Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[C:4](=[O:16])[NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].[CH2:33](I)[CH3:34]>CN(C=O)C>[CH2:33]([N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)[C:4]([N:3]([CH2:1][CH3:2])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:27])([CH3:28])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)=[O:16])[CH3:34]
Reactant: CCN(C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)N(CC)c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
A solution of methyl 4-[3-ethyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (0.25 g, 0.6 mmole) in 15 mL DMF was treated portionwise with 22 mg of sodium hydride (0.92 mmole). After 5 minutes, ethyl iodide (0.062 mL) was added and the reaction mixture was heated to 150° C. for three days. The solvent was removed in vacuo and the residue was diluted in 25 mL ethyl acetate. The organic phase was washed with two 10 mL portions of water and one 10 mL portion of HCl 1N. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 10% methanol/methylene chloride) giving 90 mg of 4-[1,3-diethyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid as a pale brown solid. M.P. 169-172° C.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccc(F)cc3)c(=O)n12
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc2nc(C(C)N)c(-c3ccc(F)cc3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(4-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.062 g, 0.19 mmol) in tetrahydrofuran (0.6 mL) and water (0.14 mL,) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.226 mL, 0.226 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and then the mixture was extracted with 1 N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step. LCMS calculated for C15H15FN3OS (M+H)+: m/z=304.1. Found: 304.1.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[N:5]12[CH2:11][C:9]([C:12]([O:14]C)=[O:13])([CH2:10]1)[CH2:8][CH2:7][CH2:6]2.[CH3:16][O:17][CH2:18][C:19](=[N:21][OH:22])[NH2:20]>CO.C(O)(=O)C>[C:12]([OH:14])(=[O:13])[C:1]([OH:17])=[O:2].[CH3:16][O:17][CH2:18][C:19]1[N:20]=[C:12]([C:9]23[CH2:11][N:5]([CH2:10]2)[CH2:6][CH2:7][CH2:8]3)[O:22][N:21]=1
Reactant: C[O-]
Reactant: COCC(N)=NO
Reactant: COC(=O)C12CCCN(C1)C2
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COCc1noc(C23CCCN(C2)C3)n1
Product: O=C(O)C(=O)O

Procedure:
A stirred solution of sodium methoxide, prepared from 290 mg (0.012 mole) of sodium in methanol (20 ml), under nitrogen was treated with methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 300 mg, 0.0019 mole), methoxyacetamide oxime (D10, 1.0 g, 0.0097 mole) and powdered 3A molecular sieves (2.5 g). The mixture was heated under reflux for 3.5 h, then cooled in an ice bath and adjusted to pH 6 by the addition of glacial acetic acid. The mixture was concentrated in vacuo and the residue basified with concentrated potassium carbonate solution, then shaken with ethyl acetate (100 ml). The mixture was filtered and the organic layer separated, dried (Na2SO4) and concentrated in vacuo to leave a yellow oil. This material was chromatographed twice on basic alumina, each time eluting initially with ether then with 20% ethyl acetate/ether to eventually give a colourless oil (80 mg). This was converted to its oxalate salt and crystallised from acetone to give the title compound (E9 ) as a white solid (12%) m.p. 102°-104° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH2:11][CH2:10][N:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]1=[O:8])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=c1ccc(I)c[nH]1
Product: CC(C)(C)[Si](C)(C)OCCn1cc(I)ccc1=O

Procedure:
The title compounds were prepared as white solids from the alkylation of 5-iodo-1H-pyridin-2-one with BrCH2CH2OTBS (Aldrich) using the procedure described in Step A of Example 38.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]1[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH:8]([C:19]([NH2:21])=[O:20])[NH:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3.C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][S:2]([N:7]1[CH:8]([C:19]([NH2:21])=[O:20])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)C1Cc2c([nH]c3ccccc23)CN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1Cc2[nH]c3ccccc3c2CC1C(N)=O
Reaction time: 8 h

