Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[CH3:16][O:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26])=[O:19]>N1C=CC=CC=1>[CH3:16][O:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[S:25]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)(=[O:27])=[O:26])=[O:19]
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccsc3C(=O)OC)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 7-amino-1H-indole-2-carboxylate (0.30 g) and pyridine (5 mL) was added 2-methoxycarbonyl-3-thiophenesulfonyl chloride (0.42 g) at 4° C., and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated, diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4-ethyl acetate.), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (550 mg, yield 92%) as pale-yellow crystals. melting point 173-174° C.
Reaction SMILES: [N:1]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:41])[N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[CH:31][CH:30]=1.C(N(CC)CC)C.O>C(C(C)=O)C>[CH2:39]([N:36]([CH2:37][CH3:38])[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:15][CH2:16][CH:11]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:3][C:2]3=[O:10])[CH2:12][CH2:13]2)=[CH:30][CH:31]=1)=[O:41])[CH3:40]
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCCCBr)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: O
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.8 %

Procedure:
4-(1,3-Dihydro-2H-benzimidazol-2-on-1-yl)piperidine (49 mg) was dissolved in methyl ethyl ketone (1.8 ml), added with the 1-bromo-3-[2-(4-diethylcarbamoylbenzyl)-phenoxy]propane (91 mg) obtained in Reference Example 1 and triethylamine (47 μl) and stirred at room temperature for 17 hours. The reaction mixture was added with water (2 ml) and extracted twice with ethyl acetate (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: dichloromethane:methanol=20:1) to obtain 49.7 mg of the title compound. Yield: 41%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH2:11]([N:13](CC)[CH2:14]C)C.CNC>ClCCl>[CH3:11][N:13]([CH3:14])[C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:9]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-pyridine-2-carbonyl chloride (1 eq) in dichloromethane was cooled to 0° C., whereupon triethylamine (2 eq) was added followed by dimethylamine (2 eq, 2M solution in THF). The solution was allowed to warm to room temperature and let stir overnight. It was then washed with 1M NaOH. The separated organic layer is dried over MgSO4, filtered, and concentrated to yield the desired product. HPLC, 1.82 min; MS: MH+=185.6
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:18]([Si:21]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[SH:22])([CH3:20])[CH3:19].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[N:7]([CH3:8])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:22][Si:21]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:18]([CH3:19])[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: CN(Cc1ccccc1I)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)[Si](Sc1ccccc1CN(C)C(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 160 °C
Yield: 167.9 %

Procedure:
(2-Iodo-benzyl)-methyl-carbamic acid tert-butyl ester (5.0 g, 14.4 mmol) in dry toluene (30 mL) was placed in two Emrys Optimizer EXP 20 mL tubes. To each tube tris(dibenzylideneacetone)dipalladium (66 mg, 0.072 mmol), bis(2-diphenylphosphinophenyl)ether (78 mg, 0.14 mmol), triisopropylsilanethiol (1.44 g, 7.56 mmol) and sodium tert-butoxide (900 mg, 9.36 mmol) were added sequentially. The tubes were sealed and subjected to microwave heating at 160° C. for 15 minutes. After cooling the mixture, the product was eluted through a plug of silica with ethyl acetate-heptane (1:10) to give 5.2 g (88%) of methyl-(2-triisopropylsilanylsulfanyl-benzyl)-carbamic acid tert-butyl ester. This product was dissolved in THF (70 mL) and cooled to 0° C. Tetrabutylammonium fluoride trihydrate (4.21 g, 13.3 mmol) dissolved in THF (40 mL) was added dropwise at 0° C. and the mixture was stirred at this temperature for 15 minutes. The crude mixture was poured onto a plug of silica gel and the product was eluted with ethyl acetate-heptane (1:2) to give 3.2 g (100%) of (2-mercapto-benzyl)-methyl-carbamic acid tert-butyl ester contaminated with traces of triisopropylsilane fluoride.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10]O)[O:8][C@@H:7]([N:12]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ClC(Cl)C(O)=O.[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=1[CH2:51][C:52](=[O:73])[CH:53]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CS(C)=O.N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:9](/[CH:10]=[CH:53]/[C:52](=[O:73])[CH2:51][C:45]2[C:46]([Cl:50])=[CH:47][CH:48]=[CH:49][C:44]=2[Cl:43])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)Cc1c(Cl)cccc1Cl
Reactant: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(Cl)Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](/C=C/C(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 23 h
Yield: 86.3 %

