(1R)-1-cyclopropylethanol

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

Procedure: To a suspension of 4-iodophenylisocyanate (0.84 g, 3.5 mmol) in CH2Cl2 (6 mL) was added (R)-1-cyclopropylethanol (0.67 mL, 6.9 mmol). The solution was then directly subjected to silica gel chromatography (CH2Cl2) to provide (R)-(4-iodo-phenyl)carbamic acid 1-cyclopropyl-ethyl ester (1.05 g, 93%).

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

Procedure: To a solution of (1R)-1-cyclopropylethanol (130 mg) in toluene (3 mL) was added sodium hydride (120 mg), and the mixture was stirred under a nitrogen atmosphere at room temperature for 15 min. A mixture of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (415 mg), BINAP (41 mg), Pd2(dba)3 (28 mg) and toluene (3 ml) was added, and the mixture was stirred under an argon atmosphere at 100° C. for 3 hr. Water was added to the reaction solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give the title compound (329 mg, 67%) as a yellow oil. was added the mixture was stirred under an argon atmosphere at 100° C. for 3 hr the resultant product was extracted with ethyl acetate The organic layer was washed with water and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by basic silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane)

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

Procedure: To a suspension of 4-iodophenylisocyanate (0.84 g, 3.5 mmol) in CH2Cl2 (6 mL) was added (R)-1-cyclopropylethanol (0.67 mL, 6.9 mmol). The solution was then directly subjected to silica gel chromatography (CH2Cl2) to provide (R)-(4-iodo-phenyl)carbamic acid 1-cyclopropyl-ethyl ester (1.05 g, 93%).

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(6-amino-pyridin-3-yl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (115 mg, 0.3 mmol), 4-nitrophenylchloroformate (91 mg, 0.45 mmol) in pyridine (1.0 mL) was stirred at 30° C. for 2 h, followed by the addition of (R)-1-cyclopropylethanol (150 μL, 1.5 mmol). The mixture was stirred at 80° C. overnight and diluted with water (10 mL) and CH2Cl2 (5 mL). The organic layer was washed with water (3×5 mL), HCl (2N, 3×5 mL), sat. aq. NaHCO3 (3×5 mL) and and purified on silica gel (CH2Cl2/EtOAc, 1:9) to provide (R)-{4-[3-cyano-1-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester (25 mg, 17%). The mixture was stirred at 80° C. overnight The organic layer was washed with water (3×5 mL), HCl (2N, 3×5 mL), sat. aq. NaHCO3 (3×5 mL) purified on silica gel (CH2Cl2/EtOAc, 1:9)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2-(4-amino-phenyl)-1-cyclobutyl-6-ethylsulfanyl-1H-indole-3-carbonitrile (230.0 mg, 0.66 mmol) was combined with p-nitrophenyl chloroformate (266 mg, 1.32 mmol), DCE (3.0 mL), and pyridine (104.7 mg, 1.32 mmol) and stirred at room temperature for 2 h. (R)-1-Cyclopropylethanol (115.0, 1.34 mmol) was added and mixture was heated at 80° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with sat. aq. K2CO3 (2×15 mL), water, and brine. The organic layer was dried, concentrated and purified on silica gel (EtOAc/hexane 10%)) to provide (R)-[4-(3-cyano-1-cyclobutyl-6-ethylsulfanyl-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (209 mg, 69%) as a white solid. was added washed with sat. aq. K2CO3 (2×15 mL), water, and brine The organic layer was dried concentrated purified on silica gel (EtOAc/hexane 10%))

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

Procedure: 2-(4-Amino-phenyl)-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indole-3-carbonitrile (100 mg, 0.25 mmol) was combined with p-nitrophenyl chloroformate (120 mg, 0.6 mmol), DCE (1 mL), and pyridine (60 μL, 0.75 mmol) and stirred at room temperature for 1 h. To this mixture was added (R)-1-Cyclopropylethanol (90 μL, 0.92 mmol) and then heated at 80° C. for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with dilute aqueous NaOH solution. The organic layer was dried, concentrated and purified by silica gel chromatography (95:5 CH2Cl2/EtOAc) to provide (R)-[4-(3-cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (105 mg, 83%) as a white solid. heated at 80° C. for 2 h washed with dilute aqueous NaOH solution The organic layer was dried concentrated purified by silica gel chromatography (95:5 CH2Cl2/EtOAc)

