Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11](=[O:40])[CH:12]([CH:20]([C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:26][CH:25]=1)[CH2:21][CH2:22][CH3:23])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:5]2.[CH3:41][O:42][C:43]1[C:48](B(O)O)=[CH:47][CH:46]=[CH:45][N:44]=1.C([O-])([O-])=O.[Na+].[Na+].[Br-]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C=O)C.C(#N)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]([CH:20]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:38][CH:39]=2)[CH2:21][CH2:22][CH3:23])[C:11]([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:48]4[C:43]([O:42][CH3:41])=[N:44][CH:45]=[CH:46][CH:47]=4)[CH:3]=3)[CH2:7]2)=[O:40])=[CH:18][CH:17]=1
Reactant: COc1ncccc1B(O)O
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OCC)cc1)C(C(=O)N1Cc2ccc(Br)cc2C1)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(C(=O)N1Cc2ccc(-c3cccnc3OC)cc2C1)c1ccc(Cl)cc1
Temperature: 125 °C

Procedure:
Ethyl N-(4-{1-[2-(5-bromo-1,3-dihydro-2H-isoindol-2-yl)-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoyl)-β-alaninate (30 mg, 0.048 mmol), trans-bis(triphenylphospine)palladium(II) chloride (3.4 mg, 4.8 μmol), 2-methoxypyridine-3-boronic acid (9.5 mg, 0.062 mmol), acetonitrile (2.0 mL) and Na2CO3 (2.0 M in H2O, 2.0 mL, 4.0 mmol) were added to a microwave vial. DMF (0.3 mL) was added to increase the solubility of the bromide. The vial was flushed with nitrogen, sealed, then heated to 125° C. for 10 minutes in a microwave reactor. The mixture was diluted with 1N HCl (aq) then extracted twice with EtOAc. The organic layers were dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by reverse-phase HPLC. Following lyophilization, this afforded the title compound as a white solid. The characterization data provided are for a single stereoisomer (of the possible four) that was the most potent glucagon receptor antagonist. 1H NMR (500 MHz, CD3OD): δ 8.09 (ddd, J=13.2, 5.1, 1.8 Hz, 1 H); 7.72 (d, J=8.1 Hz, 2 H); 7.67-7.58 (m, 1 H); 7.61 (dd, J=8.6, 2.4 Hz, 2 H); 7.49 (d, J=8.0 Hz, 2 H); 7.43-7.35 (m, 2 H); 7.37 (d, J=8.0 Hz, 1 H); 7.32 (s, 1 H); 7.23 (dd, J=13.9, 8.0 Hz, 1 H); 7.01 (ddd, J=14.0, 7.3, 5.0 Hz, 1 H); 4.90 (obs, 1 H); 4.79 (d, J=14.5 Hz, 1 H); 4.47 (d, J=16.2 Hz, 1 H); 4.31 (d, J=16.2 Hz, 1 H); 4.26 (dd, J=11.1, 2.3 Hz, 1 H); 3.90 (d, J=15.6 Hz, 3 H); 3.56 (t, J=7.0 Hz, 2 H); 3.47 (dd, J=11.2, 3.4 Hz, 1 H); 2.58 (t, J=7.0 Hz, 2 H); 1.55-1.49 (m, 1 H); 1.30 - 1.23 (m, 1 H); 1.00-0.91 (m, 2 H); 0.69 (t, J=7.3 Hz, 3 H). LC2 1.43 min. (M+H)+ 626.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[C:14]([CH3:20])[CH:13]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:19])=[O:29])=[C:14]([CH3:20])[CH:13]=1
Reactant: CSc1ccc(OCc2ncc([N+](=O)[O-])n2C)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCc2ncc([N+](=O)[O-])n2C)ccc1S(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
