Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[C:21]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:30]1([N:26]2[CH2:27][CH2:28][CH2:29][N:23]([C:21]([C@@H:9]3[CH2:10][C@H:11]([O:13][C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[CH2:12][NH:8]3)=[O:22])[CH2:24][CH2:25]2)[CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([C@@H]1C[C@H](Oc2ccc(F)cc2)CN1)N1CCCN(C2CCC2)CC1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (2S,4S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(4-fluoro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (969 mg, 2.09 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (2 mL). After 1 h, the mixture was concentrated and the residue purified by FCC to give the desired product (665 mg, 88%). MS (ESI): mass calcd. for C20H28FN3O2, 361.22; m/z found, 362.5 [M+H]+. 1H NMR (CDCl3): 6.95-6.90 (m, 2H), 6.78 (dd, J=9.0, 4.3 Hz, 2H), 4.79-4.74 (m, 1H), 3.88 (ddd, J=9.1, 6.3, 6.3 Hz, 1H), 3.81-3.69 (m, 1H), 3.58-3.47 (m, 2H), 3.47-3.37 (m, 2H), 3.08-2.76 (m, 3H), 2.59-2.28 (m, 5H), 2.00 (dd, J=16.1, 7.7 Hz, 2H), 1.95-1.72 (m, 5H), 1.69-1.53 (m, 2H).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([C:14]3[N:18]4[N:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[N:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:8]2[CH:9]=[C:10]([C:14]3[N:18]4[N:19]=[CH:20][C:21]([C:23]([F:24])([F:26])[F:25])=[N:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)=[N:30][CH:31]=1
Reactant: CC1(C)COB(c2cccc(-c3cnc4nc(C(F)(F)F)cnn34)c2)OC1
Reactant: Fc1ccc(Br)nc1
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: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cccc(-c3cnc4nc(C(F)(F)F)cnn34)c2)nc1
Temperature: 80 °C
Yield: 27.8 %

Procedure:
7-[3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.2 g, 0.53 mmol) was added to 1,2-dimethoxyethane (2 ml), 2-bromo-5-fluoropyridine (94 mg, 0.53 mmol) and 2 N Na2CO3 (0.53 ml). The mixture was degassed with a stream of nitrogen for 10 min before tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol) was added and the mixture heated at 80° C. for 6 h. The mixture was cooled to ambient temperature before partitioning between water (15 ml) and ethyl acetate (15 ml). The organic extracts were then washed with NaOH (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (silica gel, 3% MeOH/CH2Cl2) then triturated with diethyl ether to give 53 mg (28%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.51-7.56 (1H, m), 7.67 (1H, t, J 7.7 Hz), 7.83 (1H, dd, J 9.2, 4.1 Hz), 8.03 (1H, dq, J 7.7, 1.0 Hz), 8.14 (1H, dq, J 7.7, 1.0 Hz), 8.60 (1H, d, J 3.1 Hz), 8.70 (1H, s), 8.72 (1H, t, J 1.6 Hz), 8.84 (1H, s); MS (ES+) m/z 360 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: COc1ccc2c(c1)NC(=O)C2
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]cc(CCC(=O)O)c1C
Yield: 42.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (190 mg), 163 mg of 6-methoxy-2-oxindole, and 2 drops of piperidine in 2 mL of ethanol were heated to 90° C. for 3 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 140 mg of the title compound (43%) as a brown solid.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][C:2]21[CH2:16][C:15](=[O:17])[NH:14][C:13]2=[O:18].[H-].[Na+].I[CH3:22].Cl>CN(C=O)C.O>[CH3:22][N:14]1[C:15](=[O:17])[CH2:16][C:2]2([CH2:3][N:4]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH:6]=[C:5]3[CH2:1]2)[C:13]1=[O:18]
Reactant: O=C1CC2(Cc3cc4ccccc4n3C2)C(=O)N1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CC2(Cc3cc4ccccc4n3C2)C1=O
Reaction time: 17 h

Procedure:
A solution of 1.96 g of 1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indole]-2,5-dione [prepared as described in Example 11(iv)] in 10 ml of DMF was added dropwise to a stirred suspension of 330 mg of a 60% dispersion of sodium hydride in mineral oil in 10 ml of DMF. The mixture was treated with 1 ml of iodomethane and stirred for 17 hours. The mixture was diluted with water, neutralized with 1M aqueous hydrochloric acid and extracted with ethyl acetate. The extracts were washed with sodium chloride solution, dried and the solvent was removed by evaporation. Crystallization of the residue from ethyl acetate/n-hexane gave 1.81 g of 1',3'-dihydro-1-methylspiro-[pyrrolidine-3,2'-pyrrolo[1,2-a]indole]-2,5-dione of melting point 154°-156° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>COCCO>[NH:18]([C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:19]
Reactant: NN
Reactant: Clc1nccc2[nH]c(-c3ccccc3)nc12
Solvent: COCCO
Solvent: O
Product: NNc1nccc2[nH]c(-c3ccccc3)nc12

