2-N-(4-chlorophenyl)benzene-1,2-diamine

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

Procedure: The solid from step B was added to a solution of 1,3-difluoro-4,6-dinitrobenzene (46 g) in methanol (200 mL), then triethylamine (31.4 mL) was added, and stirred at rt for 4 h. The reaction mixture was filtered, and the cake was washed with methanol to give 80.6 g of red solid. The reaction mixture was filtered the cake was washed with methanol

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

Procedure: To a solution of 2-(4-chloroanilino)-nitrobenzene (57.0 g) in CH2Cl2 (40 mL) was added AcOH (90 mL), then Zn powder (105 g) was added in small portions. After Zn powder was added, the color of the mixture became light green, filtered by suction, washed with CH2Cl2. The filtrate was concentrated to dryness. Water was added, filtered, and washed with water to give a brown solid. This solid was used directly in the next step without further purification. filtered by suction washed with CH2Cl2 The filtrate was concentrated to dryness Water was added filtered washed with water to give a brown solid This solid was used directly in the next step without further purification

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

Procedure: The solid from step B was added to a solution of 1,3-difluoro-4,6-dinitrobenzene (46 g) in methanol (200 L), then triethylamine (31.4 mL) was added, and stirred at rt for 4 h. The reaction mixture was filtered, and the cake was washed with methanol to give 80.6 g of red solid. The reaction mixture was filtered the cake was washed with methanol

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

Procedure: To a solution of 2-(4-chloroanilino)-nitrobenzene (57.0 g) in CH2Cl2 (40 mL) was added AcOH (90 mL), then Zn (105 g) was added in small portions. After Zn was added, the color of the mixture became light green, filtered by suction, washed with CH2Cl2. The filtrate was concentrated to dryness. Water was added, filtered, and washed with water to give a brown solid. This solid was used directly in the next step without further purification. filtered by suction washed with CH2Cl2 The filtrate was concentrated to dryness Water was added filtered washed with water to give a brown solid This solid was used directly in the next step without further purification

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

Procedure: To a solution of N-(4-chlorophenyl)benzene-1,2-diamine (12.0 g) in a minimum quantity of ether was added benzoylformic acid (7.5 g) dissolved in ether and the mixture was stirred for 8 hours. The resulting precipitate was filtered, dried, and recrystallised from ethanol giving the title compound (11.0 g) mp 214.5°-216.5° C. The resulting precipitate was filtered dried recrystallised from ethanol giving the title compound (11.0 g) mp 214.5°-216.5° C.

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

Procedure: To a solution of N-(4-chlorophenyl)benzene-1,2-diamine (12.0 g) in a minimum quantity of ether was added benzoylformic acid (7.5 g) dissolved in ether and the mixture was stirred for 8 hours. The resulting precipitate was filtered, dried, and recrystallised from ethanol giving the title compound (11.0 g) mp 214.5°-216.5° C. The resulting precipitate was filtered dried recrystallised from ethanol giving the title compound (11.0 g) mp 214.5°-216.5° C.

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

Procedure: N-(4-Chlorophenyl)benzene-1,2-diamine (11.2 g) was added to diethyl oxalate (50 ml) and the mixture heated under reflux for 2 hours. The mixture was cooled and ethanol (40 ml) was added. The precipitated solid was filtered off and recrystallised from ethanol giving the title compound (11.2 g) mp>300° C. the mixture heated under reflux for 2 hours The mixture was cooled The precipitated solid was filtered off recrystallised from ethanol giving the title compound (11.2 g) mp>300° C.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2,2-bis(chlorocarbonyl)cyclopropanecarboxylate (2 g, crude product from last step) in dichloromethane (10 mL) was added dropwise to a solution of N1-(4-chlorophenyl)benzene-1,2-diamine (2.2 g, 10 mmol) in toluene (50 mL) and the resulting mixture was heated to 100° C. for 48 h. The solvent was evaporated and the residue was purified by CombiFlash (PE:EA=5:1) to obtained ethyl 1-(4-chlorophenyl)-2,4-dioxo-1,2,4,5-tetrahydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2′-carboxylate (500 mg, 13%). LRMS (M+H)+: 384 m/z. 1H NMR (300 MHz, CDCl3): δ 1.07-1.12 (t, J=7.2 Hz, 3H), 1.72-1.81 (m, 1H), 2.16-2.18 (m, 1H), 2.41-2.43 (br, 1H), 3.92-4.00 (m, 2H), 7.20-7.25 (m, 1H), 7.42-7.49 (m, 4H), 7.52-7.65 (m, 3H), 8.06-8.08 (m, 1H). The solvent was evaporated the residue was purified by CombiFlash (PE:EA=5:1)

