Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20]Br)=[O:4].[CH3:22][O:23][C:24](=[O:37])[CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20][N:26]([CH2:25][C:24]([O:23][CH3:22])=[O:37])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(CC2CCOCC2)c1CBr
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1CC1CCOCC1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-6-oxo-1-(tetrahydro-pyran-4-ylmethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (511 mg, 1.21 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (279 mg, 1.15 mmol), sodium iodide (362 mg, 2.42 mmol) and potassium carbonate (334 mg, 2.42 mmol) in DMF (10 mL) was stirred at r.t. for 16 h. Brine (50 mL) was added, and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-80% EtOAc/hexanes) to give 411 mg of the title compound. MS: (+) m/z 607.12, 609.08 (M+Na, 79/81Br).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:12])[CH:10]=[CH2:11]>>[C:9]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)Cl
Reactant: Oc1ccc(O)cc1
Product: C=CC(=O)Oc1ccc(O)cc1

Procedure:
Compound 5 can be prepared, for example, by the following method. Namely, hydroquinone and acrylic acid chloride are reacted to obtain 4-hydroxyphenyl acrylate (Formula 6) as a half ester. On the other hand, a 4-alkoxycarbonyloxy benzoic acid is heated and refluxed in a mixture of carbon-tetrachloride (a solvent) and thionyl chloride, and excess thionyl chloride and carbon tetrachloride (solvent) are distilled off under reduced pressure to obtain a 4-alkoxycarbonyloxy benzoic acid chloride (Formula 7). Then, in the presence of a base such as trimethylamine, the 4-hydroxyphenyl acrylate (Formula 6) and the 4-alkoxycarbonyloxy benzoic acid chloride (Formula 7) are reacted to obtain the compound 5.
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH:23]([OH:37])[CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:38])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:39]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([C:23]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:28][CH2:29]3)=[O:37])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:38])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a solution of tert-butyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](hydroxy)methyl}piperidine-1-carboxylate (200 mg, 0.36 mmol) in dichloromethane (10 mL) was added Dess-Martin reagents (226 mg, 0.54 mmol). The resulting mixture was stirred at room temperature until the reaction was complete monitoring by LC/MS and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20-30% ethyl acetate in petroleum ether) to afford 150 mg of the desired product. MS (ESI+) [(M+H)+] 550.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.C1(C)C=CC=CC=1.[OH-].[Na+]>O>[CH:1]1([C:4]2[C:5]([C:6]#[N:7])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: N#CCC(=O)C1CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Into a glass flask having an internal volume of 300 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 11.6 g (106.6 mmol) of 3-cyclopropyl-3-oxopropanenitrile, 31.0 g (96.9 mmol) of 2-amino-4′-fluorobenzophenone methanesulfonate having a purity of 97.3% and 121 mL of toluene were put in an atmosphere of nitrogen, and reaction was carried out under 0.04 MPa at 80° C. for 2 hours while distilling off the formed water. After completion of the reaction, the reaction liquid was cooled to room temperature, 60 mL of water and 13.3 mL (106.4 mmol) of a 8 mol/L sodium hydroxide aqueous solution were added thereto to make the reaction liquid basic, followed by liquid separation, and the obtained organic layer was analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 27.9 g (yield: 99%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:30][N:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32](Cl)=[O:33]>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:32](=[O:33])[N:31]([CH3:30])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)N(C)c3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
60 mg (0.14 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 22 mg (0.14 mmol, 1.0 eq.) of methyl(phenyl)carbamoyl chloride were reacted according to General Method 3. Yield: 37 mg (69% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:41]5[CH:40]=[C:39]([F:42])[CH:38]=[CH:37][C:36]=5[Cl:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cc(F)ccc5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-5-fluoro-phenylboronic acid. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Cl:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C>[Cl:23][C:24]1[N:29]=[C:28]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][S:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[C:27]([Cl:31])=[CH:26][N:25]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cccc(NS(=O)(=O)Cc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(CS(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of N-(3-aminophenyl)-1-(3-nitrophenyl)methanesulfonamide-hydrogen chloride (0.10 g, 0.29 mmol) and 2,4,5-trichloropyrimidine (0.065 g, 0.35 mmol) in DMF (1 mL) was added potassium carbonate (0.20 g, 1.4 mmol). The resulting mixture was stirred overnight at room temperature. Additional triethylamine (0.099 mL, 0.71 mmol) was added and stirred again overnight. The reaction was then quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The crude was purified by column chromatography to give the desired product (0.080 g, 60%). LCMS for C17H13Cl2N5O4S (M+H)+: m/z=453.9, 455.9.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1OS(C(F)(F)F)(=O)=O)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:14]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(C)(C)C)c1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cccc(OC)c2)c(C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A dry round bottom flask containing 8.7 (1.40 g, 4.1 mmol), 3-methoxyphenylboronic acid (available from Aldrich) (1.27 g, 8.34 mmol), tetrakis(triphenylphosphine)palladium (0.49 g, 0.42 mmol), and potassium carbonate (1.71 g, 12.36 mmol) was evacuated and backfilled three times with argon. Dry DMF (12.0 mL) was added via syringe under argon, and the mixture was then heated to 100° C. and monitored by TLC. After 2 hours, the reaction was cooled to room temperature and diluted with water. The mixture was extracted three times with EtOAc and then concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-15% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 12.1 as a colorless oil (1.01, 82%). MS ESI (pos.) m/e: 299.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=1[CH3:36].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=4[CH3:36])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: Cc1cc(C(=O)O)ccc1N1CCC(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-3-methyl-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 4-bromo-3-methyl-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9].[N:33]1([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26][N:36]2[CH2:37][CH2:38][N:33]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)[CH2:34][CH2:35]2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1OC
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ccc5ccccc5n4)CC3)c3ccccc3-c3ccccc32)cc1OC

