6-bromo-1-(chloromethyl)-2-methoxynaphthalene

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

Procedure: A mixture of (S)-tert-butyl 4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (389 mg, 1.12 mmol), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (481 mg, 1.68 mmol), NaI (253 mg, 1.68 mmol) and Cs2CO3 (549 mg, 1.68 mmol) in DMF (15.6 mL) was stirred at RT for 6 h and diluted with EtOAc. The mixture was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated to give a residue that was purified by silica gel chromatography to afford (S)-tert-butyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (321 mg, 48%) as a colorless waxy solid. MS m/z 617/619 (MNa)+ The mixture was washed with brine dried over Na2SO4 filtered the filtrate concentrated to give a residue that was purified by silica gel chromatography

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

Procedure: A mixture of (S)-tert-butyl 4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (389 mg, 1.12 mmol), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (481 mg, 1.68 mmol), NaI (253 mg, 1.68 mmol) and Cs2CO3 (549 mg, 1.68 mmol) in DMF (15.6 mL) was stirred at RT for 6 h and diluted with EtOAc. The mixture was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated to give a residue that was purified by silica gel chromatography to afford (S)-tert-butyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (321 mg, 48%) as a colorless waxy solid. MS m/z 617/619 (MNa)+ The mixture was washed with brine dried over Na2SO4 filtered the filtrate concentrated to give a residue that was purified by silica gel chromatography

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

Procedure: A mixture of (S)-tert-butyl 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.412 g, 5.07 mmol), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (1.59 g, 5.58 mmol), Cs2CO3 (1.98 g, 6.09 mmol), and NaI (913 mg, 6.09 mmol) in DMF (16.9 mL) was stirred at RT for 22 h, diluted with H2O and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and. The filtrate was concentrated to give a residue that was purified by silica gel chromatography to give (S)-tert-butyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.804 g, 67%) as an off-white solid. MS m/z 549/551 (MNa)+ extracted with EtOAc The combined extracts were washed with brine dried over Na2SO4 The filtrate was concentrated to give a residue that was purified by silica gel chromatography

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

Procedure: A mixture of methyl-[(S)-1-((S)-3-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (241 mg, 639 μmol, Eq: 1.00), NaI (95.7 mg, 639 μmol, Eq: 1.00), Cs2CO3 (312 mg, 958 μmol, Eq: 1.50), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (219 mg, 766 μmol, Eq: 1.20) in DMF (3 mL) was stirred at RT for 1 h and at 50° C. for 1 h. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated. The resulting material was purified by silica gel chromatography to afford {(S)-1-[(S)-9-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-3-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (63 mg, 16%) as an oil. washed with water, brine dried over Na2SO4 filtered concentrated The resulting material was purified by silica gel chromatography

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

Procedure: A mixture of tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate (1.1 g, 3.03 mmol, Eq: 1.00) (Example 1), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (951 mg, 3.33 mmol, Eq: 1.10), Cs2CO3 (1.08 g, 3.33 mmol, Eq: 1.10), and NaI (499 mg, 3.33 mmol, Eq: 1.1) in DMF (20 mL) was stirred for 3.5 at RT then heated at 50° C. for 1 h then at 60° C. for 30 min. The mixture was cooled, diluted with EtOAc, washed with water and brine. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (1.00 g, 1.63 mmol, 53.9%) as a light yellow foam. then heated at 50° C. for 1 h The mixture was cooled washed with water and brine The organic solution was dried over Na2SO4 concentrated The residue was purified by silica gel chromatography

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

Procedure: To a rt solution of tert-butyl(S)-1-((2S,3S)-1-(3-methoxypropanoyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (46 mg, 99.5 μmol) in DMF (249 μl) was added 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (34.1 mg, 119 μmol), cesium carbonate (42.1 mg, 129 μmol), and sodium iodide (19.4 mg, 129 μmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-5-(3-methoxypropanoyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (52.4 mg, 74%) as a white solid. MS m/z 733/735 (MNa)+. washed with H2O and sat. aq. NaCl dried over Na2SO4 filtered concentrated The crude material was purified by flash chromatography

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

Procedure: To a rt solution of tert-butyl(2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (60.3 mg, 147 μmol) in DMF (366 μl) was added 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (50.2 mg, 176 μmol), cesium carbonate (62.1 mg, 191 μmol), and sodium iodide (28.6 mg, 191 μmol). The reaction was stirred at rt for 4 h, then diluted with EtOAc (30 mL), washed with H2O (30 mL) and sat. aq. NaCl (30 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (75 mg, 78% yield) as a white solid. MS m/z 682/684 (MNa)+ washed with H2O (30 mL) and sat. aq. NaCl (30 mL) dried over Na2SO4 filtered concentrated The crude material was purified by flash chromatography