Procedure:
A solution of 2.759 g of 3'-O-acetyl-2'-deoxy-5-ethyluridine, 5.75 g of dicyclohexylcarbodiimide and 0.375 ml of dichloroacetic acid in 24 ml of dimethyl sulphoxide was stirred at room temperature for 27 hours. 0.375 ml of pyridine and 4.286 g of [3-(2,6-dichlorophenyl)-2-oxopropylidene]triphenylphosphorane were added and the mixture was stirred for a further 23 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in 100 ml of ethyl acetate and the solution was washed twice with 100 ml of water each time, dried over anhydrous sodium sulphate and evaporated. The resulting gum was subjected to flash chromatography on a column of silica gel using ethyl acetate/hexane (2:1) for the elution. There were obtained 3.84 g of (E)-3'-O-acetyl-5'-[3-(2,6-dichlorophenyl)-2-oxopropylidene]-2',5'-dideoxy-5-ethyluridine in form of a white solid of melting point 165° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[CH:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[N:7]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:30])=O>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[CH:5]=[C:4]([Cl:30])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cccc(-c2cc(=O)[nH]c(N)n2)c1
Solvent: CCN(CC)c1ccccc1
Product: N#Cc1cccc(-c2cc(Cl)nc(N)n2)c1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
2.00 g (9.42 mmol) of 3-(2-amino-6-oxo-1,6-dihydropyrimidin-4-yl)benzonitrile (from example LV) are suspended in 10 ml of phosphoryl chloride. Over a period of one hour, 180 mg (1.23 mmol) of N,N-diethylaniline are added dropwise, and over a period of a further hour, the mixture is heated to 115° C. The mixture is then heated at RF for one hour. The mixture is allowed to cool to RT and poured into ice water. The mixture is extracted twice with ethyl acetate and the solvent is removed under reduced pressure. The residue is suspended in water. With ice-cooling, the solution is neutralized by addition of conc. sodium hydroxide solution. Saturated sodium carbonate solution is added, and the mixture is stirred at RT overnight. The precipitate is filtered off with suction and washed with water. This gives the title compound.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].C(N(CC)CC)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(=O)N1CCN(N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(NC(=O)Oc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-acetyl-4-aminopiperazine dihydrochloride (300 mg) in dichloromethane (9 ml) was added triethylamine (0.77 ml) and phenyl chloroformate (0.261 ml) at ambient temperature. The mixture was stirred at the same temperature for 1 hour, and washed with water (×2). The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was crystallized from ethyl acetate and diethyl ether to give phenyl N-(4-acetyl-1-piperazinyl)carbamate (0.29 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH2:27][C:28]1[S:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:27][C:28]1[S:29][C:30]([C:33]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:34])=[CH:31][N:32]=1
Reactant: Nc1ncc(C(=O)O)s1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(N)s1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (250 mg, 0.70 mol) was dissolved in DMF (4 mL), and 2-amino-1,3-thiazole-5-carboxylic acid (110 mg, 0.76 mmol) was added. PYBOP (543 mg, 1.04 mmol) and diisopropylethylamine (0.61 mL, 3.50 mmol) were subsequently added, and the mixture was stirred at room temperature overnight. The desired product was isolated via HPLC to give the title compound (80.0 mg, 24%): HPLC MS RT=1.03 min, MH+=486.3; 1H NMR (MeOH-d4+2 drops TFA-d) δ: 7.90 (1H, d), 7.79 (1H, d), 7.50-7.60 (2H, m), 3.70 (2H, m), 3.30 (2H, d), 3.20 (2H, q), 2.10 (2H, s), 1.35 (10H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl>[OH-].[Na+].O>[CH3:32][N:33]([CH2:34][CH2:35][O:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1)[CH3:37]
Reactant: O=S(=O)(c1cccc(O)c1)n1ccc2ccccc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(S(=O)(=O)n2ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 103.2 %

Procedure:
1-(3′-Hydroxybenzenesulfonyl) indole (0.602 mmol, 0.163 grams) (obtained from preparation 1) was taken in 50 mL two neck round bottom flask and added tetrahydrofuran (7 mL). To the above mixture potassium carbonate (1.24 mmol, 0.171 grams) was added and stirred for a period of 15-20 minutes. The free base generated from 2-dimethylaminoethyl chloride hydrochloride (2.48 mmol, 0.358 grams), by dissolving it in a solution of 3 mL 40% aqueous sodium hydroxide, diluted with 5 mL water and extracting free base with toluene (3 mL) was directly charged to reaction mixture. Reaction mixture was kept on reflux temperature and the progress was monitored. After completion of reaction, the reaction mass was cooled to room temperature, poured onto 25 mL of water and extracted the product with ethyl acetate (10 mL×4). Combined organic extracts were dried over sodium sulfate and the volatiles were removed under the reduced pressure to obtain 0.214 grams crude compound. The compound was purified by column chromatography using silica gel (100-200 mesh), the eluents being ethyl acetate and n-hexane (2:3) to obtain pure compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C[Si](C)(C)[N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].I[CH2:20][CH:21]([CH3:23])[CH3:22]>C1COCC1>[CH3:20][CH:21]([CH3:23])[CH2:22][CH:13]1[CH2:14][CH2:15][NH:11][C:12]1=[O:16]
Reactant: CC(C)CI
Reactant: C[Si](C)(C)N1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1CCNC1=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 41 %

