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

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: N,N-Diisopropylethylamine (3 mL, 17.16 mmol) was added to a solution of (trans)-2-phenylcyclopropanamine hydrochloride (1.5 g, 8.58 mmol) in 70 mL of CH3CN. After complete dissolution of the amine the methyl 2-bromoacetate (930 μL, 9.44 mmol) was added and then stirred overnight at room temperature. After solvent removal the crude was purified by flash chromatography eluting with CH2Cl2/MeOH (99:1 to 90:10) to get methyl 2-((trans)-2-phenylcyclopropylamino)acetate as colourless oil (1.76 g, Yield=100%). was added After solvent removal the crude was purified by flash chromatography eluting with CH2Cl2/MeOH (99:1 to 90:10)

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

Procedure: A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and pyridine-2-carbaldehyde (0.17 mL, 1.80 mmol) in CH2Cl2 (12 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.48 g, 2.25 mmol) was slowly added and stirring continued for 2 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel [4% MeOH+1% NH3 (aq)/CH2Cl2] followed by preparative layer chromatography (5% MeOH/CH2Cl2) affording 0.08 g of N-[(trans)-2-phenylcyclopropyl]-N-(pyridin-2-ylmethyl)amine [Rf=0.3 (5% MeOH/CH2Cl2), colorless oil, 24% yield]. 1H-NMR (CDCl3, 250 MHz, δ): 8.60-8.54 (m, 1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 5H, ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H, CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H, CH2); 1.02-0.94 (m, 1H, CH2). stirring continued for 2 h The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL) the organic layer was dried over anhydrous Na2SO4 filtered after removal of the solvent the residual oil was purified by column chromatography on silica gel [4% MeOH+1% NH3 (aq)/CH2Cl2]

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

Procedure: A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.23 g, 1.36 mmol) and 4-(trifluoromethyl)benzaldehyde (0.20 mL, 1.49 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.37 g, 1.76 mmol) was slowly added and stirring continued for 30 min. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (8 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2) affording 0.15 g of N-[(trans)-2-phenylcyclopropyl]-N-[4-(trifluoromethyl)benzyl]amine [Rf=0.6 (5% MeOH/CH2Cl2), colorless oil, 38% yield]. stirring continued for 30 min The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (8 mL) the organic layer was dried over anhydrous Na2SO4 filtered after removal of the solvent the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2)

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

Procedure: A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and 4-cyanobenzaldehyde (0.22 g, 1.65 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.41 g, 1.95 mmol) was slowly added and stirring continued for 1.5 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2) affording 0.07 g of 4-({[(trans)-2-phenylcyclopropyl]amino}methyl)benzonitrile [Rf=0.6 (5% MeOH/CH2Cl2), colorless oil, 19% yield]. stirring continued for 1.5 h The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL) the organic layer was dried over anhydrous Na2SO4 filtered after removal of the solvent the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2)

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

Procedure: A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and 4-fluorobenzaldehyde (0.18 mL, 1.65 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.41 g, 1.95 mmol) was slowly added and stirring continued for 1.5 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (3% MeOH/CH2Cl2) affording 0.18 g of N-(4-fluorobenzyl)-N-[(trans)-2-phenylcyclopropyl]amine [Rf=0.5 (5% MeOH/CH2Cl2), colorless oil, 49% yield]. stirring continued for 1.5 h The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL) the organic layer was dried over anhydrous Na2SO4 filtered after removal of the solvent the residual oil was purified by column chromatography on silica gel (3% MeOH/CH2Cl2)

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

Procedure: To a suspension of (1R,2S)-2-phenyl-cyclopropylamine hydrochloride (0.85 g, 5 mmol) and rhodanine (2-thio-4-thiazolin-4-one) (0.68 g, 5 mmol) in acetonitrile (20 mL) was added DIEA (N,N-diisopropylethylamine) (2.61 mL, 15 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.35 g, 5 mmol) was added in two portions within a period of 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with ethyl acetate (500 mL). The filtrates were removed under the vacuum and the crude residue was diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to obtain 0.474 g (42% yield) of 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one as a white amorphous solid: EI-HRMS m/e calcd for C12H12N2OS (M+) 232.0670, found 232.0665. After addition to warm to room temperature The resulting black solids were filtered through a plug of celite washed with ethyl acetate (500 mL) The filtrates were removed under the vacuum the crude residue was diluted with water (100 mL) and ethyl acetate (100 mL) The two layers were separated the aqueous layer was extracted with ethyl acetate (2×100 mL) The combined organic extracts were washed with brine solution dried over anhydrous magnesium sulfate Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified

