(2R)-1-methylpyrrolidine-2-carboxylic acid

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

Procedure: The title compound was prepared in 37% yield following the procedure described above in the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(((S)-1-methylpyrrolidine-2-carboxamido)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, example 150, using (R)-1-methylpyrrolidine-2-carboxylic acid as the reactant acid. MS: m/e 655.7 (MH+), 1.73 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.94 (s, 3H) 0.96 (s, 3H) 1.03 (s, 3H) 1.05 (s, 3H) 1.17 (s, 3H) 1.71 (s, 3H) 0.85-2.25 (m, 24H) 2.14 (dd, J=17.07, 6.27 Hz, 1H) 2.48-2.62 (m, 2H) 2.90 (s, 3H) 3.15-3.25 (m, 2H) 3.50-3.57 (m, 1H) 3.67-3.76 (m, 1H) 4.04 (t, J=8.16 Hz, 1H) 4.61 (s, 1H) 4.73 (d, J=2.01 Hz, 1H) 5.29 (dd, J=6.15, 1.63 Hz, 1H) 7.21 (d, J=8.28 Hz, 2H) 7.91 (d, J=8.28 Hz, 2H) 8.24 (t, J=5.90 Hz, 1H). m/e 655.7 (MH+), 1.73 min (method 2)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of D-proline (30 g, 260.7 mmol, 1 eq) and 37% aqueous formaldehyde (80.5 mL, 782 mmol, 3eq) in H2O (900 mL) was added 10% Pd/C (30 g) under N2. The mixture was stirred at 50° C. under H2 (30 psi) overnight. The mixture was heated to boiling and filtered to remove the catalyst. The solution was concentrated under reduced pressure, and then water (150 mL) was added to the mixture and concentrated, the procedure was repeated three times so as to remove unreacted formaldehyde. The crude product was resuspended in ACN/H2O (1:1, v/v) and lyophilized. The solid product was recrystallized from EtOH/acetone, filtered, liberally washed with acetone, and dried under reduced pressure to give 1-methyl-D-proline (12.3 g, 40%) as white solid. 1H NMR (400 MHz, MeOHD) δ ppm 1.95-1.99 (s, 1H), 2.1-2.2(s, 2H), 2.4-2.5 (m, 1H), 3.05-3.15(m,1H),3.3-3.35(s,1H),3.65-3.75(m, 1H),3.75-3.85(m,1H). The mixture was heated filtered to remove the catalyst The solution was concentrated under reduced pressure water (150 mL) was added to the mixture concentrated to remove unreacted formaldehyde The solid product was recrystallized from EtOH/acetone filtered liberally washed with acetone dried under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of D-proline (30 g, 260.7 mmol, 1 eq) and 37% aqueous formaldehyde (80.5 mL, 782 mmol, 3eq) in H2O (900 mL) was added 10% Pd/C (30 g) under N2. The mixture was stirred at 50° C. under H2 (30 psi) overnight. The mixture was heated to boiling and filtered to remove the catalyst. The solution was concentrated under reduced pressure, and then water (150 mL) was added to the mixture and concentrated, the procedure was repeated three times so as to remove unreacted formaldehyde. The crude product was resuspended in ACN/H2O (1:1, v/v) and lyophilized. The solid product was recrystallized from EtOH/acetone, filtered, liberally washed with acetone, and dried under reduced pressure to give 1-methyl-D-proline (12.3 g, 40%) as white solid. 1H NMR (400 MHz, MeOHD) δ ppm 1.95-1.99 (s, 1H), 2.1-2.2(s, 2H), 2.4-2.5 (m, 1H), 3.05-3.15(m,1H),3.3-3.35(s,1H),3.65-3.75(m, 1H),3.75-3.85(m,1H). The mixture was heated filtered to remove the catalyst The solution was concentrated under reduced pressure water (150 mL) was added to the mixture concentrated to remove unreacted formaldehyde The solid product was recrystallized from EtOH/acetone filtered liberally washed with acetone dried under reduced pressure

