(3S)-3-methoxypyrrolidine

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

Procedure: To a stirred solution of 31 (0.4 g, 2.6 mmol) and (S)-3-methoxy-pyrrolidine (0.4 g, 3.2 mmol) in dichloromethane (10 mL) was added acetic acid (0.01 mL, 0.25 mmol). After 30 minutes, sodium triacetoxyborohydride (1.1 g, 5.3 mmol) was added to the above mixture and stirred at rt for 15 minutes. The reaction mixture was diluted with water (10 mL), treated with saturated NaHCO3 solution to get pH˜8 and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel flash chromatography, eluting with 2% MeOH/DCM to afford 32 (0.25 g, 40%) as a liquid. Rf: 0.3 (5% MeOH/DCM); (m/z): 238 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 9.28 (1H, d, J=2.8 Hz), 8.59-8.56 (1H, m), 7.71 (1H, d, J=8.8 Hz), 3.93-3.80 (3H, m), 3.16 (3H, s), 2.73-2.62 (2H, m), 2.56-2.53 (1H, m), 2.50-2.47 (1H, m), 2.06-2.02 (1H, m), 1.72-1.65 (1H, m). to get pH˜8 extracted with dichloromethane (2×20 mL) The combined organic layers were washed with brine (50 mL) dried (Na2SO4) evaporated The crude compound was purified by silica gel flash chromatography eluting with 2% MeOH/DCM

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (200 mg, 0.72 mmol), N,N-diisopropylethylamine (251 μL, 1.44 mmol) and (S)-3-methoxy-pyrrolidine (198 mg, 1.96 mmol) in NMP (0.5 mL) was heated at 160° C. in the microwave (Smith Personal Synthesiser) for 400 seconds. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 97:3:0.3 to 95:5:0.5. to give the product as a clear oil (102 mg, 41%). 1H NMR (400 MHz, CDCl3) δ7.36 (d, 2H), 6.90 (d, 2H), 4.02 (t, 2H), 3.96-3.88 (m, 1H), 3.28 (s, 3H), 2.86-2.52 (m, 6H), 2.18-1.96 (m, 5H), 1.88-1.66 (m, 8H), 1.38-1.16 (m, 1H); LCMS (APCI+) 343 (M+H)+. The reaction mixture was quenched with water (10 mL) extracted with dichloromethane (2×10 mL) dried over Na2SO4 filtered concentrated in vacuo The compound was purified by column chromatography on Biotage® silica gel eluting with dichloromethane

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (200 mg, 0.72 mmol), N,N-diisopropylethylamine (251 μL, 1.44 mmol) and (S)-3-methoxy-pyrrolidine (198 mg, 1.96 mmol) in NMP (0.5 mL) was heated at 160° C. in the microwave (Smith Personal Synthesiser) for 400 seconds. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 97:3:0.3 to 95:5:0.5. to give the product as a clear oil (102 mg, 41%). 1H NMR (400 MHz, CDCl3) δ7.36 (d, 2H), 6.90 (d, 2H), 4.02 (t, 2H), 3.96-3.88 (m, 1H), 3.28 (s, 3H), 2.86-2.52 (m, 6H), 2.18-1.96 (m, 5H), 1.88-1.66 (m, 8H), 1.38-1.16 (m, 1H); LCMS (APCI+) 343 (M+H)+. The reaction mixture was quenched with water (10 mL) extracted with dichloromethane (2×10 mL) dried over Na2SO4 filtered concentrated in vacuo The compound was purified by column chromatography on Biotage® silica gel eluting with dichloromethane

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

Procedure: Amide coupling of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid with (S)-3-methoxypyrrolidine utilizing HATU as coupling reagent. White solid. Yield: 100 mg (85% of theory)

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

Procedure: Amide coupling of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid with (S)-3-methoxypyrrolidine utilizing HATU as coupling reagent. White solid. Yield: 100 mg (85% of theory)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (200 mg, 0.72 mmol), N,N-diisopropylethylamine (251 μL, 1.44 mmol) and (S)-3-methoxy-pyrrolidine (198 mg, 1.96 mmol) in NMP (0.5 mL) was heated at 160° C. in the microwave (Smith Personal Synthesiser) for 400 seconds. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 97:3:0.3 to 95:5:0.5. to give the product as a clear oil (102 mg, 41%). 1H NMR (400 MHz, CDCl3) δ7.36 (d, 2H), 6.90 (d, 2H), 4.02 (t, 2H), 3.96-3.88 (m, 1H), 3.28 (s, 3H), 2.86-2.52 (m, 6H), 2.18-1.96 (m, 5H), 1.88-1.66 (m, 8H), 1.38-1.16 (m, 1H); LCMS (APCI+) 343 (M+H)+. The reaction mixture was quenched with water (10 mL) extracted with dichloromethane (2×10 mL) dried over Na2SO4 filtered concentrated in vacuo The compound was purified by column chromatography on Biotage® silica gel eluting with dichloromethane

