Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([O-:25])=[O:24])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Na+].[CH3:27]N(C)P(=O)(N(C)C)N(C)C.IC>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:23]([O:25][CH3:27])=[O:24])[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Cc1ccc(NC2(C(=O)[O-])CCN(CCc3ccccc3)CC2)cc1
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)C1(Nc2ccc(C)cc2)CCN(CCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 19 parts of sodium 4-[N-(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylate and 200 parts of hexamethylphosphoric triamide is heated to 80° C for a while. After cooling, 12.3 parts of iodomethane are added dropwise at a temperature below 15° C. Upon completion, stirring is continued for 24 hours at room temperature. The reaction mixture is poured onto 600 parts of water and the product is extracted with trichloromethane. The extract is washed twice with water, dried, filtered and evaporated. The oily residue is poured onto 200 parts of water while stirring. The supernatant aqueous phase is decanted and the residual oil is dissolved in trichloromethane. The solution is washed with water, dried, filtered and evaporated. The residue is purified twice by column-chromatography over silica gel using a mixture of trichloromethane and 7% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is suspended in 2,2'-oxybispropane. The product is filtered off and dried, yielding methyl 4-(4-methylphenylamino)- 1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 94.5° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[S:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[S:28][CH:32]=[CH:31][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: c1cscn1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4nccs4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and thiazole
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]3[N:32]4[CH2:33][CH2:34][CH2:35][N:36]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:37][C:31]4=[N:30][C:25]=3[CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:43].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]3[N:32]4[CH2:33][CH2:34][CH2:35][N:36]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:37][C:31]4=[N:30][C:25]=3[C:26]([NH2:43])=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)N1CCCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Reaction time: 0.17 h

Procedure:
mCPBA (2.96 g of 77% purity, 13.2 mmol) was added to a solution of 3-(benzyloxy)-9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline (4.648 g, 11 mmol) in chloroform (20 mL), and the reaction was stirred for 10 minutes. Additional mCPBA (1.5 g) was added and the reaction was monitored for disappearance of the starting substrate by thin-layer chromatography (TLC). Ammonium hydroxide (20 mL) was then added and the reaction was stirred for five minutes before the rapid addition of p-toluenesulfonyl chloride (2.31 g, 12.1 mmol). The reaction was stirred overnight at ambient temperature. The organic layer was separated, washed with ammonium hydroxide, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 43-minute gradient from 1:99 to 25:75) and recrystallization from isopropanol and dried in a vacuum oven at 65° C. to afford 1.1 g of 3-(benzyloxy)-9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as brown crystals, mp 235-236° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:25][CH2:26]1)(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCC(NC(=O)c3ccccc3)CC2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 31.4 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), N-(piperidin-4-yl)benzamide (0.191 g; 0.937 mmol) and triethyl amine (0.220 mL; 1.56 mmol) in tetrahydrofuran (2 mL) was heated at 110° C. in a sealed tube for 5 h. The reaction mixture was diluted with a saturated solution of sodium hydrogen carbonate, extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (15-80%) in heptane furnished 0.049 g (34%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([C:10]#[N:11])=[N:8][CH:9]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:3][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([C:10]#[N:11])=[N:8][C:9]=1[Br:1]
Reactant: BrBr
Reactant: N#Cc1ncc(N)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1nc(Br)c(N)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
Bromine (7.22 g) was added to a stirring mixture of 5-amino-3-chloro-2-cyanopyridine (4.61 g) and sodium acetate (4.81 g) in anhydrous acetic acid (150 mL) at room temperature. The mixture was stirred at 60° C. for 2 hours. The solvents and excess bromine were evaporated and the residue was recrystalliezed from ethyl acetate to give 5-amino-6-bromo-3-chloro-2-cyano-pyridine (6.23 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].O>CN1C(=O)CCC1>[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CCN(c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)CC1
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 2.0 g (7.7 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 1.33 g (8.47 mmol) piperidine-4-carboxylic acid ethyl ester using 1.18 mL (8.5 mmol) triethylamine in 12 mL NMP. Work up is performed by addition of 50 mL water to the reaction mixture and stirring for 30 min. The solid material is filtered off, washed with water (50 mL three times) yielding 1.58 g (4.15 mmol) of the desired product with sufficient purity.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[Br:8][CH2:9][CH2:10]Br>>[Br:8][CH2:9][CH2:10][N:3]1[C:2](=[O:1])[CH:6]=[C:5]([CH3:7])[O:4]1
Reactant: BrCCBr
Reactant: Cc1cc(O)no1
Product: Cc1cc(=O)n(CCBr)o1