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

Procedure: To a stirred refluxing solution of N1-(4-chlorophenyl)benzene-1,2-diamine (200 mg, 0.92 mmol) in toluene (20 mL) was added drop-wise a solution of 2,2-dimethylmalonyl dichloride (155 mg, 0.92 mmol). Then the mixture was refluxed for 1 h. The solvent was removed in vacuum, stirred with water (20 mL), extracted with DCM (20 mL×3). The combined organic layer was dried over Na2SO4. The mixture was concentrated in vacuum and the residue was purified by column chromatography (silica-gel, DCM: methanol=40:1) to give 1-(4-chlorophenyl)-3,3-dimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione as a yellow solid (167.5 mg, 58%). LRMS (M+H+) m/z: calcd 314.08. found 314. Then the mixture was refluxed for 1 h The solvent was removed in vacuum extracted with DCM (20 mL×3) The combined organic layer was dried over Na2SO4 The mixture was concentrated in vacuum the residue was purified by column chromatography (silica-gel, DCM: methanol=40:1)

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

Procedure: To a stirred refluxing solution of N1-(4-chlorophenyl)benzene-1,2-diamine (100.0 mg, 0.46 mmol) in toluene (20 mL) was added dropwise a solution of malonyl dichloride (65.00 mg, 0.46 mmol). After addition was completed, the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo, the mixture was stirred with water (20 mL), extracted with DCM (10 mL*3), and then was purified by Prep-TLC (DCM:MeOH=30:1) to give 1-(4-chlorophenyl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (80.00 mg, 60%) as a white solid. LRMS (M+H+) m/z: calcd 286.05. found 286. After addition the reaction mixture was refluxed for 1 h The solvent was removed in vacuo extracted with DCM (10 mL*3) was purified by Prep-TLC (DCM:MeOH=30:1)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of EtOH (100 ml) and NH4Cl saturated solution (15 ml), N-(4-chlorophenyl)-2-nitrobenzenamine (5.0 g, 20.1 mmol) was added, followed by iron powder (4.0 g). The reaction mixture was heated at 70° C. for 2 h. The solid was filtered and the filtrate was extracted by EA (100 mL×3), dried over Na2SO4. After the solvent was removed, the mixture was purified by Combi-flash (PE:EA=5:1) to give N1-(4-chlorophenyl)benzene-1,2-diamine (4.1 g, 93.2%) as a light yellow solid. LRMS (M+H+) m/z: calcd 218.06. found 218. 1H NMR (300 MHz, CD3OD): δ 6.52-6.59 (m, 3H), 6.70-6.74 (m, 1H), 6.81-6.87 (m, 1H), 6.90-6.99 (m, 3H). was added The solid was filtered the filtrate was extracted by EA (100 mL×3) dried over Na2SO4 After the solvent was removed the mixture was purified by Combi-flash (PE:EA=5:1)

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

Procedure: The solid from step B was added to a solution of 1,3-difluoro-4,6-dinitrobenzene (46 g) in methanol (200 mL), then triethylamine (31.4 mL) was added, and stirred at rt for 4 h. The reaction mixture was filtered, and the cake was washed with methanol to give 80.6 g of red solid. The reaction mixture was filtered the cake was washed with methanol