(1R,2S)-2-phenylcyclopropan-1-amine

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

Procedure: Over a solution of (trans)-2-phenylcyclopropanamine (intermediate A, 1.14 g, 1 eq) in 50 mL of THF, 1.25 g (1.05 eq) of K2CO3 was added and stirred 3 hours at room temperature. After removal of the solvent, CH2Cl2 was added, then washed with a saturated solution of NaHCO3 and brine. The organic layer was extracted, dried with MgSO4 and filtered. The crude was purified by silica gel chromatography (Hexane-MTBE 90:10) affording 1.89 g of tert-butyl (trans)-2-phenylcyclopropylcarbamate. Yield: 95% After removal of the solvent, CH2Cl2 was added washed with a saturated solution of NaHCO3 and brine The organic layer was extracted dried with MgSO4 filtered The crude was purified by silica gel chromatography (Hexane-MTBE 90:10)

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

Procedure: Over a solution of (trans)-2-phenylcyclopropanamine (intermediate A, 1.14 g, 1 eq) in 50 mL of THF, 1.25 g (1.05 eq) of K2CO3 was added and stirred 3 hours at room temperature. After removal of the solvent, CH2Cl2 was added, then washed with a saturated solution of NaHCO3 and brine. The organic layer was extracted, dried with MgSO4 and filtered. The crude was purified by silica gel chromatography (Hexane-MTBE 90:10) affording 1.89 g of tert-butyl (trans)-2-phenylcyclopropylcarbamate. Yield: 95% After removal of the solvent, CH2Cl2 was added washed with a saturated solution of NaHCO3 and brine The organic layer was extracted dried with MgSO4 filtered The crude was purified by silica gel chromatography (Hexane-MTBE 90:10)

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

Procedure: NaOMe (0.80 g, 11.8 mmol) was added over a solution of (trans)-2-phenylcyclopropanamine hydrochloride (2.00 g, 11.8 mmol) in MeOH (40 mL) and stirred 1 hour. The solvent was removed to dryness. The solvent was removed to dryness

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

Procedure: A solution of trans-2-phenyl cyclopropylamine.HCl (1.02 g, 6 mmol) in methanol (10 ml) was stirred with basic ion exchange resin for 5 minutes. The resin was filtered off and the filtrate was concentrated to a colorless oil. To this was added (±)-(cis)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.549 g, 2 mmol). The resulting solution was stirred in a Parr bomb at 80° C. for 12 hours 1 N NaOH 12 ml) was added and the solvent evaporated. The residual oil was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform to give tan crystals after crystallization from acetonitrile-methanol (0.221 g, 30%), m.p.=188-190° C. The resin was filtered off the filtrate was concentrated to a colorless oil was added the solvent evaporated The residual oil was chromatographed on silica gel Title compound was eluted with 5% methanol-chloroform to give tan crystals after crystallization from acetonitrile-methanol (0.221 g, 30%), m.p.=188-190° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The (trans)-2-phenylcyclopropanamine previously obtained was added to activated and dried molecular sieves (3 A), proceeding with several vacuum and argon cycles. DCM (120 mL) was added and stirred before adding chloroacetaldehyde (1.5 mL, 12.0 mmol) and stirring for 4 hours. The reaction was cooled to 0° C. and NaBH3CN (0.88 g, 14.0 mmol) was added. The mixture was stirred at room temperature overnight. NH4Cl (20 mL) was added and the organic layer was extracted, dried with MgSO4 and filtered. The crude was purified by silica gel chromatography (Hexane-MTBE 70:30) affording 1.68 g (8.56 mmol) of N-(2-chloroethyl)-N-[(trans)-2-phenylcyclopropyl]amine. Yield: 72%. 1HNMR (CDCl3) δ (ppm): 1.01 (q, 1H), 1.08 (quin, 1H), 1.93 (m, 1H), 2.37 (quin, 1H), 3.08 (t, 2H), 3.67 (t, 2H), 7.04 (d, 2H), 7.15 (t, 1H), 7.25 (t, 2H). MS (M+H): 195.88 was added dried molecular sieves (3 A), DCM (120 mL) was added stirring for 4 hours The mixture was stirred at room temperature overnight the organic layer was extracted dried with MgSO4 filtered The crude was purified by silica gel chromatography (Hexane-MTBE 70:30)

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

Procedure: NaOMe (0.80 g, 11.8 mmol) was added over a solution of (trans)-2-phenylcyclopropanamine hydrochloride (2.00 g, 11.8 mmol) in MeOH (40 mL) and stirred 1 hour. The solvent was removed to dryness. The solvent was removed to dryness