Procedure:
A mixture of 130 mg (0.568 mmol) of 4-chloro-2-phenyl-1H-imidazo[4,5-c]pyridine, 0.110 mL (114 mg, 2.4 mmol) of hydrazine hydrate, and 3 mL of 2-methoxyethanol was stirred at reflux for 2 days. The cooled solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to yield the title compound. LC-MS 226 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: OCCCCCCCCCCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OCCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a solution of 3-hydroxy-4-methoxybenzaldehyde (2.5 grams), 11-phenylundecylalcohol (4.6 grams) and triphenylphosphine (4.9 grams) in tetrahydrofuran at 0° C. is slowly added diethyl azodicarboxylate (2.9 ml). After stirring for 2 hours at room temperature the mixture is concentrated under reduced pressure and purified by column chromatography on a silica gel column using a 9:1 mixture of hexane and ethyl acetate as eluent to give 2.4 grams of a yellow oil. 1H NMR (CDCl3) δ 1H NMR (CDCl3) δ 0.82-1.89 (m, 18H), 2.35-2.70 (m, 2H), 3.95 (s, 3H), 4.00-4.08 (m, 2H), 6.95-7.45 (m, 8H), 9.84 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1
Yield: 47.2 %

Procedure:
According to a method described in [C. M. Paleos et al., J. Org. Chem. 39(24), 3594, (1974)], 16.8 g (0.1 mole) of 1,3,5-trimethoxybenzene was reacted with 35.0 g of chlorosulfonic acid in 250 ml of chloroform at −5 to 0° C., and after the reaction, the reaction solution was treated after a conventional manner, and 15.2 g of the residue was crystallized from n-hexane, filtered and dried to give 12.6 g of 2,4,6-trimethoxybenzenesulfonyl chloride as a pinkish prism crystal.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([NH:5][CH:6]=[O:7])[CH3:4].[CH2:8](OC(Cl)=O)[CH3:9].C(=O)=O>>[CH2:8]([O:7][CH:6]=[N:5][CH:3]([CH3:4])[CH:2]=[CH2:1])[CH3:9]
Reactant: C=CC(C)NC=O
Reactant: CCOC(=O)Cl
Agent: O=C=O
Product: C=CC(C)N=COCC
Reaction time: 3 h

Procedure:
A mixture of 1.0 g. of N-(1-buten-3-yl)formamide and one equivalent of ethylchloroformate is stirred under N2 for 4 hours during which time CO2 is evolved. The solution is stirred under reduced pressure for 3 hours to remove any unreacted ethylchloroformate, and a residue of ethyl-N-(1-buten-3-yl)formimidate is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([OH:16])[CH2:14][N:13]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:32][C:33]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])[CH3:34].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([O:16][Si:36]([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37])[CH2:14][N:13]([C:17](=[O:25])[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a solution of {2-[1-(4-chloro-benzoyl)-4-hydroxy-pyrrolidin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester (750 mg, 1.95 mmol) in DMF (0.25 mL) at 0° C., was added imidazole (663 mg, 9.15 mmol) and TBDMSCl (309 mg, 2.05 mmol). The reaction mixture was stirred for 2 days. EtOAc (5 mL) was added. The organic phase was washed with Sat. NH4Cl, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:MeOH: 10:1) to give the desired product (389 mg, 40% yield) as a colorless oil. MS: (ESI), M/Z, 498 (M+1). Retention time: 2.21 min (FA-polar).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
5.55 g of 4-Fluoro-3-nitro-benzoic acid were dissolved in 50 ml of methanol, 6.4 ml of concentrated sulfuric acid were added and the reaction was heated to reflux for 3 h. The reaction was cooled, poured unto ice and the precipitated product was collected by suction and dried in vacuo. 5.40 g (90%) of 4-fluoro-3-nitro-benzoic acid methyl ester were obtained.
Reaction SMILES: [ClH:1].C([CH2:9][NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[OH:18])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[ClH:1].[CH3:9][NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[OH:18]
Reactant: OC1(c2cccnc2)CCCCC1CNCCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CNCC1CCCCC1(O)c1cccnc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
11.1 g 2-[(benzylmethylamino)methyl]-1-pyridin-3-yl-cyclohexanol hydrochloride were dissolved in 110 ml glacial acetic acid under nitrogen, 2.0 g palladium-on-active charcoal (10 percent by weight) were added as a catalyst and the mixture was stirred under a hydrogen pressure of 2.0 bar until the uptake of hydrogen had ended. The mixture was filtered with suction, the filtrate was concentrated, the residue was stirred overnight with 75 ml isopropanol and the precipitate obtained was filtered off with suction and dried. 6.18 g 2-methylaminomethyl-1-pyridin-3-yl-cyclohexanol hydrochloride were obtained.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[C:18]([C:21]12[CH2:30][C:25]3([OH:31])[CH2:26][CH:27]([CH2:29][C:23]([OH:32])([CH2:24]3)[CH2:22]1)[CH2:28]2)([OH:20])=[O:19]>>[C:18]([C:21]12[CH2:30][C:25]3([O:31][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:26][CH:27]([CH2:29][C:23]([OH:32])([CH2:24]3)[CH2:22]1)[CH2:28]2)([OH:20])=[O:19]
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: O=C(O)C12CC3CC(O)(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(O)(C1)CC(C(=O)O)(C3)C2
Yield: 84 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1-carboxy-3,5-dihydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1-carboxy-3-hydroxy-5-acryloyloxyadamantane (yield: 84%, white solid) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23].C(N(CC)CC)C>ClCCl>[O:10]=[C:9]([NH:11][CH2:12][CH2:13][S:14](=[O:16])(=[O:15])[NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNS(=O)(=O)CCNC(=O)OCc1ccccc1

