1-(4-chlorophenyl)sulfonylpropan-2-one

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 300 mL reaction flask was added 2.4 g (59.3 mmole) sodium hydride (60% dispersion in oil) and 10 mL hexanes. The hexanes were removed by pipette and replaced by 60 mL dry tetrahydrofluran (THF). The suspension was cooled to -15° C. and a solution of 12.0 g (51.6 mmole) 4-chlorophenylsulfonyl acetone in 50 mL THF was added via addition funnel over 20 minutes maintaining the reaction temperature below -12° C. The resulting yellow solution was removed from the cold bath and stirred at room temperature for 30 min. The solution was recooled to -5° C. and 3.8 mL (54.1 mmole) bromoacetonitrile was added dropwise via addition funnel. After 5 min, the reaction mixture was removed from the cold bath and stirred at room temperature overnight. The reaction was quenched with 1 mL of saturated ammonium chloride and transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine. The organic layer was separated and the aqueous layer was back extracted once with 50 mL more dichloromethane. The combined organics were then dried with sodium sulfate, filtered, concentrated, and chromatographed through a bed of silica gel using 1:1 hexane: dichloromethane. Isolation gave 8.2 g (59% yield) of 3-(4-chlorophenylsulfonyl)-4-cyanobutan-2-one, a yellow oil that was 90% pure by HPLC. 1H NMR (CDCl3) indicated desired product as the major component: δ7.6 (m, 4H), 4.42 (dd, 1H), 2.78 (m, 2H), 2.48 (s, 3H). To a 300 mL reaction flask The hexanes were removed by pipette maintaining the reaction temperature below -12° C The resulting yellow solution was removed from the cold bath was recooled to -5° C. After 5 min the reaction mixture was removed from the cold bath stirred at room temperature overnight The reaction was quenched with 1 mL of saturated ammonium chloride transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine The organic layer was separated the aqueous layer was back extracted once with 50 mL more dichloromethane The combined organics were then dried with sodium sulfate filtered concentrated chromatographed through a bed of silica gel using 1:1 hexane

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 300 mL reaction flask was added 2.4 g (59.3 mmole) sodium hydride (60% dispersion in oil) and 10 mL hexanes. The hexanes were removed by pipette and replaced by 60 mL dry tetrahydrofluran (THF). The suspension was cooled to -15° C. and a solution of 12.0 g (51.6 mmole) 4-chlorophenylsulfonyl acetone in 50 mL THF was added via addition funnel over 20 minutes maintaining the reaction temperature below -12° C. The resulting yellow solution was removed from the cold bath and stirred at room temperature for 30 min. The solution was recooled to -5° C. and 3.8 mL (54.1 mmole) bromoacetonitrile was added dropwise via addition funnel. After 5 min, the reaction mixture was removed from the cold bath and stirred at room temperature overnight. The reaction was quenched with 1 mL of saturated ammonium chloride and transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine. The organic layer was separated and the aqueous layer was back extracted once with 50 mL more dichloromethane. The combined organics were then dried with sodium sulfate, filtered, concentrated, and chromatographed through a bed of silica gel using 1:1 hexane: dichloromethane. Isolation gave 8.2 g (59% yield) of 3-(4-chlorophenylsulfonyl)-4-cyanobutan-2-one, a yellow oil that was 90% pure by HPLC. 1H NMR (CDCl3) indicated desired product as the major component: δ7.6 (m, 4H), 4.42 (dd, 1H), 2.78 (m, 2H), 2.48 (s, 3H). To a 300 mL reaction flask The hexanes were removed by pipette maintaining the reaction temperature below -12° C The resulting yellow solution was removed from the cold bath was recooled to -5° C. After 5 min the reaction mixture was removed from the cold bath stirred at room temperature overnight The reaction was quenched with 1 mL of saturated ammonium chloride transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine The organic layer was separated the aqueous layer was back extracted once with 50 mL more dichloromethane The combined organics were then dried with sodium sulfate filtered concentrated chromatographed through a bed of silica gel using 1:1 hexane

