3-iodobenzohydrazide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a schlenck tube, a mixture of 3-iodobenzohydrazide (510 mg, 1.95 mmol) and 1,1,1-triethoxyethane (1.14 ml, 6.23 mmol) in acetic acid (15 ml) was heated at 150° C. for 3 h. The solvent was evaporated and the crude redissolved in ethyl acetate and washed with 4% solution of NaHCO3, water and brine. The organic layer was dried, filtered and concentrated under vacuum to give the title compound as a white solid (92% yield). The solvent was evaporated the crude redissolved in ethyl acetate washed with 4% solution of NaHCO3, water and brine The organic layer was dried filtered concentrated under vacuum

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a schlenck tube, a mixture of 3-iodobenzohydrazide (510 mg, 1.95 mmol) and 1,1,1-triethoxyethane (1.14 ml, 6.23 mmol) in acetic acid (15 ml) was heated at 150° C. for 3 h. The solvent was evaporated and the crude redissolved in ethyl acetate and washed with 4% solution of NaHCO3, water and brine. The organic layer was dried, filtered and concentrated under vacuum to give the title compound as a white solid (92% yield). The solvent was evaporated the crude redissolved in ethyl acetate washed with 4% solution of NaHCO3, water and brine The organic layer was dried filtered concentrated under vacuum

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

Procedure: To a solution of 3-iodobenzohydrazide (10.0 g, 38.16 mmol) in dry THF/DMF (100.0 ml:10.0 ml) was slowly added 3-methoxybenzoyl chloride (7.0 g, 42.03 mmol) at 0° C. under nitrogen. During addition of 3-methoxybenzoyl chloride, white solid was appeared. After addition of 3-methoxybenzoyl chloride, the reaction was allowed to warm up to room temperature. The reaction mixture was stirred for 19 hours at room temperature and then pyridine (20.0 ml) was added and stirred for additional 45 min. Water (300.0 ml) was added to reaction mixture. The white solid was obtained and collected by filtration and washed with water. After dried under vacuum, product was obtained as white powder in 12.4 g (82.0%). 1H NMR (400 MHz, DMSO-d6, δ): 10.62 (s, 1H, NH), 10.56 (s, 1H, NH), 8.25 (t, J=1.6 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), (dd, J1=8.0 Hz, J2=2.4 Hz, 1H), 3.81 (s, 3H, OCH3). at 0° C. stirred for additional 45 min The white solid was obtained collected by filtration washed with water After dried under vacuum product was obtained as white powder in 12.4 g (82.0%)

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

Procedure: To Methyl 3-iodobenzoate (25.0 g, 95.41 mmol) in ethanol (120.0 ml) was added hydrazine hydrate (50.0 ml). The reaction mixture was reflux for 18 hours. Heating was stopped and then water (300.0 ml) was added. After cooling down to room temperature, white solid was appeared. The white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white pure product was obtained in 23.0 g (92.0%). 1H NMR (400 MHz, DMSO-d6, δ): 9.85 (s, br, 1H, NH), 8.14 (t, J=1.6 Hz, 1H), 7.85 (m, 1H), 7.82 (m, 1H), 7.25 (t, J=8.0 Hz, 1H), 4.50 (s, 2H, NH2). 13C NMR (100 MHz, CDCl3) δ: 168.54, 155.38, 129.54, 126.72, 125.57, 34.90, 31.07. The reaction mixture was reflux for 18 hours Heating The white product solid was collected by filtration The product was washed with water dried under vacuum Final white pure product was obtained in 23.0 g (92.0%)

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

Procedure: 3-Iodobenzohydrazide (1.00 g, 3.82 mmol) obtained in Step 1 of Example 52 was dissolved in THF (19 mL), and the mixture was stirred at room temperature for 1 hour after adding 1,1′-carbonyldiimidazole (681 mg, 4.18 mmol). The mixture was stirred after adding 6 mol/L hydrochloric acid (20 mL) and water (20 mL), and the precipitated solid was filtered off and dried to give 5-(3-iodophenyl)-1,3,4-oxadiazol-2(3H)-one (779 mg, 71%). The mixture was stirred the precipitated solid was filtered off dried

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

Procedure: 3-Iodobenzohydrazide (500 mg, 1.91 mmol) obtained in Step 1 of Example 52 was suspended in toluene (10 mL), and the mixture was refluxed for 1 hour after adding Lawesson's reagent (772 mg, 1.91 mmol). The mixture was then purified by silica gel column chromatography to give 3-iodothiobenzohydrazide (391 mg, 74%). the mixture was refluxed for 1 hour The mixture was then purified by silica gel column chromatography

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

Procedure: N-Methylacetamide (0.087 mL, 1.14 mmol) and 2,6-lutidine (0.266 mL, 2.28 mL) were dissolved in dichloromethane (5.7 mL), and the mixture was stirred for 40 minutes after adding oxalyl chloride (0.100 mL, 1.14 mL) at 0° C. The mixture was stirred for 5 hours after adding 3-iodobenzohydrazide (300 mg, 1.14 mmol) obtained in Step 1 of Example 52, and then at 100° C. for 3 hours after adding a saturated aqueous sodium bicarbonate solution (5.7 mL). After cooling, water and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 3-(3-iodophenyl)-4,5-dimethyl-1,2,4-triazole as a crude purified product (250 mg). The resulting crude purified product (250 mg) of 3-(3-iodophenyl)-4,5-dimethyl-1,2,4-triazole, (S)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (376 mg, 1.50 mmol)) obtained in Reference Example 3, copper iodide(I) (142 mg, 0.750 mmol), and tripotassium phosphate (532 mg, 2.51 mmol) were dissolved in 1,4-dioxane (4.6 mL), and the mixture was stirred at 100° C. for 10 hours after adding ethylenediamine (0.10 mL, 1.50 mmol). Insolubles were filtered through sellite, and the residue was washed with chloroform. The filtrate was collected, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-5-[3-(4,5-dimethyl-1,2,4-triazol-3-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (74.2 mg, 15%). The mixture was stirred for 5 hours After cooling to separate the organic layer The organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The resulting residue was then purified by silica gel column chromatography

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

Procedure: 3-Iodobenzohydrazide (500 mg, 1.91 mmol) obtained in Step 1 was dissolved in DMF (3.8 mL), and the mixture was stirred at room temperature for 10.5 hours after adding pyridine (0.231 mL, 2.86 mmol) and propionyl chloride (0.183 mL, 2.10 mmol) at 0° C. Water was added to the mixture, stirred, and the precipitated solid was filtered off and dried to give 3-iodo-N′-propionylbenzohydrazide (400 mg, 66%). stirred the precipitated solid was filtered off dried

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

Procedure: Commercially available 3-iodobenzoic acid (7.41 g, 29.9 mmol) was dissolved in THF (121 mL), and the mixture was stirred at room temperature for 45 minutes after adding 1,1′-carbonyldiimidazole (5.33 g, 32.9 mmol). The mixture was further stirred at room temperature for 2 hours after adding hydrazine.monohydrate (5.3 mL, 109 mmol). The mixture was then concentrated under reduced pressure, and recrystallized from methanol and water to give 3-iodobenzohydrazide (6.08 g, 78%). The mixture was further stirred at room temperature for 2 hours The mixture was then concentrated under reduced pressure recrystallized from methanol and water