Procedure:
Methane sulphonyl chloride (0.18 ml, 2.4 mmol) was added to a stirred solution of dl 1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indole-3-amide (0.430 gm, 2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry DMF (8 ml) during 15 min at room temperature 30° C. The reaction mixture was allowed to stirr for 8 hrs. at room temperature. Water (20 ml) was added to the reaction mixture and extracted with chloroform (3×15 ml). The extract was dried over Na2SO4 and concentrated over reduced pressure to give 2-[methanesulphonyl]-1,2,3,4, -tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide which was purified by column chromatography over silica gel using 2% methanol chloroform as eluent. Yield=0.150 gm (25.60%). m.p.=234° C. Mass (FAB) m/z=294 (M+). IR (KBr cm−1): 3483, 3361, 1685, 1610, 1446, 1325, 1148, 756. H1NMR (200 MHz, CDCl3) δ 3.04 (s, 3H), δ3.20-3.63 (m, 2H), δ4.69-4.84 (m, 3H), δ6.96-7.15 (m, 3H), δ7.32-7.53 (m, 3H), δ10.89 (s, 1H). Molecular Formula=C13H15N3O3S.
Reaction SMILES: C1([CH:7]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)C=CC=CC=1.C(=O)C1C=CC=CC=1>C(O)C>[CH:7]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][NH:11][CH:10]=[CH:9][N:8]=1
Reactant: c1ccc(C2NCCNCc3ccccc32)cc1
Solvent: CCO
Solvent: O=Cc1ccccc1
Product: C1=CNCc2ccccc2C=N1

Procedure:
A mixture of 2 g (8.4 mmol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine and 1.0 g (9.2 mmol) of benzaldehyde in 40 mL of ethanol was refluxed for 30 min, cooled on ice and the product filtered off. There was obtained 2.33 g of 3,4-dihydro-1,11-diphenyl-2,5-methano-1,H, 6H-2,5-benzodiazocine, mp 175°-176°.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[S:13][CH:14]=[CH:15][C:7]1=2)=[O:5].C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[S:13][CH:14]=[CH:15][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2sccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCCCc3sccc32)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A mixture of 5.0 g of 4-(2-chloro-4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno [3,2 -b]azepine, 16.8 g of stannous chloride dihydrate in 184 ml of ethanol is heated at 80° C. under argon for 1 hour. The solution is cooled in an ice bath and made basic by the slow careful addition of 1M NaHCO3 (ca. 380 ml). The mixture is stirred for 1 hour at room temperature and extracted with 400 ml of ethyl acetate. The aqueous layer is extracted with an additional 250 ml of ethyl acetate. The extracts are combined and washed with 300 ml of brine, dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated under vacuum to give a white solid which is recrystallized from ethyl acetate to give 4.23 g of off-white crystals, m.p. 176°-179° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([CH3:28])=[C:15]3[CH2:29][C:30]([NH2:32])=[O:31])[CH:5]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C>[NH2:32][C:30](=[O:31])[CH2:29][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:33])=[O:2])[CH:13]=2)[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]=1[CH3:28]
Reactant: COC(=O)c1cccc(COc2ccc3c(c2)c(CC(N)=O)c(C)n3Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(CC(N)=O)c2cc(OCc3cccc(C(=O)O)c3)ccc2n1Cc1ccccc1
Reaction time: 7.5 h
Yield: 72.7 %

