methyl pyrrolidine-3-carboxylate;hydrochloride

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

Procedure: A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 0.30 g, 1.03 mmol), methyl pyrrolidine-3-carboxylate hydrochloride (0.21 g, 1.2 mmol), triethylamine (215 μL, 1.6 mmol), EDCI (0.19 g, 1.2 mmol) and HOBt (0.19 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 85:15 to 35:65) to give the title compound (0.35 g, 85%) as a pale yellow oil. extracted with ethyl acetate The extract was washed with saturated NaHCO3 solution and brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate 85:15 to 35:65)

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

Procedure: Benzyl carbonochloridate (3.57 mL, 25.36 mmol) at 0° C. was added to methyl pyrrolidine-3-carboxylate hydrochloride (4.00 g, 24.15 mmol) and K2CO3 (6.68 g, 48.3 mmol) in THF:water (100 mL, 1:1). The reaction mixture was stirred at room temperature for 2 hours. Ether (50 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 54% yield) as an oil. The organic layer was separated washed with brine dried over sodium sulfate After removal of the solvent the residue was purified by chromatography (hexane:ethyl acetate, 3:1)

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

Procedure: Benzyl carbonochloridate (3.57 mL, 25.36 mmol) at 0° C. was added to methyl pyrrolidine-3-carboxylate hydrochloride (4.00 g, 24.15 mmol) and K2CO3 (6.68 g, 48.3 mmol) in THF:water (100 mL, 1:1). The reaction mixture was stirred at room temperature for 2 hours. Ether (50 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 54% yield) as an oil. The organic layer was separated washed with brine dried over sodium sulfate After removal of the solvent the residue was purified by chromatography (hexane:ethyl acetate, 3:1)

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

Procedure: To methyl pyrrolidine-3-carboxylate hydrochloride (4.00 g, 24.15 mmol) and K2CO3 (6.68 g, 48.3 mmol) in 1:1 THF-water (100 mL) was added benzyl carbonochloridate (3.57 mL, 25.36 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Ether (50 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate 3:1) to give 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 54% yield) as an oil. The organic layer was separated washed with brine dried over sodium sulfate After removal of the solvent the residue was purified by chromatography (hexane:ethyl acetate 3:1)

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

Procedure: To methyl pyrrolidine-3-carboxylate hydrochloride (4.00 g, 24.15 mmol) and K2CO3 (6.68 g, 48.3 mmol) in 1:1 THF-water (100 mL) was added benzyl carbonochloridate (3.57 mL, 25.36 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Ether (50 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate 3:1) to give 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 54% yield) as an oil. The organic layer was separated washed with brine dried over sodium sulfate After removal of the solvent the residue was purified by chromatography (hexane:ethyl acetate 3:1)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DIPEA (181 μL, 1.035 mmol) was added to a mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 36.1, 100 mg, 0.207 mmol), methyl-3-pyrrolidine carboxylate hydrochloride (44.5 mg, 0.269 mmol) and iPrOH (414 μL). in MW vial, which was flushed with argon, sealed and stirred at 130° C. for 24 h. The RM was diluted with EtOAc, treated with brine and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, n-heptane/EtOAc from 40% to 100% EtOAc) followed by preparative TLC (Silica gel, eluent EtOAc). Additional lyophilization from 1,4-dioxane afforded the title compound as a white light solid. UPLC-MS (Condition 6) tR=1.09 min, m/z=492.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.90-2.02 (m, 1H) 2.02-2.14 (m, 1H) 3.06-3.20 (m, 1H) 3.23-3.48 (m, 4H) 3.61 (s, 3H) 6.35-6.48 (m, 1H) 7.34 (d, J=8.78 Hz, 2H) 7.79-7.90 (m, 1H) 7.89 (d, J=8.80 Hz, 2H) 8.03-8.13 (m, 1H) 8.70-8.83 (m, 1H) 10.26 (s, 1H). in MW vial, which was flushed with argon sealed The RM was diluted with EtOAc treated with brine extracted with EtOAc The combined extracts were dried over Na2SO4 the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, n-heptane/EtOAc from 40% to 100% EtOAc)

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

Procedure: The title compound is prepared starting from diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (30 mg, 68 μmol) and rac-pyrrolidine-3-carboxylic acid methyl ester hydrochloride (56 mg, 340 μmol) in analogy to Example 203; LC-MS*: tR=0.76 min; [M+1]+=557.17; 1H NMR (D6-DMSO): δ 1.03 (t, J=7.0 Hz, 6H), 1.21 (t, J=7.5 Hz, 3H), 1.90-1.98 (m, 2H), 2.22 (s, 3H), 2.34 (s, 3H), 2.43-2.49 (m, 1H), 2.58 (q, J=7.0 Hz, 4H), 2.67-2.77 (m, 5H), 2.80-2.95 (m, 2H), 3.73 (s, 2H), 3.74-3.77 (m, 1H), 3.78-3.84 (m, 2H), 3.91-3.98 (m, 1H), 7.72 (s, 2H), 7.80 (s, 1H).