Procedure:
A mixture of 10 g of 3-hydroxy-5-methylisoxazole and 56 g of 1,2-dibromoethane was refluxed for 6 hours. After cooling, the reaction mixture was subjected to column chromatography through silica gel eluted with a 3:1 by volume mixture of benzene and acetone. A yellow liquid separated, and this was crystallized with n-hexane, affording 2-(2-bromoethyl)-5-methyl-3-oxo-4-isoxazoline, melting at 39°-40° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13]
Reactant: COC(C)(C)CN
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(C)(C)OC)ccc21
Yield: 43 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide (78.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methoxy-2-methyl-propylamine (50.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 493; and 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, br. s), 8.20-8.17 (1H, m), 8.11 (1H, br. s), 7.81 (1H, m), 7.70 (1H, m), 7.57 (1H, m), 4.25 (2H, m), 3.37-3.35 (2H, d), 3.32 (2H, s), 3.18 (3H, s), 1.35-1.32 (3H, t), 1.14 (6H, s).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6]([O:23][CH3:24])=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([CH:11]([OH:19])[C:12]#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:36]=[CH:35][C:30]([CH2:31][N:32]=[N+:33]=[N-:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[OH:19][CH:11]([C:9]1[CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([O:23][CH3:24])=[CH:7][C:8]=1[N+:20]([O-:22])=[O:21])[C:12]1[N:34]=[N:33][N:32]([CH2:31][C:30]2[CH:35]=[CH:36][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: CCOC(=O)C#CC(O)c1cc(OC(C)C)c(OC)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(O)c2cc(OC(C)C)c(OC)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
1.5 N butyl lithium (22.6 ml, 33.8 mmol) was added to a solution of diisopropylamine (5.0 ml, 36.0 mmol) in tetrahydrofuran (75 ml) under an argon atmosphere at −78° C., and the mixture was stirred for one hr. Ethyl propiolate (2.9 ml, 28.2. mmol) and a solution of 5-isopropoxy-4-methoxy-2-nitrobenzaldehyde (4.5 g, 18.8 mmol) in tetrahydrofuran (50 ml) were then added thereto in that order, and the mixture was stirred at −78° C. for additional 1.5 hr. A solution of acetic acid (5.9 ml, 102 mmol) in tetrahydrofuran (20 ml) was added to the reaction solution. Water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, and saturated brine solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate (7.27 g). The resultant ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate was dissolved in toluene (60 ml). 4-Methoxybenzyl azide (9.2 g, 56.4 mmol) was added to the solution. The mixture was heated at 100° C. with stirring overnight. The reaction solution was cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give a 1:1 mixture (7.01 g, 75%) of ethyl 4-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and ethyl 5-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (a-2: high polar product (MP)).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])C(O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]3[O:34][C:33]4=[N:35][C:36]([N+:38]([O-:40])=[O:39])=[CH:37][N:32]4[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>>[N+:38]([C:36]1[N:35]=[C:33]2[N:32]([CH:37]=1)[CH2:31][CH2:30][CH:29]([CH2:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH2:13][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:2]([F:1])([F:6])[F:7])=[CH:23][CH:22]=4)[CH2:20][CH2:19]3)=[CH:26][CH:25]=1)[O:34]2)([O-:40])=[O:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(N3CCN(Cc4ccc(OC(F)(F)F)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (6.0 ml) was added to 4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (200 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (2.0 ml) and triethylamine (2.0 ml) were added to the residue, followed by stirring at room temperature for 5 minutes. The reaction mixture was reconcentrated under reduced pressure. 1,2-Dichloroethane (5 ml), 4-(trifluoromethoxy)benzaldehyde (124 μl) and sodium triacetoxyborohydride (185 mg) were added to the residue, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=10:0→methylene chloride:methanol=9:1) and recrystallized from methylene chloride-isopropyl ether to afford the title compound as a white powder (211 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([NH:20][C:21]1[S:22][C:23]([C:27]2[CH:28]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[C:30]([Cl:33])=[N:31][CH:32]=2)=[C:24]([CH3:26])[N:25]=1)(=[O:19])[CH3:18]>C1COCC1>[Cl:33][C:30]1[N:31]=[CH:32][C:27]([C:23]2[S:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[N:25][C:24]=2[CH3:26])=[CH:28][C:29]=1[S:34](=[O:35])(=[O:36])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(S(=O)(=O)Cl)c2)s1
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(S(=O)(=O)NCc3ccc(Cl)cc3)c2)s1
Temperature: 0 °C

