Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[C:37]([N+]([O-])=O)[CH2:38][CH:39]2[O:43][CH2:42][CH2:41][O:40]2)=[CH:32][CH:31]=1>CN(C=O)C>[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][C:19]1[C:37]([CH2:38][CH:39]2[O:43][CH2:42][CH2:41][O:40]2)=[C:36]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=2)[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])C(=Cc1ccc(F)cc1)CC1OCCO1
Reactant: CC(C)NN
Reactant: O=CCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of isopropylhydrazine hydrochloride (0.53 g, 4.8 mmol), (3-oxo-propyl)-carbamic acid benzyl ester (1.0 g, 4.8 mmol), and Et3N (1.94 g, 192 mmol) in DMF (20 mL) was stirred at rt for 18 h. The solution was treated with 2-[3-(4-fluoro-phenyl)-2-nitro-allyl]-[1,3]dioxolane (1.02 g, 3.95 mmol) and stirred at 60° C. for 18 h. The mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), and concentrated. Purification by FCC gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.[CH3:16][N:17]([CH2:19][CH2:20]Cl)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:16][N:17]([CH3:18])[CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.60 mmol), (N,N-dimethylamino)ethyl chloride hydrochloride (412 mg, 2.86 mmol) and potassium carbonate (1.07 g, 7.74 mmol) in 8 mL DMF was stirred at room temperature for 48 hours. Additional (N,N-dimethylamino)ethyl chloride hydrochloride (187 mg, 1.30 mmol) and potassium carbonate (359 mg, 2.60 mmol). Reaction was stirred for an additional 16 hours. After this time, the reaction was transferred to a separatory funnel and diluted with cold water and ethyl acetate. The aqueous was extracted twice more with ethyl acetate and the combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a yellow solid. Yield: 370 mg (54%). 1H NMR (CDCl3) δ: 8.15 (dd, J=2.7, 9.0 Hz, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.17 (d, J=9 Hz, 1H), 4.09 (t, J=7.2 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.32 (s, 6H). MS (ESI): 264.1 (M+1).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([F:13])[C:9](F)=[N:10][CH:11]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl-].[Na+]>O.C1COCC1.CN(C=O)C>[C:1]([NH:4][C:9]1[C:8]([F:13])=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: Fc1cc(Cl)cnc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ncc(Cl)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
Under a nitrogen atmosphere, DMF (14 mL) and THF (44 mL) were added to acetamide (6.6 g, 112 mmol), and the mixture was warmed to 50° C. A 1.9 M sodium hexamethyldisilazide THF solution (51 mL, 96 mmol) was added dropwise thereto, and the mixture was stirred for 3 hours at the same temperature. 5-Chloro-2,3-difluoropyridine (7.0 g) was then added, THF (1.4 mL) was further added, and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was cooled to 0° C., an aqueous solution of citric acid monohydrate (20 g) and sodium chloride (4.9 g) in water (35 mL) was added, the mixture was warmed to room temperature, and the organic layer was separated. The organic layer was washed with a 20 wt % sodium chloride aqueous solution (35 mL), and the solvent was distilled off under reduced pressure. A mixed solvent (70 mL) of heptane and tert-butyl methyl ether (15:1) and water (35 mL) were added to the residue, and the mixture was stirred for 10 minutes at room temperature. The mixture was filtered, and the obtained solid was washed twice with water (35 mL). It was further washed with a mixed solvent (70 mL) of heptane and tert-butyl methyl ether (15:1), and dried under reduced pressure to obtain the title compound (6.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester (6.0 g) in DMF (45 ml), sodium hydride (60% in oil, 0.85 g) was added, and then the reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C., and then benzyl bromide (2.64 ml) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and then sequentially washed with an aqueous 10% citric acid solution, water and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain 3-benzyl-4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester as colorless crystals (7.19 g, 90%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccc(C=O)cc2)CC1
Yield: 91.2 %

