Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=S)[NH:11][NH2:12].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[S:2][CH3:1])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CSc1ccccc1NC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccccc2SC)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of 15 g (0.07 mole) of 4-[2-(methylthio)phenyl]-3-thiosemicarbazide and 11.96 g (0.07 mole) of ethyl 2-chloroacetoacetate (97%) in 100 mL of absolute ethanol was stirred under nitrogen atmosphere for 1 hr at room temperature. The reaction was slightly exothermic and the mixture took on a yellow color as most of the solid dissolved. The mixture was treated with 50 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1.5 hr. The mixture had darkened to a deep, clear, orange color, with only a trace of insoluble material which was removed by filtering through a sintered glass filter. The solvent was removed in vacuo giving a yellow-orange solid (18.6 g). The solid was recrystallized from acetone, 17.4 g (85% yield), mp 135°-158° C. Thin layer chromatography indicated two impurities (10% methanol/benzene on silica gel). This crude product was recrystallized from benzeneligroin to give 12.1 g (59% yield), mp 126° -128° C. (some solid remained and melted at 158°-160° C.). Thin layer chromatography indicated that one of the two impurities had been removed. The solid was dissolved in methylene chloride and chromatographed on a 250 g column of Florisil® (60-100 mesh). The column was eluted with methylene chloride. The solid obtained was recrystallized from benzene-ligroin giving 4.6 g (22.5%) of product, mp 140.5°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7]2.[CH:20](OC(=O)C)=[O:21]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=[O:21])[CH2:7]2
Reactant: CCOC(=O)CNC1CCc2c(F)cc(F)cc2C1
Reactant: CC(=O)OC=O
Solvent: ClCCl
Product: CCOC(=O)CN(C=O)C1CCc2c(F)cc(F)cc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A solution of ethyl [(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]acetate (7.15 g, 25.6 mmol) in 20 mL of methylene chloride under argon was cooled to approximately 0° C. Acetic formic anhydride (9.7 mL, 67.3 mmol) was cooled to 0° C. and added over 5 to 10 minutes. The mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature. The solvent was removed by co-evaporation with toluene (3×50 mL). Crystallization of the residue under high vacuum gave ethyl [(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino]acetate (7.68 g, 25.0 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22](=[S:24])[NH2:23])=[CH:18]2)(=[O:11])=[O:10].[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[CH2:32]([O:31][C:26](=[O:30])[CH2:27][CH:28]1[S:24][C:22]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:11])=[O:10])[CH3:25])=[N:23][CH2:29]1)[CH3:33]
Reactant: CC#CC(=O)OCC
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A mixture of 7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indole-2-carbothioamide (2.3 g), ethyl but-2-ynoate (1.5 mL), tributylphosphine (1.5 mL), toluene (25 mL) and tetrahydrofuran (25 mL) was stirred for 3 hr at room temperature. The reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-5:5) to give the title compound (1.23 g, yield: 41%) as a pale-brown amorphous solid.
Reaction SMILES: [OH-].[Na+].O.NN.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[CH3:16])[N:10]=1)(=O)[CH3:7]>C(O)COCCO>[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[N:10]=1)[CH3:7]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCc1cccc(CC)n1
Temperature: 120 °C
Yield: 58.3 %

Procedure:
A mixture of NaOH (14.7 g, 0.37 mol), hydrazine monohydrate (15 mL) and 2,6-diacetylpyridine (6 g, 36.8 mmol) suspended in diethylene glycol (27 mL) was cautiously heated to 120° C. for 16 hours. The mixture was cooled to room temperature and partitioned between H2O and ether. The ether extracts were washed with 1 N NaOH, dried over MgSO4 and concentrated to a clear oil. Flash column chromatography (0% to 15% EtOAc in hexanes) gave the product as a clear oil (2.9 g, 58%). 1H NMR (400 MHz, CDCl3): δ 1.29 (t, J=7.8 Hz, 3 H), 2.80 (d, J=7.8 Hz, 2 H), 6.97 (d, J=2.0 Hz, 2 H), 7.51 (t, J=7.6 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:40][C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:30][CH:29]=5)=[N:21][N:22]([CH2:24][CH2:25][NH:26][CH3:27])[CH:23]=4)=[C:13]3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[OH-].[Na+].[CH2:43]=O.O>CO.[OH-].[OH-].[Pd+2]>[CH3:27][N:26]([CH3:43])[CH2:25][CH2:24][N:22]1[CH:23]=[C:19]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:40][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=4)=[CH:12][C:13]=23)[C:20]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:32][CH:33]=2)=[N:21]1
Reactant: C=O
Reactant: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
To N′-(4-{4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(methylamino)ethyl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea.3TFA (300 mg, 0.34 mMol) in MeOH (10 mL) was added with stirring at RT aq. 1 N NaOH (1.1 mL, 1.1 mMol), 37 wt. % CH2O in water (50 uL, 0.67 mMol) and 20% Pd(OH)2/C (Pearlman's catalyst) (˜10 mg). A balloon of H2 was attached and the reaction stirred at RT for 3 days. The reaction was evaporated to dryness under vacuum, taken up in (9:1) CHCl3/iPrOH (15 mL) and treated with excess methyl isatoic anhydride polystyrene resin (˜500 mg, >1.8 mMol/g). After stirring at RT for 4 h the reaction was filtered, rinsed with (9:1) CHCl3/iPrOH, and the filtrate concentrated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (56.6 mg, 30%) as a white solid. ESMS [M+H]+: 551.6
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cl:9][C:10]1=[C:11]([Cl:17])[C:12]([O:14][C:15]1=O)=[O:13].C(O)(=O)C>CCOCC>[CH:1]1([N:8]2[C:15](=[O:14])[C:10]([Cl:9])=[C:11]([Cl:17])[C:12]2=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: NC1C=CCCCC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1C(Cl)=C(Cl)C(=O)N1C1C=CCCCC1
Yield: 70.7 %