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

Procedure: Using the method described in Example 30 by employing 1-[(2-pyrrolidinylprop-1-enyl)sulfonyl]-4-chlorobenzene (freshly prepared before use from 4-chlorophenylsulfonylacetone (Lancaster Chemical Company), pyrrolidine and TiCl4 (2.03 g, 7.10 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.47 g, 7.10 mmol), N,N-diisopropylethylamine (1.3 mL, 7.10 mmol), piperidine (1.1 mL, 11.4 mmol), NEt3 (1.6 mL) and SnCl2 (21 mL of a 2 M soln in DMF). In this example the mixture of enamine, 2-methyl-4,6-dichloro-5-nitropyrimidine and N,N-diisopropylethylamine was stirred at 100° C. for 20 h prior to piperidine addition. The SnCl2 solution was added to the reaction mixture at 140° C. The mixture was stirred at 140° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant to give 441 g (15%) of 4-chloro-1-[((2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl)methyl)sulfonyl]benzene as a brown colored solid. This compound (0.44 g, 1.08 mmol) was dissolved in 5:1 EtOAc/MeOH (20 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.10 mL, 1.10 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 296 mg (9%) of the title compound as a white colored solid. Mp: 199-201° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.57 (m, 4), 1.65 (m, 2), 2.47 (s, 3), 3.85 (br s, 4), 5.02 (s, 2), 6.23 (s, 1), 7.65 (AB q, 4, J=6.2, 6.2), 12.20 (s, 1), 14.18 (s, 1). MS m/z: 405 (M+1 for free base). Anal. Calcd for C19H21ClN4O2S.HCl.0.9H2O: C, 49.87; H, 5.24; N, 12.25; Cl, 15.49. Found: C, 49.85; H, 5.17; N, 12.15; Cl, 15.61. The mixture was stirred at 140° C. for an additional 16 h to cool to room temperature The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 300 mL reaction flask was added 2.4 g (59.3 mmole) sodium hydride (60% dispersion in oil) and 10 mL hexanes. The hexanes were removed by pipette and replaced by 60 mL dry tetrahydrofuran (THF). The suspension was cooled to -15° C. and a solution of 12.0 g (51.6 mmole) 4-chlorophenylsulfonyl acetone in 50 mL THF was added via addition funnel over 20 minutes maintaining the reaction temperature below -12° C. The resulting yellow solution was removed from the cold bath and stirred at room temperature for 30 min. The solution was recooled to -5° C. and 3.8 mL (54.1 mmole) bromoacetonitrile was added dropwise via addition funnel. After 5 min, the reaction mixture was removed from the cold bath and stirred at room temperature overnight. The reaction was quenched with 1 mL of saturated ammonium chloride and transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine. The organic layer was separated and the aqueous layer was back extracted once with 50 mL more dichloromethane. The combined organics were then dried with sodium sulfate, filtered, concentrated, and chromatographed through a bed of silica gel using 1:1 hexane:dichloromethane. Isolation gave 8.2 g (59% yield) of 3-(4-chlorophenylsulfonyl)4-cyanobutan-2-one, a yellow oil that was 90% pure by HPLC. 1H NMR (CDCl3) indicated desired product as the major component: δ7.6 (m, 4H), 4.42 (dd, 1H), 2.78 (m, 2H), 2.48 (s, 3H). To a 300 mL reaction flask The hexanes were removed by pipette maintaining the reaction temperature below -12° C The resulting yellow solution was removed from the cold bath was recooled to -5° C. After 5 min the reaction mixture was removed from the cold bath stirred at room temperature overnight The reaction was quenched with 1 mL of saturated ammonium chloride transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine The organic layer was separated the aqueous layer was back extracted once with 50 mL more dichloromethane The combined organics were then dried with sodium sulfate filtered concentrated chromatographed through a bed of silica gel using 1:1 hexane