Procedure:
A cold (0° C.) mixture of sulfonyl chloride from Step 1 (5.54 g, 20 mmol) and glycine methyl ester hydrochloride (2.7 g, 21.5 mmol) in dichloromethane (125 mL) was treated with triethylamine (6.0 mL, 43 mmol). The resultant mixture was stirred at 0° C. for 2 hours. The product mixture was diluted with dichloromethane and was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 50% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the intermediate methyl 3-oxo-1-phenyl-2-oxa-7-thia-4,8-diazadecan-10-oate 7,7-dioxide.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>C1C=CC=CC=1>[C:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: NCc1ccccn1
Solvent: c1ccccc1
Product: S=C(NCc1ccccn1)Nc1ccccc1
Yield: 80 %

Procedure:
N-Phenyl-N'-2-pyridinylmethylthiourea is prepared by heating 19.8 g (0.147 m) phenylisothiocyanate and 13.2 g (0.122 m) 2-aminomethylpyridine in 500 ml benzene for 3 hr. The solid (22.8 g, 77% yield) which is collected with a melting point of 98°-9° C. and is analytically pure.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:11]([F:13])([F:12])[C:10]([F:15])([F:14])[C:9]([F:17])([F:16])[C:8]=2[O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[OH:33][C:29]([CH3:30])([C:31]#[C:32][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:8]2[C:9]([F:17])([F:16])[C:10]([F:14])([F:15])[C:11]([F:12])([F:13])[C:7]=2[O:6][C:5]2[CH:26]=[CH:27][C:2]([C:32]#[C:31][C:29]([CH3:30])([OH:33])[CH3:28])=[CH:3][CH:4]=2)=[CH:24][CH:23]=1)[CH3:28]
Reactant: C#CC(C)(C)O
Reactant: FC1(F)C(Oc2ccc(Br)cc2)=C(Oc2ccc(Br)cc2)C(F)(F)C1(F)F
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(OC2=C(Oc3ccc(C#CC(C)(C)O)cc3)C(F)(F)C(F)(F)C2(F)F)cc1
Yield: 48.6 %

Procedure:
39 g (0.075 mol) of 1,2-bis-(4-bromophenoxy)-3,3,4,4,5,5-hexafluorocyclopent-1-ene (obtained according to Example 1), 32 g (0.38 mol) of 2-methyl-3-butin-2-ol, 211 mg of PdCl2 (PPh3)2, 230 mg of CuI and 630 mg of triphenylphosphine were added under nitrogen to 100 ml of triethylamine. After heating to reflux for 24 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo. Recrystallization of the residue resulting here from n-hexane/ethyl acetate gave 19.1 g of product, which corresponds to 48% of theory, having a melting point of 108° to 113° C. The 1H NMR spectrum showed characteristic bands at 1.59 ppm, 6.63 ppm and 7.2 ppm, measured against tetramethylsilane as internal standard.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[N:38]1([C:42](=O)[CH2:43]Cl)[CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:42][CH2:43][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCC1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 68 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azetidin-1-yl-2-chloroethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.6 mg) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[CH3:10][C@H:11]1[CH2:16][NH:15][C@H:14]([CH3:17])[CH2:13][N:12]1[C:18](=[O:26])[C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:22])[F:21].C(N(CC)CC)C>CCOC(C)=O>[CH3:10][C@H:11]1[CH2:16][N:15]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[C@H:14]([CH3:17])[CH2:13][N:12]1[C:18](=[O:26])[C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:21])[F:22]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1cccs1
Yield: 30.5 %

Procedure:
A solution of 2-thiophene sulphonyl chloride (129 mg, 0.707 mmol) in EtOAc (10 ml) was added to a stirred mixture of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746) (150 mg, 0.59 mmol) and triethylamine (0.125 ml, 0.886 mmol) in EtOAc (15 ml). The resultant mixture was stirred at ambient temperature for 4 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbon solution and brine, dried and evaporated. The residue was recrystallized from EtOAc/hexane to give the title compound as a solid (71 mg, 0.18 mmol). Mp: 116-117° C.; NMR: 0.95 (d, 3H), 1.25 (dd, 3H), 1.65 (s, 3H), 3.2 (s, 3H), 3.3 (s, 1H), 3.5 (dd, 1H), 4.05 (s, 1H), 4.15 (s, 1H), 4.3 (s, 1H), 4.75 (s, 1H), 7.0 (dd, 1H), 7.5 (dd, 2H); m/z 399.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:20]([S:23][CH2:24][CH:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:26](=[O:27])[CH:25]([CH3:29])[CH2:24][S:23][C:20](=[O:22])[CH3:21])=[O:4]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: COC(=O)C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2N1C(=O)C(C)CSC(C)=O

Procedure:
To the stirred mixture of 5.0 g of indoline-2-carboxylic acid methyl ester [J. Am. Chem. Soc. 92, 2476 (1970)], 7.8 g of powdered potassium carbonate and 50 ml of methylene chloride, 5.1 g of 3-acetylthio-2-methylpropanoyl chloride (Belgium Pat. No. 868,532) in 20 ml of methylene chloride are added during 3 minutes at room temperature. After 2 hours the mixture is diluted with 100 ml of methylene chloride and washed with 100 ml of water, 100 ml of 1N hydrochloric acid and 100 ml of saturated aqueous sodium bicarbonate. The organic layer is dried and evaporated, to give the 1-(3-acetylthio-2-methylpropanoyl)-indoline-2-carboxylic acid methyl ester as an oil, showing in the IR-spectrum bands at 1710, 1690 and 1675 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([OH:26])=O.C(Cl)(=O)C([Cl:30])=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([Cl:30])=[O:26]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Solvent: ClCCl
Product: CC1=C(CC(=O)Cl)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1

Procedure:
(Z)-5-Fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid (20 g, 53.70 mmol) was suspended in dichloromethane (400 mL). Oxalylchloride (2M in CH2Cl2; 35 mL; 70 mmol) was added at room temperature. The reaction mixture was refluxed (24 h), and was evaporated to yield the title compound, which was used as such in the next step.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:11][C:12]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=1[OH:19].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[Cl:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[OH:19])[NH:18][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: O=C(O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C(Nc1ccc(O)c(Cl)c1)c1ccccc1O
Yield: 97.6 %

Procedure:
Salicylic acid (1.38 g.) and 2-chloro-4-aminophenol (1.44 g.) were dissolved in acetonitrile (130 ml.), to which with stirring was added as a dehydrating agent dicyclohexyl carbodiimide (1.88 g.) and stirring was continued for about an hour. The precipitated dicyclohexylurea was filtered off, rinsed with warm acetone (90 ml.), and the filtrate and the rinse were combined and evaporated to dryness under reduced pressure. A light brown powder (2.57 g.) of 3'-chloro-2,4'-dihydroxybenzanilide was obtained which was purified through column chromatography using silica-gel (Mallinkrodt Co., U.S.A.) and an ethyl acetate-methanol mixture as the elution solvent system to give needle-like crystals (0.18 g.) of 3'-chloro-2,4'-dihydroxybenzanilide. Yield: 7%. The melting point: 172.5° 173.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1CN(C)C(Cl)=O.[C:15]([Cl:18])(=[O:17])[NH2:16]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:16]([CH2:4][CH2:3][CH2:2][CH2:7][CH3:6])[C:15]([Cl:18])=[O:17]
Reactant: Cc1cccc(C)c1CN(C)C(=O)Cl
Reactant: NC(=O)Cl
Product: CCCCCN(C(=O)Cl)c1c(C)cccc1C

Procedure:
When 2,6-dimethylphenyl-N-methyl-N-methylcarbamoyl chloride in Example 7D is replaced with the above carbamoyl chloride then the products prepared are