Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[F:23].O[CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:25])=[CH:18][C:17]=1[F:23]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(Br)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Diisopropyl azodicarboxylate (1.9 M solution in toluene, 83 mL) was added to a mixture of 4-bromo-3-fluorophenol (25.0 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (25.2 g), triphenylphosphine (41.2 g), and THF (250 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 30 min, and then at room temperature for 3 hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (33.7 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[S:3]([N:6]1[CH:10]=[C:9]([CH2:11][O:12][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[N:8]=[C:7]1[C:30](=[O:32])[CH3:31])(=[O:5])=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[CH3:33][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH2:11][OH:12])[N:8]=[C:7]1[C:30](=[O:32])[CH3:31])(=[O:4])=[O:5]
Reactant: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cn1S(=O)(=O)N(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1nc(CO)cn1S(=O)(=O)N(C)C
Reaction time: 21 h

Procedure:
The compound (0.910 g) obtained in (2) was dissolved in THF (10 mL), followed by addition of TBAF (1.0 M THF solution, 4.08 mL) under stirring, and the stirring was continued for 21 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate to distill off the solvent under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=20%→100%) using amino column (product name: Hi-Flash Column 2 L, manufactured by Yamazen Corporation) to afford the title compound (0.170 g).
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=1>[OH-].[Na+]>[N+:18]([C:14]1[CH:13]=[CH:12][C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:16][C:15]=1[CH3:17])([O-:20])=[O:19]
Reactant: Oc1ccccc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Combine potassium hydroxide (3 g, 0.054 mol) and phenol (15 g, 0.16 mol), and heat to 110° C. until the potassium hydroxide is dissolved. Cool the mixture to room temperature and add 5-fluoro-2-nitrotoluene (7.75 g, 0.05 mol) in one aliquot. Heat the reaction mixture to 130° C. for 30 min, cool to room temperature, and then pour into 10% NaOH (200 mL). Extract the aqueous solution with ether (2×100 mL), combine the organic layers and wash with 10% NaOH (2×100 mL), water (2×100 mL), dry over Na2SO4 and concentrate in vacuo. Chromatograph on silica gel eluting with hexanes/ethyl acetate to give 2-nitro-5-phenoxytoluene as a solid: 1H NMR (300 MHz, CDCl3) 2.59 (s, 3H), 6.81–6.85 (m, 2H), 7.06–7.09 (m, 2H), 7.22–7.26 (m, 1H), 7.40–7.45 (m, 2H), 8.03–8.06 (m, 1H).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[CH2:6]([O:13][C:14](=[O:27])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([O:13][C:14](=[O:27])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:1][C@@H:2]([OH:3])[CH2:4][OH:5])=[CH:22][CH:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC[C@H]1CO1
Reactant: Nc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Solvent: CCO
Product: O=C(NCCCCc1ccc(NC[C@@H](O)CO)cc1)OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of (S)-(−)-glycidol (0.16 mL, 2.3 mmol) in ethanol (5 mL) was added dropwise to a stirring solution of N-[4-(4-aminophenyl)butyl]carbamic acid benzyl ester (0.59 g, 1.97 mmol) in ethanol (15 mL) at 70° C. The reaction mixture was stirred at 70° C. (oil bath) overnight. The solvent was removed under reduced pressure and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, chloroform/methanol/ammonium hydroxide, 15:1:0.1, v/v) to give 700 (0.29 g, 40%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.51 (m, 4H), 2.48 (t, 2H), 3.07 (m, 1H), 3.26 (t, 2H), 3.30 (m, 1 if), 3.57 (m, 2H), 3.80 (m, 1H), 5.00 (s, 2H), 6.59 (d, 2H), 6.99 (d, 2H), 7.33 (m, 5H). m/z (ESI) 373 [C21H28N2O4+H]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[ClH:19].CC(C)=O.N([O-])=O.[Na+]>O>[Cl:19][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: Cl
Reactant: Cc1cc(Oc2ccc(N)c(C(F)(F)F)c2)n[nH]1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)n[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
3-(4-Amino-3-trifluoromethylphenyloxy)-5-methylpyrazole (2.00 g, 7.8 mmol) was added to a mixed solution of concentrated hydrochloric acid (2.1 ml) and acetone (20 ml) at room temperature, and the mixture was stirred at room temperature for 20 minutes. After the mixture was cooled below 0° C., a solution of sodium nitrite (0.54 g, 7.8 mmol) in water (3 ml) was dropwise added, and the mixture was stirred at an ambient temperature for 30 minutes. Then, cuprous chloride (0.85 g, 8.6 mmol) was little by little added at 0° C., and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (50 ml×2). An organic layer was washed with water (50 ml×3), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellowish viscous substance of 3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole (2.12 g, yield: 98.7%). 1H-NMR (CDCl3, TMS, ppm): δ 2.25 (s, 3H), 5.64 (s, 1H), 7.23 (dd, J=3.0 and 8.8 Hz, 1H), 7.31-7.46 (m, 2H), 10.56 (br s, 1H).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([O:16]CC4C=CC=CC=4)=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C1CCCCC=1>[OH-].[Pd+2].[OH-]>[C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(COc2ccc3sc(-c4ccccc4)nc3c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Oc1ccc2sc(-c3ccccc3)nc2c1

