Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:29][CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 74 %

Procedure:
A solution of 4′-{[4-butyl-1-(4-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.3 g), ethyl 2-bromo-2-methylpropanoate (2.2 mL) and cesium carbonate (4.9 g) in dimethylacetamide (23 mL) was stirred at 100° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.1 g, 74%) as a pale-yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:40][CH2:39][CH:38]([N:33]6[CH:37]=[CH:36][N:35]=[CH:34]6)[CH2:43][CH2:42]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: c1cn(C2CCNCC2)cn1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(n3ccnc3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-imidazol-1-yl-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-Imidazol-1-yl-piperidine following General Procedure B.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].[C:5]([O:9][OH:10])([CH3:8])([CH3:7])[CH3:6].CC(=C)C>C(O)(C)(C)C>[C:2]([O:10][O:9][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OO
Reactant: CC(C)C
Agent: C=C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OOC(C)(C)C

Procedure:
In practice of the invention as set forth in FIG. 2, effluent from a reactor wherein debutanized isobutane oxidate comprised of tertiary butyl hydroperoxide and tertiary butyl alcohol is reacted with isobutylene to form ditertiary butyl peroxide is combined with an azeotropic ditertiary butyl peroxide and tertiary butyl alcohol stream and fed to dehydration zone 102 via line 101. Dehydration zone 102 is a reactor distillation column provided with a central packed bed 103 of zeolite H--Y catalyst supported by conventional means. Fractional distillation zones 104 and 105 are located respectively above and below the catalyst bed.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[K+]>>[C:10]([NH:11][C@:7]([CH3:14])([C:8]([OH:15])=[O:13])[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[NH2:9]
Reactant: [OH-]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Agent: [K+]
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O
Temperature: 95 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
First, 5-tert-butylthiomethyl-5-methylhydantoin (5 g, 23 mmol) was mixed with a 58% aqueous potassium hydroxide solution (9.2 g), and the mixture was heated to 95° C. and stirred for 22 hours. The HPLC analysis of the reaction solution showed the production of the title compound in a reaction yield of 92%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Brc1nccs1
Reactant: CC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Oc2nccs2)cc1
Temperature: 160 °C
Yield: 54.8 %

Procedure:
To a solution of 4-isopropoxyphenol (CAS #7495-77-4. 3 g, 19.7 mmole), at room temperature in DMSO (30 mL) was added in turn, 2-bromothiazole (3.23 g, 19.7 mmole) and potassium carbonate (5.44 g, 39.4 mmole), heated at 160° C. for 3 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and brine sequentially, dried over magnesium sulfate, filtered and concentrated. The residue was purified on Silica gel column using a gradient of 5 to 25% ethyl acetate in hexane and provided 2.54 g (55%) of the title compound as yellowish oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.22 (d, J=3.68 Hz, 1H) 7.15-7.21 (m, 2H) 6.86-6.95 (m, 2H) 6.76 (d, J=4.04 Hz, 1H) 4.43-4.60 (heptet, J=6.25 Hz, 1H) 1.34 (d, J=6.25 Hz, 6H). MS (ESI) m/z 236 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]=C)(=[O:5])[CH2:2][CH2:3][CH3:4].[O:27]=[O+][O-]>CO.ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]=[O:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=[O+][O-]
Reactant: C=Cc1cccc2c(Nc3ccc(O)cc3C)c(C(=O)CCC)cnc12
Solvent: CO
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccc(O)cc1C
Temperature: 25 °C
Yield: 42 %

Procedure:
3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-vinylquinoline (5.0 g, 14.4 mmol) was stirred at -60° C. in a mixture of methanol (100 ml) and dichloromethane (200 ml) and ozone bubbled through for 15 minutes. The ozone mixture was flushed out of the reaction with nitrogen. Dimethylsulphide (2.5 ml) was added and the mixture allowed to warm to room temperature. The solvent was evaporated and the residue was chromatographed (silica gel, methanol 1% in dichloromethane) to afford 3-butyryl-4-(4-hydroxy-2-methylphenylamino)quinoline-8-carbaldehyde (2.1 g, 42%) as an oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[O:10]1[CH2:15][CH2:14][N:13]([C:16]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:17])[CH2:12][CH2:11]1.C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C>[O:10]1[CH2:15][CH2:14][N:13]([C:16]([CH2:18][N:19]2[CH2:20][CH2:21][N:22]([C:7]([CH:2]3[NH:1][C:5](=[O:6])[CH2:4][CH2:3]3)=[O:9])[CH2:23][CH2:24]2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C1CCC(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)N1
Yield: 93.9 %

