Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=[CH:14][C:13]([CH:16]([N:18]([CH2:26][C:27](O)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:58][C:59]1[CH:60]=[CH:61][C:62]([C:73]([F:76])([F:75])[F:74])=[C:63]([C:65]([N:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)=[O:66])[CH:64]=1>CN(C=O)C.O>[C:22]([O:21][C:19](=[O:20])[N:18]([CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:11][CH:12]=1)[CH3:17])[CH2:26][C:27]([N:70]1[CH2:71][CH2:72][N:67]([C:65](=[O:66])[C:63]2[CH:64]=[C:59]([F:58])[CH:60]=[CH:61][C:62]=2[C:73]([F:76])([F:74])[F:75])[CH2:68][CH2:69]1)=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(c1ccc(-c2ccccc2)cc1)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(c1ccc(-c2ccccc2)cc1)N(CC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 25 %

Procedure:
DIPEA (182 mg, 0.24 mL, 1.4 mmol) was added to a stirred solution of [(1-biphenyl-4-yl-ethyl)-tert-butoxycarbonyl-amino]-acetic acid (100 mg, 0.28 mmol) in DMF (5 mL). HOBT (42 mg, 0.31 mmol) and EDCI (135 mg, 0.7 mmol) were then added at room temperature. After 2 minutes, (5-Fluoro-2-trifluoromethyl-phenyl)-piperazin-1-yl-methanone hydrochloride salt (105 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (using 60-120 silica gel and 30-50% EtOAc in hexane as eluent) to afford 43 mg (27.56% yield) of (1-biphenyl-4-yl-ethyl)-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester, LCMS Purity: 96.02%. 1H NMR (CDCl3): δ 7.78 (t 1H), 7.64-7.5 (s, 4H), 7.5-7.3 (m, 5H), 7.24 (d, 1H), 7.04 (m, 1H), 5.8-5.2 (bd, 2H), 4.0 (s, 1H), 3.8 (s, 3H), 3.6-3.2 (m, 5H), 3.1 (s, 3H), 1.5 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>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].C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: CS(=O)(=O)c1ccc(C2=C(c3cc(F)cc(F)c3)C(=O)CC2)cc1
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
To a mixture of 2-bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (664 mg, 2.11 mmol), 3,5-difluorophenylboronic acid (832 mg, 5.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (83 mg, 0.09 mmol), and triphenylphosphine (96 mg, 0.36 mmol) was added 40 mL of 3:1:1 toluene:n-propanol:water and the mixture was purged with nitrogen. After stirring 10 min, diethylamine (1.1 mL, 10.6 mmol) was added and the solution was heated to reflux for 4 h. The mixture was cooled and partitioned between 1M NaOH and EtOAc. The organic phase was washed with water, 1M HCl and brine, and dried over MgSO4. Purification by silica gel chromatography, eluting with 50% CH2Cl2 /hexanes, followed by crystallization from CH2Cl2 /ether/hexanes gave the title compound (223 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.C([Li:15])CCC>C1COCC1>[Li:15][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: [Li]N1C(C)(C)CCCC1(C)C

Procedure:
A solution of LTMP was prepared by reaction of 2,2,6,6-tetramethylpiperidine (0.151 mL, 0.896 mmol) in THF (5.6 mL) and n-butyllithium (0.358 mL, 0.896 mmol) at −30° C. and then at 0° C. for 30 min.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)C.[CH2:8]([Li])CCC.C(#N)C.[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]([OH:20])([CH3:8])[C:1]#[N:4]
Reactant: CC(C)NC(C)C
Reactant: O=Cc1ccccc1F
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(O)(C#N)c1ccccc1F
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
To a stirring solution of diisopropylamine (5.95 mL, 42.7 mmol) in tetrahydrofuran (100 mL) at −70° C. under nitrogen was added a solution of n-butyllithium (17.6 mL, 44 mmol, 2.5 M in hexane). After the addition was complete, the mixture was stirred at −70° C. for 10 minutes and removed cooling bath for 5 minutes. The mixture was cooled back to −70° C., acetonitrile (2 mL, 38.1 mmol) was added and the reaction mixture was then stirred at −70° C. for 30 minutes. 2-fluoro-benzaldehyde (5 mL, 47.4 mmol) was added and the resulting solution was allowed to warm to ambient temperature. After 18 hours at ambient temperature, saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture and it was concentrated at reduced pressure. The resulting crude product was diluted with ethyl acetate (125 mL), washed with water (75 mL) followed by saturated aqueous sodium chloride (50 mL). The organic layer was concentrated and purified by column chromatography (80 g silica gel cartridge) eluting with ethyl acetate/hexane (10%-30%) to give the product as a colorless oil (6.5 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13].N1CCCCC1>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:26]\[C:23]1[NH:22][C:21]([CH3:28])=[C:20]([C:18]([NH:17][CH2:16][CH2:15][N:14]([CH2:29][CH3:30])[CH2:12][CH3:13])=[O:19])[C:24]=1[CH3:25]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(Br)cc32)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To