tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate

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

Procedure: Dissolve 5-bromo-2-fluoro-pyridine (5.20 g, 29.53 mmol), and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (5.50 g, 29.53 mmol) in acetonitrile (100 mL) and reflux with K2CO3 (8.90 g, 64.96 mmol) for 3 h. Filter the reaction mixture and wash with EtOAc (100 mL). Concentrate the filtrate and purify the resulting crude material by silica gel chromatography, eluting with 40% EtOAc/hexanes to give 2.76 g (27%) of the title compound. LC-MS/ES m/z (81Br) 344.3 [M+H]+. Filter the reaction mixture wash with EtOAc (100 mL) Concentrate the filtrate purify the resulting crude material by silica gel chromatography eluting with 40% EtOAc/hexanes

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.190 g, 0.698 mmol), DIEA (0.365 mL, 2.10 mmol), and (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.390 g, 2.10 mmol) were placed in n-BuOH (2 mL) and heated to 135° C. for 8 hours. The reaction was then cooled to room temperature and concentrated to dryness. The residue was purified by silica gel chromatography (500:18 DCM:MeOH) to give (S)-tert-butyl 1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.240 g, 78% yield). The reaction was then cooled to room temperature concentrated to dryness The residue was purified by silica gel chromatography (500:18 DCM:MeOH)

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

Procedure: To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.94 g, 5.04 mmol), 1-(6-fluoropyridin-3-yl)ethanone (0.35 g, 2.52 mmol) in THF (10 mL) was added tetraisopropoxytitanium (1.48 mL, 5.04 mmol) and the reaction mixture was stirred at ambient temperature for 18 hours. Ethanol (2 mL) and NaBH4 (0.38 g, 10.1 mmol) were added and the mixture was stirred at ambient temperature for 2 hours. Water (10 mL), concentrated ammonium (2 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate) to give tert-butyl (3S)-1-(1-(6-fluoropyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.343 g, 44.0%) as solid. the mixture was stirred at ambient temperature for 2 hours The organic layer was separated washed with brine dried (sodium sulfate) filtered concentrated under reduced pressure The residue obtained was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate)

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

Procedure: To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (6.0 g, 32.2 mmol) and DIEA (12.5 g, 16.8 mL, 96.6 mmol) in dichloromethane (60 mL) cooled to 0° C. on an ice-bath was added benzyl chloroformate (8.7 g, 7.2 mL, 48.3 mmol), and the resulting mixture stirred at 0° C. for 2 hours. The mixture was diluted with dichloromethane (30 mL) and washed successively with cold aqueous 10% HCl, water, saturated sodium bicarbonate solution and brine. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography silica gel (Biotage, 65M; 20% ethyl acetate/hexanes) to afford (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (10 g, 97%). washed successively with cold aqueous 10% HCl, water, saturated sodium bicarbonate solution and brine The organic phase was dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by flash chromatography silica gel (Biotage, 65M; 20% ethyl acetate/hexanes)

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

Procedure: To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.502 g, 2.69 mmol), 1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone (0.464 g, 1.35 mmol) in THF (20 mL) was added tetraisopropoxytitanium (0.79 mL, 2.69 mmol) and the reaction mixture was stirred at ambient temperature for 18 hours. Ethanol (2 mL) and NaBH4 (0.204 g, 5.39 mmol) were added and the mixture was stirred at ambient temperature for 2 hours. Water (10 mL), concentrated ammonium hydroxide (2 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CH3CN/water gradient; 25 CV) to give tert-butyl (3S)-1-(1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.485 g, 69.9%) as solid. the mixture was stirred at ambient temperature for 2 hours The organic layer was separated washed with brine dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit

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

Procedure: A solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (79.8 g, 232 mmol), (S)-tert-butyl pyrrolidin-3-ylcarbamate (51.9 g, 279 mmol), and K2CO3 (44.9 g, 325 mmol) in THF (500 mL) was stirred at 56° C. for 18 hours. After cooling to ambient temperature, water (200 mL) and ethyl acetate (200 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give a thick oil. The oil was dissolved in ether (200 mL) and hexane (500 mL) was added. The solution was concentrated to about 200 mL and stirred at ambient temperature for 1 hour. Hexane (300 mL) was added, and the resulting solid was collected by filtration to give tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (68.2 g, 77.3%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes/10% (1:1 MeOH/EtOH) at 1.0 mL/min, >99% d.e. (R,S)-diastereomer). The organic layer was separated washed with brine dried (sodium sulfate) concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give a thick oil The solution was concentrated to about 200 mL Hexane (300 mL) was added the resulting solid was collected by filtration