Procedure:
Palladium hydroxide (100 mg) was added to a solution of 27 (260 mg, 0.8 mmol) of ethanol/cyclohexene (5 mL/2 mL) followed by warming for reflux for 16 h. The reaction mixture was cooled and the catalyst was removed by filtration (through Celite). The solvent was evaporated to provide compound 29 as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCc2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(CCCCCc2ccc(O)cc2)cc1
Yield: 98.5 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)pentane of Example 8 (60 g, 0.21 mole), 150 ml of hydrobromic acid (47%) and 200 ml of glacial acetic acid was refluxed for 4.5 hours. It was concentrated to a thick liquid, dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 53.0 g of a thick oil. NMR and TLC confirmed the structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:47]([O:49][C:50]([C:52]1(Br)[CH2:55][CH2:54][CH2:53]1)=[O:51])[CH3:48]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:52]3([C:50]([O:49][CH2:47][CH3:48])=[O:51])[CH2:55][CH2:54][CH2:53]3)[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(OC)c3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3cccc(OC)c3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-hydroxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 4 ml of DMF, 116 mg of cesium carbonate and 74 mg of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 3 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The crude product was used in the subsequent reaction. Yield: 90 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([Br:9])=[C:7]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([O:23][CH3:24])[N:4]=1.[OH:25]O>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]([Br:9])=[C:7]([P:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])[CH:6]=[C:5]([O:23][CH3:24])[N:4]=1
Reactant: COc1cc(P(c2ccccc2)c2ccccc2)c(Br)c(OC)n1
Reactant: OO
Solvent: CC(C)=O
Product: COc1cc(P(=O)(c2ccccc2)c2ccccc2)c(Br)c(OC)n1
Yield: 96 %

Procedure:
A round bottom flask with a magnetic stirring bar was charged with 2,6-dimethoxy-3-bromo-4-(diphenylphosphino)pyridine (4.96 g) and 50 mL acetone. To this solution was slowly added approximately 35% hydrogen peroxide (33.9 mL). The reaction was monitored by thin-layer chromatography. The product was extracted with 3×20 mL dichloromethane. The combined extract was dried with anhydrous magnesium sulfate and was concentrated in vaccuo to give a crude product which was purified by column chromatography (silica gel, CHCl3 : ethyl acetate=1:1 with 5% NEt3) to give 5.15 g pure product (96% of theoretical yield).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:12]2[N:11]=[N:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:14][CH:13]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazine-1-carboxylic acid t-butyl ester, the title compound was obtained as a white solid (47% yield). 1H NMR (400 MHz, CDCl3) δ 8.04-7.95, 6.97, 3.62-3.54, 1.59-1.44, 1.34-1.23, 0.72-0.62, 0.45-0.36, 0.06-0.04. MS (ES+) m/z 376.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2)[CH3:2].[NH4+].O[N:28]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:28])=[O:14])=[CH:8]2)[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a solution of 7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (3.4 g) in N,N-dimethylformamide (40 mL) were added under ice-cooling 1-hydroxybenzotriazole ammonium salt (2.2 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g), and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (3.4 g, yield 100%) as a pale-yellow amorphous solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[C:18]([CH2:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=O)[CH3:2].C1(C)C=CC=CC=1.[CH3:29][NH:30][NH2:31]>O>[CH3:29][N:30]1[N:31]=[C:5]([C:4]2[CH:16]=[CH:17][C:18]([CH2:20][CH3:21])=[CH:19][C:3]=2[CH2:1][CH3:2])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:10]
Reactant: CCc1ccc(C(=O)c2ccccc2C(=O)O)c(CC)c1
Reactant: CNN
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(-c2nn(C)c(=O)c3ccccc23)c(CC)c1
Yield: 55.9 %