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

Procedure: To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1 g, 4.40 mmol) in methanol (15 mL) were added (trans)-2-phenylcyclopropanamine (0.762 g, 5.72 mmol) and acetic acid (0.252 mL, 4.40 mmol), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (0.415 g, 6.60 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (10 mL) and the mixture was concentrated to remove methanol. The resulting aqueous layer was extracted with DCM (3×). The DCM extract was washed with 10% HOAc aqueous solution, dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 720 mg of product as pale yellow oil. MS: (M+H)+=345.4. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94-1.75 (m, 18H), 1.86-1.95 (m, 1H), 2.35 (dt, J=7.01, 3.69 Hz, 1H), 2.60-2.86 (m, 4H), 4.08 (br. s., 2H), 6.91-7.38 (m, 5H). the mixture was stirred at room temperature for 18 h The reaction was quenched with water (10 mL) the mixture was concentrated to remove methanol The resulting aqueous layer was extracted with DCM (3×) The DCM extract was washed with 10% HOAc aqueous solution dried (Na2SO4) concentrated The residue was purified

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

Procedure: (1R,2S)-2-phenylcyclopropanamine (1.051 g, 7.89 mmol), ethyl 4-(3-(4-formylpiperidin-1-yl)propyl)benzoate (1.9 g, 6.26 mmol) in methanol (50 mL) were heated to reflux for 5 minutes. The reaction was cooled to room temperature and added sodium cyanoborohydride (0.590 g, 9.39 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated and DCM was added and washed with water, brine, dried over MgSO4, filtered and rotovapped off solvent. The residue was purified via Biotage (0% to 100% EtOAc:Hex; to get off ethyl 4-(3-(4-(cyano(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate then 0% to 20% MeOH:DCM to get off ethyl 4-(3-(4-((((1R,2S)-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate 50 g-HP-silica gel column). Obtained 1.18 g of ethyl 4-(3-(4-(4(1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzoate 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-1.18 (m, 2H), 1.20-1.36 (m, 2H), 1.40 (t, J=7.07 Hz, 4H), 1.66-1.80 (m, 2H), 1.81-2.02 (m, 5H), 2.24-2.45 (m, 3H), 2.56-2.79 (m, 4H), 2.95 (d, J=10.86 Hz, 2H), 4.38 (q, J=7.24 Hz, 2H), 6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.21-7.38 (m, 5H), 7.97 (d, 2H); [M+H]+ 421.3 to reflux for 5 minutes The reaction was concentrated DCM was added washed with water, brine dried over MgSO4 filtered The residue was purified via Biotage (0% to 100% EtOAc

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

Procedure: To a solution of trans-2-phenylcyclopropanamine (80 mg, 0.601 mmol) in methanol (10 mL) was added trans-methyl 4-formylcyclohexanecarboxylate (102 mg, 0.601 mmol) and the reaction was heated to reflux for 2 minutes. After cooling back to the room temperature, sodium cyanoborohydride (75 mg, 1.201 mmol) was added to the reaction mixture and was stirred for 1 hour. Water (20 mL) was added. The reaction was concentrated and 20 mL of ethyl acetate was added. The layers were separated. The organic layer was washed with water, brine, and dried over MgSO4, filtered and evaporated. The resulting oil was purified on preperatory HPLC (10 to 60% AcCN:water with 0.1% formic acid as modifier). 0.5 mL of 6 M HCl was added into each fraction and the product was evaporated. trans-Methyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate (95 mg, 0.250 mmol, 41.7% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.38 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22 (m, 2H), 3.68 (s, 3H), 3.09 (d, J=7.07 Hz, 2H), 2.99 (dt, J=4.11, 7.45 Hz, 1H), 2.49 (ddd, J=3.79, 6.57, 10.36 Hz, 1H), 2.35 (tt, J=3.63, 12.28 Hz, 1H), 2.07 (dd, J=3.54, 13.39 Hz, 2H), 1.93 (dd, J=3.28, 13.14 Hz, 2H), 1.66-1.83 (m, J=3.57, 3.57, 7.70, 7.70, 15.36 Hz, 1H), 1.50-1.58 (m, 1H), 1.36-1.50 (m, 3H), 1.15 (qd, J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.83 min; MS (ESI): 288.2 [M++H]+. the reaction was heated to reflux for 2 minutes was added to the reaction mixture The reaction was concentrated 20 mL of ethyl acetate was added The layers were separated The organic layer was washed with water, brine dried over MgSO4 filtered evaporated The resulting oil was purified on preperatory HPLC (10 to 60% AcCN:water with 0.1% formic acid as modifier) 0.5 mL of 6 M HCl was added into each fraction the product was evaporated

