Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[C:8]1([CH:7]2[O:6][CH2:5][CH:3]([OH:4])[CH2:2][O:1]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCC(O)CO
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: OC1COC(c2ccccc2)OC1

Procedure:
Concentrated sulfuric acid (3 drops) was added to a mixture of glycerol (55.1 g, 0.60 mmol) and benzaldehyde (50.0 g, 0.47 mmol) in toluene (69 mL) and the resulting mixture was heated to reflux in a Dean-Stark water separator under nitrogen. When the separation of water was complete, the solvent was concentrated under reduced pressure to give a white solid which was recrystallized from ether/petroleum ether. Repeated recrystallization from the same solvent gave pure 2-phenyl-1,3-dioxan-5-ol. 1H NMR (300 MHz, CDCl3) δ 7.51-7.48 (m, 2H), 7.41-7.37 (m, 3H), 5.55 (s, 1H), 4.21-4.17 (m, 2H), 4.14-4.10 (m, 2H), 3.63 (s, 1H), 2.78 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[OH-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 57 %

Procedure:
To a suspension of 4-hydroxy-3-methoxybenzoic acid (25 g, 0.15 mole) in ethanol (150 ml), 2N NaOH aq. (74.3 g, 0.15 mole) and benzyl chloride (56.5 g, 0.45 mole) were added, continued to stir for 1 hour under reflux, then 5N NaOH aq. (150 ml) was added dropwise with stirring under reflux, and continued to stir for 1 hour under reflux. After reaction, the solvent was removed, and H2O was added to the residue and acidified with conc. hydrochloric acid to make pH 1. The resulting precipitate was filtered, washed with H2O and dried to give 22.1 g of 4-benzyloxy-3-methoxybenzoic acid as pale yellow crystals having a m.p. of 171°-172.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C.C1COCC1>[Cl:21][C:6]1([C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:12])[O:11]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
THF (25 mL) was added to 2-(4-chlorobenzoyl)benzoic acid (1 g, 3.8 mmol) followed by thionyl chloride (0.55 mL, 7.6 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature and monitored by TLC. Removal of the solvent gave 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one as a colourless oil (1.06 g, 3.8 mmol, 100%).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C([O-])(O)=O.[Na+]>C(OCC)C>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][CH:17]([F:20])[F:16])(=[O:10])=[O:11]
Reactant: OCC(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Temperature: 84 °C
Yield: 64.1 %

Procedure:
Triflic anhydride (27.9 g, 99.1 mmol) was placed in a flask and cooled with an ice bath. 2,2-Difluoroethanol (8.1 g, 99.1 mmol) was added and the reaction was heated to 84° C. for 1 hour. The reaction, was cooled in an ice bath and poured into 100 ml cold 5% NaHCO3 solution. The mixture was attracted with diethyl ether, dried over MgSO4, and concentrated under reduced pressure to remove the ether. The residue was vacuum distilled to give 2,2-difluoroethyl trifluoromethanesulfonate as a clear liquid (13.6 g, 64%, bp −55° C.). 1H NMR (400 MHz, CDCl3) δ ppm 6.17-5.88 (1H), 4.61-4.13 (2H)
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:18]O>>[Br:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9]([O:11][CH3:18])=[O:10]
Reactant: CO
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)ccc1Br
Temperature: 25 °C