the solution of 5-bromoindolin-2-one (262 mg, 1.24 mmol) in EtOH (5 ml) was added N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (298 mg, 1.12 mmol) and piperidine (112 μL, 1.13 mmol). The mixture was stirred at 80° C. for 1 hour. After cooled down to room temperature, the reaction mixture was concentrated, filtrated, and washed with EtOH to give (Z)-5-((5-bromo-2-oxoindolin-3-ylidene)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (368 mg) as orange solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]1([NH:21][C:22]2[CH:31]=[C:30]3[C:25]([C:26](=[O:39])[C:27]([CH:37]=O)=[CH:28][N:29]3[CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:24][C:23]=2[F:40])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1.C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[CH:15]1([NH:21][C:22]2[CH:31]=[C:30]3[C:25]([C:26](=[O:39])[C:27]([CH2:37][NH:41][C:42]4[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=4)=[CH:28][N:29]3[CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:24][C:23]=2[F:40])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: Nc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=c1c(CNc2ccc(O)cc2)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reaction time: 24 h

Procedure:
169 mg of sodium triacetoxyborohydride was added to a mixed solution 10 ml of 1,2-dichloroethane and 0.05 ml of acetic acid of 142 mg 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde and 66 mg of 4-aminophenol, followed by stirring for 24 hours. Aqueous saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and subsequent filtration, concentration under a reduced pressure was carried out. The resulting residue was purified by silica gel column chromatography and then crystallized from ethyl acetate to obtain 46 mg of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-{[(4-hydroxyphenyl)amino]methyl}quinolin-4(1H)-one.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:12])[CH3:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCO2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
2,3-Dihydrobenzofuran (10 g, 83.2 mmol) was dissolved in dichloromethane (400 mL). The resultant mixture was added sequentially with acetyl chloride (11.8 mL, 167 mmol) and aluminum chloride (33.3 g, 250 mmol) at −10° C., and stirred at −10° C. for 0.5 hour. The reaction solution was added with 5% aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 1-(2,3-Dihydrobenzofuran-5-yl)ethanone (13.4 g, yield 99%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][N:6]=[N+:7]=[N-:8])[CH3:2].Cl[C:11](=[CH2:14])[C:12]#[N:13].Cl>O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][N:6]1[CH:14]=[C:11]([C:12]#[N:13])[N:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C=C(Cl)C#N
Agent: Cl
Solvent: O
Product: CCOC(=O)Cn1cc(C#N)nn1
Temperature: 25 °C

Procedure:
4.1 g (31.9 mmol) azidoacetic acid ethyl ester and 2.8 g (31.9 mmol) 2-chloroacrylonitrile are stirred in 32 ml water at a bath temperature of 80° C. for 16 h. After cooling to RT, the solution is rendered acid with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. 50 ml ethanol and 10 drops of conc. sulfuric acid are added to the residue and the mixture is stirred under reflux for 16 h. For working up, the reaction mixture is concentrated in vacuo, ethyl acetate is added to the residue, the suspension is washed with half-concentrated sodium bicarbonate solution and the organic phase is dried over sodium sulfate. The solvent is removed completely on a rotary evaporator and the solid is dried in vacuo.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH:8]2[O:10][C:7]2([CH3:11])[CH2:6][CH2:5]1)=[CH2:3].[Cl-].[Li+].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(O)C>[C:2]([CH:4]1[CH2:5][CH2:6][C:7]([CH3:11])([OH:10])[CH:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)([CH3:1])=[CH2:3]
Reactant: C=C(C)C1CCC2(C)OC2C1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Product: C=C(C)C1CCC(C)(O)C(N2CCOCC2)C1
Yield: 49.5 %

Procedure:
