(2-bromophenyl)hydrazine;hydrochloride

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

Procedure: 2-Bromophenylhydrazine hydrochloride (1.00 g, 4.47 mmol) was added to a solution of 2-(hydroxymethylene)cyclohexanone (0.564 g, 4.47 mmol) in ethanol (20 mL) and the resulting solution was refluxed 3 h before being concentrated. The crude material was taken up in DCM and washed with saturated ammonium chloride, 1N NaOH, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give 1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-indazole. the resulting solution was refluxed 3 h before being concentrated washed with saturated ammonium chloride, 1N NaOH, saturated sodium chloride dried over sodium sulfate The solution was filtered concentrated in vacuo

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-bromophenylhydrazine hydrochloride (5.0 g, 22 mmol) in formamide (10 ml) was heated at 140° C. for 16 h. The reaction mixture was cooled to ambient temperature, diluted into dichloromethane (50 ml) and washed with water (3×20 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Purification by chromatography on silica gel eluting with dichloromethane gave 1-(2-bromophenyl)-1H-[1,2,4]triazole (4.80 g) as a tan solid: δH (400 MHz, CDCl3) 8.49 (1H, s), 8.14 (1H, s), 7.76 (1H, dd, J 1 and 8), 7.44-7.53 (2H, m), 7.34-7.39 (1H, m). The reaction mixture was cooled to ambient temperature washed with water (3×20 ml) The organic phase was dried over anhydrous magnesium sulfate filtered evaporated to dryness Purification by chromatography on silica gel eluting with dichloromethane

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-bromophenylhydrazine hydrochloride (5.0 g, 22 mmol) in formamide (10 ml) was heated at 140° C. for 16 h. The reaction mixture was cooled to ambient temperature, diluted into dichloromethane (50 ml) and washed with water (3×20 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Purification by chromatography on silica gel eluting with dichloromethane gave 1-(2-bromophenyl)-1H-[1,2,4]triazole (4.80 g) as a tan solid: δH (400 MHz, CDCl3) 8.49 (1H, s), 8.14 (1H, s), 7.76 (1H, dd, J 1 and 8), 7.44-7.53 (2H, m), 7.34-7.39 (1H, m). The reaction mixture was cooled to ambient temperature washed with water (3×20 ml) The organic phase was dried over anhydrous magnesium sulfate filtered evaporated to dryness Purification by chromatography on silica gel eluting with dichloromethane

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2-bromophenyl)hydrazine hydrochloride (1.5 g, 6.71 mmol; Aldrich) and the product of Example 1A (0.94 g, 6.71 mmol) was combined with a solution of HCl in acetic acid (1.0 M, 20 mL; Aldrich) and stirred at 105° C. for 18 hours. The reaction mixture was concentrated under vacuum. The residue was taken up in toluene (100 mL) and concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure was repeated a second time). The residue was dissolved in dimethyl sulfoxide (20 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4 ) δ ppm 2.05-2.13 (m, 4 H), 3.08 (pent, J=6.9 Hz, 2 H), 3.15 (pent, J=3.6 Hz, 1 H), 3.26 (pent, J=7.2 Hz, 2 H), 4.23 (s, 2 H), 6.88 (t, J=7.8 Hz, 1 H), 7.19 (d, J=7.6 Hz, 1 H), 7.27 (d, J=7.9 Hz, 1 H); MS (APCI) m/z 291/293 (M+H)+. The reaction mixture was concentrated under vacuum concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure The residue was dissolved in dimethyl sulfoxide (20 mL) purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2-bromophenyl)hydrazine hydrochloride (1.5 g, 6.71 mmol; Aldrich) and the product of Example 1A (0.94 g, 6.71 mmol) was combined with a solution of HCl in acetic acid (1.0 M, 20 mL; Aldrich) and stirred at 105° C. for 18 hours. The reaction mixture was concentrated under vacuum. The residue was taken up in toluene (100 mL) and concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure was repeated a second time). The residue was dissolved in dimethyl sulfoxide (20 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4 ) δ ppm 2.05-2.13 (m, 4 H), 3.08 (pent, J=6.9 Hz, 2 H), 3.15 (pent, J=3.6 Hz, 1 H), 3.26 (pent, J=7.2 Hz, 2 H), 4.23 (s, 2 H), 6.88 (t, J=7.8 Hz, 1 H), 7.19 (d, J=7.6 Hz, 1 H), 7.27 (d, J=7.9 Hz, 1 H); MS (APCI) m/z 291/293 (M+H)+. The reaction mixture was concentrated under vacuum concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure The residue was dissolved in dimethyl sulfoxide (20 mL) purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]

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

Procedure: A mixture of (2-bromophenyl)hydrazine hydrochloride (2.24 g, 10.0 mmol; Aldrich) and tent-butyl 4-oxopiperidine-1-carboxylate (1.99 g, 10.0 mmol; Aldrich) was combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) in a sealed tube and stirred at 100° C. for 18 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between NaOH (1.0 M, 200 mL) and CH2Cl2 (3×200 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under vacuum. The residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-80% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.86-2.94 (m, 2H), 3.24 (t, J=5.9 Hz, 2H), 4.04 (t, J=1.5 Hz, 2H), 6.89 (t, J=7.8 Hz, 1H), 7.21 (dd, J=7.6, 0.8 Hz, 1H), 7.33 (dd, J=8.0, 0.8 Hz, 1H); MS (APCI) m/z 292/294 (M+CH3CN+H)+. The reaction mixture was concentrated under vacuum The residue was partitioned between NaOH (1.0 M, 200 mL) and CH2Cl2 (3×200 mL) The combined organic extracts were dried (sodium sulfate) concentrated under vacuum The residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-80% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]

