Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]([CH3:4])[CH2:3][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH3:6])[NH:11][CH:10]=1
Reactant: C=O
Reactant: Cc1cccc2[nH]ccc12
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cccc2[nH]cc(CN(C)C)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a chilled solution of dimethyl amine (30 mL, 40% in water, 120 mmol) and formalin (13 mL, 37% in water, 84 mmol) in glacial acetic acid (30 mL) is added 4-methyl indole (21 g, 165 mmol) at 0° C. The reaction is warmed to room temperature and stirred for 3 hours. The reaction mixture is brought to pH 12 by addition of 50% NaOH and ice, and the product extracted with methylene chloride. The organic layers are dried over Na2SO4 filtered and evaporated in vacuo to give the title compound that is used without further purification (33 g, 162 mmol, 98%) LC/MS (M++1): 205.7.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)=O)(C)(C)C.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17]>ClCCl>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[CH3:12][C:10]1([OH:13])[CH2:11][NH:8][CH2:9]1
Reactant: CC1(O)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CNC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, 3-hydroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.40 g, 2.13 mmol) was dissolved in dichloromethane (20 mL). The colorless solution was cooled to 0° C. and trifluoroacetic acid (6.5 ml) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to afford 3-methyl-azetidin-3-ol trifluoroacetate as light brown oil which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH3:4].[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:20][CH2:19]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccnc2)CC1
Product: N
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-bromopyridine (7.8 g, 49.4 mmol), 1-ter-butoxycarbonylpiperazine (9.2 g, 49.4 mmol), tetrakis(triphenylphosphine)palladium(0) (286 mg, 0.247 mmol), potassium tert-butoxide (11.1 g, 98.8 mmol) and anhydrous toluene (100 ml) was stirred at 80° C. for 0.5 hours. Water (100 ml) was added and the mixture was extracted three times with ethyl acetate (75 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as an oil. Yield 1.34 g, 10%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.CN(C=O)C.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27]>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:27]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(F)c(F)cc1[N+](=O)[O-]
Yield: 20.1 %

Procedure:
By using 2.00 g of 2,4,5-trifluoronitrobenzene, 3.43 g of triethylamine, 25 ml of DMF, 25 ml of THF and 1.58 g of glycine ethyl ester hydrochloride, 0.59 g (20%) of N-(4,5-difluoro-2-nitrophenyl)glycine ethyl ester was obtained.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:32][C:33]([F:36])([F:35])[F:34])=[C:17]([NH:19][S:20]([C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH:27]=2)(=[O:22])=[O:21])[CH:18]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:32]([C:33]([F:35])([F:34])[F:36])=[O:9])=[C:17]([NH:19][S:20]([C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH:27]=2)(=[O:21])=[O:22])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(Nc1cc(Cl)ccc1SC(F)(F)F)c1cc2ccccc2o1
Solvent: ClCCl
Product: O=S(c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1)C(F)(F)F

Procedure:
Following General Procedure D using 10 equivalents of mCPBA in refluxing CH2Cl2, the title compound was prepared from N-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
Reaction SMILES: [CH3:1]SC1SC2C=CC=CC=2N=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[N:24]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]([CH3:28])=[CH:26][CH:25]=1.[I:35][C:36]([I:39])([CH3:38])C>C(OCC)(=O)C>[I-:35].[I:39][CH2:36][CH2:38][CH2:1][N+:24]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]([CH3:28])=[CH:26][CH:25]=1
Reactant: CC(C)(I)I
Reactant: CSc1nc2ccccc2s1
Reactant: Cc1ccnc2ccccc12
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Product: Cc1cc[n+](CCCI)c2ccccc12
Product: [I-]