Procedure:
A mixture of 2-cycloheptenylamine (1.01 g), dichloromaleic anhydride (1.67 g) and acetic acid (10 ml) was heated under reflux for 3 hours. After cooling, ether (20 ml) was added to the reaction mixture which was then washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The deposited crystal was purified by recrystallization from hexane to obtain 1.67 g of N-(2-cycloheptenyl)dichloromaleinimide [Compound (217)].
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[O:6]1[C:8]([CH3:10])([CH3:9])[CH2:7]1>>[CH2:1]([NH:5][CH2:7][C:8]([CH3:10])([CH3:9])[OH:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: CC1(C)CO1
Product: CC(C)CNCC(C)(C)O

Procedure:
Isobutylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isobutyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isobutyl-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2,4-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,4-1-dichlorophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]2[CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]>C1C=CC=CC=1>[C:1]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([O:9][CH3:8])=[CH:18][CH:17]=2)[CH:13]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[C:14]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)C(=O)N2
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(CCNC(C)=O)C(=O)N2C(C)=O

Procedure:
Acetic anhydride (0.5 ml) is added with stirring to N-[2-(5-methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]-acetamide (120 mg) dissolved in benzene (5 ml). The mixture is heated for 1 h in refluxing benzene. The solvent is evaporated off and the crude product is separated on a silica plate. N-[2-(1-acetyl-2-oxo-5-methoxyindol-3-yl)ethyl]acetamide (6) is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: Cl
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCN3CCOCC3)c2)c2ccc(F)cc21
Yield: 70.2 %

Procedure:
Following the general method as outlined in Example 41 Step 1, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 250 mg; 0.73 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (272 mg; 1.46 mmol), 233 mg (70%) of the title compound was obtained as a brown solid after purification by a silica gel chromatography (petroleum ether/EtOAc=1/1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:18])[C:12]=3[C:11]3=[N:19][O:20][C:21]([CH3:22])=[C:10]3[C:9]2=[O:23])[CH2:3]1.[C:24]1([NH:30][CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=N)C.CC1C=C(C)C=C(C)N=1>CN(C)C=O>[Cl:18][C:13]1[C:12]2[C:11]3[C:10](=[C:21]([CH3:22])[O:20][N:19]=3)[C:9](=[O:23])[N:8]([CH:4]3[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:32](=[O:33])[CH2:31][NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:3]3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Reactant: O=C(O)CNc1ccccc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)CNc3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous dimethylformamide (10 mL) in a nitrogen atmosphere was used to dissolve 5-(3-aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one (50 mg; 0.151 mmol), N-phenylglycine (29.6 mg; 0.196 mmol; 1.3 equiv), 1-hydroxy-7-azabenzotriazole (26.7 mg; 0.196 mmol; 1.3 equiv), 1-[3-(dimethylamino)propyl[-3-ethylcarbodiimide hydrochloride (37.6 mg; 0.196 mmol; 1.3 equiv), and 2,4,6-trimethylpyridine (199 μL; 1.51 mmol; 10 equiv). After overnight stirring at room temperature, the reaction solution was treated in a manner similar to Example 159. The resulting material was purified by three consecutive radial chromatography runs on a 2 mm thick silica gel rotor with a 1% methanol/dichloromethane (v/v) mobile phase, a 1% methanol/0.25% triethylamine/dichloromethane (v/v/v) mobile phase, and a 5% acetonitrile/dichloromethane mobile phase. The desired product was isolated as a white solid 56% yield (30 mg). MS(ES) calc'd: [M+M]+=465.16 m/z; [M−H]−=463.16 m/z; [M+OAc]−=523.16 m/z. Found: 465.1 m/z; 463.2 m/z; 523.2 m/z.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.Br[CH2:24][CH2:25][CH2:26][Cl:27]>O1CCCC1>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:12][CH2:11]1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: ClCCCBr
Reactant: CCCCCCC(=O)NC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCC(=O)NC1CCN(CCCCl)CC1