Procedure:
A mixture of 470 mg (1.06 mmol) of 3-[[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid methyl ester and 2 mL of 2N NaOH in 10 mL of THF and 40 mL of ethanol was stirred for 7.5 hours, the mixture made acidic with 5N HCl and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was crystallized from methylene chloride/ethanol to give 330 mg (72% yield) of 3-[[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid, mp, 176°-179° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([S:14][CH3:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([CH:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]([CH:30]([NH:40][C:1]([C:4]2[CH:13]=[C:12]([S:14][CH3:15])[C:11]3[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CSc1cc(C(=O)O)nc2cc(Cl)ccc12
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(SC)c3ccc(Cl)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added Mel (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%-2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1 N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCI (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%-3% MeOH in CH2Cl2 afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4-3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[O:42])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[C:43]([Mg]Br)#[C:44][CH3:45].C([Mg]Br)#C>O1CCCC1>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]([OH:42])[C:43]#[C:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CC#C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: C#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(O)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 71-(a) except for using 1.01 g (1.62 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 15-(a), and using 3.6 ml of tetrahydrofuran solution containing 0.5M propynyl magnesium bromide in place of tetrahydrofuran solution containing ethynyl magnesium bromide, whereby 1.07 g of the title compound was obtained as a pale brownish foam substantially quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[S:32])[CH:19]([CH3:21])[CH3:20])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)C(=O)Nc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C(=S)Nc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 110 °C
Yield: 46.3 %

Procedure:
To N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)isobutyramide (50 mg, 0.16 mmol) in toluene (2 mL) at 110° C. was added Lawesson's reagent (35 mg, 0.09 mmol). The resulting solution was heated at 110° C. for 7 h. After cooling, the solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, then dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 13.8 mg (26%) of the title compound (LCMS RT=7.36 min, MH+331.2)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.[C:18](OC(=O)C)(=[O:20])[CH3:19].[C:25]([O-])(=[O:27])[CH3:26].[Na+]>O>[CH3:16][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][C:25](=[O:27])[CH3:26])=[C:2]([CH3:1])[CH:3]=2)[CH:14]=[CH:13][C:12]=1[NH:15][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2ccc(N)c(C)c2)ccc1N
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccc(NC(C)=O)c(C)c2)cc1C
Temperature: 90 °C
Reaction time: 0.03 h

Procedure:
3,3'-Dimethyl-4,4'-diaminobiphenyl (12.74 grams, 0.12 --NH2 equivalent) is ground to a fine powder and added to a beaker containing stirred, 90° C. deionized water (1200 milliliters). After two minutes, aqueous 36.5% hydrochloric acid (12.00 grams, 0.12 mole) is added to the stirred, 90° C. suspension. The solution which formed in six minutes is cooled to 70° C. Acetic anhydride (15.04 grams, 0.473 mole) is added to the stirred solution and mixed therein for 20 seconds before addition of an aqueous sodium acetate solution (prepared by dissolution of anhydrous sodium acetate [19.69 grams, 0.24 mole]in deionized water [60.0 grams]). After thoroughly stirring the white slurry, it is maintained at 4° C. for 16 hours, followed by filtration to remove the precipitated product. The recovered filter cake is washed with two portions (150 milliliters) of deionized water then dried in a vacuum oven at 60° C. and 5 mm Hg to a constant weight of 16.92 grams. The product is recovered as a white crystalline powder. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product confirms the product structure: disappearance of the absorbances observed for the --NH2 group, appearance of solid state >NH stretching absorbances at 3283 (3183 slight shoulder) cm-1, a solid state amide I carbonyl stretching absorbance at 1656 cm-1, a solid state amide II carbonyl stretching absorbance at 1516 cm-1 (masking the aromatic ring absorbance) and a C--H out-of-plane bending vibration at 819 cm-1 due to the paradisubstituted aromatic rings. Proton nuclear magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([OH:31])[CH:23]=1>C1(C)C(C)=CC=CC=1.C(N(C(C)C)C(C)C)C.CCO>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:31][C:24]3[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A suspension of 7-(benzyloxy)-4-chloro-6-methoxyquinoline (20.00 g, 70.92 mmol) and p-nitrophenol (13.83 g, 100 mmol) in xylene (40 mL) and N-ethyldiisopropylamine (90 mL) was refluxed for 12 h. The mixture was cooled to rt and diluted with EtOH (200 mL). The solid was collected by filtration and dried in vacuo at 60° C. overnight to give the title compound as a pale yellow solid (22.6 g, 84.3%).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F.C(OCC)(=O)C>CN(C=O)C.CCCCCC>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH:2]([C:1]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCOC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
Benzyl ethyl malonate (2.9 g, 12.6 mmol) in dry DMF (20 ml) was cooled in an ice bath and the temperature monitored whilst sodium hydride (504 mg, 12.6 mmol) was added portionwise. This was stirred at room temperature for 10 minutes until H2 evolution ceased. 3,4-Difluoronitrobenzene (2 g, 12.6 mmol) was added under an argon atmosphere and gave a dark red colour change. The reaction mixture was heated at 100° C. for 20 hours under argon. Thin layer chromatography (20% ethyl acetate in hexane) showed completion of the reaction. The reaction mixture was cooled to room temperature and partitioned between 2N Hydrochloric acid (75 ml) and ethyl acetate (75 ml). The aqueous layer was extracted with ethyl acetate (2×75 ml) and the combined organic fractions were evaporated to a yellow oil. Purification by chromatography on silica gel eluting with 0-20% ethyl acetate in hexane gave the title compound as a yellow oil (3.86 g, 10.6 mmol).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH3:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.Br[CH2:29][C:30]([O:32][C:33](C)(C)[CH3:34])=[O:31]>C1COCC1>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cnccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cnccn1
Temperature: 2.5 °C
Yield: 49.9 %

