3-(3-chlorophenyl)-3-oxopropanenitrile

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

Procedure: A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product (566 mg, 75%). HPLC (4 minute 10-95 gradient) tR 2.97 min; MS m/z 283.2 [M+H]+; 1H NMR (CDCl3), δ 8.06 (d, J=13.2 Hz, 1 H), 7.85 (m, 2 H), 7.46 (m, 4 H), 7.27 (m, 4 H) ppm. The solution was cooled The resulting solid was filtered dried

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

Procedure: A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product (566 mg, 75%). HPLC (4 minute 10-95 gradient) tR 2.97 min; MS m/z 283.2 [M+H]+; 1H NMR (CDCl3), δ 8.06 (d, J=13.2 Hz, 1 H), 7.85 (m, 2 H), 7.46 (m, 4 H), 7.27 (m, 4 H) ppm. The solution was cooled The resulting solid was filtered dried

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

Procedure: A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2 h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product (566 mg, 75%). HPLC (4 minute 10-95 gradient) tR 2.97 min; MS m/z 283.2 [M+H]+; 1H NMR (CDCl3), δ 8.06 (d, J=13.2 Hz, 1 H), 7.85 (m, 2 H), 7.46 (m, 4 H), 7.27 (m, 4 H) ppm. The solution was cooled The resulting solid was filtered dried

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

Procedure: A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2 h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product (566 mg, 75%). HPLC (4 minute 10-95 gradient) tR 2.97 min; MS m/z 283.2 [M+H]+; 1H NMR (CDCl3), δ 8.06 (d, J=13.2 Hz, 1 H), 7.85 (m, 2 H), 7.46 (m, 4 H), 7.27 (m, 4 H) ppm. The solution was cooled The resulting solid was filtered dried

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

Procedure: A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product (566 mg, 75%). HPLC (4 minute 10-95 gradient) tR 2.97 min; MS m/z 283.2 [M+H]+; 1H NMR (CDCl3), δ 8.06 (d, J=13.2 Hz, 1 H), 7.85 (m, 2 H), 7.46 (m, 4 H), 7.27 (m, 4 H) ppm. The solution was cooled The resulting solid was filtered dried

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

Procedure: A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2 h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product (566 mg, 75%). HPLC (4 minute 10-95 gradient) tR 2.97 min; MS m/z 283.2 [M+H]+; 1H NMR (CDCl3), δ 8.06 (d, J=13.2 Hz, 1H), 7.85 (m, 2H), 7.46 (m, 4H), 7.27 (m, 4H) ppm. The solution was cooled The resulting solid was filtered dried

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

Procedure: A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2 h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product (566 mg, 75%). HPLC (4 minute 10-95 gradient) tR 2.97 min; MS m/z 283.2 [M+H]+; 1H NMR (CDCl3), δ 8.06 (d, J=13.2 Hz, 1H), 7.85 (m, 2H), 7.46 (m, 4H), 7.27 (m, 4H) ppm. The solution was cooled The resulting solid was filtered dried

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of LAH (16 g, 90 mmol) in dry THF (200 mL) was added a solution of 3-(3-chlorophenyl)-3-oxopropanenitrile (10.4 g, 270 mmol) in dry THF (200 mL) dropwise at 0° C. under nitrogen atmosphere. The mixture was warmed to 25° C. and then heated at 60° C. for 3 hours. After cooling to 0° C., a saturated solution of sodium hydroxide was added dropwise and extracted with ethyl acetate (200 mL). The solution was dried over anhydrous sodium sulfate and concentrated to dryness. The crude 3-amino-1-(3-chloro-phenyl)-propan-1-ol obtained was used in the next step without further purification. (Yield 14.5 g, crude). heated at 60° C. for 3 hours After cooling to 0° C. extracted with ethyl acetate (200 mL) The solution was dried over anhydrous sodium sulfate concentrated to dryness

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

Procedure: Compound 13 was synthesised following similar procedures outlined in Example 1 (Compound 37), using 3-chlorobenzoylacetonitrile instead of 2-chlorobenzoyl acetonitrile in Step 1.

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

Procedure: Compound 13 was synthesised following similar procedures outlined in Example 1 (Compound 37), using 3-chlorobenzoylacetonitrile instead of 2-chlorobenzoyl acetonitrile in Step 1.

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

Procedure: To a stirring solution of 3-(3-chlorophenyl)-3-oxo-propionitrile (2 g, 11.1 mmol) in absolute ethanol (20 mL) was added hydrazine hydrate (3.24 mL, 67 mmol). The reaction mixture was stirred at 80° C. for 15 h, cooled to room temperature, concentrated in vacuo, and absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 1.53 g (70%) of 5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine as a green solid. 1H NMR (d6-DMSO) δ: 11.6 and 11.9 (2 broad s, 1H, NH+tautomer), 7.69 (s, 1H), 7.60 (d, 1H), 7.38 (t, 1H), 7.29 (d, 1H), 5.77 (broad s, 1H), 4.98 (broad s, 2H, NH2). cooled to room temperature concentrated in vacuo absorbed on silica gel Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of LAH (16 g, 90 mmol) in dry THF (200 mL) was added a solution of 3-(3-chlorophenyl)-3-oxopropanenitrile (10.4 g, 270 mmol) in dry THF (200 mL) dropwise at 0° C. under nitrogen atmosphere. The mixture was warmed to 25° C. and then heated at 60° C. for 3 hours. After cooling to 0° C., a saturated solution of sodium hydroxide was added dropwise and extracted with ethyl acetate (200 mL). The solution was dried over anhydrous sodium sulfate and concentrated to dryness. The crude 3-amino-1-(3-chloro-phenyl)-propan-1-ol obtained was used in the next step without further purification. (Yield 14.5 g). LC-MS: [M+H]+ 186. heated at 60° C. for 3 hours After cooling to 0° C. extracted with ethyl acetate (200 mL) The solution was dried over anhydrous sodium sulfate concentrated to dryness