(1R,2S)-2-(4-bromophenyl)cyclopropan-1-amine

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

Procedure: This compound was synthesized using the same methodology described in Intermediate D, using as starting material 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene (intermediate F). Yield: 10%. 1HNMR (CD3OD): 1.45 (m, 2H), 2.61 (m, 1H), 2.86 (m, 1H), 6.98 (d, 2H), 7.11 (d, 2H). MS (M+H): 211.9. This compound was synthesized

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

Procedure: This compound was synthesized using the same methodology described in Intermediate D, using as starting material 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene. 10% yield. 1HNMR (CD3OD): 1.45 (m, 2H), 2.61 (m, 1H), 2.86 (m, 1H), 6.98 (d, 2H), 7.11 (d, 2H). MS (M+H): 211.9 This compound was synthesized

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

Procedure: To a solution of tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (250 mg, 0.824 mmol) in methanol (50 mL) was added trans-2-(4-bromophenyl)cyclopropylamine (210 mg, 0.989 mmol). The reaction mixture was refluxed for 2 minutes then cooled down to room temperature. Sodium cyanotrihydroborate (78 mg, 1.236 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. Water (50 mL) was added. The reaction was concentrated and 50 mL of dichloromethane was added. The layers were separated. The organic was washed with 10% acetic acid (50 mL). The layers were separated and 50 mL of brine was added and the formed solid was filtered. The solid was refluxed in 1 M HCl for 30 min, then cooled to 0° C. and after 1 hour the solid was filtered. 4-((4-(((trans-2-(4-bromophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (120 mg, 0.221 mmol, 26.8% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.14 (d, J=8.34 Hz, 2H), 7.71 (d, J=8.34 Hz, 2H), 7.48 (d, J=8.59 Hz, 2H), 7.15 (d, J=8.34 Hz, 2H), 4.44 (br. s., 2H), 3.55 (d, J=10.36 Hz, 2H), 3.06-3.25 (m, 4H), 3.01 (dt, J=3.98, 7.71 Hz, 1H), 2.59 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.02-2.29 (m, 3H), 1.53-1.80 (m, 3H), 1.41 (q, 1H); LC-MS Rt=0.61 min; MS (ESI): 445.2 [M+H]+. The reaction mixture was refluxed for 2 minutes The reaction was concentrated 50 mL of dichloromethane was added The layers were separated The organic was washed with 10% acetic acid (50 mL) The layers were separated 50 mL of brine was added the formed solid was filtered The solid was refluxed in 1 M HCl for 30 min cooled to 0° C. and after 1 hour the solid was filtered

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

Procedure: To a solution of tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (250 mg, 0.824 mmol) in methanol (50 mL) was added trans-2-(4-bromophenyl)cyclopropylamine (210 mg, 0.989 mmol). The reaction mixture was refluxed for 2 minutes then cooled down to room temperature. Sodium cyanotrihydroborate (78 mg, 1.236 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. Water (50 mL) was added. The reaction was concentrated and 50 mL of dichloromethane was added. The layers were separated. The organic was washed with 10% acetic acid (50 mL). The layers were separated and 50 mL of brine was added and the formed solid was filtered. The solid was refluxed in 1 M HCl for 30 min, then cooled to 0° C. and after 1 hour the solid was filtered. 4-((4-(((trans-2-(4-bromophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (120 mg, 0.221 mmol, 26.8% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.14 (d, J=8.34 Hz, 2H), 7.71 (d, J=8.34 Hz, 2H), 7.48 (d, J=8.59 Hz, 2H), 7.15 (d, J=8.34 Hz, 2H), 4.44 (br. s., 2H), 3.55 (d, J=10.36 Hz, 2H), 3.06-3.25 (m, 4H), 3.01 (dt, J=3.98, 7.71 Hz, 1H), 2.59 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.02-2.29 (m, 3H), 1.53-1.80 (m, 3H), 1.41 (q, 1H); LC-MS Rt=0.61 min; MS (ESI): 445.2 [M+H]+. The reaction mixture was refluxed for 2 minutes The reaction was concentrated 50 mL of dichloromethane was added The layers were separated The organic was washed with 10% acetic acid (50 mL) The layers were separated 50 mL of brine was added the formed solid was filtered The solid was refluxed in 1 M HCl for 30 min cooled to 0° C. and after 1 hour the solid was filtered

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

Procedure: To a solution of tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (250 mg, 0.824 mmol) in methanol (50 mL) was added trans-2-(4-bromophenyl)cyclopropylamine (210 mg, 0.989 mmol). The reaction mixture was refluxed for 2 minutes then cooled down to room temperature. Sodium cyanotrihydroborate (78 mg, 1.236 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. Water (50 mL) was added. The reaction was concentrated and 50 mL of dichloromethane was added. The layers were separated. The organic was washed with 10% acetic acid (50 mL). The layers were separated and 50 mL of brine was added and the formed solid was filtered. The solid was refluxed in 1 M HCl for 30 min, then cooled to 0° C. and after 1 hour the solid was filtered. 4-((4-(((trans-2-(4-bromophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (120 mg, 0.221 mmol, 26.8% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.14 (d, J=8.34 Hz, 2H), 7.71 (d, J=8.34 Hz, 2H), 7.48 (d, J=8.59 Hz, 2H), 7.15 (d, J=8.34 Hz, 2H), 4.44 (br. s., 2H), 3.55 (d, J=10.36 Hz, 2H), 3.06-3.25 (m, 4H), 3.01 (dt, J=3.98, 7.71 Hz, 1H), 2.59 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.02-2.29 (m, 3H), 1.53-1.80 (m, 3H), 1.41 (q, 1H); LC-MS Rt=0.61 min; MS (ESI): 445.2 [M+H]+. The reaction mixture was refluxed for 2 minutes The reaction was concentrated 50 mL of dichloromethane was added The layers were separated The organic was washed with 10% acetic acid (50 mL) The layers were separated 50 mL of brine was added the formed solid was filtered The solid was refluxed in 1 M HCl for 30 min cooled to 0° C. and after 1 hour the solid was filtered

