Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1.[H-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39](=O)[CH3:40]>O1CCCC1>[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](/[CH:9]=[C:39](\[C:33]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=2[F:31])/[CH3:40])[CH:8]=1
Reactant: CC(=O)c1cc(F)ccc1F
Reactant: Brc1cncc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C(=C/c1cncc(Br)c1)c1cc(F)ccc1F
Yield: 21.1 %

Procedure:
To a stirred solution of 3-bromo-5-((tri-phenylphosphino)methyl)pyridine bromide salt (200 mg, 0.337 mmol) in tetrahydrofuran (Volume: 4 mL) was added sodium hydride (90 mg, 0.843 mmol) at 0° C. A half hour later, 2′,5′-difluoroacetophenone (47.0 mL, 0.371 mmol) in tetrahydrofuran (Volume: 1 mL) was added to above solution. Ice bath was removed and heat it to reflux for overnight. Next morning, 10 mL water was added slowly then was extracted by ether (10 mL×3), combined all organic layers, dried over magnesium sulfate, concentrated and obtained a yellow oil which was purified by Preparative HPLC (Preparative HPLC Method 21) and obtained (Z)-3-bromo-5-(2-(2,5-difluorophenyl)prop-1-enyl)pyridine (22 mg, 0.071 mmol, 21.04%). 1H NMR (500 MHz, DMSO-d6) δ 8.45 (d, J=2.1 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.49 (t, J=2.0 Hz, 1H), 7.36-7.17 (m, 3H), 6.71 (s, 1H), 2.20 (d, J=1.2 Hz, 3H), Mass spec.: 312.1 (MH)+. and (E)-3-bromo-5-(2-(2,5-difluorophenyl)prop-1-enyl)pyridine (18 mg, 0.058 mmol, 17.21%). 1H NMR (500 MHz, DMSO-d6) δ 8.64 (dd, J=6.7, 1.8 Hz, 2H), 8.11 (t, J=1.8 Hz, 1H), 7.38 (ddd, J=9.3, 6.1, 3.2 Hz, 1H), 7.32 (td, J=9.7, 4.7 Hz, 1H), 7.28-7.21 (m, 1H), 6.72 (s, 1H), 2.23 (t, J=1.5 Hz, 3H), Mass spec.: 312.1 (MH)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14].C(O)C>CO>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)[CH2:11][NH:14][CH2:13][CH2:12][NH2:15]
Reactant: NCCN
Reactant: CSc1ccc(C2CO2)cc1
Solvent: CCO
Solvent: CO
Product: CSc1ccc(C(O)CNCCN)cc1
Reaction time: 16 h

Procedure:
2-(4-Methylthiophenyl)oxirane (37 g.) is added, over the course of 20 minutes and at 30° C., to a solution of ethylenediamine (75 cc.) in methanol (56 cc.). After 16 hours at 20° C., ethanol (250 cc.) is added; the precipitate which forms is filtered off. Distilled water (375 cc.) is added to the ethanol solution and the oily impurity which separates out is extracted with diisopropyl ether (200 cc.). After concentrating the aqueous ethanolic solution under reduced pressure, N-[2-hydroxy-2-(4-methylthiophenyl)ethyl]ethylenediamine (37.9 g.) is obtained in the form of an oil.
Reaction SMILES: [Cl:1][CH:2]([C:8]([CH3:10])=O)[C:3](OCC)=[O:4].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].[Na]>C(O)(C)C>[OH:4][C:3]1[C:2]([Cl:1])=[C:8]([CH3:10])[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CS
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: [Na]
Solvent: CC(C)O
Product: COC(=O)c1sc(C)c(Cl)c1O

Procedure:
Prepared by the method described in Example 1 from ethyl α-chloroacetoacetate (59 g, 0.35 moles), methyl thioglycolate (102 g, 0.70 moles) and sodium (19.7 g, 0.86 moles). The product is obtained from the crystalline precipitate by fractional recrystallization from isopropanol to give 2.8 g; mp 105°-107° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Nc1c(Cl)cccc1C(=O)Nc1ccccc1Cl
Yield: 78.8 %