Procedure:
4-Chlorobenzylamine (0.17 mL) and triethylamine (0.12 mL) were added in turn to a stirred slurry of 5-(2-acetamido-4-methyl-1,3-thiazol-5-yl)-2-chloropyridine-3-sulfonyl chloride (250 mg) in THF (20 mL) that had been cooled to 0° C. The resultant mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic solution was washed with a saturated aqueous sodium chloride solution, filtered, dried over magnesium sulfate and evaporated. The material so obtained was purified by ‘basic reversed-phase chromatography’ (Waters ‘Xterra’ C18 reversed-phase silica, 150×21 mm, solvent gradient of 5-50% acetonitrile in water (containing 1% aqueous ammonium hydroxide (d=0.88) solution). The material so obtained was triturated under diethyl ether, isolated and dried at 55° C. under vacuum. There was thus obtained the title compound as a white solid (155 mg); 1H NMR Spectrum: (DMSOd6) 2.22 (s, 3H), 2.40 (s, 3H), 4.24 (s, 2H), 7.25 (s, 4H), 8.06 (m, 1H), 8.63 (m, 1H), 9.06 (br s, 1H), 12.54 (br s, 11H); Mass Spectrum: M+H+ 471 and 473.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
4-Nitro-1H-indazole (1.00 g; 6.13 mmol), benzyl bromide (1.15 g; 6.74 mmol) and potassium carbonate (1.69 g; 12.3 mmol) were mixed with DMF (15 mL) and stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was added to water (50 mL) and extracted into ethyl acetate. The combined extracted were dried (sodium sulfate), filtered and evaporated under reduced pressure to give a brown solid. The material was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1 to 10:1 to 5:1). The first component to elute was the desired regioisomer, which was obtained as a yellow solid (730 mg). The other regioisomer was the second component to elute (650 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[NH3:17]>C1COCC1>[NH2:17][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:9][N+:10]([O-:12])=[O:11]
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Reactant: N
Solvent: C1CCOC1
Product: NC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 48.8 %

Procedure:
To 2.59 g (0.01 mole) of 1-(4-chlorobenzyl)amino-1-methylthio- 2-nitroethylene were added 45 ml of EtQH, 10 ml of THF and 1.02 g of 25% aqueous ammonia and the mixture was stirred at an external temperature of 60° C. for 5.5 hours. During this period, 1.02 g each of 25% aqueous ammonia was added after 1, 2 and 3 hours of reaction. The reaction mixture was ice-cooled and stirred, whereupon crystals separated out. The crystals were collected by filtration, washed with EtOH and ether in that order, and dried. The procedure gave 1.11 g of the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([NH2:16])[N:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:23][CH:24]=O>CC(O)C>[Br:1][C:2]1[C:15]2[N:14]3[CH:23]=[CH:24][N:16]=[C:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2c(Br)cccc2c2ccccc12
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Brc1cccc2c3ccccc3c3nccn3c12
Temperature: 75 °C
Yield: 62.6 %

Procedure:
To a mixture of 4-bromo-6-aminophenanthridine (19.11 g, 69.91 mmole), sodium bicarbonate (12.3 g, 146 mmole) in 2-propanol (200 ml) was added chloroacetaldehyde (50% aqueous soln. 17.35 g). After the reaction mixture was heated at 75° C. for 5 hrs., the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by chromagraphy on silica gel using hexane/ethyl acetate (80/20) to obtain the title compound (13 g, 62%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[Cl:17])[OH:21])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccccc1Cl
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccccc1Cl)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2-chlorobenzoic acid
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:13]([O-])=O.[Na+]>O>[C:1]1([S:7]([N:10]=[N+:11]=[N-:13])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNS(=O)(=O)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
26.3 g of benzenesulphonohydrazide, 100 ml of water, 21 ml of 10N hydrochloric acid and 1.3 g of Emulgator ED (a fatty alcohol/ethylene oxide addition product) are stirred for 30 minutes, 60 g of ice are added and a solution of 19.5 g of sodium nitrite in 50 ml of water is then added dropwise in the course of about 30 minutes. The batch is stirred for 30 minutes, excess nitrite is then destroyed with a small amount of sulphamic acid, and excess acid is neutralised with about 5 ml of 10N sodium hydroxide solution. An emulsion of benzenesulphonyl azide is obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16]CC)=O)=[C:7]2[OH:19])#[N:2].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C(Cl)Cl.CCOCC>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:14]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([C:7]=2[OH:19])=[CH:5][C:4]([CH2:3][C:1]#[N:2])=[CH:13][CH:12]=3)=[O:16])=[CH:23][CH:22]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(CC#N)cc2c1O
Solvent: ClCCl
Solvent: CCOCC
Product: N#CCc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 180 °C

Procedure:
A suspension of 4-aminobenyl cyanide (6.61 g) and diethyl ethoxymethylene-malonate (10.1 mL) is heated to 95° C. for 1 hour. The reaction is cooled to room temperature and poured into 50 mL hexanes to wash away impurities. The desired enamine intermediate formed upon cooling and is filtered and collected. In a 3-necked roundbottom connected to a Dean-Stark trap, 75 mL of diphenyl ether is added to the enamine and the solution is heated at 250° C. for 2 hours. The crude product is washed with hot MeOH and dried to yield 3.40 g of ethyl 6-cyanomethyl-4-hydroxyquinoline-3-carboxylate as an orange solid. A mixture of this ester (0.50 g) and p-chlorobenzylamine (3.5 mL) are heated at 180° C. for 1 hour. The reaction is cooled to room temperature and diluted with CH2Cl2 and ether. The solvents are evaporated. The residue is chromatographed on silica, eluting with 3% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized with EtOAc/hexanes to yield 0.162 g of the desired product as a light yellow solid.