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

Procedure: A solution of 0.52 g (2.3 mmol) of (R/S)-1-benzyl-pyrrolidin-3-yl carboxylic acid, methyl ester (from Step A) in 5 mL of 1,2-dichloroethane was treated with 0.3 mL (2.7 mmol) of 1-chloroethyl chloroformate (ACE-Cl). The resulting mixture was stirred at rt for 3 h, then at reflux for 30 min. The reaction was cooled and concentrated. The residue was warmed to reflux in 5 mL of MeOH for 1 h. The reaction was cooled and concentrated. The crude product was used in Step C without further purification. at reflux for 30 min The reaction was cooled concentrated The residue was warmed to reflux in 5 mL of MeOH for 1 h The reaction was cooled concentrated The crude product was used in Step C without further purification

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

Procedure: A suspension of 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.21 g, 3.26 mmol) in DCL (25 mL) was slowly added to a solution of 3-(methoxycarbonyl)pyrrolidine hydrochloride (0.46 g, 3.58 mmol) and DIPLA (5.6 mL, 32.6 mmol) in DCE (80 mL). The reaction mixture was stirred for 3 h and the solvent was concentrated. The product was purified by MPLC on silica gel using EtOAc as eluent to provide the title compound as white solid. Yield: 0.60 g (39%); 1H NMR (400 MHz, CDCl3) δ 1.49-1.56 (m, 3 H), 1.55-1.58 (m, 1 H), 1.59 (s, 9 H), 1.93-2.13 (m, 2 H), 2.20-2.36 (m, 1 H), 2.89-3.01 (m, 1 H), 3.28-3.41 (m, 5 H), 3.60 (s, 3 H), 3.61-3.66 (m, 1 H), 3.94-4.06 (m, 2 H), 4.25 (d, J=7.42 Hz, 2 H), 7.44 (dd, J=8.50, 0.49 Hz, 1 H), 7.72 (dd, J=8.59, 1.76 Hz, 1 H), 8.24 (dd, J=1.76, 0.59 Hz, 1 H); MS (ESI) (M+H)+=464.0. the solvent was concentrated The product was purified by MPLC on silica gel

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (140 mg, 0.433 mmol), methylpyrrolidine-3-carboxylate hydrochloride (107.7 mg, 0.65 mmol), X-Phos (115 mg, 0.24 mmol) and Cs2CO3 (580 mg, 1.78 mmol) in 60 mL of dry dioxane was added Pd2(dba)3 (60 mg, 0.065 mmol) in one portion at room temperature under nitrogen. Then the reaction mixture was degassed by nitrogen for 15 minutes. The mixture was then stirred at 95° C. under nitrogen for 24 hours. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting a mixture of ethyl acetate and petroleum ether (2:1)) to give methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxylate (160 mg, 88.7%) as a yellow solid. LC-MS: 416.1 [M+H]+, tR=1.60 min. Then the reaction mixture was degassed by nitrogen for 15 minutes The solvent was evaporated at 40° C. at reduced pressure the residue was purified by silica gel chromatography (silica gel 200-300 mesh eluting a mixture of ethyl acetate and petroleum ether (2:1))

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

Procedure: Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (0.300 g, 0.801 mmol) and methylpyrrolidine-3-carboxylate hydrochloride (0.199 g, 1.20 mmol), according to Reference R and general procedure for reductive amination afforded the racemic mixture of methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylate. MS (ESI) m/z: Calculated: 487.2; Observed: 488.0 (M++1). The enantiomers of methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylate were separated by SFC chromatography (Column: Chiralpak AS-H (21×250 mm, 5 um); A: Liquid CO2; B: Isopropanol (0.2% DEA); Isocratic: 56:44 (A:B); Flow rate: 70 mL/min; Outlet Pressure: 100 bar) to give (R)-methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylate and (S)-methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylate. amination afforded The enantiomers of methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylate were separated by SFC chromatography (Column

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

Procedure: A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 0.30 g, 1.03 mmol), methyl pyrrolidine-3-carboxylate hydrochloride (0.21 g, 1.2 mmol), triethylamine (215 μL, 1.6 mmol), EDCI (0.19 g, 1.2 mmol) and HOBt (0.19 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 85:15 to 35:65) to give the title compound (0.35 g, 85%) as a pale yellow oil. extracted with ethyl acetate The extract was washed with saturated NaHCO3 solution and brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate 85:15 to 35:65)