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

Procedure: This compound was synthesized using the same methodology described in Intermediate B, using as starting material 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene. 10% yield. 1HNMR (CD3OD): 1.45 (m, 2H), 2.61 (m, 1H), 2.86 (m, 1H), 6.98 (d, 2H), 7.11 (d, 2H). MS (M+H): 211.9 This compound was synthesized

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

Procedure: This compound was synthesized using the same methodology described in Intermediate B, using as starting material 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene. 10% yield. 1HNMR (CD3OD): 1.45 (m, 2H), 2.61 (m, 1H), 2.86 (m, 1H), 6.98 (d, 2H), 7.11 (d, 2H). MS (M+H): 211.9 This compound was synthesized

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

Procedure: Zn dust (1.97 g, 30 mol) was added in small portions, over a period of 30 min, to a vigorously stirred solution of 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene (Intermediate A, 0.73 g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution 2.7 N, 30 mmol). After 17 h the mixture was filtered through a pad of celite, that was washed with 10 mL of methanol. The filtrate was concentrated and 10 mL of water were added, washing with CH2Cl2 (3×15 mL). The organic layers were dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (10% MeOH/CH2Cl2) affording 0.06 g of (trans)-2-(4-bromophenyl)cyclopropanamine [white solid. 10% yield]. After 17 h the mixture was filtered through a pad of celite, that was washed with 10 mL of methanol The filtrate was concentrated 10 mL of water were added washing with CH2Cl2 (3×15 mL) The organic layers were dried over anhydrous Na2SO4 filtered After removal of the solvent the crude product was purified by column chromatography on silica gel (10% MeOH/CH2Cl2)

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

Procedure: This compound was synthesized using the same methodology described in Intermediate D, using as starting material 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene (intermediate F). Yield: 10%. 1HNMR (CD3OD): 1.45 (m, 2H), 2.61 (m, 1H), 2.86 (m, 1H), 6.98 (d, 2H), 7.11 (d, 2H). MS (M+H): 211.9. This compound was synthesized

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

Procedure: This compound was synthesized using the same methodology described in Intermediate D, using as starting material 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene (intermediate F). Yield: 10%. 1HNMR (CD3OD): 1.45 (m, 2H), 2.61 (m, 1H), 2.86 (m, 1H), 6.98 (d, 2H), 7.11 (d, 2H). MS (M+H): 211.9. This compound was synthesized

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

Procedure: This compound was synthesized using the same methodology described in Intermediate D, using as starting material 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene. 10% yield. 1HNMR (CD3OD): 1.45 (m, 2H), 2.61 (m, 1H), 2.86 (m, 1H), 6.98 (d, 2H), 7.11 (d, 2H). MS (M+H): 211.9 This compound was synthesized

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

Procedure: To a solution of tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (250 mg, 0.824 mmol) in methanol (50 mL) was added trans-2-(4-bromophenyl)cyclopropylamine (210 mg, 0.989 mmol). The reaction mixture was refluxed for 2 minutes then cooled down to room temperature. Sodium cyanotrihydroborate (78 mg, 1.236 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. Water (50 mL) was added. The reaction was concentrated and 50 mL of dichloromethane was added. The layers were separated. The organic was washed with 10% acetic acid (50 mL). The layers were separated and 50 mL of brine was added and the formed solid was filtered. The solid was refluxed in 1 M HCl for 30 min, then cooled to 0° C. and after 1 hour the solid was filtered. 4-((4-(((trans-2-(4-bromophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (120 mg, 0.221 mmol, 26.8% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.14 (d, J=8.34 Hz, 2H), 7.71 (d, J=8.34 Hz, 2H), 7.48 (d, J=8.59 Hz, 2H), 7.15 (d, J=8.34 Hz, 2H), 4.44 (br. s., 2H), 3.55 (d, J=10.36 Hz, 2H), 3.06-3.25 (m, 4H), 3.01 (dt, J=3.98, 7.71 Hz, 1H), 2.59 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.02-2.29 (m, 3H), 1.53-1.80 (m, 3H), 1.41 (q, 1H); LC-MS Rt=0.61 min; MS (ESI): 445.2 [M+H]+. The reaction mixture was refluxed for 2 minutes The reaction was concentrated 50 mL of dichloromethane was added The layers were separated The organic was washed with 10% acetic acid (50 mL) The layers were separated 50 mL of brine was added the formed solid was filtered The solid was refluxed in 1 M HCl for 30 min cooled to 0° C. and after 1 hour the solid was filtered