Procedure:
Butyl lithium (2.5M in hexane-2560 mL) was added within 2 hours into a 10 L flask charged with THF (3350 mL) and diisopropylamine (658 g) while the temperature was maintained at 0-5° C. with an ice bath. The LDA solution was then precooled to −50° C. and a mixture of methylpyrazine (606 g) and THF (590 mL) was added within 2 hours under vigorous stirring at −40 to −30° C. The deep red anion solution is then pumped to a cooled (−60° C.) mixture of tert-butyl bromoacetate (1255 g) and THF (3360 mL) in a 20 L reactor. During the addition of the anion solution, the temperature in the reaction vessel did not exceed −55° C. After the addition, the mixture is stirred for further 30 min at −55° C. and then transferred to a 30 L reactor (the transesterification and removal of solvents can be done for two runs at once). A solution of sodium ethylate (142 g) dissolved in EtOH (2200 mL) was then added to the orange mixture and about 12 L of solvents were distilled off until a temperature of 80° C. was reached in the distillation head and 100° C. in the boiling liquid. The mixture was cooled to approximately 30° C. and then toluene (840 mL), AcOEt (840 mL), and water (1180 mL) were added. After separation of the phases, the organic layer was extracted three times with AcOEt (420 mL) and toluene (170 mL) each. The combined organic phases were then concentrated in vacuo and the residue was distilled over a Vigreux column (bp 115 to 130° C. @ 0.07 mbar) giving the title compound (579 g).
Reaction SMILES: C(O)C.[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:43])=[C:10]([N:12]([CH2:29][C:30]([N:32]([N:34]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35]2)[CH3:33])=[O:31])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH3:21])=[O:15])[CH:11]=1)#[N:5].C([O-])(=O)C.[Na+].[Cl-].[OH:50][NH3+:51]>C(OCC)(=O)C.CCCCCC>[NH2:5][C:4](=[N:51][OH:50])[C:6]1[CH:7]=[CH:8][C:9]([CH3:43])=[C:10]([N:12]([CH2:29][C:30]([N:32]([N:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:42]2)[CH3:33])=[O:31])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH3:21])=[O:15])[CH:11]=1
Reactant: [NH3+]O
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(C#N)ccc1C)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(C(N)=NO)ccc1C)C(=O)OC(C)(C)C
Yield: 102.3 %

Procedure:
To ethanol (20 ml) were added the compound (1.10 g, 2.00 mmol) of Example 2, step A, sodium acetate (347 mg, 4.23 mmol) and hydroxylammonium chloride (292 mg, 4.20 mmol) and the mixture was heated under reflux for 210 min. The reaction mixture was cooled, diluted with an ethyl acetate-hexane=1:1 mixed solvent, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a colorless amorphous solid (1.19 g).