Procedure:
A mixture of 4-fluorobenzaldehyde (10 gm, 0.08 moles) and N-methylpiperazine (14 gm, 0.14 moles) in water (80 mL) containing sodium carbonate (12.7 gm, 0.12 moles) was stirred and refluxed for 21 hours. After cooling, the mixture was poured into a separatory funnel containing water (200 mL) and the oily product was extracted into methylene chloride (3×50 mL). The combined extracts were washed with water and were then stripped under vacuum. The product, which was isolated as an oil, solidified into a tan solid upon cooling. The solid product was triturated in hexane and isolated by filtration. After drying, there was obtained 14.9 gm (91%) of N-(4-formylphenyl)-N′-methylpiperazine as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CC(C)([O-])C.[K+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=1>CN(C=O)C.O>[CH3:18][N:15]1[C:16]([CH3:17])=[C:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=3)=[C:2]([F:1])[CH:3]=2)=[O:11])[C:13](=[O:25])[N:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(C(=O)Nc2ccc(O)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.6 %

Procedure:
To a solution of N-(3-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (7.18 g, 21.1 mmol) in DMF (200 mL) was added potassium tert-butoxide (7.08 g, 63.2 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (4.27 g, 25.2 mmol). The reaction was heated at 120° C. for 3 hours, then cocentrated to 2 mL in vacuo, and diluted with water (60 mL). The precipitate was obtained by filtration, and then washed with water (10 mL). The crude product was purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v/v)=1/1/0.05) to give the title compound as a yellow solid (4.15 g, 43% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[Cl:24][C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1OC(C)=O

Procedure:
700 mg of 3-acetoxy-4-methoxy-benzoic acid were suspended in 6 ml of anhydrous DCM and 24 μl of DMF were added. Then 5.0 ml of a 2 M solution of oxalyl chloride in DCM were added dropwise. The mixture was stirred until the evolution of gas had ceased (about 30 min). The volatiles were removed in vacuo, the residue was dissolved in 10 ml of DCM and evaporated to yield 750 mg of the title compound which was used in the subsequent step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].CO.O>C(O)(=O)C>[CH:4]1[C:5](/[CH:6]=[C:14]2\[C:13]([NH:12][C:11]([S:10]\2)=[O:16])=[O:15])=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NC(=O)/C(=C\c2ccc(O)cc2)S1

Procedure:
A mixture of 4-hydroxy benzaldehyde, 53 (3 g, 24.6 mmol), 2,4-thiazolidinedione, 54 (2.9 g, 24.8 mmol), pipieridine (2.5 mL) and methanol (100 mL) was refluxed for 18 h. The reaction mixture was poured into water and acidified with acetic acid to give 55, which was recrystallised from methanol. Yield 4.7 g (86%); mp 296-298° C.; MS (FAB) 222 (M++1); IR (KBr) 3404, 3123, 1723, 1678; 1H NMR (200 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.46 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].N1CCCCC1>C(O)C>[CH:4]1[C:5](/[CH:6]=[C:14]2\[C:13]([NH:12][C:11]([S:10]\2)=[O:16])=[O:15])=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C\c2ccc(O)cc2)S1