Procedure:
A mixture of 2-(2,4-diethylbenzoyl)benzoic acid (40 g, 0.14 mol), toluene (120 mL) and methyl hydrazine (7.5 mL) were refluxed for 3 hours with removal of water via a Dean Stark trap. Additional toluene (100 mL) and methyl hydrazine (4.0 mL) were added and the mixture was refluxed until 2.8 mL of water was collected. The mixture was cooled, extracted with CH2Cl2 /2N NaOH, then 1N HCl and the organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was crystallized from ethanol/water and recrystallized from ethanol/water to afford 22.86 g (55.9%) of 2-methyl-4-(2,4-diethylphenyl)-1-(2H)-phthalazinone, m.p. 94.5°-96.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=1[O:40][CH3:41])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=2[O:40][CH3:41])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2OC)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (600 mg, 0.003 mol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (1.80 g, 0.014 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,3-dimethoxy-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dimethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (430 mg, 33%) as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:26]3[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(C(=O)Cc2csc(-c3cnn(C(C)(C)C)c3-c3ccc(F)cc3)n2)CC1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and ethyl isonipecotate and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:29][O:30][CH2:31][CH3:32].Cl>O1CCCC1>[CH2:31]([O:30][CH2:29][O:21][C:20](=[O:22])[CH2:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([C:6](=[O:7])[C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[CH3:23])[CH3:32]
Reactant: CCOCCl
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCOC(=O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a mixture of 3.6 g of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid and 50 ml of dry tetrahydrofuran was added 0.5 g of 50% sodium hydride and the mixture was stirred for 30 minutes. To this mixture was further added 2.5 g of chloromethylethyl ether and the whole was reacted for 3 hours at room temperature. After the reaction was complete, the solvent was removed by distillation under reduced pressure. The residue thus obtained was neutralized with diluted hydrochloric acid, and then extracted with ethyl ether. The ether layer separated was washed with water and dried. The ether was removed by distillation to yield crystals. Recrystallization of the crystals from petroleum ether yielded 3.0 g of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid-ethoxymethyl ester as colorless prisms, melting at 60°-61° C. Analysis--Calculated for C22H22ClNO5 : C, 63.48; H, 5.17; N, 3.42. Found: C, 63.53; H, 5.33; N, 3.37.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[I:27]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[I:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(I)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.742 g, 2.11 mmol), in dry THF (15 mL) at −78° C., was added n-BuLi (1.7 M solution in hexanes, 1.6 mL, 2.72 mmol) dropwise over about 5 min. After stirring the mixture at −78° C. for 20 min, solid I2 (0.729 g, 2.87 mmol) was added and the reaction mixture was allowed to slowly warm to room temperature. The mixture was then quenched with saturated NH4Cl and saturated Na2S2O3, diluted with water and extracted with EtOAc (×3). The combined organic phase was washed (H2O, brine), dried (Na2SO4) and concentrated to give the title compound as a yellow orange solid (0.800 g) which was used in subsequent steps without further purification. An analytical sample was obtained by recrystallization from hexane (5° C.) to afford the pure iodide as a cream coloured powder:
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([N:12]1[C:16]([NH2:17])=[N:15][N:14]=[N:13]1)[CH2:10][CH3:11]>>[CH2:9]([N:12]1[C:16]([NH:17][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:8])=[N:15][N:14]=[N:13]1)[CH2:10][CH3:11]
Reactant: O=C(O)C1CCCC1
Reactant: CCCn1nnnc1N
Product: CCCn1nnnc1NC(=O)C1CCCC1
Yield: 45 %

Procedure:
Employing 0.30 g (2.6 mmol) of cyclopentane carboxylic acid and 0.33 mg (2.6 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above and elution with CH2Cl2/MeOH/Et3N (9.3:0.5:0.2) gave the product in 45% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[C:4]([F:17])[CH:3]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:38][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=3)[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1/C=C/c1nc(CCl)co1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3F)n2)cc1
Yield: 23.8 %

Procedure:
Using 2-[(E)-2-(4-chloro-2-fluorophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (243 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (35.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (105 mg) as a colorless crystal powder.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:17])=O.Cl>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:17])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(=O)Oc1cccc(C(=O)Cl)c1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
In a flask, 60.0 g of 3-acetoxy-2-methylbenzoic acid are suspended under nitrogen in 140.0 g of xylene. The suspension is heated to 70° C. and 42.9 g of thionyl chloride are added dropwise. The mixture is heated further. At approx. 75° C., vigorous gas evolution (SO2, HCl) commences. The liquid phase temperature rises continuously and reaches 108° C. after approx. 4 h. The solution is cooled to approx. 50° C. under nitrogen and the reflux condenser is replaced by Vigreux column. At atmospheric pressure and later under reduced pressure, first xylene and thionyl chloride residues and then the product are distilled over. The product distills over at 15 mbar and 147.0-148.0° C. 59.6 g of 3-acetoxy-2-methylbenzoyl chloride (97.3%) are obtained. This corresponds to 91.0% of theory.