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 300 mL reaction flask was added 2.4 g (59.3 mmole) sodium hydride (60% dispersion in oil) and 10 mL hexanes. The hexanes were removed by pipette and replaced by 60 mL dry tetrahydrofuran (THF). The suspension was cooled to -15° C. and a solution of 12.0 g (51.6 mmole) 4-chlorophenylsulfonyl acetone in 50 mL THF was added via addition funnel over 20 minutes maintaining the reaction temperature below -12° C. The resulting yellow solution was removed from the cold bath and stirred at room temperature for 30 min. The solution was recooled to -5° C. and 3.8 mL (54.1 mmole) bromoacetonitrile was added dropwise via addition funnel. After 5 min, the reaction mixture was removed from the cold bath and stirred at room temperature overnight. The reaction was quenched with 1 mL of saturated ammonium chloride and transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine. The organic layer was separated and the aqueous layer was back extracted once with 50 mL more dichloromethane. The combined organics were then dried with sodium sulfate, filtered, concentrated, and chromatographed through a bed of silica gel using 1:1 hexane:dichloromethane. Isolation gave 8.2 g (59% yield) of 3-(4-chlorophenylsulfonyl)4-cyanobutan-2-one, a yellow oil that was 90% pure by HPLC. 1H NMR (CDCl3) indicated desired product as the major component: δ7.6 (m, 4H), 4.42 (dd, 1H), 2.78 (m, 2H), 2.48 (s, 3H). To a 300 mL reaction flask The hexanes were removed by pipette maintaining the reaction temperature below -12° C The resulting yellow solution was removed from the cold bath was recooled to -5° C. After 5 min the reaction mixture was removed from the cold bath stirred at room temperature overnight The reaction was quenched with 1 mL of saturated ammonium chloride transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine The organic layer was separated the aqueous layer was back extracted once with 50 mL more dichloromethane The combined organics were then dried with sodium sulfate filtered concentrated chromatographed through a bed of silica gel using 1:1 hexane

