tert-butyl N-(pyrrolidin-2-ylmethyl)carbamate

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

Procedure: To a solution of 3,4-dichlorobenzene-1-sulfonyl chloride (490 mg, 2.00 mmol) was added tert-butyl pyrrolidin-2-ylmethylcarbamate (400 mg, 2.00 mmol), followed by triethylamine (0.278 mL, 2.00 mmol). The reaction was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with 1N HCl, H2O and brine, dried over Na2SO4 and decanted. The solvent was evaporated under reduced pressure and the crude product was purified on a 24 g silica gel cartridge using 0 to 100% EtOAc in hexane for 15 min, then 0 to 20% MeOH in DCM for 15 min to provide Intermediate 2A (800 mg, 1.95 mmol, 98% yield) as a white solid. HPLC/MS (Method D) RT=2.12 min, [M+1]+ 309.1. washed with 1N HCl, H2O and brine dried over Na2SO4 decanted The solvent was evaporated under reduced pressure the crude product was purified on a 24 g silica gel cartridge for 15 min

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

Procedure: To a solution of 3,4-dichlorobenzene-1-sulfonyl chloride (490 mg, 2.00 mmol) was added tert-butyl pyrrolidin-2-ylmethylcarbamate (400 mg, 2.00 mmol), followed by triethylamine (0.278 mL, 2.00 mmol). The reaction was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with 1N HCl, H2O and brine, dried over Na2SO4 and decanted. The solvent was evaporated under reduced pressure and the crude product was purified on a 24 g silica gel cartridge using 0 to 100% EtOAc in hexane for 15 min, then 0 to 20% MeOH in DCM for 15 min to provide Intermediate 2A (800 mg, 1.95 mmol, 98% yield) as a white solid. HPLC/MS (Method D) RT=2.12 min, [M+1]+ 309.1. washed with 1N HCl, H2O and brine dried over Na2SO4 decanted The solvent was evaporated under reduced pressure the crude product was purified on a 24 g silica gel cartridge for 15 min

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

Procedure: A mixture of 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step E, 0.050 g, 0.117 mmol), cesium carbonate (0.076 g, 0.235 mmol), tert-butyl (pyrrolidin-2-ylmethyl)carbamate (0.047 g, 0.235 mmol), Pd(OAc)2 (0.008 g, 0.035 mmol) and BINAP (0.022 g, 0.035 mmol) in toluene (2 mL) was heated at reflux overnight. The reaction mixture was cooled to ambient temperature, filtered and concentrated in vacuo to give crude tert-butyl ((1-(1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)pyrrolidin-2-yl)methyl)carbamate as brown solid, which was used for next step without further purification. was heated at reflux overnight filtered concentrated in vacuo

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

Procedure: A mixture of 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step E, 0.050 g, 0.117 mmol), cesium carbonate (0.076 g, 0.235 mmol), tert-butyl (pyrrolidin-2-ylmethyl)carbamate (0.047 g, 0.235 mmol), Pd(OAc)2 (0.008 g, 0.035 mmol) and BINAP (0.022 g, 0.035 mmol) in toluene (2 mL) was heated at reflux overnight. The reaction mixture was cooled to ambient temperature, filtered and concentrated in vacuo to give crude tert-butyl ((1-(1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)pyrrolidin-2-yl)methyl)carbamate as brown solid, which was used for next step without further purification. was heated at reflux overnight filtered concentrated in vacuo

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

Procedure: Six vials containing a solution of 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (325 mg, 1.67 mmol) in 12 mL ethanol added to tert-butyl(pyrrolidin-2-ylmethyl)carbamate (333 mg, 1.67 mmol) were prepared. The reaction mixtures were microwaved at 140° C. for 55 minutes. The solutions were combined and the solvents were removed in vacuo. The resulting residue was purified by HPLC to afford two diastereomers of tert-butyl({1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]pyrrolidin-2-yl}methyl)carbamate: were prepared The reaction mixtures were microwaved at 140° C. for 55 minutes the solvents were removed in vacuo The resulting residue was purified by HPLC

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

Procedure: Prepared analogously to Example 1g from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, TBTU, diisopropylethylamine, and rac.-2-tert-butoxycarbonylaminomethylpyrrolidine in DMF followed by treatment with trifluoroacetic acid analogously to Example 17. Yield: 47%; C21H21Cl2N5O2 (446.34); mass spectrum: (M+H)+=446/448/450 (chlorine isotope).

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

Procedure: Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl pyrrolidin-2-ylmethylcarbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 2.98 minutes; C21H21Cl2N5O2 (446.34); mass spectrum: (M+H)+=446.2. HPLC-MS results

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

Procedure: Prepared analogously to Example I d from 2-chloro-4-cyanobenzoic acid, TBTU, N,N-diisopropylethylamine, and rac.-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidine in tetrahydrofuran. Yield: quantitative; Rf value: 0.52 (silica gel; dichloromethane/ethanol=95:5); C18H22ClN3O3 (363.85); mass spectrum: (M+H)+=364/366 (chlorine isotope). Prepared analogously to Example I

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

Procedure: To a solution of 3,4-dichlorobenzene-1-sulfonyl chloride (490 mg, 2.00 mmol) was added tert-butyl pyrrolidin-2-ylmethylcarbamate (400 mg, 2.00 mmol), followed by triethylamine (0.278 mL, 2.00 mmol). The reaction was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with 1N HCl, H2O and brine, dried over Na2SO4 and decanted. The solvent was evaporated under reduced pressure and the crude product was purified on a 24 g silica gel cartridge using 0 to 100% EtOAc in hexane for 15 min, then 0 to 20% MeOH in DCM for 15 min to provide Intermediate 2A (800 mg, 1.95 mmol, 98% yield) as a white solid. HPLC/MS (Method D) RT=2.12 min, [M+1]+ 309.1. washed with 1N HCl, H2O and brine dried over Na2SO4 decanted The solvent was evaporated under reduced pressure the crude product was purified on a 24 g silica gel cartridge for 15 min

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

Procedure: A mixture of 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step E, 0.050 g, 0.117 mmol), cesium carbonate (0.076 g, 0.235 mmol), tert-butyl (pyrrolidin-2-ylmethyl)carbamate (0.047 g, 0.235 mmol), Pd(OAc)2 (0.008 g, 0.035 mmol) and BINAP (0.022 g, 0.035 mmol) in toluene (2 mL) was heated at reflux overnight. The reaction mixture was cooled to ambient temperature, filtered and concentrated in vacuo to give crude tert-butyl ((1-(1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)pyrrolidin-2-yl)methyl)carbamate as brown solid, which was used for next step without further purification. was heated at reflux overnight filtered concentrated in vacuo

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

Procedure: Six vials containing a solution of 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (325 mg, 1.67 mmol) in 12 mL ethanol added to tert-butyl(pyrrolidin-2-ylmethyl)carbamate (333 mg, 1.67 mmol) were prepared. The reaction mixtures were microwaved at 140° C. for 55 minutes. The solutions were combined and the solvents were removed in vacuo. The resulting residue was purified by HPLC to afford two diastereomers of tert-butyl({1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]pyrrolidin-2-yl}methyl)carbamate: were prepared The reaction mixtures were microwaved at 140° C. for 55 minutes the solvents were removed in vacuo The resulting residue was purified by HPLC