Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[C:26](Br)[CH:27]=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC.[F-].[Cs+].O>CN1C(=O)CCC1.[Pd].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[C:26]([CH:30]=[CH2:31])[CH:27]=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2ccc(Br)cn12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: C=Cc1ccc2ncc(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)n2c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
A mixture of N-(1-benzyl-1H-indazol-4-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide (Example 155; 75 mg; 0.168 mmol), tributyl(vinyl)stannane (59 mg; 0.185 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg; 0.0025 mmol), bis(tri-tert-butylphosphine)palladium(0) (2.6 mg; 0.0050 mmol) and cesium fluoride (56 mg; 0.37 mmol) in NMP was stirred under nitrogen at 60° C. for 5 hours. Additional amounts of the palladium catalysts and the tributyl(vinyl)tin (similar quantities to those added initially) were added and the mixture was heated for an additional 12 hours. The mixture was added to water (20 mL) and extracted into ethyl acetate. The combined extracts were washed with water and brine and dried (sodium sulfate). The filtered solution was concentrated under reduced pressure. The material was purified by silica gel chromatography, eluting with ethyl acetate, to provide the desired product as an oil (66 mg) which solidified on standing.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](I)=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[N:12][CH:13]=1
Reactant: Brc1ccc(I)nc1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Clc1ccc(-c2ccc(Br)cn2)cc1
Temperature: 110 °C

Procedure:
Under an N2 atmosphere 11 mL 2 M Na2CO3 solution and 240 mg (0.21 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 3.00 g (10.6 mmol) 5-bromo-2-iodo-pyridine and 3.37 g (21.1 mmol) 4-chlorophenyl-boric acid in 60 mL 1,4-dioxane and 15 mL MeOH and the reaction mixture is heated to 110° C. for 3 h. The mixture is evaporated down i. vac., the residue is combined with 50 mL water, 10 mL 3% NH3 solution and 150 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc).
Reaction SMILES: ON1C(=O)[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[O-:13]O.C1(C(C)C)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:3]([O:12][OH:13])[C:4]1[CH:5]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: [O-]O
Solvent: Cc1ccccc1
Solvent: CC(C)c1ccccc1
Product: OOCc1ccccc1
Reaction time: 8 h

Procedure:
0.3 mmol of N-hydroxyphthalimide and 0.6 mmol of cumene hydroperoxide are added at a temperature of 125° C. to 30 mmol of toluene in a round-bottomed flask having an attached reflux condenser. The reaction mixture is stirred for 8 hours at said temperature under an oxygen atmosphere of 1 bar. Benzyl hydroperoxide is obtained at a selectivity of 51.7% at a toluene conversion rate of 8%. Other products are benzaldehyde (24.6%) and benzoic acid (23.6%).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:6]=2[N:7]=1)#N.CC[O:16]CC.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>C(OCC)(=O)C.CC(O)C>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([CH:1]=[O:16])[S:4][C:5]=2[CH:11]=1
Reactant: COc1ccc2nc(C#N)sc2c1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C=O)sc2c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
2-Cyano-6-methoxybenzothiazole (10.0 g, 52.6 mmol) was suspended in a mixture of anhydrous ether (400 ml) and 2-propanol (36 ml). The suspension was cooled to about -30° C. by a dry-ice bath. Lithium aluminum hydride (7.0 g, 184.5 mmol) was added slowly while keeping the reaction temperature below -30° C. under argon atmosphere. The reaction mixture was stirred for 1 hr after the addition of lithium aluminum hydride and then poured slowly into a mixture of 2 N sulfuric acid (900 ml) and ethyl acetate (500 ml). After stirring for 10 min the organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic phase was washed with water (200 ml) and then dried with anhydrous sodium sulfate (50 g) overnight. The dried solution was concentrated and then flash chromatographed on silica gel to give 3.1 g (30.5%) of a yellowish solid.
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22](=[O:24])[CH3:23].C(=O)=O.[N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=1.C1CC2N(C3N(C4N2CCCC4)CCCC3)CC1>CN(C)C=O.C(OCC)C.CO>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22](=[O:24])[CH2:23][CH:33]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: C1=NCCCC1
Agent: C1CCN2C(C1)N1CCCCC1N1CCCCC21
Agent: COC(=O)[O-]
Agent: O=C=O
Solvent: CCOCC
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(C(=O)CC2CCCCN2)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
Magnesium methyl carbonate (approximately 1 mole of a 2 M solution in dimethylformamide) is heated to 120°C. under an atmosphere of carbon dioxide and 45.0 g (0.25 mole) of 2',5'-dimethoxyacetophenone added thereto. Nitrogen is substituted for the carbon dioxide and the mixture is stirred at 120°C. for 5 hours while allowing the methanol that forms to escape. The mixture is cooled under carbon dioxide and 25.3 g (0.30 mole) of 2,3,4,5-tetrahydropyridine (as the trimer, α-tripiperidein) added. The resulting mixture is stirred at room temperature in an atmosphere of carbon dioxide for 40 hours, poured into 3 liters of ethyl ether and the resulting precipitate is collected by filtration. The filtrate is acidified with a mixture of 300 ml of concentrated HCl-ice and the resulting precipitate is collected by filtration. The filtrate is made alkaline with 2N NaOH, extracted with ethyl ether, the extracts dried (Na2SO4) and the solvent removed. The resulting oily residue is converted to the hydrochloride salt by the addition of isopropanolic HCl. The two portions are combined and recrystallized from isopropanolwater to yield 56.0 g (75% of theory) of 2',5'-dimethoxy-2-(2-piperidyl)acetophenone as the hydrochloride salt having a M.P. of 186°-188°C. (dec.)
Reaction SMILES: C1(N(CCCCl)C2C=CC=CC=2)C=CC=CC=1.Cl.CC1C=C(C2CCNCC2)C=CC=1.[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+].[C:40]([OH:47])(=[O:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44].[C:48]1([N:54]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:55][CH2:56][CH2:57][N:58]2[CH2:63][CH2:62][CH:61]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([CH3:70])[CH:65]=3)[CH2:60][CH2:59]2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(O)CCC>[C:40]([OH:47])(=[O:46])[CH:41]=[CH:42][C:43]([OH:45])=[O:44].[C:48]1([N:54]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:55][CH2:56][CH2:57][N:58]2[CH2:59][CH2:60][CH:61]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([CH3:70])[CH:65]=3)[CH2:62][CH2:63]2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(O)CCC(=O)O
Agent: Cc1cccc(C2CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Agent: Cc1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: CCCCO
Product: O=C(O)C=CC(=O)O