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

Procedure: Using the method described in Example 30 by employing 1-[(2-pyrrolidinylprop-1-enyl)sulfonyl]-4-chlorobenzene (freshly prepared before use from 4-chlorophenylsulfonylacetone (Lancaster Chemical Company), pyrrolidine and TiCl4 (2.03 g, 7.10 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.47 g, 7.10 mmol), N,N-diisopropylethylamine (1.3 mL, 7.10 mmol), piperidine (1.1 mL, 11.4 mmol), NEt3 (1.6 mL) and SnCl2 (21 mL of a 2 M soln in DMF). In this example the mixture of enamine, 2-methyl-4,6-dichloro-5-nitropyrimidine and N,N-diisopropylethylamine was stirred at 100° C. for 20 h prior to piperidine addition. The SnCl2 solution was added to the reaction mixture at 140° C. The mixture was stirred at 140° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant to give 441 g (15%) of 4-chloro-1-[((2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl)methyl)sulfonyl]benzene as a brown colored solid. This compound (0.44 g, 1.08 mmol) was dissolved in 5:1 EtOAc/MeOH (20 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.10 mL, 1.10 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 296 mg (9%) of the title compound as a white colored solid. Mp: 199-201° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.57 (m, 4), 1.65 (m, 2), 2.47 (s, 3), 3.85 (br s, 4), 5.02 (s, 2), 6.23 (s, 1), 7.65 (AB q, 4, J=6.2, 6.2), 12.20 (s, 1), 14.18 (s, 1). MS m/z: 405 (M+1 for free base). Anal. Calcd for C19H21ClN4O2S.HCl.0.9H2O: C, 49.87; H, 5.24; N, 12.25; Cl, 15.49. Found: C, 49.85; H, 5.17; N, 12.15; Cl, 15.61. The mixture was stirred at 140° C. for an additional 16 h to cool to room temperature The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 300 mL reaction flask was added 2.4 g (59.3 mmole) sodium hydride (60% dispersion in oil) and 10 mL hexanes. The hexanes were removed by pipette and replaced by 60 mL dry tetrahydrofluran (THF). The suspension was cooled to -15° C. and a solution of 12.0 g (51.6 mmole) 4-chlorophenylsulfonyl acetone in 50 mL THF was added via addition funnel over 20 minutes maintaining the reaction temperature below -12° C. The resulting yellow solution was removed from the cold bath and stirred at room temperature for 30 min. The solution was recooled to -5° C. and 3.8 mL (54.1 mmole) bromoacetonitrile was added dropwise via addition funnel. After 5 min, the reaction mixture was removed from the cold bath and stirred at room temperature overnight. The reaction was quenched with 1 mL of saturated ammonium chloride and transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine. The organic layer was separated and the aqueous layer was back extracted once with 50 mL more dichloromethane. The combined organics were then dried with sodium sulfate, filtered, concentrated, and chromatographed through a bed of silica gel using 1:1 hexane: dichloromethane. Isolation gave 8.2 g (59% yield) of 3-(4-chlorophenylsulfonyl)-4-cyanobutan-2-one, a yellow oil that was 90% pure by HPLC. 1H NMR (CDCl3) indicated desired product as the major component: δ7.6 (m, 4H), 4.42 (dd, 1H), 2.78 (m, 2H), 2.48 (s, 3H). To a 300 mL reaction flask The hexanes were removed by pipette maintaining the reaction temperature below -12° C The resulting yellow solution was removed from the cold bath was recooled to -5° C. After 5 min the reaction mixture was removed from the cold bath stirred at room temperature overnight The reaction was quenched with 1 mL of saturated ammonium chloride transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine The organic layer was separated the aqueous layer was back extracted once with 50 mL more dichloromethane The combined organics were then dried with sodium sulfate filtered concentrated chromatographed through a bed of silica gel using 1:1 hexane

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

Procedure: Using the method described in Example 30 by employing 1-[(2-pyrrolidinylprop-1-enyl)sulfonyl]-4-chlorobenzene (freshly prepared before use from 4-chlorophenylsulfonylacetone (Lancaster Chemical Company), pyrrolidine and TiCl4 (2.03 g, 7.10 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.47 g, 7.10 mmol), N,N-diisopropylethylamine (1.3 mL, 7.10 mmol), piperidine (1.1 mL, 11.4 mmol), NEt3 (1.6 mL) and SnCl2 (21 mL of a 2 M soln in DMF). In this example the mixture of enamine, 2-methyl-4,6-dichloro-5-nitropyrimidine and N,N-diisopropylethylamine was stirred at 100° C. for 20 h prior to piperidine addition. The SnCl2 solution was added to the reaction mixture at 140° C. The mixture was stirred at 140° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant to give 441 g (15%) of 4-chloro-1-[((2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl)methyl)sulfonyl]benzene as a brown colored solid. This compound (0.44 g, 1.08 mmol) was dissolved in 5:1 EtOAc/MeOH (20 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.10 mL, 1.10 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 296 mg (9%) of the title compound as a white colored solid. Mp: 199-201° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.57 (m, 4), 1.65 (m, 2), 2.47 (s, 3), 3.85 (br s, 4), 5.02 (s, 2), 6.23 (s, 1), 7.65 (AB q, 4, J=6.2, 6.2), 12.20 (s, 1), 14.18 (s, 1). MS m/z: 405 (M+1 for free base). Anal. Calcd for C19H21ClN4O2S.HCl.0.9H2O: C, 49.87; H, 5.24; N, 12.25; Cl, 15.49. Found: C, 49.85; H, 5.17; N, 12.15; Cl, 15.61. The mixture was stirred at 140° C. for an additional 16 h to cool to room temperature The residue was purified by flash chromatography on silica gel with 100% EtOAc as eluant