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

Procedure: A mixture of (2-bromophenyl)hydrazine hydrochloride (2.24 g, 10.0 mmol; Aldrich) and tent-butyl 4-oxopiperidine-1-carboxylate (1.99 g, 10.0 mmol; Aldrich) was combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) in a sealed tube and stirred at 100° C. for 18 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between NaOH (1.0 M, 200 mL) and CH2Cl2 (3×200 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under vacuum. The residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-80% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.86-2.94 (m, 2H), 3.24 (t, J=5.9 Hz, 2H), 4.04 (t, J=1.5 Hz, 2H), 6.89 (t, J=7.8 Hz, 1H), 7.21 (dd, J=7.6, 0.8 Hz, 1H), 7.33 (dd, J=8.0, 0.8 Hz, 1H); MS (APCI) m/z 292/294 (M+CH3CN+H)+. The reaction mixture was concentrated under vacuum The residue was partitioned between NaOH (1.0 M, 200 mL) and CH2Cl2 (3×200 mL) The combined organic extracts were dried (sodium sulfate) concentrated under vacuum The residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-80% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]

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

Procedure: A mixture of (2-bromophenyl)hydrazine hydrochloride (1.1 g, 4.92 mmol; Aldrich) and 1-methyl-4-piperidone (0.56 g, 4.92 mmol; Aldrich) was combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) and stirred at 70° C. for 18 hours in a sealed tube. The reaction mixture was concentrated under vacuum. The residue was taken up in toluene (100 mL) and concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure was repeated a second time). The residue was dissolved in dimethyl sulfoxide (20 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.54 (s, 3H), 2.85-2.90 (m, 2H), 2.93-2.98 (m, 2H), 3.66 (t, J=1.5 Hz, 2H), 6.88 (t, J=7.8 Hz, 1H), 7.19 (dd, J=7.8, 0.8 Hz, 1H), 7.32 (dd, J=7.8, 0.8 Hz, 1H); MS (DCI) m/z 265/267 (M+H)+. The reaction mixture was concentrated under vacuum concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure The residue was dissolved in dimethyl sulfoxide (20 mL) purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]

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

Procedure: A mixture of (2-bromophenyl)hydrazine hydrochloride (1.1 g, 4.92 mmol; Aldrich) and 1-methyl-4-piperidone (0.56 g, 4.92 mmol; Aldrich) was combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) and stirred at 70° C. for 18 hours in a sealed tube. The reaction mixture was concentrated under vacuum. The residue was taken up in toluene (100 mL) and concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure was repeated a second time). The residue was dissolved in dimethyl sulfoxide (20 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.54 (s, 3H), 2.85-2.90 (m, 2H), 2.93-2.98 (m, 2H), 3.66 (t, J=1.5 Hz, 2H), 6.88 (t, J=7.8 Hz, 1H), 7.19 (dd, J=7.8, 0.8 Hz, 1H), 7.32 (dd, J=7.8, 0.8 Hz, 1H); MS (DCI) m/z 265/267 (M+H)+. The reaction mixture was concentrated under vacuum concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure The residue was dissolved in dimethyl sulfoxide (20 mL) purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]

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

Procedure: A mixture of (2-bromophenyl)hydrazine hydrochloride (1.1 g, 4.92 mmol; Aldrich) and 1-methyl-4-piperidone (0.56 g, 4.92 mmol; Aldrich) was combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) and stirred at 70° C. for 18 hours in a sealed tube. The reaction mixture was concentrated under vacuum. The residue was taken up in toluene (100 mL) and concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure was repeated a second time). The residue was dissolved in dimethyl sulfoxide (20 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.54 (s, 3H), 2.85-2.90 (m, 2H), 2.93-2.98 (m, 2H), 3.66 (t, J=1.5 Hz, 2H), 6.88 (t, J=7.8 Hz, 1H), 7.19 (dd, J=7.8, 0.8 Hz, 1H), 7.32 (dd, J=7.8, 0.8 Hz, 1H); MS (DCI) m/z 265/267 (M+H)+. The reaction mixture was concentrated under vacuum concentrated under vacuum to remove most of the acetic acid (the azeotrope procedure The residue was dissolved in dimethyl sulfoxide (20 mL) purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]

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

Procedure: 15 g 2-bromophenylhydrazine hydrochloride are suspended in 400 ml of toluene and combined with 240 ml of 1 N sodium hydroxide solution. The mixture is stirred for 1 hour and the phases are separated. The organic phase is dried on magnesium sulphate and the solvents are eliminated in vacuo. The crude product thus obtained is further reacted directly. the phases are separated The organic phase is dried on magnesium sulphate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2-bromophenyl)hydrazine hydrochloride (14 g) in ethanol (60 mL), 5-acetylvaleric acid (9.0 g) was added. The reaction mixture was stirred at 50° C. for 40 minutes, and concentrated sulfuric acid (6.0 mL) was added thereto, followed by heating under reflux for 16 hours. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution which was then extracted with ethyl acetate and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound (15 g) having the following physical properties. by heating under reflux for 16 hours was then extracted with ethyl acetate dried over anhydrous sodium sulfate followed by concentration under reduced pressure The resulting residue was purified by column chromatography (hexane:ethyl acetate=8:1)