Procedure:
In the first step, 2-methylthiobenzothiazole (Aldrich Chemical Company, Milwaukee, Wis. is quaternized by heating at 120° C. with an equivalent of methyl p-toluenesulfonate (Compound 1A, also commercially available from TCI, Portland, Oreg.). N-(3-iodopropyl)-4-methylquinolinium iodide (Compound 1B) is prepared by heating lepidine (5.0 g, 35 mmol) with 100 g (340 mmol) of diiodopropane at about 100° C. for one hour. Ethyl acetate is added and filtered. Compounds 1A and 1B are condensed to yield 4-(3-methyl-2,3-dihydro-(benzothiazol)-2-yliden-(4)-methyl)-1-(3'-iodopropyl)-quinolinium iodide (compound 1C) using methods known in the art [e.g. Brooker, et al., supra]. For instance when 12.0 g (27.3 mmol) of 1B is stirred with 10.0 g (27.2 mmol) of 1A in 200 mL of methylene chloride in the presence of 3.8 mL of triethylamine overnight at room temperature, 11.14 g of 1C is obtained by filtration. A mixture of 0.72 g of 1C is then dimerized by heating in a sealed tube with 69 mg of N,N,N',N'-tetramethylpropanediamine in 5 mL of DMF at 130° C. for one hour. After the reaction mixture cools down to room temperature, 40 mL of MeOH is added and stored at -20° C. overnight. The red solid is filtered and recrystallized from DMF/MeOH again to yield the pure product. TOTO-1 TM has a quantum yield of 0.34 bound to calf thymus DNA.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][OH:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:26]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]=1[OH:39])[C:33](Cl)=[O:34])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:40]([C:37]1[CH:36]=[C:32]([CH:31]=[C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:38]=1[OH:39])[C:33]([O:19][CH2:18][CH2:17][S:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=1)=[O:34])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1cc(SCCO)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(SCCOC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
A solution of 9.8 g of 2-(3,5-di-tert-butyl-4-hydroxyphenylthio) ethanol and 3.1 g of pyridine in 40 ml of toluene was added at 15°-20° C. over five minutes to a solution of 9.4 g of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride in 50 ml of toluene. The reaction mixture was stirred at room temperature for 15 hours and then the resultant precipitate of triethylamine hydrochloride was removed by filtration. The solvent was removed in vacuo and the residue was recrystalized from n-heptane to give 15 g (84%) of a white solid, mp 136°-139° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[C:8]([CH:19]=1)[O:9][CH2:10][CH:11]([OH:18])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-:3])=[O:2].[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([F:26])([F:25])[C:21]([F:22])([F:23])[F:24])=[C:8]([CH:19]=1)[O:9][CH2:10][CH:11]([O:18][C:27](=[O:29])[CH3:28])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC(O)CN2CCCC2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OC(COc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F)CN1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Dissolved 1-(5-nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol (3.5 g) in CH2Cl2 (15 ml) added TEA (2.55 ml) and cooled to 0° C. Acetyl chloride (781.3 μl) was added dropwise, forming a suspension. The mixture was warmed to RT and stirred for 1.5 h. Additional acetyl chloride (200 μl) was added and the mix was stirred for another h. The mixture was diluted with CH2Cl2 and washed with sat. NaHCO3. The organic layer was removed, washed with brine and back extracted with CH2Cl2. Dried the combined organic layers over Na2SO4, filtered and concentrated in vacuo. The residue was purified over silica gel column (5:94.5:0.5 MeOH: CH2Cl2:NH4OH) to provide acetic acid 2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethyl ester as a yellow brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.Cl[C:15]1C(CO)=CC=C(C(F)(F)F)N=1.C(=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:15])[CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=1
Reactant: OCc1cc(Cl)nc(C(F)(F)F)c1
Reactant: OCc1ccc(C(F)(F)F)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc(Cl)nc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of [2-chloro-6-(trifluoromethyl)pyridin-4-yl]methanol (0.84 g, 4.0 mmol) and [2-chloro-6-(trifluoromethyl)pyridin-3-yl]methanol (0.84 g, 4.0 mmol) (as a mixture of regioisomers from Step A) in N,N-dimethylformamide (8.6 mL) was added potassium carbonate (3.3 g, 24 mmol), followed by methyl iodide (0.99 mL, 16 mmol). The reaction was stirred overnight. Additional DMF (10 mL), methyl iodide (2.0 mL, 32 mmol) and potassium carbonate (3.3 g, 24 mmol) were added and the reaction was stirred for 72 hours. Water was added into the reaction and the product was extracted with three portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/Hexanes allowed for isolation of desired isomer, contaminated with a small amount of the undesired isomer. Desired isomer: 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 7.50 (s, 1H), 4.53 (dd, 2H), 3.48 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([SH:33])[CH2:31][CH3:32].C(OCC)(=O)C>C(#N)CCC>[CH3:16][O:15][C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]([S:33][CH2:30][CH2:31][CH3:32])=[C:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:4]=[N:5]2)=[CH:8][CH:9]=1)=[O:14]
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(C(=O)OC)cc1