Procedure:
Pyroglutamic acid (1.6 g), 2.1 g of 1-(morpholinocarbonylmethyl)piperazine, 2.47 g of DCC and 130 ml of acetonitrile were heated to reflux for 48 hours with stirring. The insoluble matter was removed by filtering the reaction mixture and the solvent was evaporated from the filtrate in vacuo. The residue was subjected to a silica gel column chromatography to give 3.0 g of the product. This was recrystallized from a mixture of ethyl acetate, isopropanol and n-hexane to give 2.6 g of desired product, m.p. 167°-169° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17](OC)=O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=CC=1.C1([C:27]2C3C(=C(CO)C=CC=3)C=C[N:28]=2)C=CC=CC=1>>[CH:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:27]#[N:28])[C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc2c(-c3ccccc3)nccc12
Reactant: OCc1cccc2c(-c3ccccc3)nccc12
Product: N#CCc1cccc2c(C3CCC3)nccc12

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and cyclobutanecarbonyl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-cyclobutylcarbonylamino-2-(2-hydroxymethylphenyl)ethane as in oil. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-cyclobutylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-cyclobutylisoquinoline-5-acetic acid having a decomposition point of 202.8° to 209.8° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:19])[CH2:17]O)([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[C:9]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:17])[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(Br)cc1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](COc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Bromophenol (0.2 g, 1.14 mmol), ((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.2 g, 1.14 mmol) and triphenylphosphine (0.45 g, 1.71 mmol) were dissolved in anhydrous toluene (10 ml) under an atmosphere of nitrogen. A solution of di-tert-butyl azodicarboxylate (0.39 g, 1.71 mmol) in toluene (5 ml) was added slowly ensuring that the temperature did not exceed 35° C. The reaction mixture was heated to 80° C. and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and subsequently washed with 1M HCl, water, brine then dried over magnesium sulfate, filteted and concentrated in vacuo. Purification by Flash Chromatography using 10% ethyl acetate/cyclohexane as the elutant gave the final product. Yield 80 mg, 21%. LCMS method: 2, RT: 6.17 min; MI: 330-332 [M+1].
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:6][C:5](=[O:15])[CH:4]=1.[CH:16]1([C:21]2([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[O:26][C:25](=[O:27])[CH2:24][C:23](=[O:28])[CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([C:21]2([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[O:26][C:25](=[O:27])[C:24]([CH2:2][C:3]3[N:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[NH:6][C:5](=[O:15])[CH:4]=3)=[C:23]([OH:28])[CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=c1cc(CCl)nc(-c2ccccn2)[nH]1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3cc(=O)[nH]c(-c4ccccn4)n3)C(=O)O2)cc1
Yield: 11 %

Procedure:
The title compound was prepared as described in Example B(53), using 6-(chloromethyl)-2-pyridin-2-ylpyrimidin-4(3H)-one in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 11%.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].[OH:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Reactant: Fc1cccc(CBr)c1
Agent: CCNC(=O)[O-]
Product: CC1c2cc(Cl)c(OCc3cccc(F)c3)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5 Step A) and 3-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H23ClFNO3+H: 404, observed: 404.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Se](=O)=[O:14]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:14])[C:7]2=[O:12]
Reactant: O=C1CCCc2c(Cl)cccc21
Reactant: O=[Se]=O
Product: O=C1C=Cc2c(Cl)cccc2C1=O

Procedure:
Treatment of 5-chloro-tetralone with selenium dioxide as described in Reference Example 1A yielded 5-chloro-[1,2]naphthoquinone which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described in Reference Example 1A to yield the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:17][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)COc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CBr)c1
Temperature: 0 °C
Yield: 71.1 %