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-3,4-dimethoxy-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: Br[CH:2]([C:7](=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH2:18]([N:25]1[CH2:30][NH:29][C:28](=[S:31])[NH:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH2:18]([N:25]1[CH2:30][N:29]2[C:7]([OH:17])([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[S:31][C:28]2=[N:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CC(Br)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: S=C1NCN(Cc2ccccc2)CN1
Solvent: CO
Product: O=C(O)CC1SC2=NCN(Cc3ccccc3)CN2C1(O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 3-bromo-3-(m-nitrobenzoyl)propionic acid (3.78 g, 0.0125 mole) in methanol (50 ml) was mixed with a suspension of 5-benzyl-3,4,5,6-tetrahydro-s-triazin-2(1H)thione (2.6 g, 0.0125 mole) in the same solvent (150 ml). The mixture was warmed until a clear solution was obtained and allowed to stand for two hours. Evaporation of the solvent gave a yellow solid foam (5.3 g, 83%). 2.5 Grams of this material were dissolved in warm ethanol and a colourless solid gradually crystallised and was collected to give 3-benzyl-7-carboxymethyl-6-hydroxy-6-(m-nitrophenyl)-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazine hydrobromide (1.2 g), m.p. 147°-148° C. (decomposition).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].[CH2:6]([O:8][CH:9]=[CH2:10])[CH3:7].OS([O-])(=O)=O.[K+]>C([O-])([O-])=O.[Na+].[Na+]>[CH3:7][CH:6]([O:5][CH:2]([C:3]#[CH:4])[CH3:1])[O:8][CH2:9][CH3:10]
Reactant: C#CC(C)O
Reactant: C=COCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C#CC(C)OC(C)OCC
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of 200 g of but-3-yn-2-ol and 240 g of ethylvinyl ether was added dropwise, at 30° and under nitrogen atmosphere, to 2 g of previously dried KHSO4. After stirring for 2 hours at 30° the reaction mixture was neutralized with 10 g of Na2CO3, then filtered, the organic phase being finally distilled on a VIGREUX column to give 369 g (91% yield) of 2-(3-oxa-pent-2-yloxy)-but-3-yne having b.p. 31°/16 Torr.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@H:19]([O:26]C2CCCCO2)[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C@H:15]([O:33]C2CCCCO2)[CH2:14][C@H:13]1[Cl:40])(=[O:3])[CH3:2]>C(O)(=O)C.O.O1CCCC1>[C:1]([NH:4][C:5](=[O:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[C@H:15]([OH:33])[CH2:14][C@H:13]1[Cl:40])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](CCC=C(C)C)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@H]1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC=C(C)C)[C@H](O)C[C@H]1Cl
Yield: 59.7 %

Procedure:
460 mg of (13E)-(8R,9R,11R,12R,15R)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-19-methyl-13,18-prostadienoic acid acetylamide was stirred under argon at room temperature for 17 hours with 10 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then concentrated under vacuum, and the residue was purified by column chromatography on silica gel with hexane/0-100% ethyl acetate as the eluent, thus obtaining 197 mg of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.[H-].[Na+].ClC1[C:42]2[C:37](=[CH:38]C=C(S(N[C@@H]3CC[C@H](C(OC(C)(C)C)=O)CC3)(=O)=O)C=2)[C:36](Cl)=CN=1.NC(N)=N>COCCOC.C1(C)C=CC=CC=1.CCOC(C)=O.CCCCCC.CCOC(C)=O.CC(N(C)C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([O:25][C:37]([CH3:42])([CH3:38])[CH3:36])=[O:24])[CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CC1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H]3CC[C@@H](C(=O)O)CC3)cc12
Agent: Cl
Agent: N=C(N)N
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CC1
Temperature: 60 °C