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

Procedure: 2-(4-Amino-phenyl)-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indole-3-carbonitrile (100 mg, 0.25 mmol) was combined with p-nitrophenyl chloroformate (120 mg, 0.6 mmol), DCE (1 mL), and pyridine (60 μL, 0.75 mmol) and stirred at room temperature for 1 h. To this mixture was added (R)-1-Cyclopropylethanol (90 μL, 0.92 mmol) and then heated at 80° C. for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with dilute aqueous NaOH solution. The organic layer was dried, concentrated and purified by silica gel chromatography (95:5 CH2Cl2/EtOAc) to provide (R)-[4-(3-cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (105 mg, 83%) as a white solid. heated at 80° C. for 2 h washed with dilute aqueous NaOH solution The organic layer was dried concentrated purified by silica gel chromatography (95:5 CH2Cl2/EtOAc)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Amino-phenyl)-6-(2-chloro-ethoxy)-1-cyclobutyl-1H-indole-3-carbonitrile (800 mg, 2.19 mmol) was dissolved in phosgene in toluene (2M, 10 mL, 5.00 mmol) and stirred for 2 h at 80° C. in a sealed tube. Solvent was removed and the white solid obtained was suspended in 1 ml of DCE. To this solution was added (R)-1-cyclopropylethanol (400 uL, 5.28 mmol) and DMAP (268 mg, 2.19 mmol). Solution was stirred in a sealed tube for 16 h at room temperature. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether to generate 800 mg (77% yield) of {4-[6-(2-Chloro-ethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, as a white solid. Solvent was removed the white solid obtained Solution was stirred in a sealed tube for 16 h at room temperature extracted with EtOAc (2×100 mL) dried over MgSO4 concentrated Solid product was triturated with ether

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Amino-phenyl)-6-(2-chloro-ethoxy)-1-cyclobutyl-1H-indole-3-carbonitrile (800 mg, 2.19 mmol) was dissolved in phosgene in toluene (2M, 10 mL, 5.00 mmol) and stirred for 2 h at 80° C. in a sealed tube. Solvent was removed and the white solid obtained was suspended in 1 ml of DCE. To this solution was added (R)-1-cyclopropylethanol (400 uL, 5.28 mmol) and DMAP (268 mg, 2.19 mmol). Solution was stirred in a sealed tube for 16 h at room temperature. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether to generate 800 mg (77% yield) of {4-[6-(2-Chloro-ethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, as a white solid. Solvent was removed the white solid obtained Solution was stirred in a sealed tube for 16 h at room temperature extracted with EtOAc (2×100 mL) dried over MgSO4 concentrated Solid product was triturated with ether

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

Procedure: To a solution of (1R)-1-cyclopropylethanol (130 mg) in toluene (3 mL) was added sodium hydride (120 mg), and the mixture was stirred under a nitrogen atmosphere at room temperature for 15 min. A mixture of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (415 mg), BINAP (41 mg), Pd2(dba)3 (28 mg) and toluene (3 ml) was added, and the mixture was stirred under an argon atmosphere at 100° C. for 3 hr. Water was added to the reaction solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give the title compound (329 mg, 67%) as a yellow oil. was added the mixture was stirred under an argon atmosphere at 100° C. for 3 hr the resultant product was extracted with ethyl acetate The organic layer was washed with water and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by basic silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane)

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

Procedure: To a suspension of 4-iodophenylisocyanate (0.84 g, 3.5 mmol) in CH2Cl2 (6 mL) was added (R)-1-cyclopropylethanol (0.67 mL, 6.9 mmol). The solution was then directly subjected to silica gel chromatography (CH2Cl2) to provide (R)-(4-iodo-phenyl)carbamic acid 1-cyclopropyl-ethyl ester (1.05 g, 93%).

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

Procedure: To a solution of (1R)-1-cyclopropylethanol (130 mg) in toluene (3 mL) was added sodium hydride (120 mg), and the mixture was stirred under a nitrogen atmosphere at room temperature for 15 min. A mixture of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (415 mg), BINAP (41 mg), Pd2(dba)3 (28 mg) and toluene (3 mL) was added, and the mixture was stirred under an argon atmosphere at 100° C. for 3 hr. Water was added to the reaction solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give the title compound (329 mg, 67%) as a yellow oil. was added the mixture was stirred under an argon atmosphere at 100° C. for 3 hr the resultant product was extracted with ethyl acetate The organic layer was washed with water and saturated brine dried the solvent was evaporated under reduced pressure The residue was purified by basic silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane)