Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][CH:5]=1.[CH2:12]([Br:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C>[Br-:19].[CH2:12]([N+:6]1[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:11])[CH:9]=[CH:8][C:7]=1[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)[n+](Cc2ccccc2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.5 %

Procedure:
To a solution of 6-methylnicotinic acid methyl ester (10 g, 66 mmol) in ethyl acetate (70 ml) was added benzyl bromide (9.5 ml, 80 mmol) and the mixture was stirred at 60–70° C. for 3 hours. The mixture was cooled to room temperature and was filtered. The residue was washed twice with ethyl acetate/hexane and dried in vacuo to give 1-benzyl-5-(methoxycarbonyl)-2-methylpyridinium bromide (1.59 g, 7%).
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[I-:11].[Na+].[CH2:13]([N:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>CC(C)=O>[I-:11].[I:11][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N+:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(Cl)Cl)cc1
Reactant: CCCCN(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCC[N+](CCCC)(CCCC)Cc1ccc(CI)cc1
Temperature: 25 °C

Procedure:
To a mixture of α,α-dichloro-p-xylene (50 g, 28.6 mmol) and sodium iodide (8.6 g, 57 mmol) in acetone (100 mL) was added tri-n-butylamine (3.7 g, 20.0 mmol). The reaction mixture was stirred at room temperature under argon for several days after which time TLC examination showed completion of the reaction. The reaction mixture was filtered and the solvent was removed under reduced pressure to give an oily residue. The residue was washed with pentane several times and dried to give a yellow solid. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][CH:11](O)[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2.S(Cl)([Cl:27])=O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][CH:11]([Cl:27])[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C2CCC(C2)C1CCC(O)CCC1C2CCC(C2)C1(C)C
Solvent: c1ccncc1
Product: CC1(C)C2CCC(C2)C1CCC(Cl)CCC1C2CCC(C2)C1(C)C
Temperature: 25 °C

Procedure:
A solution of 16.6 gm. of 1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentanol in 25 ml. of dry pyridine is cooled to -10° C. There is then added with good agitation, 14.3 gm. of thionyl chloride over a 15 minute period. The solution is allowed to warm to room temperature and gradually heated over a period of 4 to 5 hours to 100° C. After an additional two hours at 100° C. the excess thionyl chloride is removed by vacuum stripping and the reside mixed with cracked ice. Three 100 ml. ether extractions are used to remove the halide, the diethyl ether extracts are washed with 4 × 200 ml. ice water, the ether layer separated, dried over anhydrous magnesium sulfate, filtered and stripped. The residue of di-substituted pentyl chloride may be further purified by distillation in vacuo or is suitable for further reaction as such.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=O)cc1OC
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tryptamine (5.0 g, 0.0312 mol) and 3,4-dimethoxy benzaldehyde (5.7 g, 0.0312 mol) in CH2Cl2 (220 mL) was added TFA (4.5 mL, 0.0584 mol). The deep blue solution was stirred at room temperature for 20 h. The reaction mixture was neutralized with NaHCO3 (4.9 g, 0.0584 mol) in H2O (50 mL) and the organic layer washed with brine (2×100 mL). The reaction mixture was dried with MgSO4 and the solvent evaporated. Product was isolated by column chromatography (silica gel; CH3OH:EtOAc=1:9) as a yellowish oil, which solidified slowly upon standing at room temperature.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:46])[C@@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@H:32]3[S:31][CH2:30][C:29]=2[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[S:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C(OC([C@@H]2N3C(=O)[C@@H](NC(=O)CC4C=CC=CC=4)[C@H]3SC=C2C2C=CC=CC=2)=S)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:46])[C@@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C@H:32]3[S:31](=[O:9])[CH2:30][C:29]=2[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:27])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3ccccc3)CS[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2[C@@H](C(=S)OC(c3ccccc3)c3ccccc3)C(c3ccccc3)=CS[C@H]12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3ccccc3)CS(=O)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of 410 mg (2.03 mmols) of m-chloroperbenzoic acid in 10 ml of methylene chloride is added to a solution of 1.10 g (1.85 mmols) of a mixture of isomers consisting of 7β-phenylacetylamino-3-phenylthio-3-cephem-4-carboxylic acid diphenylmethyl ester and 7β-phenylacetylamino-3-phenylthio-2-cephem-4α-carboxylic acid diphenylmethyl ester in 11 ml of methylene chloride at 0° C. and the mixture is stirred in an ice bath for 30 minutes. The reaction mixture is diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and the organic phase is dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on silica gel thick layer plates with toluene/ethyl acetate, 1:1. 7β-Phenylacetylamino-3-phenylthio-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide of Rf value ~0.38 (silica gel; toluene/ethyl acetate, 1:1) is obtained and after recrystallisation from methylene chloride/diethyl ether melts at 180° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH:10]1[C:15]([N+]([O-])=O)=CC=C(O)[CH:11]=1.S(=O)(=O)(O)O.[OH-].[Na+]>OCC(CO)O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[N:7]=[CH:15][CH:10]=[CH:11]2
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: COc1ccc2ncccc2c1
Temperature: 70 °C
Yield: 83.8 %