(+)-Limonene oxide (13.2 g, 0.087 moles) was dissolved in ethanol (40 ml) and lithium chloride (5.9 g, 0.14 moles) was added with stirring. Morpholine (11.4 g, 0.13 moles) was added and the reaction mixture was heated at 60° for 48 hours. The solvent was evaporated under reduced pressure and the residue taken up in dichloromethane. Washed with water. Extracted into 2M hydrochloric acid and washed with dichloromethane. Basified to pH 10 by addition of 2M sodium hydroxide. Extracted with diethyl ether and washed with water. Dried over anhydrous magnesium sulphate and evaporated the solvent under reduced pressure to give the product as a yellow oil (10.3 g)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:18][CH:17]([C:19](=[O:21])[CH3:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[NH:15]1[CH2:18][CH:17]([C:19](=[O:21])[CH3:20])[CH2:16]1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1CNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (8 mL) was added to a suspension of 3-acetyl-azetidine-1-carboxylic acid tert-butyl ester (800 mg, 4.0 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 4 hours and concentrated to dryness to afford the title product as a colorless gum (800 mg, 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:41][CH3:42])=[C:7]([CH:40]=1)[CH2:8][C@H:9]1[C:15](=[O:16])[N:14]([C:17]([NH:19][C@@H:20]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([N+:33]([O-])=O)[CH:25]=2)[CH2:21][CH2:22][CH3:23])=[O:18])[CH2:13][C:12](=[N:36][O:37][CH2:38][CH3:39])[NH:11][CH2:10]1.C(OCC)(=O)C>[Zn].C(O)(=O)C>[NH2:33][C:26]1[CH:25]=[C:24]([C@H:20]([NH:19][C:17]([N:14]2[C:15](=[O:16])[C@H:9]([CH2:8][C:7]3[CH:40]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=3[O:41][CH3:42])[CH2:10][NH:11][C:12](=[N:36][O:37][CH2:38][CH3:39])[CH2:13]2)=[O:18])[CH2:21][CH2:22][CH3:23])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: CCC[C@@H](NC(=O)N1CC(=NOCC)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC[C@@H](NC(=O)N1CC(=NOCC)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
To the compound 101 (2.76 g) in an ethyl acetate (32 ml) and acetic acid (16 ml) suspension, zinc powder (2.88 g) was added under ice cooling, and the mixture was stirred at that temperature for 20 minutes and at room temperature for 4 hours. The reaction mixture was filtered by a glass filter spread with Celite®, then the residue was washed with ethyl acetate (50 ml). The filtrate and the washings were combined, then the mixture was successively washed with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, then concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate/methanol=6/6/1) to obtain the title compound (2.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[F:34][C:35]([F:56])([F:55])[O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][O:36][C:35]([F:56])([F:34])[F:55])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:50][CH2:51]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: FC(F)(F)OCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCC(Nc3nc4ccccc4n3CCOC(F)(F)F)CC2)(c2ccccc2)C1
Reaction time: 48 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.86 g, 1.83 mmol), (1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydrochlorici acid salt (1.66 mmol), triethylamine (1.0 mL, 7.2 mmol), and sodium iodide (0.31 g) in acetonitrile (24 mL). Heat to reflux. After 48 hours, evaporate in vacuo to give a residue. Partition the residue between dichloromethane and a saturated aqueous sodium, bicarbonate solution. Separate the layers and extract the organic layer with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:14]=1[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:11])=[O:10].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:11])=[O:10]
Reactant: COc1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(S(N)(=O)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(O)ccc1NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 2-(2,3-dichloro-benzenesulfonylamino)-5-methoxy-benzenesulfonamide (4.8 g, 11.68 mmol) in DCM (200 mL) at −20° C., BBr3 (1M in DCM, 60 mL, 60 mmol) was added dropwise over 30 minutes. The reaction mixture was allowed to warm to RT and the stirring was continued overnight. The reaction mixture was then cooled to −20° C., quenched by addition of methanol (20 mL) and volatiles were removed under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (100 mL). The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from methanol to afford the title compound (4.6 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:29][OH:30]>C1(C)C=CC=CC=1>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:13](=[O:16])[CH2:14][C:29](=[O:30])[CH2:8][CH2:7][C:6]4[CH:15]=[CH:2][CH:3]=[CH:4][CH:5]=4)=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)CC(=O)CCc5ccccc5)c4c(c23)C1=O
Temperature: 20 °C
Yield: 53 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 8 mL of toluene, magnetically stirred at 20° C., 95 mg of the compound of example 21 were added. The mixture was refluxed during 4.5 hours and then allowed to cool to 20° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 81 mg (yield: 53%) of the desired product (formula below) as a red powder.