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

Procedure: To a stirred solution of 31 (0.4 g, 2.6 mmol) and (S)-3-methoxy-pyrrolidine (0.4 g, 3.2 mmol) in dichloromethane (10 mL) was added acetic acid (0.01 mL, 0.25 mmol). After 30 minutes, sodium triacetoxyborohydride (1.1 g, 5.3 mmol) was added to the above mixture and stirred at rt for 15 minutes. The reaction mixture was diluted with water (10 mL), treated with saturated NaHCO3 solution to get pH˜8 and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel flash chromatography, eluting with 2% MeOH/DCM to afford 32 (0.25 g, 40%) as a liquid. Rf: 0.3 (5% MeOH/DCM); (m/z): 238 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 9.28 (1H, d, J=2.8 Hz), 8.59-8.56 (1H, m), 7.71 (1H, d, J=8.8 Hz), 3.93-3.80 (3H, m), 3.16 (3H, s), 2.73-2.62 (2H, m), 2.56-2.53 (1H, m), 2.50-2.47 (1H, m), 2.06-2.02 (1H, m), 1.72-1.65 (1H, m). to get pH˜8 extracted with dichloromethane (2×20 mL) The combined organic layers were washed with brine (50 mL) dried (Na2SO4) evaporated The crude compound was purified by silica gel flash chromatography eluting with 2% MeOH/DCM

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

Procedure: To a stirred solution of 31 (0.4 g, 2.6 mmol) and (S)-3-methoxy-pyrrolidine (0.4 g, 3.2 mmol) in dichloromethane (10 mL) was added acetic acid (0.01 mL, 0.25 mmol). After 30 minutes, sodium triacetoxyborohydride (1.1 g, 5.3 mmol) was added to the above mixture and stirred at rt for 15 minutes. The reaction mixture was diluted with water (10 mL), treated with saturated NaHCO3 solution to get pH˜8 and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel flash chromatography, eluting with 2% MeOH/DCM to afford 32 (0.25 g, 40%) as a liquid. Rf: 0.3 (5% MeOH/DCM); (m/z): 238 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 9.28 (1H, d, J=2.8 Hz), 8.59-8.56 (1H, m), 7.71 (1H, d, J=8.8 Hz), 3.93-3.80 (3H, m), 3.16 (3H, s), 2.73-2.62 (2H, m), 2.56-2.53 (1H, m), 2.50-2.47 (1H, m), 2.06-2.02 (1H, m), 1.72-1.65 (1H, m). to get pH˜8 extracted with dichloromethane (2×20 mL) The combined organic layers were washed with brine (50 mL) dried (Na2SO4) evaporated The crude compound was purified by silica gel flash chromatography eluting with 2% MeOH/DCM

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

Procedure: In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with (S)-3-methoxy-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3072.

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

Procedure: In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with (S)-3-methoxy-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O4 [(M+H)+] 749.3344, observed 749.3340.

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

Procedure: Amide coupling of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid with (S)-3-methoxypyrrolidine utilizing HATU as coupling reagent. White solid. Yield: 100 mg (85% of theory)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (200 mg, 0.72 mmol), N,N-diisopropylethylamine (251 μL, 1.44 mmol) and (S)-3-methoxy-pyrrolidine (198 mg, 1.96 mmol) in NMP (0.5 mL) was heated at 160° C. in the microwave (Smith Personal Synthesiser) for 400 seconds. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 97:3:0.3 to 95:5:0.5. to give the product as a clear oil (102 mg, 41%). 1H NMR (400 MHz, CDCl3) δ7.36 (d, 2H), 6.90 (d, 2H), 4.02 (t, 2H), 3.96-3.88 (m, 1H), 3.28 (s, 3H), 2.86-2.52 (m, 6H), 2.18-1.96 (m, 5H), 1.88-1.66 (m, 8H), 1.38-1.16 (m, 1H); LCMS (APCI+) 343 (M+H)+. The reaction mixture was quenched with water (10 mL) extracted with dichloromethane (2×10 mL) dried over Na2SO4 filtered concentrated in vacuo The compound was purified by column chromatography on Biotage® silica gel eluting with dichloromethane