Procedure:
A mixture of p-methoxyaniline (24.6 g, 0.2 mol), ferrous sulfate (8.34 g, 0.03 mol), glycerol (73.6 g, 60 mL), p-nitrophenol (16.68 g, 0.12 mol), and concentrated sulfuric acid (10 mL) was heated gently to 70° C. Then a second portion of concentrated sulfuric acid (25 mL) was added dropwise to the reaction mixture and it was stirred at reflux for 8 hours. After cooling down to room temperature, the reaction mixture was basified to pH=5.5 with 15% aqueous sodium hydroxide solution in an ice bath. The resulting precipitate was filtered, dried and 16 g of 6-methoxy-quinoline was obtained as a yellow solid (50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:5]([NH:7][C@H:8]([CH2:26][CH2:27][OH:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22](=NO)[CH3:23])[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6].[BH4-].[Na+].[CH2:38]1[CH2:42][O:41]CC1.C[OH:44]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:34])[CH3:35])[C:5]([NH:7][C@H:8]([CH2:26][CH2:27][OH:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22]3([CH3:23])[O:44][CH2:38][CH2:42][O:41]3)[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6]
Reactant: CO
Reactant: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn(C)c(C4(C)OCCO4)n3)cc2)cc1Cl
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 3 (3.0 g, 10.8 mmol) in THF/MeOH (10 mL/10 mL) was slowly added NaBH4 (407 mg, 10.8 mmol). The mixture was stirred for 10 min, quenched by saturated NH4Cl and partitioned between EtOAc and H2O. The organic layer was washed with Sat NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give 4 (3.0 g, 99%), which was used without further purification. LRMS (M+H+) m/z 281.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)(=[O:32])=[O:31].O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:40][CH:39]=3)[N:10]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Cc1c(Br)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cn2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
To a solution of 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (Int. 15, 55 mg, 0.148 mmol) in DMF (3 mL) was added cesium carbonate (58 mg, 0.177 mmol) followed by 4-(methylsulfonyl)benzyl bromide (40 mg, 0.163 mmol) and the mixture was stirred at RT for 20 hrs. Further amounts of cesium carbonate (25 mg) and 4-(methylsulfonyl)benzyl bromide (20 mg) were added and stirring was continued for 2 hrs. Water was added and the mixture was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as a yellow solid (49 mg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](Cl)=[O:11].[OH:13][C:14]12[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[C:18]1([NH:27][C:28](=[O:30])[CH3:29])[C:17]1[CH:31]=[CH:32][C:33]([CH:35]([CH3:37])[CH3:36])=[CH:34][C:16]=1[O:15]2>C1COCC1>[C:10](=[O:11])([O:9][CH3:8])[O:15][C:16]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:17]=1[C:18]1([NH:27][C:28](=[O:30])[CH3:29])[C:19](=[O:26])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]1=[O:13]
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.1 %

