(1R)-1-(3-chlorophenyl)ethanamine

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylsulfonyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile and 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylsulfinyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (20 mg) was mixed with (R)-1-(3-chlorophenyl)ethanamine (33 mg) in i-propanol (0.5 mL). The reaction mixture was heated at 90° C. in the microwave for 1 hour. The reaction was cooled to room temperature and concentrated under vacuum. The residue was diluted with water, filtered and washed with water followed by 20% ethanol/water mixture. The solid was dried under high vacuum to give 2 mg of the product, 5-(1-(3-chlorophenyl)ethylamino)-7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile. LCMS (M+1=463) The reaction was cooled to room temperature concentrated under vacuum The residue was diluted with water filtered washed with water The solid was dried under high vacuum

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylsulfonyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile and 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylsulfinyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (20 mg) was mixed with (R)-1-(3-chlorophenyl)ethanamine (33 mg) in i-propanol (0.5 mL). The reaction mixture was heated at 90° C. in the microwave for 1 hour. The reaction was cooled to room temperature and concentrated under vacuum. The residue was diluted with water, filtered and washed with water followed by 20% ethanol/water mixture. The solid was dried under high vacuum to give 2 mg of the product, 5-(1-(3-chlorophenyl)ethylamino)-7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile. LCMS (M+1=463) The reaction was cooled to room temperature concentrated under vacuum The residue was diluted with water filtered washed with water The solid was dried under high vacuum

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

Procedure: A 20 mL vial was charged with sodium triacetoxyborohydride (1.0 g, 4.8 mmol), (R)-1-(3-chlorophenyl)ethanamine 55 (0.413 g, 2.7 mmol), 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carbaldehyde 54 (0.500 g, 2.4 mmol), 10 mL of DCE, and 5 drops of AcOH. This mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3. The mixture was extracted with DCM, dried, concentrated, and purified by column chromatography on silica gel (3% to 7% MeOH in DCM) to give 4-({[(1R)-1-(3-chlorophenyl)ethyl]amino}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one 56 as a 1:1 mixture of diastereomers. Mass spectrum: calculated for C19H20ClFN2O 346.1; found 347.2 (M++1). then quenched with saturated aqueous NaHCO3 The mixture was extracted with DCM dried concentrated purified by column chromatography on silica gel (3% to 7% MeOH in DCM)

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

Procedure: The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(3-chlorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 537/538/539 [M+H]+.

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

Procedure: A solution of (R)-1-(3-chlorophenyl)ethanamine 107 (0.701 g, 4.50 mmol), 1-(3-bromo-4-chlorophenyl)ethanone 106 (1.00 g, 4.29 mmol), and triethylamine (1.79 mL, 12.9 mmol) in dry DME was chilled to −78° C. in a dry ice bath. Via syringe, titanium(IV) chloride (4.50 mL, 4.50 mmol) was added dropwise to the reaction mixture. The reaction was warmed to ambient temperature and it was stirred under N2 for 10 h. A solution of sodium cyanoborohydride (0.674 g, 10.7 mmol) in 4 mL of MeOH was then added slowly to the reaction mixture and the reaction solution was stirred for another 3 h. The reaction was quenched by the addition of saturated NH4Cl. The solution was diluted with ether and water, and the mixture was extracted with water (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 3% to 30% gradient of EtOAc in hexanes as the eluent. The desired fractions were combined and concentrated to give 1-(3-bromo-4-chlorophenyl)-N—((R)-1-(3-chlorophenyl)ethyl)ethanamine 108 (1.04 g, 65.0% yield) as a colorless oil. the reaction solution was stirred for another 3 h The reaction was quenched by the addition of saturated NH4Cl The solution was diluted with ether and water the mixture was extracted with water (2×) and brine The organic layer was dried over MgSO4 filtered concentrated in vacuo The crude material was purified by silica gel chromatography concentrated

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

Procedure: A solution of (5-(bromomethyl)-2-chlorophenoxy)(tert-butyl)dimethylsilane 81 (1.00 g, 2.98 mmol) and potassium carbonate (0.453 g, 3.28 mmol) in DMF was stirred at room temp under N2. (R)-1-(3-Chlorophenyl)ethanamine (0.464 g, 2.98 mmol) was added to the solution and the reaction was stirred at room temperature for 8 h. The reaction was checked by TLC for completion. The reaction mixture was diluted with water and ether. The ether solution was washed with water (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 5% to 30% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give (R)—N-(3-(tert-butyldimethylsilyloxy)-4-chlorobenzyl)-1-(3-chlorophenyl)ethanamine 82 (0.612 g, 50.1% yield) as a colorless oil. The product was carried forth to the next step without further purification. The ether solution was washed with water (2×) and brine The organic layer was dried over MgSO4 filtered concentrated in vacuo The crude material was purified by silica gel chromatography concentrated

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

Procedure: To a solution of 4-methoxy-3-(morpholinosulfonyl)benzoic acid 42 (0.824 g, 2.73 mmol) in DMF (6 mL) was added EDCI (0.686 g, 3.58 mmol) and HOBT (0.536 g, 3.50 mmol), the solution was stirred for 30 min and (R)-1-(3-chlorophenyl)ethanamine (0.673 g, 4.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc and water. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 60% to 100% EtOAc in hexanes) gave (R)—N-(1-(3-chlorophenyl)ethyl)-4-methoxy-3-(morpholinosulfonyl)benzamide 43 (1.14 g, 95.0% yield) as a white solid. Mass spectrum: calculated for C20H23ClN2O5S 438.1. found 439.1 (M++1). The reaction mixture was stirred at room temperature for 16 h The organic phase was washed with water (2×), brine (1×) dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel (eluted with 60% to 100% EtOAc in hexanes)