Procedure:
Sulfuric acid (2 eq) was added to a solution of 2-bromo-5-methoxybenzoic acid (1 eq) in methanol (0.30 M) at 0° C. under N2. The solution was allowed to warm to RT and then refluxed for 5 h. After cooling to RT, the solution was concentrated in vacuo, the residue dissolved in ethyl acetate and washed with 1N NaOH solution (2×). The combined aqueous layers were extracted with ethyl acetate and the combined organics dried over MgSO4. Concentration in vacuo gave methyl 2-bromo-5-methoxybenzoate as a clear oil. EI-MS m/z 245, 247 (M+H)+
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H][H]>CCO.[Pd].[C]>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 1-6 (4.0 g, 13.9 mmol) and 10% Pd/carbon (4.0 g) in EtOH (100 mL) was stirred under a balloon of hydrogen for 4 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/methanol) to give 1-7 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
450 g (3 mol) of 4-methylphenyl-acetic acid (Aldrich), 1.13 l (12 mol) of tert-butanol and 90 g (0.74 mol) of 4-(N,N-dimethylamino)pyridine are dissolved in 2 l of dichloromethane. After addition of 680 g (3.3 mol of dicyclohexylcarbodiimide, dissolved in 400 ml of dichloromethane, the mixture is stirred at 25° C. for 20 h, the precipitated urea is filtered off with suction and washed with 200 ml of dichloromethane, and the organic phase is washed twice each with 500 ml of 2M hydrochloric acid and water. The organic phase is concentrated and distilled.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:14][C:15]([CH:17]3[N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22][C:19]4([CH2:21][CH2:20]4)[CH2:18]3)=[O:16])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH2:20]1[C:19]2([CH2:22][CH2:23][NH:24][CH:17]([C:15]([NH:14][C:11]3([C:8]4[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=4)[CH2:12][CH2:13]3)=[O:16])[CH2:18]2)[CH2:21]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3C(=O)OC(C)(C)C)CC4)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3)CC4)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-butyl 5-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (D55) (19.7 g) was dissolved in DCM (220 ml) before adding TFA (35 ml). The reaction was stirred at RT for 18 hrs. After solvent evaporation the title compound (D89) (27 g) was isolated.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+]>C1(C)C(C)=CC=CC=1.CO>[C:7]1([CH:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: CCCCC(O)c1ccccc1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium (II) chloride (1.9 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 1.3 μmol, 0.33 mol %) were dissolved in xylene (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 140° C. After the mixture was cooled to room temperature, pentanophenone (0.4 mmol), xylene (2 mL) and a solution of potassium hydroxide in methanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 12 h under H2 (10 atm) at 25° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/8). Accordingly, pure 1-phenylpentanol was obtained and the ee value (ee=99.6%) was measured by GC analysis.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:10][CH2:11][CH2:12]O)[CH:8]=[CH2:9].C([O-])(O)=O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:6][CH2:12][CH2:11][O:10][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C=CCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOCCOC(=O)C(=C)C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
A three-necked flask equipped with stirrer, thermometer, reflux condenser and Dean-Stark trap is charged with methacrylic acid (137.7 g, 1.6 mol), ethylene glycol monoallyl ether (80.7 g, 0.8 mol), p-toluenesulfonic acid (0.76 g, 4.0 mmol) and toluene (650 mL). After allowing the reaction to proceed at 120° C. for 5 hours, 0.12 g of p-toluenesulfonic acid is added, and the reaction is further allowed to proceed at the same temperature for 6 hours. Then, 0.1 g of p-toluenesulfonic acid is added, and the reaction is further allowed to proceed at the same temperature for 9 hours, whereupon the reaction is completed. During the whole reaction period, methacrylic acid and ethylene glycol monoallyl ether are monitored with liquid chromatography. The final conversion amounted to 98%. The reaction mixture is neutralized by adding an aqueous solution of NaHCO3 and allowed to separate into two layers. The aqueous layer is extracted once with toluene. The combined organic layer is dried over CaCl2 and the volatile matter is distilled off under reduced pressure. The crude product is distilled under reduced pressure (60, 2 mmHg) to give 98.7 g (73% yield) of 2-allyloxyethyl methacrylate shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.CO.[I:12]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:7]([I:12])=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CO
Product: Cc1nc(N)nc(Cl)c1I
Temperature: 60 °C
Yield: 55.7 %

Procedure:
4-Chloro-6-methylpyrimidin-2-ylamine (5 g, 0.04 mol) was suspended in acetonitrile (50 mL) and methanol (50 mL) and N-iodosuccinimide (12 g, 0.05 mol, 1.5 equiv.) added to the resulting mixture. The mixture was heated to 60° C. under a nitrogen atmosphere for 3 h. A solid precipitated in the resulting brown mixture and was isolated by filtration and washed with cyclohexane to give a white crystalline solid 6 g, 65%. Additional product (˜2.5 g) was present in the mother liquors. LCMS m/e 270 35Cl/272 37Cl (M++1);
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].OO.[OH:28]S(O)(=O)=O>C(Cl)CCl.O>[CH:11]1[C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]([Cl:18])=[C:7]([N:6]2[N:5]=[C:4]([C:19]#[N:20])[C:3]([S+:21]([O-:28])[C:22]([F:25])([F:24])[F:23])=[C:2]2[NH2:1])[C:12]=1[Cl:13]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: ClCCCl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Temperature: 13.5 °C
Yield: 74.4 %