Procedure:
A solution of LDA (2.0M, 111 mL, 222 mmol) and THF (300 mL) is cooled to -78° C. and a solution of 1-trimethylsilyl-2-pyrrolidinone (29.4 g, 221 mmol) in THF (145 mL) is added. After stirring for 45 minutes at -78° C., the enolate solution is added via cannula over 1 hour to a solution of 1-iodo-2-methylpropane (42.7 g, 232 mmol) in THF (200 mL) at -78° C. The solution is allowed to warm slowly and stirred at room temperature overnight. The reaction is quenched by the addition of 50 mL of acetic acid. Aqueous workup (EtOAc, MgSO4) and purification by column chromatography (30→100% EtOAc/hexane) gives 12.8 g of the title compound as an oil.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:46][CH2:45][C:19]4([N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][N:21]([CH2:30][C:31]5[CH:43]=[CH:42][CH:41]=[CH:40][C:32]=5[C:33]([O:35]C(C)(C)C)=[O:34])[C:20]4=[O:44])[CH2:18][CH2:17]3)[C:5]2=[O:47])[CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:46][CH2:45][C:19]4([N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][N:21]([CH2:30][C:31]5[CH:43]=[CH:42][CH:41]=[CH:40][C:32]=5[C:33]([OH:35])=[O:34])[C:20]4=[O:44])[CH2:18][CH2:17]3)[C:5]2=[O:47])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)n(C4CC4)c4ccccc43)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)n(C4CC4)c4ccccc43)CC2)C1=O
Yield: 28.6 %

Procedure:
A solution of tert-butyl 2-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (230 mg, 0.362 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 5 h. The mixture was concentrated in vacuo and purified using preparative thin layer chromatography in 10% methanol in dichloromethane. The pure extract was treated with 4M hydrogen chloride solution in dioxane to afford the hydrogen chloride salt of the title compound as cream crystals (60 mg, 28.8%); 1H NMR (400 MHz, DMSO-d6): δ 0.86-0.90 (m, 2H); 1.01-1.06 (m, 2H); 1.98 (d, 2H, J=14.4 Hz); 2.13 (bs, 2H); 2.88-2.99 (m, 3H); 3.2 (bs, 2H); 3.65-3.73 (m, 4H); 3.91 (t, 2H, J=6.8 Hz); 4.67 (s, 2H); 4.93 (s, 2H); 6.80 (t, 1H, J=7.2 Hz); 7.01 (d, 2H, J=8.4 Hz); 7.08-7.10 (m, 2H); 7.19-7.24 (m, 2H); 7.26-7.28 (m, 1H); 7.31 (d, 1H, J=7.6 Hz); 7.43 (t, 1H, J=6.8 and 7.6 Hz); 7.55-7.59 (m, 1H); 7.92 (dd, 1H, J=1.2 Hz); 10.50 (bs, 1H); 13.2 (bs, 1H); MS for C34H37N5O4 m/z 580.12 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:14]([F:17])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23]>C(Cl)(Cl)Cl>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH:23][S:6]([CH2:5][CH2:4][CH2:3][C:2]([F:1])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)CCCC(F)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCCN
Solvent: ClC(Cl)Cl
Product: CN(C)CCCNS(=O)(=O)CCCC(F)(C(F)(F)F)C(F)(F)F
Yield: 93 %