Procedure:
4-(Thiazolidin-2,4-dione-5-ylidinemethyl)-phenol (55) was synthesized by the condensation of 4-hydroxy benzaldehyde (53) with commercially available 2,4-thiazolidinedione (54) using piperidine as base in refluxing ethanol, according to a known procedure (Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sohda, T. Chem. Pharm. Bull. 1991, 39, 1440.) (Scheme 5).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[NH:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(Cl)(Cl)Cl>[CH:8]1[CH:9]=[C:10]2[C:5](=[C:6]([S:11]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21]3)(=[O:13])=[O:12])[CH:7]=1)[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: C1CNCCNC1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cccc2cnccc12)N1CCCNCC1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
40 liters of a chloroform solution containing 5.0 kg of 5-isoquinolinesulfonyl chloride was added dropwise to 40 liters of a chloroform solution containing 8.8 kg of homopiperazine over 1 hour while cooling with ice, to obtain a mixture. Subsequently, the obtained mixture was stirred for 1 hour while cooling with ice, to effect a reaction and then the resultant reaction mixture was subjected to extraction with a 2N aqueous solution of HCl, followed by separation of an aqueous phase. The aqueous phase was adjusted to a pH value of 10 with a 10% aqueous solution of NaOH to thereby obtain a solution having a pH value of 10. The obtained solution was subjected to extraction with 80 liters of chloroform, followed by separation of a chloroform phase. The resultant chloroform phase was washed with water and then dried over anhydrous sodium sulfate, and subsequently, the solvent was removed by distillation under reduced pressure to obtain a residue. The obtained residue was subjected to column chromatography using 150 kg of silica gel (Wakogel C-200, manufactured and sold by Wako Pure Chemical Industries, Ltd., Japan) and a mixed solvent of methanol and chloroform (5 v/v % methanol) as a developing solvent, and purified to obtain 6.01 kg of fasudil (yield 89%). The results of elemental analysis of fasudil: found (calculated) C: 57.59 (57.71), H: 5.92 (5.88), N: 14.29 (14.42), S: 10.83 (11.00) (wt %)
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:13]([O-])=O)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:13])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2nc(O)c(O)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1cccc2nc(O)c(O)nc12

Procedure:
2.0 g of 2,3-dihydroxy-5-nitroquinoxaline was dissolved in 100 g of a 1:1 methanol and dioxane solvent, after which the reaction system was well purged with argon, followed by further addition of 1 g of 5% Pd/C (hydrous). Thereafter, the system was purged with hydrogen, followed by reaction at room temperature for 20 hours. After completion of the reaction, the reaction product was dispersed in a solution of 6.00 g of potassium carbonate in 130 ml of water and then dissolved therein. 35% hydrochloric acid was gradually added to the solution obtained after filtration thereby obtaining a precipitate.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](=[O:14])([O-])[O-].[Na+].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>C(Cl)(Cl)Cl.[Pd]>[CH3:2][N:6]1[C@H:5]2[C@@:17]([CH3:21])([C:17]3[CH:21]=[CH:9][C:8]([C:2]4[O:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:7][C:18]=3[CH2:19][CH2:4]2)[CH2:18][CH2:19][C:11]1=[O:14]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc2ccccc2o1
Agent: [Pd]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4nc5ccccc5o4)cc3CC[C@@H]12
Yield: 20 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2-chlorobenzoxazole (110 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 18 h. Additional palladium reagent (23 mg) was added, and the mixture was heated an additional 48 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (90-100% ethyl acetate/hexanes eluent) to give 45 mg (20%) of the title compound as an amorphous foam. FDMS: m/e=346.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13])([O-])=O.C(O)C.C(O)(=O)C.[H][H]>[Pd].[Fe].O>[F:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cc([N+](=O)[O-])ccc1F
Yield: 85.6 %

Procedure:
To a 500 ml Parr hydrogenation reactor were charged 8.1 g (0.0438 mole) of 2,4-dinitrofluorobenzene, 0.5 g of 5% palladium on carbon catalyst, 1.0 g (0.018 mole) of powdered iron, 150 ml of ethanol, 50 ml of glacial acetic acid, and 5 ml of water. The reaction was stopped after 152 psi of hydrogen had been absorbed. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure leaving a red solid. This solid was passed through a pad of silica gel, eluting with methylene chloride. The solvent was evaporated from the eluate, producing 5.85 g of crude 2-fluoro-5-nitroaniline, m.p. 94°-96° C. Analysis of the nmr spectrum of this material showed it to be >90% pure 2-fluoro-5-nitroaniline.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10](Cl)[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C@H:22]([NH2:26])[C:23]([OH:25])=O)[CH2:17][CH2:16]1.Cl.Cl.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][NH2:39])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([NH:26][C@H:22]([C:23](=[O:25])[NH:39][CH2:38][CH2:37][NH:36][C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[CH2:21][CH:18]3[CH2:17][CH2:16][CH2:15][CH2:20][CH2:19]3)[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2nc(Cl)oc2c1
Reactant: NCCNc1ccc(F)cc1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Product: COC(=O)c1ccc2nc(N[C@@H](CC3CCCCC3)C(=O)NCCNc3ccc(F)cc3)oc2c1