29.3 g (0.1 mol) of 1-methyl-2-(3-methyl-4-methylthiophenyloxymethyl)-5-nitro-imidazole are dissolved in 200 ml of chloroform, and the solution is added dropwise while stirring at 25° C. to a solution of 17.25 g (0.1 mol) of 3-chloroperbenzoic acid in 70 ml of chloroform. The reaction mixture is stirred for 1 hour at 25° C., shaken with dilute sodium carbonate solution, the chloroform phase is separated, dried over sodium sulfate and concentrated by evaporation. The residue is recrystallized from ethanol with an addition of charcoal, to yield 21.0 g (68% of the theoretical yield) of 1-methyl-2-(3-methyl-4-methylsulfinylphenyl-oxymethyl)-5-nitro-imidazole in the form of yellow crystals, m.p. 121° C.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:36])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+].O>O1CCOCC1>[CH2:37]([O:36][C@@H:23]1[C@@H:22]([CH2:21][O:20][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
In 50 ml of dioxane was dissolved 10 g of 2'-deoxy-5'-O-trityl-5-fluorouridine. To the solution were added 2.9 ml of benzyl bromide and 14.6 g of particles of potassium hydroxide. The mixture was stirred at room temperature for 1 hour. Thereto was added 40 ml of water. The mixture was adjusted to a pH of about 3 to about 4 and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The sodium sulfate was separated by filtration and the solvent was distilled off, giving as an intermediate 16.0 g of 2'-deoxy-3'-O-benzyl-5'-O-trityl-5-fluorouridine.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:18]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.[Cl:27][CH:28]([Cl:47])[C:29]([N:31]1[C@H:35]([CH2:36][F:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=2)[O:33]C1(C)C)=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([C:41]3[CH:42]=[CH:43][C:38]([C@@H:34]([OH:33])[C@H:35]([NH:31][C:29](=[O:30])[CH:28]([Cl:27])[Cl:47])[CH2:36][F:37])=[CH:39][CH:40]=3)=[CH:14][CH:13]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: NC1(c2ccc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A mixture of tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (252 mg, 0.7 mmol), 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone (250 mg, 0.56 mmol), Cs2CO3 (365 mg, 1.12 mmol) in dioxane (4 mL) and water (1 mL) is bubbled with nitrogen gas for 2 minutes. Pd(PPh3)4 (64 mg, 0.056 mmol) is added and the resulting reaction mixture heated at 80° C. for 4 hours. After cooling to room temperature, the reaction is diluted with water (10 ml) and extracted with ethyl acetate (3×10 mL). Combined organic extracts are dried over Na2SO4 and concentrated. Crude compound dissolved in DCM (3 mL) and stirred with TFA (0.6 mL) at room temperature for 1 hour. Reaction is diluted with toluene (10 mL) and concentrated to a syrup. Crude compound is basified slowly using saturated aq. NaHCO3, saturated with NaCl, and extracted with ethyl acetate (3×30 mL). Combined extracts dried over Na2SO4 and concentrated. Solid dissolved in DMF (2 mL) and purified using HPLC eluting from 5 to 95% water/acetonitrile to give the title compound (90 mg): 1HNMR (400 MHz, DMSO-d6) δ: 1.16-1.28 (m, 2H), 1.31-1.41 (m, 2H), 4.15-4.36 (m, 1.5H), 4.38-4.47 (m, 0.5H) 4.55-4.62 (m, 0.5H), 4.65-4.74 (m, 0.5H), 4.90 (bs, 1H) 5.98 (bs, 1H), 6.54 (bs, 1H), 7.41-7.53 (m, 4H), 7.64 (d, 2H, J=8.0 Hz), 7.72 (d, 2H, J=8.0 Hz), 8.63 (d, 1H, J=8 Hz), 8.66-8.79 (bs, 3H), m/z (Cl) 411 [M+1].
