzothiazolyl)-2-pyrazoline of melting point 247°-249° C. are obtained. under reflux for 5 hours After cooling The insoluble material is filtered off washed thoroughly with water, acetone and ether in succession After drying