Procedure:
The title compound was prepared from 2-Chloro-benzooxazole-6-carboxylic acid methyl ester, L-cyclohexylalanine and N1-(4-fluoro-phenyl)-ethane-1,2-diamine-2HCl using the procedure analogous to that described in example 2. HPLC-MS calcd. for C26H31FN4O4 (M+H+)483.23, found 483.5.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[NH:6][C:7]1[S:8][C:9]([CH3:14])=[CH:10][C:11]=1[C:12]#[N:13])([O-])=O.[ClH:19]>C(O)C>[ClH:19].[NH2:13][C:12]1[C:11]2[CH:10]=[C:9]([CH3:14])[S:8][C:7]=2[NH:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:1]=1
Reactant: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N

Procedure:
To a stirred slurry of 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (3 g, 0.011 mol) in ethanol (35 mL) at 50° C. was added, over 10 minutes, a solution of anhydrous stannous chloride (6.95 g, 0.037 mol) in hydrochloric acid (26 mL, 5M). The mixture was stirred under reflux for 1 hour, concentrated under reduced pressure and allowed to crystallise over night at 5° C. The salt was filtered, washed with a small amount of water, dried (4.3 g) m.p. >250° C., and used without further purification in the next stage.
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(=O)CCCCC1>C1(C)C=CC=CC=1>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: CC(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: CC(=O)c1ccccc1

Procedure:
5.0 g (40.9 mmol) of 1-phenylethanol, 15.0 g (153 mmol) of cyclohexanone and 1.0 g of catalyst from Example 9 in 30 g of toluene were heated at 70° C. under argon. After a reaction time of 10 hours, the reaction mixture was analyzed by gas chromatography. The yield of product was 94.2 percent.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=12.[C:17](Cl)([Cl:19])=[O:18]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[NH:10][C:11](=[O:12])[C:5]2=[CH:4][S:3][C:2]([CH3:1])=[C:6]12)=[O:18]
Reactant: Cc1scc2c1Nc1ccccc1NC2=O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O

Procedure:
From 4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and phosgene in a mixture of dioxane and toluene, 4-chlorocarbonyl-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one was obtained;
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8]>>[N:1]([CH2:4][CH2:5][O:6][Si:11]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [N-]=[N+]=NCCO
Product: CC(C)(C)[Si](C)(C)OCCN=[N+]=[N-]

Procedure:
Scheme 1 shows the general method of synthesis. 2-Azidoethanol, (1), is treated with tert-butylchlorodimethylsilane to produce 1-azido-2-(tert-butyldimethylsiloxy)ethane (2). This is then treated with methyllithium (or other organometallic) to produce the corresponding 3-alkylated triazene (3). This compound is then acylated (4) either by treatment with an isocyanate or by treatment with KH in presence of a phase transfer catalyst to form an anion followed by reaction with an acyl halide, acid anhydride or similar acylating agents. The hydroxy group is then deprotected by treatment with tetra-n-butylammonium fluoride to produce the 2-hydroxyethyl triazene (5), and the chloride is then produced by reaction with Ph3P/CCl4 (6).
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
After dissolving 120 mg of t-butyl 4-{[(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)amino]carbonyl}-1-piperidine carboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Sodium bicarbonate water and 5N aqueous sodium hydroxide were added and extraction was performed with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. After adding 5 ml of tetrahydrofuran, 26 mg of acetic acid, 92 mg of sodium triacetoxyborohydride and 0.5 ml of formaldehyde (37% in water) to the residue, the mixture was stirred at room temperature for 10 minutes. Sodium bicarbonate water and 5N aqueous sodium hydroxide were added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with brine and then passed through a glass filter coated with NH type silica gel. The silica gel was washed thoroughly with ethyl acetate, the ethyl acetate layers were combined and subjected to distillation under reduced pressure, and the residue was solidified with ethyl acetate and hexane to obtain 80 mg of a colorless powder.