2-(4-bromophenyl)propanenitrile

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

Procedure: A solution of 50.0 g (225.0 mmol) of 4-bromophenylacetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound. The solution was then cooled washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine The organic portion was dried (MgSO4) filtered concentrated in vacuo The residue was distilled under vacuum through a short path distillation apparatus

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

Procedure: A solution of 50.0 g (225.0 mmol) of 4-bromophenyl-acetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound. The solution was then cooled washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine The organic portion was dried (MgSO4) filtered concentrated in vacuo The residue was distilled under vacuum through a short path distillation apparatus

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

Procedure: A solution of 50.0 g (225.0 mmol) of 4-bromophenyl-acetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound. The solution was then cooled washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine The organic portion was dried (MgSO4) filtered concentrated in vacuo The residue was distilled under vacuum through a short path distillation apparatus

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

Procedure: A solution of 50.0 g (225.0 mmol) of 4-bromophenyl-acetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound. The solution was then cooled washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine The organic portion was dried (MgSO4) filtered concentrated in vacuo The residue was distilled under vacuum through a short path distillation apparatus

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

Procedure: A solution of 50.0 g (225.0 mmol) of 4-bromophenyl-acetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound. The solution was then cooled washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine The organic portion was dried (MgSO4) filtered concentrated in vacuo The residue was distilled under vacuum through a short path distillation apparatus

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

Procedure: To a stirred solution of 2-(4-bromo-phenyl)-propionitrile (27 g, 128.5 mmol) in pyridine (225 mL) was added paraformaldehyde (15.7 g, 514.3 mmol) and a 40% Triton-B solution (in methanol) (14.4 mL). Then the reaction mixture stirred at room temperature for 16 h. At this time, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with a 2N aqueous hydrochloric acid solution (2×200 mL), water (2×100 mL), sodium bicarbonate (2×50 mL), a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Flash chromatography afforded 2-(4-bromo-phenyl)-3-hydroxy-2-methyl-propionitrile as colorless oil (25.9 g, 84%). extracted with ethyl acetate (300 mL) The organic layer was washed with a 2N aqueous hydrochloric acid solution (2×200 mL), water (2×100 mL), sodium bicarbonate (2×50 mL) a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate concentrated in vacuo

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

Procedure: To a stirred solution of 2-(4-bromo phenyl) acetonitrile (20 g, 102.04 mmol) in dry tetrahydrofuran (200 mL) was added sodium bis(trimethylsilyl)amide (18.71 g, 102.04 mmol) at 0° C. under a nitrogen atmosphere. After stirring for 20 minutes at room temperature, methyl iodide (14.48 g, 102 mmol) was added and then stirred for 1 h at room temperature. The reaction mixture was quenched with an aqueous ammonium chloride solution and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (2×100 mL), a saturated aqueous sodium chloride solution (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (3-4% ethyl acetate/hexanes) afforded 2-(4-bromo-phenyl)-propionitrile as a light yellow liquid (11.5 g, 53.6%). stirred for 1 h at room temperature The reaction mixture was quenched with an aqueous ammonium chloride solution extracted with ethyl acetate (2×150 mL) The combined organic layers were washed with water (2×100 mL) a saturated aqueous sodium chloride solution (2×25 mL), dried over anhydrous sodium sulfate filtered concentrated in vacuo

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

Procedure: To a stirred solution of 2-(4-bromo phenyl) acetonitrile (20 g, 102.04 mmol) in dry tetrahydrofuran (200 mL) was added sodium bis(trimethylsilyl)amide (18.71 g, 102.04 mmol) at 0° C. under a nitrogen atmosphere. After stirring for 20 minutes at room temperature, methyl iodide (14.48 g, 102 mmol) was added and then stirred for 1 h at room temperature. The reaction mixture was quenched with an aqueous ammonium chloride solution and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (2×100 mL), a saturated aqueous sodium chloride solution (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (3-4% ethyl acetate/hexanes) afforded 2-(4-bromo-phenyl)-propionitrile as a light yellow liquid (11.5 g, 53.6%). stirred for 1 h at room temperature The reaction mixture was quenched with an aqueous ammonium chloride solution extracted with ethyl acetate (2×150 mL) The combined organic layers were washed with water (2×100 mL) a saturated aqueous sodium chloride solution (2×25 mL), dried over anhydrous sodium sulfate filtered concentrated in vacuo

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

Procedure: A solution of 50.0 g (225.0 mmol) of 4-bromophenyl-acetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound. The solution was then cooled washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine The organic portion was dried (MgSO4) filtered concentrated in vacuo The residue was distilled under vacuum through a short path distillation apparatus

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

Procedure: A solution of 50.0 g (225.0 mmol) of 4-bromophenylacetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound. The solution was then cooled washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine The organic portion was dried (MgSO4) filtered concentrated in vacuo The residue was distilled under vacuum through a short path distillation apparatus

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

Procedure: A solution of 50.0 g (225.0 mmol) of 4-bromophenylacetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound. The solution was then cooled washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine The organic portion was dried (MgSO4) filtered concentrated in vacuo The residue was distilled under vacuum through a short path distillation apparatus

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Stir together bis(dibenzylideneacetone)palladium(0) (35 mg, 0.06 mmol) and tricyclohexylphosphine (39 mg, 0.06 mmol) in N,N-dimethylacetamide (4 mL) at room temperature under nitrogen for 20 min. Add racemic 2-(4-bromo-phenyl)-propionitrile (420 mg, 2.00 mmol), then 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (521 mg, 2.05 mmol) and potassium acetate (294 mg, 3.00 mmol) and stir at 80° C. for 16 hr. Cool reaction to room temperature, add 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (307 mg, 1.00 mmol), potassium carbonate (332 mg, 2.40 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0050 g, 0.0056 mmol) and water (2 mL), then stir at 120° C. for 8 hr. Cool to room temperature, purify by SCX-2® chromatography washing with methanol then eluting with 2 M ammonia in methanol. Further purify (silica gel chromatography, eluting with 0:100 to 20:80 methanol:DCM), to give the free base racemate 2-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-propionitrile as a powder (433 mg, 107%). MS (ES): m/z=402 [M+H]+. Cool reaction to room temperature Cool to room temperature purify by SCX-2® chromatography washing with methanol then eluting with 2 M ammonia in methanol Further purify (silica gel chromatography, eluting with 0:100 to 20:80 methanol:DCM)