Reaction SMILES: [C:1]1([S:7]([N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[N:20][O:21][CH2:22][CH2:23][OH:24])[CH3:19])=[CH:14][CH:13]=2)[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:26]1[CH:58]=[CH:57][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:56])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([S:7]([N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[N:20][O:21][CH2:22][CH2:23][O:24][C:26]3[CH:58]=[CH:57][C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]4=[O:56])=[CH:28][CH:27]=3)[CH3:19])=[CH:14][CH:13]=2)[CH3:11])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Yield: 36.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 667 mg of 2-(1-{4-[N-(phenylsulfonyl)-N-methylamino]phenyl}ethylideneaminooxy)ethanol (prepared as described in Preparation 37), 1.02 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 383 mg of diethyl azodicarboxylate, 554 mg of the title compound were obtained as a crystalline powder, melting at 143°-145° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1>O>[C:1]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C

Procedure:
Acetic anhydride (7.lml) was added to a suspension of 4-amino-2,6-dichlorophenol (5.34 g) in-water (50 ml). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and the crude product was collected by filtration, washed with water and then washed with pentane to give 4-acetamido-2,6-dichlorophenol as a solid (5.6 g), m.p. 151°-152°; NMR ([CD3 ]2SO): 2.0(3H,s), 7.58(2H,s) and 9.92(2H,br s); m/z 220 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([OH:22])[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C:12]#[N:13])(C(C)(C)C)(C)C.CO[C:25](OC)([CH3:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:15]=[C:14]([CH:11]([CH:10]2[CH2:9][O:8][C:25]([CH3:27])([CH3:26])[O:22]2)[C:12]#[N:13])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(C#N)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)OCC(C(C#N)c2ccc(Cl)c(Cl)c2)O1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of (2RS,3RS)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3,4-dichlorophenyl)-3-hydroxybutanenitrile (152 g) in toluene (1000 ml) were added 2,2-dimethoxypropane (131.8 g) and p-toluenesulfonic acid (8.02 g), and the mixture was stirred under nitrogen purging at 80° C. for 2 hr. Under ice-cooling, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was crystallized from diisopropyl ether to give the title compound (99 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[CH2:28][C:27](=[O:29])[NH:26][CH2:25][C:24]1=[O:30].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[O:30]=[C:24]1[CH2:25][NH:26][C:27](=[O:29])[CH2:28][N:23]1[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)CN1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CC(=O)NCC2=O)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 11.7 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), piperazine-2,5-dione (570 mg, 5 mmol), copper(I) iodide (115 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(2,5-dioxo-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (46 mg, 11%) as a grey solid: LC/MS m/e calcd for C22H23N3O4 (M+H)+: 394.45, observed: 394.1.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:9](O)=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1.O.P(Cl)(Cl)([Cl:19])=O>>[Cl:1][C:2]1[S:3][C:4]2[C:9]([Cl:19])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C(F)(F)F)nc2nc(Cl)sc12
Solvent: O
Product: FC(F)(F)c1nc(Cl)c2sc(Cl)nc2n1

Procedure:
To a solution of the compound (1.35 g) obtained in Step 7 in phosphorus oxychloride (20 ml) was added water (190 mg) with stirring under ice-cooling, and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and partitioned by adding chloroform and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give the title compound (1.17 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH2:19][CH2:20]I)[CH:16]=2)[C:11]([C:24]2[N:32]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=2)=[CH:10]1>>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH2:19][CH2:20][N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[CH:16]=2)[C:11]([C:24]2[N:32]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=2)=[CH:10]1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Reactant: OC1CCNCC1
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCN1CCC(O)CC1
Yield: 92.4 %

Procedure:
1-{2-[1-methyl-5-methoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-6-yloxy]ethyl}piperidin-4-ol is prepared by following the procedure described in example 147b, but using 0.089 g of 4-hydroxypiperidine and 0.265 g of 2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. After purification by flash-pack chromatography (silica, 90/10 by volume dichloromethane/methanol as eluents, argon), 0.234 g of 1-{2-[1-methyl-5 methoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-6-yloxy]ethyl}piperidin-4-ol is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH:23][C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1)[CH3:22].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[CH3:22][CH2:21][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([C:18]([C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[CH:12]=2)=[O:20])[CH2:32][CH2:31]1
Reactant: O=C(O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: CCNc1cccnc1N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCNc1cccnc1N1CCN(C(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16 and making non-critical variations but starting with 5-benzyloxyindole-2-carboxylic acid (1.0 g), 1-(3-ethylamino-2-pyridinyl)piperazine (International Publication WO 87/01706, 0.81 g), 1,1'-carbonyldiimidazole (0.61 g) and THF (7 ml), the title compound is obtained, mp 192°-193°.