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

Procedure: To a suspension of (1R,2S)-2-phenyl-cyclopropylamine hydrochloride (0.85 g, 5 mmol) and rhodanine (2-thio-4-thiazolin-4-one) (0.68 g, 5 mmol) in acetonitrile (20 mL) was added DIEA (N,N-diisopropylethylamine) (2.61 mL, 15 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.35 g, 5 mmol) was added in two portions within a period of 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with ethyl acetate (500 mL). The filtrates were removed under the vacuum and the crude residue was diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to obtain 0.474 g (42% yield) of 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one as a white amorphous solid: EI-HRMS m/e calcd for C12H12N2OS (M+) 232.0670, found 232.0665. After addition to warm to room temperature The resulting black solids were filtered through a plug of celite washed with ethyl acetate (500 mL) The filtrates were removed under the vacuum the crude residue was diluted with water (100 mL) and ethyl acetate (100 mL) The two layers were separated the aqueous layer was extracted with ethyl acetate (2×100 mL) The combined organic extracts were washed with brine solution dried over anhydrous magnesium sulfate Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified

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

Procedure: To a round bottom flask was added chlorosulfonyl isocyanate (0.4 mL, 4.64 mmol) and methylene chloride (5 mL) under an atmosphere of argon. The mixture was cooled in an ice bath and 2-bromoethanol (0.535 mL, 7.55 mmol) in methylene chloride (1 mL) was added dropwise. After stirring for 30 minutes at 0° C., triethylamine (2.28 mL, 16.4 mmol) and trans-2-phenylcyclopropylamine hydrochloride (0.867 g, 5.11 mmol), 6a, in methylene chloride (5 mL) was added at such a rate that the reaction temperature was maintained between 0° C. and 10° C. The resulting solution was stirred at rt for 5 h and then partitioned between 1N HCl and water. The organic layer was dried with sodium sulfate, filtered and concentrated. The crude was purified by chromatography to give 569 mg of a waxy solid, 8a. The mixture was cooled in an ice bath was maintained between 0° C. and 10° C The resulting solution was stirred at rt for 5 h partitioned between 1N HCl and water The organic layer was dried with sodium sulfate filtered concentrated The crude was purified by chromatography

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 trans-2-phenylcyclopropanamine hydrochloride (1.087 g, 6.41 mmol) in N,N-dimethylformamide (DMF) (30 mL) was added potassium carbonate (1.771 g, 12.81 mmol) followed by benzyl 4-(bromomethyl)piperidine-1-carboxylate (1 g, 3.20 mmol). The reaction mixture was refluxed overnight. Water (80 mL) was added followed by 80 mL of ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated. The oil was purified via silica gel column (DCM to 100% EtOAc). The fractions were collected and evaporated. The oil was further purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. Benzyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (150 mg, 0.391 mmol, 12.21% yield) was isolated as yellow liquid. 1H NMR (400 MHz, METHANOL-d4) 67.28-7.41 (m, 5H), 7.18-7.27 (m, 2H), 7.09-7.16 (m, 1H), 7.03-7.09 (m, 2H), 5.12 (s, 2H), 4.00-4.29 (m, 2H), 2.67-2.97 (m, 2H), 2.61 (d, J=6.82 Hz, 2H), 2.26-2.36 (m, 1H), 1.92 (ddd, J=3.28, 5.87, 9.28 Hz, 1H), 1.64-1.84 (m, 3H), 0.91-1.24 (m, 4H); LC-MS Rt=0.83 min; MS (ESI): 365.5 [M+H]+. The reaction mixture was refluxed overnight The organic layer was separated washed with brine dried over MgSO4 filtered evaporated The oil was purified via silica gel column (DCM to 100% EtOAc) The fractions were collected evaporated The oil was further purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier) The fractions were collected concentrated extracted with ethyl acetate The organic layer was washed with brine dried over MgSO4 evaporated

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

Procedure: To a solution of trans-2-phenylcyclopropanamine hydrochloride (1.087 g, 6.41 mmol) in N,N-dimethylformamide (DMF) (30 mL) was added potassium carbonate (1.771 g, 12.81 mmol) followed by benzyl 4-(bromomethyl)piperidine-1-carboxylate (1 g, 3.20 mmol). The reaction mixture was refluxed overnight. Water (80 mL) was added followed by 80 mL of ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated. The oil was purified via silica gel column (DCM to 100% EtOAc). The fractions were collected and evaporated. The oil was further purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. Benzyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (150 mg, 0.391 mmol, 12.21% yield) was isolated as yellow liquid. 1H NMR (400 MHz, METHANOL-d4) δ 7.28-7.41 (m, 5H), 7.18-7.27 (m, 2H), 7.09-7.16 (m, 1H), 7.03-7.09 (m, 2H), 5.12 (s, 2H), 4.00-4.29 (m, 2H), 2.67-2.97 (m, 2H), 2.61 (d, J=6.82 Hz, 2H), 2.26-2.36 (m, 1H), 1.92 (ddd, J=3.28, 5.87, 9.28 Hz, 1H), 1.64-1.84 (m, 3H), 0.91-1.24 (m, 4H); LC-MS Rt=0.83 min; MS (ESI): 365.5 [M+H]+. The reaction mixture was refluxed overnight The organic layer was separated washed with brine dried over MgSO4 filtered evaporated The oil was purified via silica gel column (DCM to 100% EtOAc) The fractions were collected evaporated The oil was further purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier) The fractions were collected concentrated extracted with ethyl acetate The organic layer was washed with brine dried over MgSO4 evaporated