Procedure:
A solution containing ethyl 3-(hydroxymethyl)phenoxyacetate (2.6 g.) and carbon tetrabromide (8.3 g.) in DMF (30 ml.) was treated with a solution of triphenylphosphine (6.55 g.) in DMF (20 ml.) with stirring. The temperature was maintained below 15° C. during the addition using an ice bath. After 1 hour the mixture was poured into ice-water (300 ml.) and the aqueous mixture was extracted with ether (3×100 ml.). The combined extracts were washed with water (3×100 ml.) and saturated brine (100 ml.), dried (MgSO4) and concentrated. The resultant oil was purified by flash column chromatography, eluting with petrol (60°-80° )/ether (80:20 v/v) to give ethyl 3 (bromomethyl)phenoxyacetate (2.4 g.) as a colourless oil, NMR: 1.3 (3H,t), 4.25 (2H,q), 4.4 (2H,s), 4.6 (2H,s) and 6.7-7.4 (4H,m)ppm.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.C(=O)=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][C:24]#[N:25]>C1COCC1.CO.N1C=CC=CC=1>[C:24]([CH2:23][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([NH:13][C:1]([C:6]3[NH:5][CH:9]=[CH:8][CH:7]=3)=[O:2])[CH:15]=2)[NH:19][CH:18]=1)#[N:25]
Reactant: c1cc[nH]c1
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: O=C(Cl)Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccncc1
Product: N#CCc1c[nH]c2ccc(NC(=O)c3ccc[nH]3)cc12
Reaction time: 3 h

Procedure:
Phosgene was passed slowly into 50 ml THF until 4.46 g (0.045 mole) had been collected. To this solution was added 3.04 ml (0.844 mole) of pyrrole and the mixture stirred at 5° for 3 hours. The excess phosgene was driven off by heating and trapped in a NaOH trap to monitor CO2 evolution. The reaction mixture was cooled, treated with 10 ml pyridine followed by a solution of 2.0 g (0.012 mole) of 5-aminoindole-3-acetonitrile, Example 1, in 50 ml THF and stirred 18 hours. Methanol was added to effect complete solution and 100 g silica gel added to adsorb desired product. The solvent was removed in vacuo and treated silica gel washed with 1.5 l of EtOAc which was then concentrated in vacuo to give crude product. This was further purified by column chromatography (EtOAc/Hexane (4:1) on silica gel) to give 1.16 g (37%) desired product: m.p. 216°-218°.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>>[Br:1][C:2]1[C:3]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:4][C:5]2[NH:11][C:10](=[S:40])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Br)c(OCCCN3CCOCC3)cc2N1
Product: S=C1CN=C(c2ccccc2Cl)c2cc(Br)c(OCCCN3CCOCC3)cc2N1

Procedure:
7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4benzodiazepin-2-thione (IIj) was prepared by reacting 0.0011 moles of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ij) with Lawesson's reagent in a manner analogous to Example 38. MH+/Z=508.
Reaction SMILES: [N+]([O-])(O)=[O:2].C(O)(=O)C[O:7][CH2:8][C:9]([OH:11])=[O:10]>>[C:9]([OH:11])(=[O:10])[C:8]([OH:7])=[O:2].[C:9]([OH:11])(=[O:10])[CH2:8][OH:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)COCC(=O)O
Product: O=C(O)C(=O)O
Product: O=C(O)CO

Procedure:
After termination of the reaction, an aqueous reaction mixture, containing approximately 5-30% by weight of HNO3 and about 20-40% by weight of diglycolic acid, in addition to minor proportions of impurities, such as oxalic acid and glycolic acid, is obtained. According to the state of the art this solution is worked up by evaporating all of the water and nitric acid under vacuum. The thus-separated diglycolic acid is recrystallized once more, if necessary.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:13]=1[O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:19][CH:20]=1>O>[CH2:1]([NH:3][C:22](=[O:23])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]2[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:12]=2[Cl:11])[CH:16]=1)[CH3:2]
Reactant: CCN
Reactant: O=C(Cl)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Product: CCNC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reaction time: 1 h
Yield: 97.6 %