Procedure:
tert-butyl 5-chloro-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylate (Intermediate #9) (2.016 g, 6.0 mmol) was dissolved in butyronitrile (30 mL), potassium carbonate (2.48 g, 18 mmol) and propanethiol (678 μL, 7.5 mmol) were added and the mixture heated to reflux for 5 h. Ethyl acetate (150 mL) was added and the mixture washed with water (4×25 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (120 g silica 0-25% EtOAc/isohexane) to give the title compound as a clear pale yellow oil that slowly crystallised on standing to a white solid. (2.01 g, 89%)
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl.[NH2:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12].C(OCC)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([NH:16][C:14](=[O:15])[C@H:9]([CH2:10][C:11](=[O:13])[NH2:12])[NH2:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NC(=O)C[C@H](N)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: C=C(C)C(=O)NC(=O)[C@@H](N)CC(N)=O
Reaction time: 12 h

Procedure:
A 11.3 ml portion of methacrylic acid chloride, 1 g of asparagineamide hydrochloride (mfd. by Kokusan Kagaku) and 50 ml of diethyl ether were put into a 300 ml capacity eggplant type flask and stirred on an ice bath. Next, 20 ml of saturated potassium carbonate aqueous solution was added dropwise thereto. Thereafter, this was stirred on an ice bath for 30 minutes and then at room temperature for 12 hours. Diethyl ether layer in the thus obtained reaction liquid was discarded, and the water layer was dissolved in 100 ml of methanol. After filtration, the filtrate was concentrated under a reduced pressure and fractionated by a silica gel column using methanol as the developing solvent. The thus obtained amide compound fraction was purified using an ion exchange resin (“Dynaion (trade name) PA 412” mfd. by Mitsubishi Kagaku) After concentration under a reduced pressure and subsequent drying under a reduced pressure, 0.43 g of colorless crystals were obtained.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.Cl[C:31]([O:33][CH3:34])=[O:32]>C1COCC1>[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:14][CH2:15][C:16]([C:31]([O:33][CH3:34])=[O:32])([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a chilled solution of diisopropylamine (3.5 mL, 24.7 mmol) in THF (20 mL) at −78° C. was added n-BuLi (2M in hexane, 14.8 mL, 1.2 equiv.). The reaction mixture was stirred for 1 h. A solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (5 g, 20.6 mmol, 1 equiv.) in THF (15 mL) was added dropwise at −78° C. The reaction mixture was stirred for 1 h. Methyl chloroformate (1.7 mL, 22.6 mmol, 1.1 equiv.) was added to the above mixture. The reaction mixture was warmed to rt slowly while stirring. After 3 h, the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give 1-tert-butyl 4,4-dimethyl piperidine-1,4,4-tricarboxylate (6.2 g, quant.), which was used without further purification. LRMS (M+H+-Boc) m/z 202.1.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:25][C:23](=[O:24])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>CCOCC>[CH3:28][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39]([CH:22]1[CH2:21][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[O:25][C:23]1=[O:24])=[O:40])[CH3:27]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: O=C1CCC(c2ccc(F)cc2)O1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1CC(c2ccc(F)cc2)OC1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (1.40 g, 0.013 mol) in 90 mL ether, n-BuLi (0.013 mol) was added dropwise followed by 45 mL ether. After stirring for 5 minutes at -78° C. under a nitrogen atmosphere, a solution of γ-(4-fluorophenyl)-γ-butyrolactone (2.50 g, 0.013 mol) in 23 mL ether was added dropwise and the resulting solution was stirred for 20 minutes at -78° C. A solution of 2,6-diisopropylphenyl isocyanate in 23 mL ether was then added dropwise and the reaction mixture was allowed to gradually warm to room temperature and stir for 16 hours under a nitrogen atmosphere (J. F. Wolfe, et al, Synthetic Communications 17, 13 (1987)). The reaction mixture was then quenched with a saturated solution of ammonium chloride and extracted with methylene chloride. The layers were separated and the organic layer was washed two times with water, dried (Na2SO4) and concentrated in vacuo (30° C.) to afford a white residue. The residue was washed with hexane, filtered, and oven-dried (30° C.) to yield a white solid, 3.77 g (0.009 mol, 71.2%) of the title compound, mp 203°-205° C.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[C:4]1([S:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12](O)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=P(Cl)(Cl)Cl>C1C=CC=CC=1.ClC1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:12]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:10][C:11]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1
Reactant: O=C(O)C(Sc1ccccc1)c1ccc(Cl)cc1
Reactant: C[N-]C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: Clc1ccccc1
Product: CN(C)c1c(-c2ccc(Cl)cc2)sc2ccccc12