Procedure:
A mixture of 4-heptanoylaminopiperidine (7.49 g; preparation 16), triethylamine (9.79 ml) and 1-bromo-3-chloropropane (5.38 ml) in 200 ml of dry tetrahydrofuran was refluxed for 4 hours, then a further 9.79 ml of triethylamine and 5.38 ml of 1-bromo-3-chloropropane were added. The reaction mixture was refluxed overnight, then concentrated to dryness, treated with 100 ml of saturated aqueous potassium carbonate solution and extracted with ethyl acetate (2×100 ml). The organic extracts were pooled, dried over sodium sulfate and concentrated to dryness to give 15 g of an oil which was purified by silica gel chromatography (eluent chloroformlmethanol 9:1) to give, after crystallization from 30 ml of hexane, 6.12 g of the product, m.p. 68-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]3[C:14]4=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]4[CH:18]=[CH:19][CH:20]=3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
A mixture of 4-chlorophenylboronic acid (407 mg), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (240 mg), diacetoxycopper (316 mg), triethylamine (0.604 mL), and powdered 4A MS (1.5 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (132 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8](=[O:13])[C:7]([C:14]([NH:16][C:17]2[C:22]([CH2:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:25][CH3:26])=[O:15])=[C:6]1[CH3:27])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[Br:34]Br>C(Cl)Cl>[Br:34][C:9]1[C:8](=[O:13])[C:7]([C:14]([NH:16][C:17]2[C:18]([CH2:25][CH3:26])=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:23][CH3:24])=[O:15])=[C:6]([CH3:27])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10]=1[CH2:11][CH3:12]
Reactant: BrBr
Reactant: CCCCn1c(CC)cc(=O)c(C(=O)Nc2c(CC)cccc2CC)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCn1c(C)c(C(=O)Nc2c(CC)cccc2CC)c(=O)c(Br)c1CC
Reaction time: 6 h
Yield: 72.3 %