Procedure:
A mixture of 7.37 g. (0.030 moles) of 3-[N,N-diphenylamino]-1-chloropropane, 6.0 g. (0.024 moles) of 4-(3-methylphenyl)-piperidine hydrochloride, 3.92 g. (0.024 moles) of potassium iodide, and 5.30 g. (0.050 moles) of sodium carbonate in 60 ml. of n-butanol is refluxed for about 16 hours. Solvent is evaporated and the residue is dissolved in chloroform and washed with water. The chloroform solution is dried and passed through a column of silica gel. The product is eluted with acetonitrile. The product fractions are combined, concentrated, and converted to the maleate salt in ether. The resulting crystals recrystallized from acetonitrile to give 7.2 g. of N,N-diphenyl-4-[3-methylphenyl]-1-piperidinepropanamine butanedioate (1:1), mp. 137.5°-139.5° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:5][CH:4]=[C:3]1[C:19]([O:21]CC)=O.[OH-].[NH4+:25]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:5][CH:4]=[C:3]1[C:19]([NH2:25])=[O:21]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O
Agent: [OH-]
Product: CC(C)COc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Yield: 83 %

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-isobutoxyphenyl)-pyrimidine-5-carboxylate (10.0 g., 0.0316 mole) and ammonium hydroxide (110 ml., d=0.9) was heated in a sealed steel bomb for 4.5 hours. The solution was partially evaporated and the residue acidified with 6N hydrochloric acid. The mixture was filtered and the collected solid recrystallized from N,N-dimethylformamide to give the title compound (7.5 g., 83% yield), m.p. 230°-231°.
Reaction SMILES: ClC1C=CC2NCCCC(=O)C=2C=1.ClC1C=CC2N(C(=O)C3C=CC([N+]([O-])=O)=CC=3C)CCCC(=O)C=2C=1.ClC1C=CC2N(C(=O)C3C=CC(NC(=O)C4C=CC=CC=4C)=CC=3C)CCCC(=O)C=2C=1.[Cl:71][C:72]1[CH:73]=[CH:74][C:75]2[N:81]([S:82]([C:85]3[CH:90]=[CH:89][C:88]([CH3:91])=[CH:87][CH:86]=3)(=[O:84])=[O:83])[CH2:80][CH2:79][CH:78](C(OCC)=O)[C:77](=[O:97])[C:76]=2[CH:98]=1.Cl>O.C(O)(=O)C>[Cl:71][C:72]1[CH:73]=[CH:74][C:75]2[N:81]([S:82]([C:85]3[CH:90]=[CH:89][C:88]([CH3:91])=[CH:87][CH:86]=3)(=[O:83])=[O:84])[CH2:80][CH2:79][CH2:78][C:77](=[O:97])[C:76]=2[CH:98]=1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)cc2C1=O
Agent: Cc1cc([N+](=O)[O-])ccc1C(=O)N1CCCC(=O)c2cc(Cl)ccc21
Agent: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3cc(Cl)ccc32)cc1