Procedure:
Prepared according to Procedure A using 2-amino-3-chlorobenzoic acid (1.0 g, 5.82 mmol) and SOCl2 (1.1 mL, 14.6 mmol) in benzene (25 mL), followed by 2-chloroaniline (1.2 mL, 11.7 mmol) and CHCl3 (25 mL). The product was recrystallized from MeOH to provide 1.29 g of a yellow solid (78%). 1H NMR (CDCl3) δ: 8.43 (dd, J=1.4, 8.3 Hz, 1H); 8.30 (br s, 1H); 7.47 (dd, J=1.1, 8.0 Hz, 1H); 7.42 (d, J=8.0 Hz, 2H); 7.33 (dt, J=1.4, 7.9 Hz, 1H); 7.09 (dt, J=1.5, 7.7 Hz, 1H); 6.68 (t, J=7.9 Hz, 1H); 6.13 (br s, 2H). MS (ES): m/z 281.0 (M+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.Br[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:20][CH2:19][N:18]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: BrCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
NaH (60% strength in mineral oil, 709 mg, 29.52 mmol) was added to a mixture of 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (2.5 g, 9.84 mmol) in DMF (50 ml) at 0° C., the mixture was stirred at room temperature for 2 h, 4-(bromomethyl)-pyridine HCl (2.42 mg, 14.76 mmol) was then added and the mixture was stirred at room temperature for 16 h. Finally, ice was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase methanol/methylene chloride). Yield: 35%
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:14]([NH2:16])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5]>CO.O.[Pd]>[NH2:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:14]([NH2:16])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5]
Reactant: NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
8.19 g of Z-β-Ala-His-NH2 are hydrogenated at room temperature under normal pressure for 15 hours in 200 ml of methanol/water (95:5) with 0.82 g of palladium-on-carbon (5% Pd). After filtering off the catalyst, evaporating off the solvent and drying, H-β-Ala-His-NH2 is obtained in the form of a colourless powder; Rf (L)=0.01.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.4 %

Procedure:
A mixture of methyl-4-(aminomethyl)benzoate (50 g, 0.302 mol) and benzaldehyde (32 g, 0.302 mol) in EtOH (1 L) was refluxed for 5 h. After cooling to r.t, NaBH4 (11.5 g, 0.302 mol) was added portionwise. The reaction mixture was stirred at r.t. for 10 h. The solvent was removed under reduced pressure and the compound was purified by acid-base work up to give N-(4-methoxycarbonylbenzyl)benzylamine (25 g, 33%).
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1O>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:1][C@@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CC[C@@H](O)C(=O)OC
Reactant: Cc1ccc(Cl)c(O)c1
Product: CC[C@H](Oc1cc(C)ccc1Cl)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (R)-methyl 2-hydroxybutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenol instead of the m-cresol.
Reaction SMILES: [CH:1](/[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].CO>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:20][CH:21]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
A suspension of (E)-tert-butyl 4-styrylbenzoate (0.1 g, 0.36 mmol), palladium on carbon (10%, 100 mg) in methanol (20 mL) was stirred at 20° C. under hydrogen atmosphere (4 atm) for 24 hours. Once the start material has been consumed, the mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to give tert-butyl 4-phenethylbenzoate (90 mg, 89%). 1H NMR (300 MHz, CDCl3): δ 7.90-7.89 (m, 2H), 7.27-7.18 (m, 7H), 2.95-2.94 (m, 4H), 1.59 (s, 9H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([OH:7])=O.P(Cl)(Cl)(Cl)=O.[NH2:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27][O:28][C:29](=[O:31])[NH2:30])[CH2:25][S:26][C@H:21]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([NH:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27][O:28][C:29](=[O:31])[NH2:30])[CH2:25][S:26][C@H:21]12)=[O:7]
Reactant: CON=C(C(=O)O)c1nsc(N)n1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.01 g) and phosphorus oxychloride (3.06 g) in methylene chloride (25 ml) was stirred for 2 hours at ambient temperature, cooled to 0° C. and thereto was added N,N-dimethylformamide (2.0 ml), followed by stirring for an additional 45 minutes at 0° C. A mixture of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (4.9 g) and trimethylsilylacetamide (11 g) in methylene chloride (100 ml) was warmed to make a clear solution. The solution was cooled to -15° C. and added to the above obtained solution, followed by stirring for 30 minutes at 0° C. The reaction mixture was poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated and thereto was added ethyl acetate. The resulting mixture was adjusted to pH 2 with 10% hydrochloric acid, filtered to remove an insoluble material and then saturated with sodium chloride. The ethyl acetate layer was separated, dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give a crude product of the title compound (1.2 g). The crude material was dissolved in an aqueous solution of sodium bicarbonate, and reprecipitated with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give the title compound (0.35 g), mp. 185° to 190° C. (dec.).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31].[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]#[C:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][O:22][C:16]1[N:15]2[N:14]=[C:34]([CH3:35])[C:33]([C:32]([O:37][CH2:38][CH3:39])=[O:36])=[C:20]2[CH:19]=[C:18]([CH3:21])[CH:17]=1
Reactant: CC#CC(=O)OCC
Reactant: Cc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.9 %

