1-(chloromethyl)-2-methoxynaphthalene

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)-8-cyano-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (65 mg, 127 μmol) in DMF (316 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (31.4 mg, 152 μmol), cesium carbonate (53.6 mg, 165 μmol), and sodium iodide (24.7 mg, 165 μmol). The reaction was stirred at rt for 1 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)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (75 mg, 87%) as a white solid. MS m/z 706 (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(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (406 mg, 1.28 mmol) in DMF (3.21 ml) was added 1-(chloromethyl)-2-methoxynaphthalene (318 mg, 1.54 mmol) and cesium carbonate (1.25 g, 3.85 mmol). 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(3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (448 mg, 72%) as an off-white solid. MS m/z 509 (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(S)-1-((2S,3S)-1-acetyl-8-cyano-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (53 mg, 120 μmol) in DMF (299 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (29.6 mg, 143 μmol), cesium carbonate (50.6 mg, 155 μmol), and sodium iodide (23.3 mg, 155 μmol). The reaction was stirred at rt for 1 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)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (60 mg, 82%) as a white solid. MS m/z 636 (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(S)-1-((2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (108 mg, 207 μmol) in DMF (518 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (47.1 mg, 228 μmol), cesium carbonate (81.0 mg, 248 μmol), and sodium iodide (37.2 mg, 248 μmol). The reaction was stirred at rt for 1.5 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 then reverse phase preparative HPLC to provide tert-butyl(S)-1-((3S,4S)-7-cyano-1-((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-ylamino)-1-oxopropan-2-yl(methyl)carbamate (55 mg, 38%) as a white solid. MS m/z 714 (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(S)-1-((2S,3S)-1-acetyl-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (72 mg, 172 μmol) in DMF (430 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (42.7 mg, 206 μmol), cesium carbonate (72.9 mg, 224 μmol), and sodium iodide (33.5 mg, 224 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-((2S,3S)-1-acetyl-5-((2-methoxynaphthalen-1-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (49.8 mg, 49%) as an off-white solid. MS m/z 611 (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 methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (141 mg, 284 μmol) in DMF (710 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (64.6 mg, 312 μmol), cesium carbonate (111 mg, 341 μmol), and sodium iodide (51.1 mg, 341 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-((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-ylamino)-1-oxopropan-2-yl(methyl)carbamate (151 mg, 80%) as a white solid. MS m/z 689 (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 room temperature solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (prepared as in Example RK-1, Step 3, 75 mg, 154 μmol) in N,N-dimethylformamide (500 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (38 mg, 184 μmol), cesium carbonate (65 mg, 200 μmol), and sodium iodide (30 mg, 200 μmol). The reaction was stirred at room temperature for 16 h. After this time, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL) the aqueous layer was then extracted with ethyl acetate (2×20 mL) and the organic layers combined and then washed with a saturated aqueous sodium chloride solution (30 mL), dried over magnesium sulfate, filtered, and the filterate concentrated in vacuo. The crude material was purified by flash chromatography to afford tert-butyl(S)-1-((3S,4S)-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (53 mg, 52%) as a light yellow foam: LC-MS m/z 681 [M+Na]+. To a room temperature washed with water (20 mL) the aqueous layer was then extracted with ethyl acetate (2×20 mL) washed with a saturated aqueous sodium chloride solution (30 mL) dried over magnesium sulfate filtered the filterate concentrated in vacuo The crude material was purified by flash chromatography