Procedure:
Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro-1H-1-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-1-p-toluenesulfonyl-1H-1-benzazepine, and then reacted with polyphospholic acid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][Cl:17].[Cl-].[Na+]>CN(C)C=O.O>[Cl:17][CH2:16][CH2:15][CH2:14][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1
Reactant: ClCCCBr
Reactant: OCc1ccc(O)cn1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(OCCCCl)cn1
Reaction time: 0.5 h

Procedure:
To the stirred solution of 32.32 g of 5-hydroxy-2-pyridinemethanol hydrochloride in 200 ml of dimethylformamide is added 18.2 g of sodium hydride (50% mineral oil dispersion) in portions while maintaining a temperature of 50°-55° of the mixture. Then the mixture is stirred at 50°-55° for 30 minutes and then is added a solution of 31.5 g of 1-bromo-3-chloropropane in 50 ml of dimethylformamide, while maintaining a temperature below 50° of the mixture. After that, the mixture is allowed to come to room temperature and is additionally stirred at room temperature for 2 hours and 30 minutes. Then the mixture is poured into 1,200 ml of water, the aqueous mixture is saturated with sodium chloride and the resulting saturated solution extracted three times with ether. The ether extracts are combined, the combined ether solution is washed and dried over anhydrous magnesium sulfate. The ether solution is filtered and the filtrate evaporated to yield 5-(3-chloropropoxy)-2 -pyridinemethanol.
Reaction SMILES: [K].[CH3:2][N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH:11]([CH3:13])[CH3:12].[O:14]=O.Cl>C(O)(C)(C)C.C(OP(OCC)OCC)C.O=P(N(C)C)(N(C)C)N(C)C>[OH:14][C:11]([C:4]1[N:3]([CH3:2])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1)([CH3:13])[CH3:12]
Reactant: O=O
Reactant: CC(C)c1ncc([N+](=O)[O-])n1C
Agent: CCOP(OCC)OCC
Agent: Cl
Agent: [K]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)(C)O
Product: Cn1c([N+](=O)[O-])cnc1C(C)(C)O
Temperature: 0 °C
Yield: 74 %

Procedure:
A total of 21.5 g of potassium were dissolved in 450 ml of tert.-butanol with vigorous stirring and the solution heated to reflux. 300 ml of hexametapol were added to the cooled solution. The mixture was then cooled to -25°, a solution of 42.5 g of 1-methyl-2-isopropyl-5-nitroimidazole in 60 ml of triethylphosphite and 150 ml of hexametapol was added and dry oxygen was conducted through the mixture for 5 hours at -20° to -25° with vigorous stirring. The mixture was poured into a mixture of 1.5 liter of ice-water and 45 ml of 36% hydrochloric acid and extracted six times with 400 ml portions of ether. The combined ether extracts were washed twice with 250 ml portions of water and evaporated. The crude 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole (40.5 g; 87%) was purified by crystallization from 300 ml of water. There were obtained 30.2 g of pure 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole, melting point 106°-108° and a second crop of 4.2 g, melting point 102°-105° (total yield 74%).
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:7]3=[C:8]2[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][Cl:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:9]3[C:4]([N:5]=[C:6]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:7]=24)=[CH:3][CH:2]=[N:1]3)=[CH:15][CH:14]=1
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 18.3 %