Procedure:
1.62 g (3.60 mmol, 1.0 eq.) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 36 ml of DMF, and 0.84 ml (7.19 mmol, 2.0 eq.) of ethyl but-2-ynoate [CAS No: 4341-76-8] were added. 0.994 g (7.19 mmol, 2.0 eq.) of potassium carbonate was added and the mixture was stirred at RT for 1.5 h. Subsequently, the mixture was poured onto 150 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 440 mg of the title compound were obtained (45% of theory, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13](=[N:21][S@@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:9])=[CH:4][CH:3]=1.[CH2:28]([Mg]Br)[CH:29]=[CH2:30]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C@@:13]([NH:21][S@@:22]([C:24]([CH3:26])([CH3:25])[CH3:27])=[O:23])([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:30][CH:29]=[CH2:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Br
Reactant: C[C@H](NCCC(=N[S@](=O)C(C)(C)C)c1ccc(F)cc1)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: C=CC[C@](CCN[C@@H](C)c1ccc(Br)cc1)(N[S@](=O)C(C)(C)C)c1ccc(F)cc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of (R)—N-(3-((1S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl) propylidene)-2-methylpropane-2-sulfinamide (13.3 g, 29.3 mmol) in THF (300 mL) was added 1M allylmagnesium bromide (88 mL, 0.088 mol) under nitrogen at −78° C. The mixture was stirred for 2 h. The reaction was quenched with satd aq NH4Cl. The organic phase was separated and concentrated to give crude (R)—N—((R)-1-((S)-1-(4-bromophenyl)ethylamino)-3-(4-fluorophenyl)hex-5-en-3-yl)-2-methylpropane-2-sulfinamide (14 g, 100%), which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.O.O>[CH2:16]([O:23][C:24](=[O:25])[NH:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ncccc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ncccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-amino-2-methoxypyridine (3.93 g, 31.7 mmol) in THF/H2O (1:1) (120 mL) was added Cs2CO3 (12.4 g, 38.0 mmol) and benzylchloroformate (5.33 mL, 37.9 mmol) and the reaction stirred at room temperature for 5 hours. The mixture was diluted with water, extracted with EtOAc, dried over MgSO4, filtered, and the solvent was removed. The crude product was purified by chromatography (silica gel, 25% EtOAc/hexanes). MS 259 (M+H)+.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1([CH2:10][CH2:11][C:12]([O:14]C)=O)[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9]>O1CCCC1>[CH3:2][C:3]1([CH2:10][CH2:11][C:12](=[O:14])[NH2:1])[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9]
Reactant: N
Reactant: COC(=O)CCC1(C)C(=O)CCC1=O
Solvent: C1CCOC1
Product: CC1(CCC(N)=O)C(=O)CCC1=O
Yield: 41 %

Procedure:
A 1 ml quantity of 25% aqueous ammonia solution was added to 1.6 g of 2-methyl-2-(β-carbomethoxyethyl)-cyclopentan-1,3-dione which was known and disclosed for example in J. Org. Chem., 31, 1489 (1966). The mixture was reacted at room temperature for 5 hours. After reaction, 10 ml of tetrahydrofuran (THF) was added. The insolubles were filtered and recrystallized from ethanol to obtain 0.6 g of Compound mentioned above (yield: 41%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[Mg]Br.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([OH:24])([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)c1ccc2ccccc2c1
Temperature: -25 °C
Reaction time: 4 h