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

Procedure: A solution of 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (0.55 g, 1.60 mmol), K2CO3 (0.33 g, 2.40 mmol), and (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.42 g, 2.24 mmol) in THF (8 mL) was stirred at 50° C. for 20 hours. Water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/ethyl acetate) to give tert-butyl (3S)-1-(1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (0.45 g, 74.0%) as a white solid. The organic layer was separated washed with brine dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (3:1 hexane/ethyl acetate)

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

Procedure: A suspension of 2-allyloxy-4,6,7-trichlorobenzo[de]isoquinoline-1,3-dione (0.44 g, 1.2 mmol, from Example I4), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (0.3 g, 1.5 mmol), triethylamine (0.2 g, 2.0 mmol), and 20 mL of acetonitrile was stirred at room temperature for 6 hours. The solvent was removed in vacuo and the residue partitioned between water and dichloromethane. The organic layer was dried and evaporated in vacuo. The residue was chromatographed on silica gel (ICN 230-400 mesh) eluting with dicholromethane/ethyl acetate (80:20) to give 0.35 g of the title compound, mp 123-125° C. The solvent was removed in vacuo the residue partitioned between water and dichloromethane The organic layer was dried evaporated in vacuo The residue was chromatographed on silica gel (ICN 230-400 mesh) eluting with dicholromethane/ethyl acetate (80:20)

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

Procedure: A suspension of 2-allyloxy-4,6,7-trichlorobenzo[de]isoquinoline-1,3-dione (0.44 g, 1.2 mmol, from Example I4), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (0.3 g, 1.5 mmol), triethylamine (0.2 g, 2.0 mmol), and 20 mL of acetonitrile was stirred at room temperature for 6 hours. The solvent was removed in vacuo and the residue partitioned between water and dichloromethane. The organic layer was dried and evaporated in vacuo. The residue was chromatographed on silica gel (ICN 230-400 mesh) eluting with dicholromethane/ethyl acetate (80:20) to give 0.35 g of the title compound, mp 123-125° C. The solvent was removed in vacuo the residue partitioned between water and dichloromethane The organic layer was dried evaporated in vacuo The residue was chromatographed on silica gel (ICN 230-400 mesh) eluting with dicholromethane/ethyl acetate (80:20)

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

Procedure: Following the procedure of Example B2, 2-benzyloxy-6-chloro-5-cyano-benzo[de]isoquinoline-1,3-dione (0.20 g, 0.55 mmol, from Example A2), (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (0.11 g, 0.60 mmol), triethyl amine (0.11 g, 1.1 mmol) were reacted at ambient temperature for 5 hours. Column chromatography of the crude product on silica using chloroform/methanol (20:1) gave 0.18 g of the title compound. were reacted at ambient temperature for 5 hours

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

Procedure: Following the procedure of Example B2, 2-benzyloxy-6-chloro-5-cyano-benzo[de]isoquinoline-1,3-dione (0.20 g, 0.55 mmol, from Example A2), (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (0.11 g, 0.60 mmol), triethyl amine (0.11 g, 1.1 mmol) were reacted at ambient temperature for 5 hours. Column chromatography of the crude product on silica using chloroform/methanol (20:1) gave 0.18 g of the title compound. were reacted at ambient temperature for 5 hours

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

Procedure: Following the procedure of Example W1, 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.40 g, 0.94 mmol, from Example S1-A), (S)-pyrrolidin-3-yl-carbamic acid, tert-butyl ester (0.38 g, 2.1 mmol) and triethyl amine (0.18 g, 1.9 mmol) in DMF (5 mL) were reacted at 80° C. for 48 hours to give 0.43 g of the title compound. were reacted at 80° C. for 48 hours