Procedure:
Triethylamine (0.24 ml, 1.77 mmol) and methylchloroformate (0.11 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.10 g, 14%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][C:10]1([CH3:18])[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12](O)[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:9][C:10]1([CH3:18])[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12]([O:2][C:1]2[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=2)[CH2:11]1
Reactant: CC1CC(O)CC(C)(C)C1
Reactant: Oc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CC(Oc2cccc(O)c2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
In a four necked flask (1 L) sufficiently dried, substituted with nitrogen, and equipped with a dropping funnel, Dimroth condenser tube, thermometer and stirring blade, resorcinol (42 g, 0.38 mol), 3,3,5-trimethylcyclohexanol (54 g, 0.57 mol) and triphenylphosphine (150 g, 0.57 mol) were dissolved in dried tetrahydrofuran (200 ml) under a nitrogen gas stream, and a mixed solution of diisopropyl azodicarboxylate (100 g, 0.5 mol) and dried tetrahydrofuran (150 ml) was dropped for 1 hour while cooling with an iced saline solution. Next, it was stirred at room temperature for 12 hours. After the reaction terminated, 30% hydrogen peroxide (75 ml) was dropped through the dropping funnel for 10 minutes, then the reaction solution was dissolved in 1 L toluene, and washed three times with 500 ml water. Toluene was distilled away by evaporation, and the residue was purified by column chromatography using hexane and ethyl acetate as developing solvents, to obtain a red brown objective product (hereinafter, referred to as R-4A) (19.5 g, 22% yield, 99% GC purity).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.[O:21]=[C:22]1[CH:27]([N:28]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1>>[O:21]=[C:22]1[CH:27]([N:28]2[C:18](=[O:20])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH2:7][C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:12]2=[O:14])[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1
Reactant: Cc1ccc(CNc2cccc(C(=O)O)c2C(=O)O)o1
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: Cc1ccc(CNc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)o1
Yield: 20 %

Procedure:
3-[(5-Methyl-furan-2-ylmethyl)-amino]-phthalic acid (5 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The residue was purified by preparative HPLC (Symmetry C18, isocratic, 35/65 acetonitrile/water) to give 0.31 g (20%) of product as a yellow solid: mp 305-307° C.; 1H NMR (DMSO-d6) δ 11.10 (s, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H), 6.93 (t, J=6.0 Hz, 1H), 6.22 (d, J=2.9 Hz, 1H), 5.98 (d, J=1.9 Hz, 1H), 5.07 (dd, J=5.3 and 12.5 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 2.97-2.82 (m, 1H), 2.62-2.44 (m, 2H), 2.22 (s, 3H), 2.06-1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.77, 170.02, 168.77, 167.21, 151,04, 150.02, 145.80, 136.04, 132.08, 117.57, 110.96, 109.63, 108.27, 106.34, 48.55, 38.94, 30.95, 22.10, 13.24; Anal. Calcd. For C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 61.75; H, 4.71; N, 11.15.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][OH:19])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C(C)=CC=CC=1C.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:12][CH2:11]1)[CH3:8])=[O:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C[C@H]1CC[C@H](C#CCO)CC1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CN(C[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 8.16 g (29 mmol) of trans-[4-(3-hydroxy-prop-1-ynyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester in 230 ml methylenechloride was treated at 0° C. with 2.48 ml (31.9 mmol) of methanesulfonylchloride and 5.05 ml (43.5 mmol) of 2,6-lutidine. The reaction mixture was stirred over night to room temperature. The reaction was cooled (0° C.) and treated again with 0.68 ml (8.7 mmol) of methanesulfonylchloride and 1.68 ml (14.5 mmol) of 2,6-lutidine and stirred for 24 hours. Water (35 ml) was added and the reaction was stirred for 5 minutes. After extraction with aqueous saturated NaHCO3/ether (3×), the organic phases were washed with aqueous 10% NaCl, dried over sodium sulfate and evaporated to yield 12.5 g of crude trans-methanesulfonic acid 3-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexyl}-prop-2-ynyl ester as brown oil, MS: 360 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:17]([C:18]([O-:20])=O)=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[NH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:17]([C:18]([NH2:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3cccc(C(=O)[O-])c3[nH]2)cc1
Reactant: N
Product: COc1ccc(-c2nc3cccc(C(N)=O)c3[nH]2)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
The acetate salt of methyl (2-(4′-methoxy-phenyl)benzimidazole-4-carboxylate was dissolved in excess liquid ammonia and heated at 100° C. in a sealed pressure vessel at 40 atmospheres overnight. The ammonia was allowed to evaporate, and the solid residue was collected and washed with ice cold water (3×5 ml). Recrystallisation from aqueous methanol afforded the title compound (226.4 mg, 80%); mp 261-263° C.; Found: C, 66.07; H, 4.23; N, 15.29. C15H13N3O2. 0.2CH3OH requires C, 66.70; H, 5.08; N, 15.35; vmax/cm−1 3321.47, 3140.72, 1656.23, 1608.25, 1421.43, 1242.55; δH (d6DMSO, 200 MHz) 3.96 (3H, s, OMe), 7.23-7.27 (2H, d, J=8.6, Ph-3/3′H), 7.37-7.45 (1H, t, Ar-5H), 7.78-7.82 (1H, d, Ar-4H), 7.87 (1H, br s, Imz-H), 7.93-7.96 (1H, d, Ar-6H), 8.27-8.31 (2H, d, J=8.6, Ph-2/2′H), 9.4-9.5 (1H, br s, —CONH), 13.3-13.4 (1H, br s, —CONH); m/z (EI) 267 (M+), 249, 222, 206, 77, 32.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+]>O1CCOCC1.O>[CH3:13][O:12][C:9]1[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1COc1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of (6-methoxy-2′-phenoxymethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.24 mmol) in 1,4-dioxane and H2O was added lithium hydroxide (a spatula tip), and the reaction was stirred at 55° C. overnight. After work-up, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH:9][C:10]2([C:23]([OH:25])=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[ClH:1].[ClH:1].[C:3]1([NH:9][C:10]2([C:23]([O:25][CH2:31][CH3:32])=[O:24])[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 19 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylic acid dihydrochloride, 14.4 parts of sulfuric acid and 64 parts of ethanol is stirred and refluxed for 16 hours. The solvent is decanted. The residue is dissolved in water. The aqueous solution is alkalized with ammonium hydroxide and extracted with a mixture of methylbenzene and 2,2'-oxybispropane. The combined organic layers are dried over magnesium sulfate, filtered and evaporated. The oily residue is dissolved in 200 parts of 2,2'-oxybispropane and gaseous hydrogen chloride is introduced into the solution. The precipitated hydrochloride is filtered off, washed with 2-propanol, filtered off again and dried, yielding 11.5 parts of ethyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate dihydrochloride; mp. 212°-214.4° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][CH2:11]1>>[CH:10]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC1=C2CCCC1
Reactant: C1=Cc2ccccc2C1
Product: c1ccc2c(c1)CCC2
Product: c1ccc2c(c1)Cc1ccccc1-2