Procedure:
A solution of 2-naphthylmagnesium bromide in tetrahydrofuran (0.5 M, 8.26 mL, 4.13 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (0.3 g, 1.67 mmol) in tetrahydrofuran (10 mL) with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 4 hours, 15% aqueous ammonium chloride solution was added and mixture extracted with ethyl acetate. The combined organic layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-hydroxy-3-naphthalen-2-yl-1,3-dihydro-indol-2-one as a red solid. This was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.Cl.[NH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:7][C:5]1[N:6]=[C:2]([N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[S:3][CH:4]=1
Reactant: OC1CNC1
Reactant: Brc1csc(Br)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OC1CN(c2nc(Br)cs2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
A mixture of 2,4-dibromothiazole (1.00 g, 4.12 mmol), azetidin-3-ol hydrochloride (0.543 g, 4.96 mmol), and cesium carbonate (4.03 g, 12.37 mmol) in acetonitrile (30 mL) was stirred for 18 h at 70° C. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford 1-(4-bromothiazol-2-yl)azetidin-3-ol (0.535 g, 53%) as a light yellow solid. MS (ESI, pos. ion) m/z 235, 237 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16]
Reactant: Cc1ccc(O)c(Br)c1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(COc1ccc(C)cc1Br)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 2 L round bottom flask was cooled to 0° C. a solution of 2-bromo-4-methylphenol (25 g, 133.66 mmol) in anhydrous DMF (940 ml). Then NaH (10.7 g 60% in mineral oil, 267.3 mmol) was slowly added in small portions and the reaction was warmed to room temperature (approx. 0.5 h) after which 2-bromo-1,1-dimethoxy ethane (31.6 ml, 267.4 mmol) was added. The reaction was warmed to room temperature for 3 h and then to 100° C. for 4 h. The reaction was cooled, pass through a silica plug, and concentrated. The brown mixture was diluted with EtOAc, passed through a silica plug again to remove brown solids and concentrated to 24.0 g (65%) amber colored oil: 1H NMR (300 MHz, DMSO-d6): δ 2.23 (3H, s), 3.37 (6H, s), 4.00 (2H, d, J=5.2 Hz), 4.68 (1H, t, J=5.2 Hz), 7.03 (1H, d, J=8.4 Hz), 7.12 (1H, dd, J=8.4 Hz, 1.7 Hz), 7.40 (1H, d, J=1.7 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:30][Mg]Br>C(OCC)(=O)C.CCCCCC>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:30])[CH3:2]
Reactant: CC(=O)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)(C)O)cc1)CO2
Yield: 42 %

Procedure:
Using N-(3-(4-acetylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 176 and methylmagnesium bromide, the title compound was synthesized in the same manner as in Example 22. Yield: 42%. Melting point: 132-134° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23].[CH:24]1([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][C:30]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(NC(=O)CC4CCCC4)cc23)c(OC)c1

Procedure:
Starting from amino-ester (A), and using a similar procedure to that described in Example 4, except using cyclopentylacetyl chloride (see also Example 98), the title compound was obtained in quantitative yield as a foam; partial NMR (250 MHz, DMSO-d6): 1.2-1.8(3m,8H, cyclopentyl ring); 2.24(m,3H, CH2CONH and --CHCH2); 3.83(s,3H, OMe); 3.93(s,3H, OMe); 3.99(br s,2H, CH2Ar); 9.57(br s,1H, NHCO); 10.79(br d,1H, --NH--).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:27]1[CH2:32][CH2:31][CH:30]([CH:33]([OH:35])[CH3:34])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:27]4[CH2:32][CH2:31][CH:30]([CH:33]([OH:35])[CH3:34])[CH2:29][CH2:28]4)=[O:26])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(O)C1CCNCC1
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Product: CC(O)C1CCN(C(=O)c2cc(C(=O)NCCc3ccc(-c4ccc(Cl)c(Cl)c4)o3)[nH]n2)CC1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 1-(piperidin-4-yl)ethanol. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-90:10). 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.30-1.41 (3H, m), 1.62 (1H, m), 1.77 (1H, m), 2.00 (1H, m), about 2.78 (1H, m), 3.01 (2H, t), about 3.18 (1H, m), about 3.64 (1H, m), 3.77 (2H, q), about 4.48 (1H, m), about 4.75 (1H, m), 6.20 (1H, d), 6.58 (1H, d), 7.02 (1H, s), about 7.28 (1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorted dd), 7.75 (1H, d), 11.44 (1H, broad s).
Reaction SMILES: [CH3:1][N+:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CN(C)CCCCCCCC.[C:24](=[O:29])([O:27]C)[O:25]C>CO>[C:24](=[O:25])([O-:29])[O-:27].[CH3:1][N+:2]([CH3:11])([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:12][N+:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH3:11])[CH3:1]
Reactant: COC(=O)OC
Agent: CCCCCCCCN(C)C
Agent: CCCCCCCC[N+](C)(C)C
Solvent: CO
Product: O=C([O-])[O-]

Procedure:
Among these preparation methods, preferred are those by anion exchange with a quaternary ammonium carbonate. A specific example for preparation of a quaternary ammonium salts of a carboxyl-containing polymer, in the case of a trimethyloctylammonium salt of polyacrylic acid, is as follows: Into a pressure vessel, are charged dimethyloctylamine (1 mole) and dimethyl carbonate (1 mole or more) together with methanol, and reacted at an elevated temperature (at about 120° C.) under pressure (about 5 kg/cm2) to obtain a solution in methanol of trimethyloctylammonium carbonate. Then, the solution is added at a temperature of 80-90° C. gradually to an aqueous solution of polyacrylic acid, whereby carbon dioxide is simultaneously generated vigorously. Generated carbon dioxide and methanol are distilled off to obtain an aqueous solution of trimethyl-octylammonium salt of polyacrylic acid.