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

Procedure: To a solution of (R)-1-(3-chlorophenyl)ethanamine (0.426 g, 2.74 mmol) and 4-chloro-3-sulfamoylbenzoic acid 37 (0.452 g, 1.92 mmol) in DMF (5 mL) at room temperature was added EDCI (0.439 g, 2.29 mmol) and HOBT (0.368 g, 2.40 mmol). The reaction mixture was stirred at room temperature for 16 h, and diluted with EtOAc and water. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 50% to 80% EtOAc in hexanes) yielded 3-(aminosulfonyl)-4-chloro-N-((1R)-1-(3-chlorophenyl)ethyl)benzamide 38 (0.643 g, 89.8% yield) as a white solid. Mass spectrum: calculated for C15H14Cl2N2O3S 372.0. found 373.1 (M++1). The organic phase was washed with water (2×), brine (1×) dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel (eluted with 50% to 80% EtOAc in hexanes)

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

Procedure: To a solution of 3-bromo-4-chlorobenzoic acid 31 (4.209 g, 17.9 mmol) in DMF (40 mL) at room temperature was added HOBT (3.31 g, 21.6 mmol) and EDCI (4.13 g, 21.5 mmol). The solution was stirred for 15 min and (R)-1-(3-chlorophenyl)ethanamine (2.92 g, 18.8 mmol) was added. The reaction mixture was stirred at room temperature for 14 h and diluted with EtOAc. The aqueous phase was extracted with EtOAc (1×), and the combined organic extracts were washed with water (2×), brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 40% EtOAc in hexanes) gave (R)-3-bromo-4-chloro-N-(1-(3-chlorophenyl)ethyl)benzamide 32 (6.659 g, 99.9% yield) as a white solid. Mass spectrum: calculated for C15H12BrCl2NO 371.0. found 372.0 (M++1). The reaction mixture was stirred at room temperature for 14 h The aqueous phase was extracted with EtOAc (1×) the combined organic extracts were washed with water (2×), brine dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel (eluted with 20% to 40% EtOAc in hexanes)

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

Procedure: To a solution of 4-chloro-3-nitrobenzaldehyde 1 (1.71 g, 9.2 mmol) and (R)-1-(3-chlorophenyl)ethanamine (1.115 g, 7.2 mmol) in DCE (15 mL) at room temperature was added acetic acid (2.0 mL, 35 mmol) and NaBH(OAc)3 (2.23 g, 11 mmol). The reaction mixture was stirred at room temperature for 2 d, quenched with saturated NaHCO3, and diluted with EtOAc. The organic phase was washed with NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 10% to 40% EtOAc in hexanes) gave (R)—N-(4-chloro-3-nitrobenzyl)-1-(3-chlorophenyl)ethanamine 30 (2.03 g, 87% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.37 (d, J=6.7 Hz, 3H), 3.66 (s, 2H), 3.77 (q, J=6.7 Hz, 1H), 7.18-7.32 (m, 5H), 7.44-7.48 (m, 2H), 7.83 (s, 1H). Mass spectrum: calculated for C15H14Cl2N2O2 324.0. found 325.1 (M++1). quenched with saturated NaHCO3 diluted with EtOAc The organic phase was washed with NaHCO3 (1×), brine (1×) dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel (eluted with 10% to 40% EtOAc in hexanes)

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

Procedure: To a solution of N-(2-chloro-5-formylphenyl)-5-methylisoxazole-3-carboxamide 3 (0.117 g, 0.44 mmol) in DCE (3 mL) was added (R)-1-(3-chlorophenyl)ethanamine (0.079 g, 0.51 mmol), acetic acid (0.030 mL, 0.52 mmol), and NaBH(OAc)3 (0.108 g, 0.51 mmol). The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 60% EtOAc in hexanes) gave (R)—N-(2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenyl)-5-methylisoxazole-3-carboxamide 4 (0.131 g, 73% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.5 Hz, 3H), 2.53 (s, 3H), 3.60 (d, J=13.7 Hz, 1H), 3.66 (d, J=13.7 Hz, 1H), 3.79 (q, J=6.5 Hz, 1H), 6.53 (s, 1H), 7.04 (d, J=8.2 Hz, 1H), 7.21-7.36 (m, 6H), 8.41 (s, 1H), 9.10 (s br, 1H). Mass spectrum: calculated for C20H19Cl2N3O2 403.1. found 404.1 (M++1). The organic phase was washed with saturated NaHCO3 (1×), brine (1×) dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel (eluted with 20% to 60% EtOAc in hexanes)

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

Procedure: General procedure B was followed using (3S)-3-[4-(Morpholine-4-carbonyl)phenyl]-cyclopentanone (preparation 15) as the ketone and (R)-1-(3-chlorophenyl)ethanamine as the amine. 1H NMR (600 MHz, DMSO) δ 7.44-7.42 (m, 1H), 7.35-7.22 (m, 7H), 3.76 (q, J=6.6 Hz, 1H), 3.57 (br m, 4H), 3.33 (br m, 4H), 3.27-3.19 (m, 1H), 3.02 (m, 1H), 2.07 (m, 1H), 1.93 (m, 1H), 1.77-1.41 (m, 4H), 1.23 (d, J=5.3 Hz, 3H).