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].Br[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(O)C.C(OCC)(=O)C>O>[CH2:12]([O:11][C:9]([C:8]1[N:2]=[C:1]([SH:3])[S:4][CH:7]=1)=[O:10])[CH3:13]
Reactant: NC(=S)[S-]
Reactant: CCOC(=O)C(=O)CBr
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1csc(S)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ammonium dithiocarbamate ##STR5## (1.10 g) in water (10 ml) were added ethyl bromopyruvate (1.95 g) and ethanol (5 ml) at ice-cooling. After stirring at room temperature for 1 hour, the mixture was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with saturated sodium chloride solution (×2), dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give 4-ethoxycarbonyl-2-mercaptothiazole (1.21 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH2:35])=[CH:4][N:3]=1.O=[C:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH:35][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CN)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NC/C=C/c2cnc(N)c3c(-c4ccc(NC(=O)c5cc6ccccc6n5C)c(OC)c4)csc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of N-(4-{4-amino-7-[(1E)-3-aminoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.050 g, 0.104 mmol) and ethyl 4-oxo-1-piperidinecarboxylate (0.017 g, 0.087 mmol) in dichloroethane (1.5 mL) was added sodiumtriacetoxy borohydride (0.036 g, 0.173 mmol). The resulting solution was allowed to stir at room temperature for 12 hours. Upon completion, the reaction solution was treated with an aqueous solution of 10% sodium hydroxide (3 mL) and dichloromethane (3 mL). The two layers were stirred for 15 minutes, followed by filtration through an Empore™ cartridge, and removal of the solvent. The resulting crude product was purified by trituration of the residue in ethanol and collection of the title compound (0.030 g, 45%) as a white powder. LCMS (Conditions a) Rt 3.57 minutes, 639.4 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.01 (dd, J=8.2 Hz, J=7.8 Hz, 1H), 7.95 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.35 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.08 (dd, J=8.2 Hz, 1.9 Hz, 1H), 6.67 (d, J=16.0 Hz, 1H), 6.29 (td, J=16.4 Hz, J=5.9 Hz, 1H), 5.61 (s (br), 1H), 4.04 (s, 3H), 4.02 (q, J=7.02 Hz, 2H), 3.91 (s, 3H), 3.88 (m, 2H), 3.42 (d, J=5.5 Hz, 2H), 2.87 (m, 2H), 2.67 (m, 1H), 1.83 (m, 2H), 1.19 (m, 2H), 1.18 (t, J=7.02 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>ClCCl.O>[CH3:25][N:26]([CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4])[CH2:27][CH2:28][O:29][CH3:30]
Reactant: CNCCOC
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COCCN(C)CC(=O)N1CCc2cc(OC)c(N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and N-methyl-2-(methyloxy)ethanamine (1.4 g, 15.2 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT overnight. The reaction mixture was diluted with 100 mL of water, the organic solvents were washed with water (2×100 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting residue was dissolved in 10 mL of EA, 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added, and the reaction was stirred at RT overnight under a balloon of H2 pressure. The catalyst was removed via filtration and the solvent was evaporated under reduced pressure to yield the 1-({methyl[2-(methyloxy)ethyl]amino}acetyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine as a white solid (3.1 g, 89%). 1HNMR (400 MHz, DMSO-d6) δ ppm: 2.28(s, 3H), 2.62 (t, J=5.77 Hz, 2H), 2.94 (t, J=8.24 Hz 2 H), 3.19 (s, 3H), 3.25(s, 2H), 3.41 (t, J=5.77 Hz, 2 H), 3.68(s, 3H), 4.04 (t, J=8.33 Hz,2H), 4.61 (s, 2H), 6.67 (s, 1 H), 7.52 (s, 1 H).