2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamine

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

Procedure: To a mixture of rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (40.5 mg, 0.10 mmol) and triethylamine (TEA, 20.0 mg, 0.20 mmol) in CH2Cl2 (1 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (29.4 mg, 0.20 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated and diluted with CH2Cl2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (23.5 mg, 43.8%, 2 steps) as a white amorphous. HRMS (ES+) m/z Calcd for C27H32Cl2FN3O3+H [(M+H)+]: 536.1878; Found: 536.1879. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which The reaction mixture was concentrated diluted with CH2Cl2 washed with water and brine The organic phase was separated filtered dried over Na2SO4 The mixture was then concentrated purified by RP-HPLC

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

Procedure: To a mixture of rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (40.5 mg, 0.10 mmol) and triethylamine (TEA, 20.0 mg, 0.20 mmol) in CH2Cl2 (1 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (29.4 mg, 0.20 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated and diluted with CH2Cl2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (23.5 mg, 43.8%, 2 steps) as a white amorphous. HRMS (ES+) m/z Calcd for C27H32Cl2FN3O3+H [(M+H)+]: 536.1878; Found: 536.1879. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which The reaction mixture was concentrated diluted with CH2Cl2 washed with water and brine The organic phase was separated filtered dried over Na2SO4 The mixture was then concentrated purified by RP-HPLC

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

Procedure: To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl chloride (0.34 g, 0.7 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.1 g, 0.71 mmol) and triethylamine (0.15 mL, 1 mmol). The reaction mixture was stirred at room temperature for 30 min. An aqueous HCl solution (1 N, 5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and NaHCO3 (sat.) solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (EtOAc) to afford rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 28%). HRMS (ES+) m/z Calcd for C27H31Cl2F2N3O3+H [(M+H)+]: 554.1784; Found: 554.1785. The reaction mixture was stirred at room temperature for 1 h The solvents were removed the residue was partitioned between ethyl acetate and NaHCO3 (sat.) solution The organic layer was separated washed with water, brine dried over MgSO4 concentrated The residue was purified by column chromatography (EtOAc)

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

Procedure: To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl chloride (0.34 g, 0.7 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.1 g, 0.71 mmol) and triethylamine (0.15 mL, 1 mmol). The reaction mixture was stirred at room temperature for 30 min. An aqueous HCl solution (1 N, 5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and NaHCO3 (sat.) solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (EtOAc) to afford rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 28%). HRMS (ES+) m/z Calcd for C27H31Cl2F2N3O3+H [(M+H)+]: 554.1784; Found: 554.1785. The reaction mixture was stirred at room temperature for 1 h The solvents were removed the residue was partitioned between ethyl acetate and NaHCO3 (sat.) solution The organic layer was separated washed with water, brine dried over MgSO4 concentrated The residue was purified by column chromatography (EtOAc)

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

Procedure: A mixture of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (0.2 g, 0.41 mmol), 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1 mmol), HATU (0.23 g, 0.6 mmol) and iPr2NEt (0.29 mL, 1.68 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 20 h. The reaction mixture was quenched with water was and the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was dissolved into tetrahydrofuran (7 mL), and aqueous HCl solution (1 N, 3 mL, 3 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed, and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (5% MeOH in EtOAc) to give rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-N—((S)-3,4-dihydroxy-butyl)-acetamide as an off-white solid (0.1 g, 42%). HRMS (ES+) m/z Calcd for C28H33Cl2F2N3O3+H [(M+H)+]: 568.1940; Found: 568.1943. The reaction mixture was quenched with water the organic layer was separated the aqueous layer was extracted with ethyl acetate dried over Na2SO4 concentrated was added to the solution The reaction mixture was stirred at room temperature for 0.5 h The solvent was removed the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution The organic layer was separated washed with water, brine dried over Na2SO4 concentrated The residue was purified by chromatography (5% MeOH in EtOAc)

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

Procedure: A mixture of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (0.2 g, 0.41 mmol), 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1 mmol), HATU (0.23 g, 0.6 mmol) and iPr2NEt (0.29 mL, 1.68 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 20 h. The reaction mixture was quenched with water was and the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was dissolved into tetrahydrofuran (7 mL), and aqueous HCl solution (1 N, 3 mL, 3 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed, and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (5% MeOH in EtOAc) to give rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-N—((S)-3,4-dihydroxy-butyl)-acetamide as an off-white solid (0.1 g, 42%). HRMS (ES+) m/z Calcd for C28H33Cl2F2N3O3+H [(M+H)+]: 568.1940; Found: 568.1943. The reaction mixture was quenched with water the organic layer was separated the aqueous layer was extracted with ethyl acetate dried over Na2SO4 concentrated was added to the solution The reaction mixture was stirred at room temperature for 0.5 h The solvent was removed the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution The organic layer was separated washed with water, brine dried over Na2SO4 concentrated The residue was purified by chromatography (5% MeOH in EtOAc)