Procedure:
cis-4-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride ##STR58## Guanidine hydrochloride (286 mg, 3.0 mmol) was added in one portion to a stirred suspension of NaH (56 mg, 80% dispersion by wt in mineral oil, 1.82 mmol) in DME (5 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of t-butyl cis-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (346 mg, 0.75 mmol) in DME (15 mL) was added and the mixture heated at 90° C. for 2 h. A second portion of guanidine (0.75 mmol)[prepared from guanidine hydrochloride (72 mg) and NaH (22 mg)] in DME (5 mL) was added and the mixture heated at 90° C. for 1 h. DMA (10 mL) was then added to the heterogeneous reaction mixture and the now homogeneous mixture heated for an additional 6 h. The solvents were evaporated in vacuo, the residue was quenched aqueous NH4Cl (10 mL), diluted with water (150 mL) and extracted with EtOAc (2×150 mL). The combined organic extracts were washed with water (100 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by repeated column chromatography upon silica gel using (i), pentane-EtOAc (100:0 to 25:75) and then (ii), PhMe-EtOAc (50:50 to 0:100) as eluant to give t-butyl cis-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (247 mg, 0.51 mmol). [A small amount of t-butyl trans-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyllamino}cyclohexanecarboxylate (20 mg) was also isolated.]
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(SC2C=CC=CC=2C(O)=O)C=CC=CC=1.S(Cl)(Cl)=O.[OH-].[NH4+:38]>CC(C)=O>[C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:38])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1Sc1ccccc1
Reactant: [NH4+]
Agent: O=C(O)c1ccccc1Sc1ccccc1
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: NC(=O)c1ccccc1Sc1ccccc1

Procedure:
Following the procedure described in Example 1, 2-(phenylthio)benzoyl chloride is prepared from 0.065 mole of 2-(phenylthio)benzoic acid and excess thionyl chloride. A solution of the oily acid chloride in 50 ml. of acetone is added dropwise with stirring to 100 ml. of concentrated ammonium hydroxide. The mixture is heated to refluxing for 3 hours. On cooling, the product separates and is collected.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[O:26]=[C:25]1[CH:24]([N:23]2[C:16](=[O:18])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][CH2:5][C:4]3[CH:19]=[CH:20][CH:21]=[C:2]([CH3:1])[CH:3]=3)[C:10]2=[O:12])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1cccc(COc2cccc(C(=O)O)c2C(=O)O)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(COc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Yield: 49.6 %

Procedure:
A mixture of 3-(3-methyl-benzyloxy)-phthalic acid (1.8 g, 6.4 mmol), alpha-amino-glutarimide hydrochloride (1.1 g, 6.8 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(3-methyl-benzyloxy)-isoindole-1,3-dione as a white solid (1.2 g, 48% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.16 min (99.9%); mp, 195-197° C.; 1H NMR (DMSO-d6) δ 2.00-2.07 (m, 1H, CHH), 2.33 (s, 3H, CH3), 2.54-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.33 (s, 2H, CH2), 7.15-7.85 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.00, 21.96, 30.92, 48.74, 70.08, 115.49, 116.58, 120.19, 124.40, 127.85, 128.40, 128.60, 133.26, 136.03, 136.98, 137.64, 155.53, 165.30, 166.77, 169.91, 172.75. Anal Calcd For C21H18N2O5: C, 66.66; H, 4.79; N, 7.40. Found: C, 66.50; H, 4.79; N, 7.34.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CC(C)=O>[CH3:15][O:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CN1CCNCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(=O)O
Temperature: 25 °C
Yield: 24 %

Procedure:
To solution of 5-chlorosulphonyl-2-methoxy-benzoic acid (0.5 g, 1.99 mmol) in acetone (5 ml) was added N-methylpiperazine (0.219 g, 2.19 mmol) and triethylamine (0.33 ml, 2.3 mmol) and the mixture stirred at RT. After 2 hours the reaction mixture was filtered and the collected solid washed with acetone, water and then diethylether to yield 2-methoxy-5-(4-methyl-piperazine-1-sulphonyl)-benzoic acid (150 mg, 24%). (LC/MS (acidic method): Rt 0.34, [M+H]+ 315).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[CH:11]([Cl:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Cl:13][CH2:11][CH2:12][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(Cl)Br
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: ClCCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
A mixture of benzimidazole (4.72g, 40 mmol), bromochloroethane (3.4 ml, 41 mmol), potassium carbonate (5.52 g, 40 mmol) and dimethylformamide (60 ml) was stirred at room temperature for 20 hours. To the reaction mixture were added ethyl acetate and water, which was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous sodium chloride solution, followed by drying (anhydrous sodium sulfate). The solvent was distilled off, and the residue was subjected to a silica gel chromatography (3.0×40 cm: ethyl acetate-hexane=2:1) to give 1-(2-chloroethyl)benzimidazole (5.56 g, 38%) as a colorless oily substance.