Procedure:
A solution of 15.3 g (50 mmol) of the dimethylamide of α-phenylthio-p-chloro-phenylacetic acid (colourless rods in a mixture of petroleum ether and benzene, mp 81°-83°) and of 23.0 g (150 mmol) of POCl3 in 160 milliliters of chlorobenzene is refluxed for 6 hours. By treatment similar to that of Example 29 the 3-dimethylamino-2-(4-chloro-phenyl)-benzo(b)thiophene is obtained in the form of a crude oily product which crystallises after trituration with ethanol: 11.1 g (77% of theory), yellow rods, mp 114°-116° (ethanol).
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:22]1([S:28]([NH:31][C:32]2[CH:33]=[C:34]([C@@H:38]([OH:58])[CH2:39][NH:40][C:41]([CH3:57])([CH3:56])[CH2:42][CH2:43][N:44]3[C:52]4[C:47](=CC(C(O)=O)=C[CH:51]=4)[CH:46]=[CH:45]3)[CH:35]=[CH:36][CH:37]=2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.CNC.[CH2:71]1[CH2:75][O:74][CH2:73][CH2:72]1>CN(C=O)C>[CH3:2][N:3]([CH3:4])[C:73]([C:72]1[CH:71]=[C:75]2[C:45](=[CH:46][CH:47]=1)[N:44]([CH2:43][CH2:42][C:41]([NH:40][CH2:39][C@@H:38]([C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([NH:31][S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:29])=[O:30])[CH:33]=1)[OH:58])([CH3:56])[CH3:57])[CH:52]=[CH:51]2)=[O:74]
Reactant: C1CCOC1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(CCn1ccc2cc(C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
EDCI (75 mg, 0.39 mmol) and HOBt (49 mg, 0.36 mmol) are added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid-hydrotrifluoroacetate (Example 6; 100 mg, 0.16 mmol) in 2 ml DMF. Then the reaction mixture is stirred for 60 minutes at RT and combined with DIPEA (66 μl, 0.39 mmol). After 10 minutes stirring at RT a solution of dimethylamine in THF (2.0M; 2.5 ml, 5.0 mmol) is added. After 22 hours stirring at RT the solvent is eliminated in vacuo and the residue is chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0]. After freeze-drying the salt is converted into the base in ethyl acetate with semisaturated sodium hydrogen carbonate solution.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[N:18]1[C:25](Cl)=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20]>CC(C)=O.O>[Cl:20][C:19]1[N:18]=[C:25]([NH:8][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)[N:24]=[C:22]([NH:8][CH:6]2[CH2:7][C:2]([CH3:11])([CH3:1])[NH:3][C:4]([CH3:10])([CH3:9])[CH2:5]2)[N:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
62.4 g of 2,2,6,6-tetramethyl-4-amino-piperidine in 200 ml of acetone and, at the same time, 42.4 g of sodium carbonate dissolved in 100 ml of water are added to a finely dispersed suspension of cyanuric chloride, prepared by adding 36.9 g of the latter in 200 ml of boiling acetone to 400 ml of ice water. The temperature is kept at 0°-5° C. by means of external cooling. After the addition is complete, the reaction mixture is allowed slowly to warm to room temperature and is stirred at this temperature for 3 hours. Filtering and recrystallisation of the product from ethyl acetate/hexane gives 46.3 g of a white crystalline product, melting point 270° C.
Reaction SMILES: [OH:1][C:2]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8](O)=[O:9])=O.O.[NH2:17][NH2:18]>>[OH:1][C:2]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]1[CH2:6][CH2:7][C:8](=[O:9])[NH:17][N:18]=1
Reactant: O=C(O)CCC(=O)c1cccc(O)c1O
Reactant: NN
Solvent: O
Product: O=C1CCC(c2cccc(O)c2O)=NN1

Procedure:
3-(2,3-Dihydroxybenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3 (i) to give 6-(2,3-dihydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Cl.C([N:4]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH3:35])[O:27][C:26]=1[C:36]([OH:38])=O.N>O.N1C=CC=CC=1>[CH3:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH3:35])[O:27][C:26]=1[C:36]([NH2:4])=[O:38]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1c(C)oc(C(=O)O)c1C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1c(C)oc(C(N)=O)c1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (248 mg, 1.30 mmol) and 1-hydroxybenzotriazole monohydrate (199 mg, 1.30 mmol) were added to a pyridine (4 ml) solution of the 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (250 mg, 1.18 mmol) obtained in Example 2 (1). After a 28% aqueous ammonia solution (0.19 ml, 11.8 mmol) was added, heated to 80° C. and stirred for 4 hours. The mixture was cooled to room temperature with stirring, and after addition of water to reaction mixture, precipitate was collected by filtration, thereby giving 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxamide (176 mg, 71%) as a white solid.