Procedure:
1.5 liter of ethylene dichloride & 421.0 gms of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluromethylphenyl)-4-trifluromethylthio pyrazole was charged in a reactor flask with overhead stirring & condenser system. This mass was then cooled to 12-15° C. and 68.0 gms of H2O2 (50.0% w/w) & 500.0 gms of H2SO4 (90.0% w/w) were simultaneously added over a period of 3.0 to 4.0 hours. The reaction temperature was then raised to 28-30° C. & maintained for about 2.0 hours. The reaction mass obtained thereafter was slowly added into 1700 ml of chilled water at 10-20° C. over a period of 2.0 hours. To this mass, 1500 ml of ethylene dichloride was added and the mixture was heated to 60° C. in order to separate the aqueous and organic layers. The obtained organic phase was washed with water & then with 5% NaHCO3 solution followed by water wash, till a neutral pH was obtained. The crude yield of fipronil after removal of solvent was 425.0 gms. The crude fipronil was crystallized from same solvent after partial evaporation to yield 325 gms of crystalline fipronil with 94.0% purity.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](=O)([O:15]C(C)(C)C)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1.O.C(N(CC)CC)C>[C:11]([O:10][C:9]([N:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Ketopiperidine hydrochloride (48.3 g) and di-tert-butyl carbonate (93.2 g) were dissolved in a dioxane-water equivolume mixture (1000 ml), and triethylamine (119 ml) was added to the resultant mixture. The mixture was stirred at room temperature for five hours and concentrated under reduced pressure. Water and ethyl acetate were added to the residue. After separation of the organic phase, the organic phase was washed with a saturated solution of potassium hydrogensulfate and water, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby obtain the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([O:4][F:5])=[O:3].C(O)[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O.[O:18]([F:20])[F:19].[CH2:21]([O:23][C:24](=[O:56])[C@H:25]([CH2:29][C:30]1[C:35]([Sn](C)(C)C)=[CH:34][C:33]([O:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:32]([O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:31]=1)[NH:26][CH:27]=[O:28])[CH3:22]>C(Cl)(Cl)(Cl)F.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:56])[C@H:25]([CH2:29][C:30]1[C:35]([F:5])=[CH:34][C:33]([O:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:32]([O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:31]=1)[NH:26][CH:27]=[O:28])[CH3:22].[CH3:1][C:2]([O:4][F:5])=[O:3].[O:18]([F:20])[F:19]
Reactant: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1[Sn](C)(C)C)NC=O
Agent: CC(=O)OF
Agent: FOF
Agent: OC[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: FC(Cl)(Cl)Cl
Product: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1F)NC=O

Procedure:
The electrophilic fluorinating agent, CH3COOF (prepared from 200 μmol) of F2 in 1% He, (Bida, G. T., Satyamurthy, N. and Barrio, J. R. (1984) The synthesis of 2-[18F]fluoro-2-deoxy-D-glucose using glycals: A reexamination. J. Nucl. Med. 25, 1327) F2 (1% in He, 200 μmol) or OF2 (1% in He, 200 μmol), was bubbled into a solution of trimethyltin derivative 6 (0.123 g, 200 μmol) in Freon-11 (CFCl3) (20 mL) at room temperature over a period of 30 min. The reaction mixture was diluted with methylene chloride (25 mL) and the organic phase was washed with 1M Na2S2O5 (2×20 mL), water (2×20 mL) and dried (MgSO4). Evaporation of solvents gave a yellow syrup which was chromatographed (silica gel, diethyl ether) to yield a colorless viscous oil 9 (41 mg, 43% in the case of CH3COOF), (65 mg, 69% for F2), (62 mg, 66% for OF2).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CC(O)CCCCC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, rac-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 88 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[Cl-:11].[Al+3].[Cl-:13].[Cl-].ClCl>C(Cl)Cl>[Cl:11][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([Cl:13])[C:2]=1[CH3:1])[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of p-toluic acid (95.0 g, 0.698 mole) in methylene chloride (1 liter), was added aluminum chloride (260.0 g, 1.948 mole) portionwise keeping the reaction temperature below 10° C. (ice-water bath). When the addition was completed (approx. 30 minutes) chlorine gas was bubbled in at such a rate as to keep the temperature below 10° C. The reaction was followed by gas-liquid chromatography. After about 4 hours, most of the starting material had been converted to the expected compound. The resulting mixture was poured into ice and concentrated hydrochloric acid and then extracted with ethyl acetate several times. The combined organic layers were then washed with water and dried over anhydrous sodium sulfate. Removing the solvent in a rotavap yielded the crude product as a white solid. Recrystallization from acetone/water or ethyl acetate/hexane yielded 3,5-dichloro-4-methylbenzoic acid with minor impurities 115.4 g (81% yield of product).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:7]1[O:14]C(=O)C[O:10][C:8]1=[O:9].[Si]([O-])([O-])([O-])[O-].[Al+3].[Si]([O-])([O-])([O-])[O-].[Si]([O-])([O-])([O-])[O-].[Al+3].[Al+3].[Al+3]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:8]([OH:10])(=[O:9])[CH2:7][OH:14]
Reactant: O=C1COC(=O)CO1
Agent: CC(O)C(=O)O
Agent: [Al+3]
Agent: [O-][Si]([O-])([O-])[O-]
Product: O=C(O)CO
Reaction time: 3 h