Procedure:
To a mixture of 700 mg (1.90 mmol) of 1-butyl-6-ethyl-N-(2,6-diethylphenyl)-1,4-dihydro-2-methyl-4-oxo-3-pyridinecarboxamide, 14 ml of methylene chloride and 1.2 g (7.40 mmol) of sodium carbonate was added a solution of 303 mg (1.90 mmol) of bromine in 5 ml of methylene chloride under vigorous stirring. After the completion of addition the mixture was stirred for 6 hours. The insoluble product in methylene chloride was filtered off and the filtrate was concentrated in vacuo to give a crystalline residue. The residue was recrystallized from benzene and cyclohexane to afford 615 mg of the title compound having mp. 132.5°-133.5° C.
Reaction SMILES: [CH2:1]([C:11]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][S:21][C:15]=3[C:14]=2[S:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:22]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:22][C:12]1[S:13][C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[S:17][C:18]=2[C:11]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCc1csc2c1sc1ccsc12
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCc1c(Br)sc2c1sc1ccsc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3-decanyldithieno[3,2-b:2′,3′-d]thiophene (91) (9.03 g, 0.027 mol) was dissolved in DMF (100 mL). To this solution, N-bromosuccinimide (NBS) (4.78 g, 0.027 mol) in DMF(50 mL) was added dropwise in the dark under argon. The resulting mixture was stirred at 0° C. for three hours. GC/MS showed a single peak at 415. This solution was poured into water (500 mL). Organic solution was extracted with hexane (3'100 mL). The combined organic solutions were washed with brine (2×50 mL) and water (50 mL). After drying over MgSO4, the hexane was evaporated. The crude product was purified by column chromatography and eluted with hexane to yield the target compound (10.1 g, 90.2%). 1H NMR: solvent, CD2Cl2. δ 7.39 (d, 1H), 7.29 (d, 1H), 2.74 (t, 2H), 1.74-1.33 (m, 16H), 0.89 (t, 3H). 13C NMR: 140.89, 140.63, 136.00, 131.55, 129.22, 126.58, 121.04, 108.89, 32.31, 29.94, 29.73 (overlap), 29.35, 28.49, 23.09, 14.27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[S:63]1[C:71]2[CH2:70][CH2:69][NH:68][CH2:67][C:66]=2[CH:65]=[CH:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][C:71]3[S:63][CH:64]=[CH:65][C:66]=3[CH2:67]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1cc2c(s1)CCNC2
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCc4sccc4C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[O:14][C:15](=[O:29])[CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C:18](=O)[CH2:17]4)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].Cl.[CH3:31][O:32][NH2:33].N1C=CC=CC=1.[Cl-].[NH4+]>C(O)C>[CH3:31][O:32][N:33]=[C:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([C:15](=[O:29])[O:14][C:13]3[C@H:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:10][CH2:11]4)[CH2:17]1
Reactant: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)CC1C(=O)O3
Reactant: CON
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CC[C@]2(C)C3=C(OC(=O)C2C1)[C@@H]1CC[C@H]([C@@H](C)CCCC(C)C)[C@@]1(C)CC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
Compound 1 (40 mg, 0.10 mmol) obtained in Example 1 was dissolved in ethanol (5 mL), and O-methylhydroxyamine hydrochloride (25 mg, 0.30 mmol) and pyridine (0.024 mL, 0.03 mmol) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative thin layer chromatography to obtain the title compound (39 mg, 93%) as an E/Z mixture.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:41])=[C:11]([CH3:40])[C:12]=1[C:13]([C:15]1[CH:34]=[CH:33][C:18]([O:19][S:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([OH:32])[CH:24]=2)(=[O:22])=[O:21])=[C:17]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43].[I-].[Mg+2].[I-]>CCOCC>[C:42]([O:32][C:25]1[CH:24]=[C:23]([S:20]([O:19][C:18]2[CH:33]=[CH:34][C:15]([C:13]([C:12]3[C:11]([CH3:40])=[C:10]([CH3:41])[O:9][C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])=[CH:16][C:17]=2[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:22])=[O:21])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])(=[O:44])[CH3:43]
Reactant: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccccc4)oc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
A stirred solution containing 4-[4-(2-benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.235 g, 0.409 mmol), acetic anhydride (3.3 mL) and magnesium iodide (0.113 g, 0.409 mmol) in ether (8 mL) was refluxed for 0.5 h. The reaction was allowed to cool to ambient temperature, quenched with H2O (100 mL), extracted with ether and concentrated. The mixed anhydride/product was dissolved in THF (6 mL), treated with H2O (6 mL) and refluxed for 0.5 h. The reaction was allowed to cool to ambient temperature, quenched with H2O (100 mL), extracted with ether and concentrated. Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 18 & 25% EtOAc/pet ether step gradient followed by crystallization from acetone/hexane gave 0.201 g (80%) of the title compound as an off white solid, mp 55-90° C. 1H NMR (DMSO-d6) δ 1.23-1.32 (m, 2 H), 1.50-1.53 (m, 2 H), 1.64-1.72 (m, 4 H), 1.76 (s, 3 H), 2.17 (s, 3 H), 2.23 (s, 3 H), 2.92 (quintet, 1 H), 3.79 (s, 2 H), 6.98-7.00 (m, 2 H), 7.15-7.23 (m, 4 H), 7.53 (dd, 1 H), 7.58 (d, 1 H), 7.84 (d, 1 H), 7.88 (dd, 1 H), 8.12 (d, 1 H) 13.7 (br s, 1 H). mass spectrum (-ESI) m/z 615 (M-H). Anal. Calcd. for C34H32O9S.0.5H2O: C, 65.27; H, 5.32; N, 0.00. Found: C, 65.33; H, 5.30; N, 0.03.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10](O)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BrH:13]>C(O)(=O)C.C(Cl)Cl>[Br:13][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:11]
Reactant: CC(O)c1cccc([N+](=O)[O-])c1
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(Br)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
26.15 g (156 mmol) of 1-(3-nitrophenyl)ethanol are dissolved in 130 ml of glacial acetic acid, and 55 ml (313 mmol) of 33% HBr in glacial acetic acid are added dropwise with ice cooling. The reaction mixture is stirred at room temperature for 5 days. The mixture is subsequently diluted with 300 ml of DCM, washed with 3×200 ml of H2O and 200 ml of saturated NaHCO3 solution, dried over sodium sulfate and evaporated to dryness, and the residue is crystallised from petroleum ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.BrC1C=CC=C2C=1NC=C2.C([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:27]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: c1ccc2[nH]ccc2c1
Agent: Brc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(N2CCNCC2)c2[nH]ccc2c1
Temperature: 25 °C
Yield: 54 %

Procedure:
The Boc protected indole (200 mg, 1.5 mmol) prepared from 7-bromoindole and N-Boc piperazine as described in Step 1 of Preparation 54A is dissolved in DCM (1 mL). TFA (1 mL) is added and the mixture is stirred at r.t. for about an hour. The mixture is then concentrated to oil, which is taken up in methanol and freebased via SCX purification to afford about 164 mg (54%) of the final compound.