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

Procedure: tert-Butyl N-[(3S)-5-[4-[(3S)-3-(tert-butoxycarbonylamino)-2-oxo-3,4-dihydro-1H-1,5-benzodiazepine-5-carbonyl]benzoyl]-2-oxo-3,4-dihydro-1H-1,5-benzodiazepin-3-yl]carbamate (27.6 mg, 0.0403 mmol), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (25.3 mg, 0.0887 mmol), and cesium carbonate (39.4 mg, 0.121 mmol) where combined in DMF (2 mL) and stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate, washed with water, brine and dried over anhydrous magnesium sulfate. Concentration gave an oil that was chromatographed over silica gel to give tert-butyl N-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-1-[4-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-(tert-butoxycarbonylamino)-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]benzoyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]carbamate (31 mg, 65%) as a white foam. washed with water, brine dried over anhydrous magnesium sulfate Concentration gave an oil that was chromatographed over silica gel

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

Procedure: To a solution of ((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (Intermediate 2) (6.5 g, 23.48 mmol) in THF (100 mL) at −78° C. was added 1 M LiHMDS (4.7 g, 28 mL, 28 mmol). The cooling bath was removed and the mixture stirred at RT for 1 h. The mixture was cooled to −78° C. and a mixture of 6-bromo-1-chloromethyl-2-methoxy-naphthalene (8.0 g, 28.12 mmol) and NaI (4.2 g, 28.12 mmol) in dry THF (30 mL) was added dropwise. The cooling bath was removed and the mixture stirred at RT for 18 h. The mixture was diluted with saturated NH4Cl, extracted with ethyl acetate and the organic layer washed with water, brine, dried (Na2SO4) and concentrated to give a material which was purified by silica gel chromatography to afford the title compound (9 g, 72%) as a yellow solid. LC-MS: 528.0 (M+H). The cooling bath was removed The mixture was cooled to −78° C. was added dropwise The cooling bath was removed the mixture stirred at RT for 18 h The mixture was diluted with saturated NH4Cl extracted with ethyl acetate the organic layer washed with water, brine dried (Na2SO4) concentrated to give a material which was purified by silica gel chromatography

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

Procedure: A mixture of (S)-tert-butyl 4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (389 mg, 1.12 mmol), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (481 mg, 1.68 mmol), NaI (253 mg, 1.68 mmol) and Cs2CO3 (549 mg, 1.68 mmol) in DMF (15.6 mL) was stirred at RT for 6 h and diluted with EtOAc. The mixture was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated to give a residue that was purified by silica gel chromatography to afford (S)-tert-butyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (321 mg, 48%) as a colorless waxy solid. MS m/z 617/619 (MNa)+ The mixture was washed with brine dried over Na2SO4 filtered the filtrate concentrated to give a residue that was purified by silica gel chromatography

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

Procedure: A mixture of (S)-tert-butyl 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.412 g, 5.07 mmol), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (1.59 g, 5.58 mmol), Cs2CO3 (1.98 g, 6.09 mmol), and NaI (913 mg, 6.09 mmol) in DMF (16.9 mL) was stirred at RT for 22 h, diluted with H2O and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and. The filtrate was concentrated to give a residue that was purified by silica gel chromatography to give (S)-tert-butyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.804 g, 67%) as an off-white solid. MS m/z 549/551 (MNa)+ extracted with EtOAc The combined extracts were washed with brine dried over Na2SO4 The filtrate was concentrated to give a residue that was purified by silica gel chromatography

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

Procedure: A mixture of methyl-[(S)-1-((S)-3-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (241 mg, 639 μmol, Eq: 1.00), NaI (95.7 mg, 639 μmol, Eq: 1.00), Cs2CO3 (312 mg, 958 μmol, Eq: 1.50), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (219 mg, 766 μmol, Eq: 1.20) in DMF (3 mL) was stirred at RT for 1 h and at 50° C. for 1 h. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated. The resulting material was purified by silica gel chromatography to afford {(S)-1-[(S)-9-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-3-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (63 mg, 16%) as an oil. washed with water, brine dried over Na2SO4 filtered concentrated The resulting material was purified by silica gel chromatography