Reaction SMILES: [NH2:1][C:2](=[S:15])[CH:3]([N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]1)[CH3:4].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)=O>>[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[N:1]=[C:2]([CH:3]([N:5]3[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]3)[CH3:4])[S:15][CH:17]=2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cnn(C(C)C(N)=S)c1
Product: CCOC(=O)c1cnn(C(C)c2nc(-c3ccc(Cl)c(Cl)c3)cs2)c1
Yield: 90.6 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (227 mg, 1.00 mmol) obtained in Example 14b and 2-bromo-1-(3,4-dichlorophenyl)ethanone (268 mg, 1.00 mmol), the title compound (359 mg, 90%) was obtained as a colorless oil.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([NH2:16])=[CH:10][C:9]=1[OH:17].[F:18][CH2:19][C:20](OC)=[O:21].C[O-].[Na+]>C(O)(=O)C.O>[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([NH:16][C:20](=[O:21])[CH2:19][F:18])=[CH:10][C:9]=1[OH:17]
Reactant: COC(=O)CF
Reactant: COc1cc(C)c(O)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)c(O)cc1NC(=O)CF
Yield: 13.9 %

Procedure:
Into 15 ml of benzene were added 2.10 g (13.7 mmol) of 2-methyl-4-methoxy-5-aminophenol, 1.28 g (13.9 mmol, 1.0 eq.) of methyl fluoroacetate and 1.64 g (30.4 mmol) of sodium methoxide and the mixture was heated under reflux for 6.5 hours. After allowing to cool, the mixture was poured into 300 ml of water, and neutralized with acetic acid and extracted with 200 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain dark-brown crystals. The crystals were purified by silica gel column chromatography (Silica Gel 60, trade name, manufactured by Merck Co., 70-230 mesh, 200 g, eluent: ethyl acetate) and pale brown solid matters were obtained from the 600-900 ml fraction. The solid matters were recrystallized from the solvent mixture of hexane/ethyl acetate (2:1 by volume) to give 230 mg (1.9 mmol) of 2-methyl-4-methoxy-5-fluoroacetylaminophenol. The yield was 8%.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.Cl[C:16]([O:18][CH3:19])=[O:17].O>C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16]([O:18][CH3:19])=[O:17]
Reactant: Nc1ccccc1F
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
2-Fluoroaniline (10.0 mL, 0.104 mol) was dissolved in ethyl acetate (40 mL) to prepare a solution. Pyridine (10.0 mL, 0.124 mol) was added to the solution, and the mixture was cooled under ice cooling. A solution of methyl chloroformate (8.80 mL, 0.114 mol) in 10 mL of ethyl acetate was added dropwise to the cooled mixture over a period of 30 min. The reaction solution was warmed to room temperature followed by stirring for 3 hr. The disappearance of 2-fluoroaniline from the reaction solution was confirmed by high performance liquid chromatography. Thereafter, 20 mL of water was added thereto under ice cooling to stop the reaction. Next, 50 mL of ethyl acetate and 50 mL of water were added to the reaction mixture to carry out extraction. The organic layer was washed with 40 mL of water and 30 mL of a saturated sodium hydrogencarbonate solution and was then dried over an hydrous magnesium sulfate. The solvent was then removed from the organic layer by distillation to give 16.5 g of 2-fluoro-N-methoxycarbonylaniline as a substantially single product (yield 94.4%).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH2:11]([CH:13]1[NH:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][S:14]1)[CH3:12]>[OH-].[Na+]>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([N:17]1[CH:16]([C:18]([OH:20])=[O:19])[CH2:15][S:14][CH:13]1[CH2:11][CH3:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CCC1NC(C(=O)O)CS1
Reactant: CC(=O)SCC(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC1SCC(C(=O)O)N1C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Acetylthio-2-methylpropanoic acid chloride (5.4 g. prepared from 3-acetylthio-2-methylpropanoic acid and thionyl chloride, b.p. 80°) and 2 N sodium hydroxide (15 ml.) are added to a solution of 2-ethyl-4-thiazolidinecarboxylic acid [Z. Naturforschg, 17b, 765 (1962)] (5.2 g.) in normal sodium hydroxide (30 ml.) chilled in an ice-water bath. After three hours stirring at room temperature, the mixture is extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to yield 3-(3-acetylthio-2-methylpropanoyl)-2-ethyl-4- thiazolidinecarboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]4[O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:21]=4[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:9][C:8]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[N:7]1)C.[OH-].[K+].Cl>C1COCC1.CO>[CH:20]1[C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][C:22]=2[C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH:10]3[N:6]([CH2:5][C:4]([OH:38])=[O:3])[N:7]=[C:8]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)[CH2:9]3)=[CH:16][CH:15]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)CN1N=C(c2ccc(OC)cc2)CC1c1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2=NN(CC(=O)O)C(c3ccc(-c4cccc5c4oc4ccccc45)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A solution of [5-(4-dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid ethyl ester (0.120 g, 0.275 mmol) in THF (2 mL) and methanol (6 mL) was treated with 10% aq KOH (0.5 mL, 1 mmol) and stirred at room temperature. After 2 h, the solution was acidified with 0.5 N HCl to PH 2-3 and extracted with ethyl acetate (3×15 mL). Purification by flash column chromatography (50% ethyl acetate in heptane) provided [5-(4-dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid (0.108 g, 95%) as a white crystalline solid.