Procedure:
0.7 g of ethylamine and 1.5 g of triethylamine were dissolved in 20 ml of N,N'-dimethylacetamide at 0° C., followed by addition of 3.5 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetyl chloride. The reaction was allowed to proceed at 0° C. for 1 hour and then at room temperature for further 3 hours to complete the reaction. After completion of the reaction, 50 ml of water was added to the liquid reaction mixture, followed by extraction twice with 30 ml portions of ether. The ether layer was washed with dilute hydrochloric acid and water and dried over anhydrous sodium sulfate, and the ether was distilled off under reduced pressure. As a result, there was obtained 3.5 g of N-ethyl-3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetamide.
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].CI.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([N:9]([CH3:15])[CH3:10])(=[O:7])=[O:8]
Reactant: CNS(=O)(=O)CC(=O)C=C(C)N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(N)=CC(=O)CS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3.8 g of 4-amino-N-methyl-2-oxo-3-pentenesulfonamide and 1.9 ml of methyl iodide in 50 ml of dimethylformamide was treated with 6 g of finely ground dry potassium carbonate and the mixture was thereupon stirred intensively at room temperature under argon for 6 hours. The organic salts were then filtered off, rinsed with methylene chloride and the filtrate was concentrated to dryness under reduced pressure. The residue was partitioned between water and methylene chloride, the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The solid product was recrystallized from isopropanol, whereby there were obtained 2.5 g of 4-amino-N,N-dimethyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 137°-140°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:23])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:24][C@H:25]([C:30]([OH:32])=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27].C(N(CC)CC)C.C(O)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([NH:24][C@H:25]([C:30]([OH:32])=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 24.5 %

Procedure:
The title compound is prepared by the procedure of Example 255 using 14.73 g of product from Example 254, 6.07 g of L-isoleucine, 12.73 ml of triethylamine and 556 ml of 4:1 ethyl alcohol:water to give 3.52 g of the desired product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:9]([N+:20]([O-:22])=[O:21])=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13](O)=[O:14])[CH2:5][CH2:6][Cl:7].O=S(Cl)[Cl:25]>CN(C=O)C>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:9]([N+:20]([O-:22])=[O:21])=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([Cl:25])=[O:14])[CH2:5][CH2:6][Cl:7]
Reactant: O=C(O)c1cc(N(CCCl)CCCl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(N(CCCl)CCCl)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Treatment of (6) with excess SOCl2 containing a drop of DMF under reflux for 20 min, followed by concentration to dryness and azeotroping with benzene, gave crude 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzoyl chloride (VI: X=Cl; Y1 =Cl). This was dissolved in Me2CO (20 mL), cooled to 0° C., treated with excess 40% aqueous methylamine. The product was purified by chromatography on silica gel, elution with EtOAc/petroleum ether (1:1) giving N-methyl [N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (8) (Ib: X=Cl, R=CONHMe), mp (EtOAc/petroleum ether) 180.5° C. 1H NMR (CD3COCD3) δ 8.53 (s, 1 H, ArH3), 7.75 (br, 1 H, CONH), 7.56 (s, 1 H, H-6), 3.88-3.80 (m, 8 H, NCH2CH2Cl), 2.90, 2.89 (2 s, 3 H, CONHMe). 13C NMR δ 165.89 (CONH), 148.43 (C-5), 140.05, 138.26 (C-2,4), 138.94 (C-1), 125.05, 122.45 (C-3,6), 54.20 (CH2N), 42.10 (CH2Cl), 26.69 (CONHCH3). Anal. (C12H14Cl2N4O5) C,H,N,Cl.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18](O)[C:13]=3[C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>P(Cl)(Cl)(Cl)=O.ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([Cl:28])[C:13]=3[C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ncc2c(c1Cl)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A solution of 9-benzenesulfonyl-3-chloro-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1.9 g, 4.94 mmol) and phosphorus pentachloride (3.1 g, 14.8 mmol) in phosphorus oxychloride (8 mL) was heated at 105° C. for 2 hours. The reaction mixture was cooled to ambient temperature and then the solvent removed in-vacuo to afford a residue. The resultant residue was dissolved in dichloromethane (300 mL) and then the solution was diluted with ice/water (300 mL). The layers were separated and the aqueous layer further extracted with dichloromethane. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with diethyl ether and dried to afford the title compound as a tan solid (1.17 g, 59%). 1H NMR (400 MHz, CDCl3): 9.81 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.26-8.22 (m, 2H), 7.66-7.66 (m, 1H), 7.53-7.53 (m, 2H).