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

Procedure: The title compound was prepared in 37% yield following the procedure described above in the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(((S)-1-methylpyrrolidine-2-carboxamido)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, example 150, using (R)-1-methylpyrrolidine-2-carboxylic acid as the reactant acid. MS: m/e 655.7 (MH+), 1.73 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.94 (s, 3H) 0.96 (s, 3H) 1.03 (s, 3H) 1.05 (s, 3H) 1.17 (s, 3H) 1.71 (s, 3H) 0.85-2.25 (m, 24H) 2.14 (dd, J=17.07, 6.27 Hz, 1H) 2.48-2.62 (m, 2H) 2.90 (s, 3H) 3.15-3.25 (m, 2H) 3.50-3.57 (m, 1H) 3.67-3.76 (m, 1H) 4.04 (t, J=8.16 Hz, 1H) 4.61 (s, 1H) 4.73 (d, J=2.01 Hz, 1H) 5.29 (dd, J=6.15, 1.63 Hz, 1H) 7.21 (d, J=8.28 Hz, 2H) 7.91 (d, J=8.28 Hz, 2H) 8.24 (t, J=5.90 Hz, 1H). m/e 655.7 (MH+), 1.73 min (method 2)

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

Procedure: To a solution of 1 eq of methyl-14-cyclohexyl-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-11-carboxylate (prepared as described in Example 18, Step 5) in DCM (0.06 M), 1.5 eq of 1-methyl-D-proline (prepared according to literature precedent J. Org. Chem. 2003, 68, 2652) in DCM (0.2 M), 1.5 eq of DIPEA and 1.5 eq of TBTU were added and the mixture stirred at RT overnight. Volatiles were removed in vacuo and the crude was used in the next step without further purification; MS (ES+) m/z 518 (M+H)+. Volatiles were removed in vacuo the crude was used in the next step without further purification

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of D-proline (30 g, 260.7 mmol, 1 eq) and 37% aqueous formaldehyde (80.5 mL, 782 mmol, 3eq) in H2O (900 mL) was added 10% Pd/C (30 g) under N2. The mixture was stirred at 50° C. under H2 (30 psi) overnight. The mixture was heated to boiling and filtered to remove the catalyst. The solution was concentrated under reduced pressure, and then water (150 mL) was added to the mixture and concentrated, the procedure was repeated three times so as to remove unreacted formaldehyde. The crude product was resuspended in ACN/H2O (1:1, v/v) and lyophilized. The solid product was recrystallized from EtOH/acetone, filtered, liberally washed with acetone, and dried under reduced pressure to give 1-methyl-D-proline (12.3 g, 40%) as white solid. 1H NMR (400 MHz, MeOHD) δ ppm 1.95-1.99 (s, 1H), 2.1-2.2(s, 2H), 2.4-2.5 (m, 1H), 3.05-3.15(m,1H),3.3-3.35(s,1H),3.65-3.75(m, 1H),3.75-3.85(m,1H). The mixture was heated filtered to remove the catalyst The solution was concentrated under reduced pressure water (150 mL) was added to the mixture concentrated to remove unreacted formaldehyde The solid product was recrystallized from EtOH/acetone filtered liberally washed with acetone dried under reduced pressure

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

Procedure: The title compound was prepared in 37% yield following the procedure described above in the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(((S)-1-methylpyrrolidine-2-carboxamido)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, example 150, using (R)-1-methylpyrrolidine-2-carboxylic acid as the reactant acid. MS: m/e 655.7 (MH+), 1.73 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.94 (s, 3H) 0.96 (s, 3H) 1.03 (s, 3H) 1.05 (s, 3H) 1.17 (s, 3H) 1.71 (s, 3H) 0.85-2.25 (m, 24H) 2.14 (dd, J=17.07, 6.27 Hz, 1H) 2.48-2.62 (m, 2H) 2.90 (s, 3H) 3.15-3.25 (m, 2H) 3.50-3.57 (m, 1H) 3.67-3.76 (m, 1H) 4.04 (t, J=8.16 Hz, 1H) 4.61 (s, 1H) 4.73 (d, J=2.01 Hz, 1H) 5.29 (dd, J=6.15, 1.63 Hz, 1H) 7.21 (d, J=8.28 Hz, 2H) 7.91 (d, J=8.28 Hz, 2H) 8.24 (t, J=5.90 Hz, 1H). m/e 655.7 (MH+), 1.73 min (method 2)