Procedure:
The 4,5,5,5-tetrafluoro-4-trifluoromethyl-pentanesulfonyl chloride (7.1 grams) can be dissolved in 40 mL of chloroform and added to a solution of 8.6 mL of 3-dimethylaminopropylamine in 40 mL of chloroform at 0° C.-5° C. drop-wise over 45 minutes (Tmax=5° C.) to form a mixture. The mixture can be washed successively with saturated bicarbonate solution (80 mL), water (80 mL), and brine (80 mL). The organic layer can be separated, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford 8 grams (93%) of 4,5,5,5-tetrafluoro-4-trifluoromethyl-pentane-1-sulfonic acid (3-dimethylamino-propyl)-amide by NMR and LC/MS analysis.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14](=O)[CH3:15]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]([CH3:15])=[CH2:2]
Reactant: CC(=O)c1cc(F)ccc1Br
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C(C)c1cc(F)ccc1Br
Reaction time: 89 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (5.69 g, 15.91 mmol) in diethyl ether (80 mL) at room temperature was added n-BuLi (2.5 M in hexanes, 6.37 mL, 15.91 mmol) dropwise. The reaction immediately turned bright orange and the resulting solution was stirred for 35 min at room temperature after which time a solution of l-(2-bromo-5-fluorophenyl)ethanone (3.14 g, 14.47 mmol) in diethyl ether (20 mL) was added dropwise. The reaction lost the bright yellow color and became almost completely white with a significant amount of white precipitate, the reaction was stirred for 89 h after it was quenched by addition of water and extracted with diethyl ether (3×), the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-5% Diethyl Ether/Hexanes) to afford 1-bromo-4-fluoro-2-(prop-1-en-2-yl)benzene. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (dd, J=8.8, 5.3 Hz, 1H), 6.92 (dd, J=9.0, 3.1 Hz, 1H), 6.85 (td, J=8.3, 3.1 Hz, 1H), 5.24 (t, J=1.7 Hz, 1H), 4.96 (s, 1H), 2.08 (d, J=1.4 Hz, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:3][N:2]=1.[OH-].[Na+]>CO.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:3][N:2]=1
Reactant: CCOC(=O)CCCCCCCc1cncc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Ethyl 8-(isoquinolin-4-yl)octanoate (0.8 g) was dissolved in a mixture of methanol (10 ml) and water (5 ml) followed by addition of sodium hydroxide (1 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was adjusted to pH 5 with 2N-HCl and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure, and the resulting crude crystalline crop was recrystallized from ethyl acetate to provide the title compound (0.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])=[N:23][NH:24][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccccc2OC)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(-c3ccccc3OC)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(2-methoxybenzoyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([CH2:30][CH2:31][Cl:32])=[CH:23][C:10]=1[NH:11][C:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])(O)[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([CH2:30][CH2:31][Cl:32])=[C:23]2[C:10]=1[NH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:18]2[C:19]([O:21][CH3:22])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(O)(Nc1cc(CCCl)c([N+](=O)[O-])cc1OCc1ccccc1)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1[nH]c2c(OCc3ccccc3)cc([N+](=O)[O-])c(CCCl)c2c1C(=O)OC
Yield: 23 %

Procedure:
2-(5-Amino-4-benzyloxy-2-nitro)phenylethanol was heated at 25-100° C., preferably refluxing, with dimethyl acetylenedicarboxylate in methanol to give dimethyl 2-[2-benzyloxy-5-(2-hydroxyethyl)-4-nitroanilino]malate in 96% yield. Subsequent treatment of dimethyl 2-[2-benzyloxy-5-(2-hydroxyethyl)-4-nitroanilino]malate at 0-50° C., preferably at room temperature, with carbon tetrachloride in methylene chloride and triphenylphosphine provided dimethyl 2-[2-benzyloxy-5-(2-chloroethyl)-4-nitroanilino]malate in 85% yield. Next, dimethyl 2-[2-benzyloxy-5-(2-chloroethyl)-4-nitroanilino]malate was treated with Palladium (II) acetate in N,N-dimethylacetamide at 40-120° C., preferably at 70° C., to give dimethyl 7-benzyloxy-4-(2-chloroethyl)-5-nitroindole-2,3-dicarboxylate in 23% yield. Treatment of dimethyl 7-benzyloxy-4-(2-chloroethyl)-5-nitroindole-2,3-dicarboxylate with 10% palladium-on-carbon in THF at an atmospheric pressure of hydrogen and at 0-35° C., preferably at room temperature, gave an amine intermediate which was directly coupled at 0-50° C., preferably at room temperature, with 5,6,7-trimethoxyindole-2-carboxylic acid and 5-(benzofuran-2-carboxamido)indole-2-carboxylic acid in the presence of EDCI in DMF at room temperature for three days to give the target achiral seco-duocarmycin analogue dimethyl 4-(2-chloroethyl)-7-hydroxy-5-(5,6,7-trimethoxyindole-2-carboxamido)indole-2,3-dicarboxylate and dimethyl 4-(2-chloroethyl)-7-hydroxy-5-[5-(benzofuran-2-carboxamido)indole-2-carboxamido]indole-2,3-dicarboxylate in 20 and 16% yield, respectively.