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

Procedure: A suspension of (S)-4-(2-azido-ethyl)-2,2-dimethyl-[1,3]dioxolane as a yellow oil (18.7 g, 0.11 mol) and PtO2 (2.5 g) in ethyl acetate (100 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 18 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine as a colorless oil (14 g, 88%). The mixture was filtered through a short pad of celite The filtrate was concentrated

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

Procedure: To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (126.9 mg, 0.30 mmol) and triethylamine (TEA, 120.0 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.40 mL, 0.4 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine* (65.2 mg, 0.45 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2Cl2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated under reduced pressure and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (62.5 mg, 39.5%, 2 steps) as a white amorphous. HRMS (ES+) m/z Calcd for C27H3Cl2F2N3O3+H [(M+H)+]: 554.1784; Found: 554.1787. *Preparation of intermediate 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which The reaction mixture was concentrated under reduced pressure the residue was diluted with CH2Cl2 washed with water and brine The organic phase was separated filtered dried over Na2SO4 The mixture was then concentrated under reduced pressure purified by RP-HPLC

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

Procedure: To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (126.9 mg, 0.30 mmol) and triethylamine (TEA, 120.0 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.40 mL, 0.4 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine* (65.2 mg, 0.45 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2Cl2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated under reduced pressure and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (62.5 mg, 39.5%, 2 steps) as a white amorphous. HRMS (ES+) m/z Calcd for C27H3Cl2F2N3O3+H [(M+H)+]: 554.1784; Found: 554.1787. *Preparation of intermediate 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which The reaction mixture was concentrated under reduced pressure the residue was diluted with CH2Cl2 washed with water and brine The organic phase was separated filtered dried over Na2SO4 The mixture was then concentrated under reduced pressure purified by RP-HPLC

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

Procedure: To a solution of rac-(2′S,3′S,4′S)-4′-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 40 (70 mg, 0.12 mmol) in dichloromethane (5 mL) was added saturated aqueous NaHCO3 solution (5 mL). The temperature of the mixture was lowered to 0° C., and a toluene solution (Aldrich, 20%) of phosgene (0.12 mL, 0.22 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichlormethane twice. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated. The residue was dissolved into tetrahydrofuran (5 mL), and 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 7 (36 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. An aqueous HCl solution (1 N, 5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (15% MeOH in EtOAc) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(4-hydroxy-2,2-dimethyl-butyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (Yield 13 mg, 18%). was lowered to 0° C. The organic layer was separated the aqueous layer was extracted with dichlormethane twice The combined organic layers were washed with water, brine dried over MgSO4 concentrated was added The reaction mixture was stirred at room temperature for 1 h The reaction mixture was stirred at room temperature for 1 h The solvents were removed the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution The organic layer was separated the aqueous layer was extracted with ethyl acetate washed with water, brine dried over MgSO4 concentrated The residue was purified by chromatography (15% MeOH in EtOAc)

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

Procedure: To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(3-hydroxy-2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 32 (60 mg, 0.14 mmol) in dichloromethane (5 mL) was added saturated aqueous NaHCO3 solution (5 mL). The temperature of the mixture was lowered to 0° C., and a toluene solution (Aldrich, 20%) of phosgene (0.13 mL, 0.25 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichlormethane twice. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated. The residue was dissolved into tetrahydrofuran (5 mL), and 2-((S)-2,2-dimethyl-[1,3]-dioxolan-4-yl)-ethylamine prepared in Example 7 (24 mg, 0.16 mmol) and triethylamine (0.038 mL, 0.27 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 h. An aqueous HCl solution (1 N, 2 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (15% MeOH in EtOAc) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (Yield 16 mg, 20%). was lowered to 0° C. The organic layer was separated the aqueous layer was extracted with dichlormethane twice The combined organic layers were washed with water, brine dried over MgSO4 concentrated were added sequentially The reaction mixture was stirred at room temperature for 1 h The reaction mixture was stirred at room temperature for 1 h The solvents were removed the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution The organic layer was separated the aqueous layer was extracted with ethyl acetate washed with water, brine dried over MgSO4 concentrated The residue was purified by chromatography (15% MeOH in EtOAc)

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

Procedure: To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride (0.14 g, 0.28 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 7 (49 mg, 0.34 mmol) and triethylamine (0.078 mL, 0.56 mmol). The reaction mixture was stirred at room temperature for 1 h. An aqueous HCl solution (1 N, 2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 h. The solvents were removed and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (Yield 75 mg, 50%). The reaction mixture was stirred at room temperature for 0.5 h The solvents were removed the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution The organic layer was separated the aqueous layer was extracted with ethyl acetate washed with water, brine dried over MgSO4 concentrated The residue was triturated with dichlormethane and hexanes