Procedure:
The lactide obtained in Example 2 (10 g) and glycolide (10 g) were put into a 100-ml reaction vessel equipped with a stirrer and a nitrogen-introducing tube. After substitution of nitrogen gas was carried out three times, the temperature was raised to 150°±5° C., and the mixture was molten over 3 hours with stirring. To the resulting mixture was added 0.4 g of synthetic light aluminum silicate (Tomita Pharmaceutical Co., Ltd.), and the temperature was raised to 195°±5° C. The pressure was reduced gradually to 20 mmHg over 30 minutes, followed by stirring for 3 hours. After the pressure was reduced gradually to 1 mmHg over 30 minutes, the mixture was stirred at 195°±5° C. for 7 hours to give lactic acid-glycolic acid copolymer in the molten state. The product was cooled to room temperature to give 11.50 g of light brown copolymer. The weight-average molecular weight of this copolymer was 65,000.
Reaction SMILES: [CH2:1]1[O:8]C(=O)C[O:4][C:2]1=[O:3].[C:9]1(=[O:16])[O:15][CH2:14][CH2:13][O:12][C:10]1=[O:11]>>[C:2]([OH:4])(=[O:3])[CH2:1][OH:8].[C:9]1(=[O:16])[O:15][CH2:14][CH2:13][O:12][C:10]1=[O:11]
Reactant: O=C1COC(=O)CO1
Agent: O=C1OCCOC1=O
Product: O=C(O)CO

Procedure:
Polymerization and post-treatment were performed in the same manner as in Polymer Preparation Example 1 except that a mixture of 210 g of glycolide and 10 g of ethylene oxalate (1,4-dioxane-2,3-dione) was used in place of 220 g of glycolide, thereby obtaining a glycolic acid-ethylene oxalate copolymer [Polymer (P-2)]. The same process was conducted repeatedly to prepare a necessary amount of Polymer (P-2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCc3ccccc32)cc1
Yield: 73.1 %

Procedure:
To a stirred refluxing mixture of 119 g (1 mole) of indoline, 800 ml of toluene (other solvents, e.g. isopropyl alcohol, are satisfactory), and 207 g (1.5 mole) of pulverized, anhydrous potassium carbonate is added dropwise 126.5 g (1 mole) of benzyl chloride. When addition is complete, refluxing is continued until evolution of gas ceases as evidenced by a gas meter (about three hours). The mixture is allowed to cool, and the solids are removed by filtration. The filtrate is evaporated, and the residue is distilled to give 153 g (73%) of 1-benzylindoline, b.p. 162°-165° (4.5 mm).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16](=[N:18][CH:19]([CH3:21])[CH3:20])[CH3:17])=[C:10](F)[CH:9]=1.C(Cl)Cl>CNC=O>[Br:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]2[N:15]=[C:16]([CH3:17])[N:18]([CH:19]([CH3:21])[CH3:20])[C:10]=2[CH:9]=1
Reactant: CC(=NC(C)C)Nc1c(F)cc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CNC=O
Solvent: ClCCl
Product: Cc1nc2c(F)cc(Br)cc2n1C(C)C
Temperature: 100 °C
Yield: 99.9 %

Procedure:
Add potassium tert-butoxide (811.43 mg) to a solution of N-(4-bromo-2,6-difluoro-phenyl)-N′-isopropyl-acetamidine (2 g) in N-methyl formamide (20 mL). Heat the mixture at 100° C. for 2 h. Cool to RT, add DCM (150 mL), wash three times with saturated sodium chloride aqueous (brine, 300 mL), dry over magnesium sulfate and remove the solvent under vacuum. Add hexane and shake over ultrasound for a few minutes. Filter the solid, repeat addition of hexane/filtration twice to afford 1.86 g of the title compound. MS (ES+): m/z=272 (M+H)+.