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

Procedure: To a solution of 1-cyclohexylethanone (95 mg, 0.751 mmol) in 1,2-dichloroethane (DCE) (40 mL) and acetic acid (0.052 mL, 0.901 mmol) was added [(trans)-2-phenylcyclopropyl]amine (100 mg, 0.751 mmol). The reaction mixture was stirred for 2 hour at room temperature, then sodium triacetoxyborohydride (477 mg, 2.252 mmol) was added and the reaction mixture was stirred 3 hours at room temperature. The reaction mixture was quenched with saturated NH4Cl. Water (20 mL) followed by dichloromethane (40 mL) were added. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The solid was suspended in diethylether, sonicated and filtered. trans-N-(1-Cyclohexylethyl)-2-phenylcyclopropanamine (48 mg, 0.187 mmol, 24.95% yield) was isolated as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.11-9.35 (m, 1H), 8.80-9.03 (m, 1H), 7.27-7.42 (m, 2H), 7.13-7.27 (m, 3H), 3.23 (br. s., 1H), 2.91 (d, J=2.78 Hz, 1H), 2.57 (ddd, J=3.54, 6.44, 9.98 Hz, 1H), 1.68-1.87 (m, 4H), 1.57-1.68 (m, 2H), 1.46-1.57 (m, 1H), 1.26-1.42 (m, 1H), 1.18-1.24 (m, 3H), 0.95-1.18 (m, 4H); LC-MS Rt=0.83 min; MS (ESI): 244.2 [M+H]+. the reaction mixture was stirred 3 hours at room temperature The reaction mixture was quenched with saturated NH4Cl were added The layers were separated the organic layer was washed with brine dried over MgSO4 filtered evaporated sonicated filtered

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

Procedure: A solution of (1R,2S)-2-phenylcyclopropanamine (1.051 g, 7.89 mmol) and ethyl 4-(3-(4-formylpiperidin-1-yl)propyl)benzoate (1.9 g, 6.26 mmol) in methanol (50 mL) was heated to reflux for 5 minutes. The reaction was cooled to room temperature and sodium cyanoborohydride (0.590 g, 9.39 mmol) was added. The reaction was stirred at room temperature for 16 hours. After concentrating, dichloromethane was added and the solution was washed with water followed by brine and dried over MgSO4, filtered and concentrated. The residue was purified via Biotage (0% to 100% EtOAc:Hex; to get off impurity then 0% to 20% MeOH:DCM to get off product 50 g-HP-silica gel column) to yield 1.18 g 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-1.18 (m, 2H), 1.20-1.36 (m, 2H), 1.40 (t, J=7.07 Hz, 4H), 1.66-1.80 (m, 2H), 1.81-2.02 (m, 5H), 2.24-2.45 (m, 3H), 2.56-2.79 (m, 4H), 2.95 (d, J=10.86 Hz, 2H), 4.38 (q, J=7.24 Hz, 2H), 6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.21-7.38 (m, 5H), 7.97 (d, 2H) MS (ES); [M+H]+ 421.3 to reflux for 5 minutes After concentrating dichloromethane was added the solution was washed with water dried over MgSO4 filtered concentrated The residue was purified via Biotage (0% to 100% EtOAc to get off impurity

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 (6.7 g, 22.08 mmol) in methanol (50 mL) was added (1R,2S)-2-phenylcyclopropanamine (3.53 g, 26.5 mmol). The reaction mixture was refluxed for 5 minutes then cooled down to the room temperature. Sodium cyanotrihydroborate (2.082 g, 33.1 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 organics were washed with 10% acetic acid (50 mL). The layers were separated and 50 mL of brine was added slowly as a solid crashed out. The solid was filtered and suspended in isopropanol. The suspension was sonicated and filtered. tert-Butyl 4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (5.8 g, 13.65 mmol, 61.8% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.07 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.08 Hz, 2H), 7.28-7.37 (m, 2H), 7.10-7.28 (m, 3H), 4.43 (br. s., 2H), 3.54 (d, J=10.86 Hz, 2H), 3.08-3.26 (m, 4H), 3.03 (dt, J=3.76, 7.39 Hz, 1H), 2.54-2.71 (m, 1H), 2.03-2.29 (m, 3H), 1.67-1.84 (m, 2H), 1.58-1.67 (m, 10H), 1.40 (q, J=6.82 Hz, 1H); LC-MS Rt=0.76 min; MS (ESI): 421.4 [M+H]+. The reaction mixture was refluxed for 5 minutes The reaction was concentrated 50 mL of dichloromethane was added The layers were separated The organics were washed with 10% acetic acid (50 mL) The layers were separated 50 mL of brine was added slowly as a solid The solid was filtered The suspension was sonicated filtered