Procedure:
A portion of the 2:1 fraction (by molar ratio) of indene and tetrahydrofluorene obtained in Example 1 was charged in an autoclave, and was then reacted and processed in a similar manner as in Example 1 except that Pd/Al2O3 (5% Pd supported on alumina) was added as a catalyst in a proportion of 1%. As a result of an analysis by gas chromatography, fluorene and indane were found to have been formed with a yield of 96% (based on tetrahydrofluorene) and with a yield of 95% (based on indene), respectively.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH2:28]O)=[C:21]3[C:25]([OH:27])=[O:26])=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2].[NH2:39][N:40]1[C:44]([N:45]2[C:49]([CH3:50])=[CH:48][C:47]([CH3:51])=[N:46]2)=[N:43][N:42]=[C:41]1[SH:52].C(=O)([O-])[O-].[Na+].[Na+].Cl>CC(C)=O.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[C:21]([C:25]([OH:27])=[O:26])=[C:20]([CH2:28][S:52][C:41]4[N:40]([NH2:39])[C:44]([N:45]5[C:49]([CH3:50])=[CH:48][C:47]([CH3:51])=[N:46]5)=[N:43][N:42]=4)[CH2:19][S:18][C@H:17]23)=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2]
Reactant: Cc1cc(C)n(-c2nnc(S)n2N)n1
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CO)CSC23)c2ccc(O)cc2)C(=O)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(-n5nc(C)cc5C)n4N)CS[C@H]23)c2ccc(O)cc2)C(=O)C1=O
Reaction time: 2 h

Procedure:
A suspension of 294.78 mg. of 7-[2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)acetamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, 3-acetate and 157.7 mg. of 4-amino-5-(3,5-dimethyl-1-pyrazolyl)-4H-1,2,4-triazole-3-thiol in 10 ml. of water is adjusted to pH 6.5 with aqueous sodium carbonate. A 2 ml. portion of acetone is added producing solution. This solution is stirred at 60°-63° C. for 51/2 hours, then stripped free of acetone under reduced pressure and acidified to pH 2.0 with 2 N hydrochloric acid. The resulting solid is filtered, washed repeatedly with ethyl acetate, then with ether and dried, giving 190 mg. of the desired product as a yellow solid.