Procedure:
To a solution of 4-(6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-yl)-phenol (60 mg, 0.2 mmol) in DMF (1 mL) was added 1-bromo-3-chloropropane (67 mg, 0.4 mol) and K2CO3 (45 mg, 0.3 mmol). The mixture was stirred at 80° C. for 5 hours, then cooled, diluted with EtOAc (3 mL) and washed with H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified via preparative LCMS to give 10-[4-(3-chloro-propoxy)-phenyl]-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (13 mg, 32% yield).
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]/[OH:6].CO.[CH3:23][NH2:24].O>C1(C)C=CC=CC=1>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:3]([NH:24][CH3:23])=[O:2]
Reactant: CN
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CNC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
To crude E-α-hydroxyimino-2-phenoxyphenylacetic acid methyl ester (39.6 g, 0.0747 mole, purity: 51.2%) were added methanol (100 ml) and 40% aqueous solution of methylamine (15.45 g, 0,199 mole) and the mixture was stirred at room temperature for 15 hours. Then, 40% aqueous solution of methylamine (7.73 g, 0.0995 mole) was added to the mixture which was stirred in an oil bath at 70° C. for 6 hours. After completion of the reaction, water (200 ml) and toluene (100 ml) were added to the reaction mixture, which was stirred with ice cooling for one hour. The precipitated crystals were filtered off and recrystallized (methanol/toluene) to obtain E-2-hydroxyimino-N-methyl-2-(2-phenoxyphenyl)acetamide (12.31 g, yield: 60.1%) as colorless crystals (melting point: 183°-184.5° C.).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2.C(O)(=[O:25])C>>[CH2:21]([O:20][C:18]([C:15]1[N:4]2[C:5]3[C:10]([NH:11][C:2](=[O:25])[C:3]2=[N:17][N:16]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=3)=[O:19])[CH3:22]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1nnc2c(Cl)nc3cc([N+](=O)[O-])ccc3n12
Product: CCOC(=O)c1nnc2c(=O)[nH]c3cc([N+](=O)[O-])ccc3n12
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of 1.5 g (~4.7 mmol) of 4-chloro-1-ethoxycarbonyl-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline and 25 ml of glacial acetic acid was refluxed for 60 min. After cooling to 25° C. the precipitate was filtered off to give 1.5 g of a crude product. Purification by column chromatography (silica gel; eluent: ethyl acetate) gave 1.2 g (~90%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O-].[Na+].Cl.Cl[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12][N:11]=1>COCCO.COC(O)C.C1COCC1>[CH2:20]([C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][N:11]=[C:10]2[CH2:9][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][CH:16]=1)[CH3:21]
Reactant: COCC[O-]
Reactant: CCc1ccc2c(c1)C(CCl)=NCC2
Agent: COC(C)O
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)C(CCCOC)=NCC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Under cooling in an ice bath, a mixture of sodium hydride (suspension of 8 g of sodium hydride in mineral oil (60%) washed with hexane) in THF (10 mL) was added to methoxyethanol (100 mL) under stirring over 20 minutes to produce sodium 2-methoxyethoxide, followed by further stirring for 2 hours. A solution of sodium 2-methoxyethoxide in 2-methoxyethanol (55 mL) was added with stirring to a solution of 1-(chloromethyl)-7-ethyl-3,4-dihydroisoquinoline hydrochloride (8.5 g) in methoxyethanol (50 mL) under cooling in an ice bath, for 5 minutes. The reaction mixture was heated at 60° C., followed by stirring for 3 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and diluted with THF (150 mL), followed by filtration. The filtrate was concentrated under reduced pressure. To the resulting residue was added a saturated aqueous ammonium chloride solution and the residue was extracted with EtOAc. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain 7-ethyl-1-[(2-methoxyethyl)methyl]-3,4-dihydroisoquinoline (2.13 g).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].Cl[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[Br:1][C:2]1[N:3]([CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: ClCSc1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CSc3ccccc3)c2c1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (1.00 g, 2.97 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 139 mg, 3.47 mmol) under ice-cooling, and the mixture was stirred for 1 hr. To this reaction mixture was added chloromethylsulfanylbenzene (0.38 ml, 2.94 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1-7:1) to give methyl 2-bromo-3-cyclohexyl-1-phenylsulfanylmethyl-1H-indole-6-carboxylate (1.10 g, yield 84.0%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[CH3:27][CH:28]([CH3:52])[CH2:29][NH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[C:33](OS(C(F)(F)F)(=O)=O)[C:32]=1[N+:49]([O-:51])=[O:50].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:26][CH:25]=2)[C:33]2[C:32]([N+:49]([O-:51])=[O:50])=[C:31]([NH:30][CH2:29][CH:28]([CH3:52])[CH3:27])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)=[CH:18][CH:19]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3c(NCC(C)C)c2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
Triethyl amine (40.4 mL, 0.290 mol) and N,N-bis(4-methoxybenzyl)amine (62.0 g, 242 mmol) were sequentially added to a solution of [4-(2-methylpropyl)amino-3-nitroquinolin-2-yl]trifluoromethanesulfonate (Nikolaides et al, U.S. Pat. No. 5,395,937, Example 1, 95.0 g, 242 mmol) in toluene (300 mL) at ambient temperature. The solution was stirred at ambient temperature for a few minutes, heated at reflux for two hours, and allowed to cool to ambient temperature. Ethyl acetate and saturated aqueous sodium bicarbonate (300 mL) were added. The organic layer was separated and washed twice with saturated aqueous sodium bicarbonate. The combined aqueous fractions were filtered to remove a solid, and the filtrate was extracted with ethyl acetate (3×150 mL). The combined extracts were washed once with saturated aqueous sodium bicarbonate. All organic fractions were then combined and dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum for three days to provide N2,N2-bis(4-methoxybenzyl)-N4-(2-methylpropyl)-3-nitroquinoline-2,4-diamine as a red oil, which was used without purification.