Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][C:7](B3OCCNCCO3)=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Br[C:39]1[C:48]([O:49][CH:50]([F:52])[F:51])=[C:47]2[C:42]([C:43](=[O:61])[C:44]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:45][N:46]2[CH:53]2[CH2:55][CH2:54]2)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(Cl)Cl.C(OCC)(=O)C>[CH:53]1([N:46]2[C:47]3[C:42](=[CH:41][CH:40]=[C:39]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[C@@H:2]([CH3:1])[N:3]([C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:4]5)[C:48]=3[O:49][CH:50]([F:52])[F:51])[C:43](=[O:61])[C:44]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:45]2)[CH2:55][CH2:54]1
Reactant: C[C@@H]1c2ccc(B3OCCNCCO3)cc2CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(Br)ccc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(-c3ccc4c(c3)CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]4C)ccc2c1=O
Yield: 89.5 %

Procedure:
In a mixed solvent of 2 ml of water and 5 ml of ethyl acetate is suspended 1.34 g of 2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocane and to this suspension are added 1.0 g of ethyl 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.55 g of sodium carbonate and 0.05 g of bis(triphenylphosphine)palladium(II) chloride, after which the resulting mixture is heated under reflux for 3 hours in a nitrogen atmosphere. The reaction mixture is added to a mixed solvent of 10 ml of methylene chloride and 10 ml of water and the organic layer is separated. The organic layer obtained is washed with saturated saline and then dried over anhydrous magnesium sulfate, after which the solvent is removed from the layer by distillation under reduced pressure. The residue obtained is recrystallized from ethanol to obtain 1.55 g of ethyl 1-cyclopropyl-8-difluoromethoxy-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.
Reaction SMILES: O=[C:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].O.[OH-].[Na+]>C(Cl)Cl>[CH2:9]([O:8][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)CCCC(=O)c1cn(-c2cccnc2)c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCCCc1cn(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 0.5 g of 3-(1-oxo-4-ethoxycarbonylbutyl)-N-(3-pyridyl)-indole in 15 ml of methylene chloride are added first 0.40 g of aluminum chloride and subsequently 0.175 g of dimethylamine borane complex. The reaction mixture is stirred at room temperature for 24 hours. The mixture is cooled to 0° and 10 ml of water are added dropwise. After ten minutes, 35 ml of 1N aqueous sodium hydroxide are added to adjust pH to 8. The methylene chloride layer is separated, the aqueous layer is further extracted with methylene chloride; the methylene chloride extracts are combined, washed with water, dried and evaporated to dryness to yield 3-(4-ethoxycarbonylbutyl)N-(3-pyridyl)-indole. Hydrolysis with dilute sodium hydroxide yields 3-(4-carboxybutyl)-N-(3-pyridyl)-indole.
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[F:11][C:10]([F:13])([F:12])[C:9]1[C:2]2[S:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cccc(C(F)(F)F)c2s1

Procedure:
Using 5.0 g (26.0 mmol) of 2-fluoro-3-trifluoromethylbenzaldehyde, 1.56 g (39.0 mmol) of sodium hydride (60% pure) and 3.0 g (28.6 mmol) of methyl mercaptoacetate, 5.4 g (79.7% of theory) of the title compound are obtained.
Reaction SMILES: C1C(=O)N([O:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]2[S:19][CH2:18][C@@H:17]3[NH:20][C:21]([NH:23][C@H:16]23)=[O:22])=[O:10])C(=O)C1>CS(C)=O>[OH:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[C@@H:16]2[C@@H:17]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:19]1)=[O:8]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CCC2=O)N1
Solvent: CS(C)=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 2 h

Procedure:
The coating process as described in Example 12 is repeated but instead of colouring 10 mM solution of biotin N-hydroxysuccinimide ester in dimethyl sulfoxide is added. After 2 hours of incubation, the tube is washed with dimethyl sulfoxide, ethanol and water, then dried. As a result of the treatment, biotin is bound by covalent bond to the free amino groups of the layer formed. Binding of the biotin was proved by titration with labelled 125I-streptavidine solution. 125I-streptavidin/PBS (Phosphate Buffered Saline) solution (pH 7,4) of 400,000 cpm/ml radioactive concentration is added into a piece of tube of 10 cm length and then it is incubated for 1 hour at ambient temperature. The composition of the PBS solution is as follows: 8 g NaCl, 0.2 g KCl, 1.15 g Na2HPO4.2H2O, 0.2 g KH2PO4, diluted with distilled water to a volume of 3 liters; pH is adjusted with NaOH to 7.4. After removing the titrant, the tube is washed three times with PBS solution (pH 7,4), then its radioactivity is measured. It was established that the tube has bound 97.4% of the labelled streptavidin. Consequently, the process described in the example is suitable for the formation of a layer containing functional groups; the layer can be modified by appropriate reagents.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[NH2:10][OH:11].C([O-])(O)=O.[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:10][OH:11])[CH:2]=1
Reactant: NO
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: ON=Cc1cccnc1
Yield: 97 %

Procedure:
3-Pyridine carboxaldehyde (21.4 g, 200 mmol) and hydroxylamine hydrochloride (14.6 g, 210 mmol) were dissolved in CH3OH (125 ml) and heated at reflux for 12 hours. The solution was then concentrated under vacuum to give a white solid. To this solid was added saturated NaHCO3 solution, with stirring until slightly basic. A white precipitate was obtained which was filtered, washed with water, and dried in vacuo, to give 3-pyridine aldoxime as a white solid, 23.6 g, 97% yield, mp 148°-150° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
4.62 ml (0.03 mol) of ethyl piperidine-4-carboxylate were dissolved in 50 ml of dimethylformamide and treated with 4.98 ml (0.036 mol) of triethylamine. 3.9 ml (0.033 mol) of benzyl bromide were added while cooling with ice and the mixture was stirred for 10 min., warmed to 40° and stirred under an argon atmosphere for 18 hrs. The solvent was then distilled off, the residue was added to 100 ml of water, extracted three times with 100 ml of ether each time and the organic phase was dried over magnesium sulfate. 5.33 g (72%) of ethyl 1-benzyl-piperidine-4-carboxylate were obtained as a yellow oil. MS: me/e=248 (C15H22NO2+).
Reaction SMILES: [Li+:1].[CH3:2][CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[SH:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>C1COCC1>[Li+:1].[CH3:2][CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[F:15][C:16]([F:23])([F:22])[C:17]([C:12]1[S:11][C:10]([SH:9])=[N:14][CH:13]=1)=[O:18]
Reactant: Sc1nccs1
Reactant: CCOC(=O)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.38 h

Procedure:
A solution of LDA (95.4 mmol) in THF was prepared at −10° C. and cooled to −78° C. To the LDA was added a solution of 2-mercaptothiazole (10.00 g, 85.3 mmol) in 25 mL of THF. After 15-30 min of stirring, ethyl trifluoroacetate (13.2 mL, 110.9 mmol) in 15 mL of THF was added. The solution was brought to −10° C. and quenched with NH4Cl followed by HCl (10%) and diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4. The solvent was evaporated and the residue chromatographed on silica gel (toluene/acetone; 8:2 with 1% methanol) to give the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]=2[N+:18]([O-])=O)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe]>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(6-methyl-5-nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (3.4 g, 0.010 mol), ethanol (60 mL, 1 mol), and the solution was heated at 85° C. Ammonium chloride (6 g, 0.1 mol) in water (15 mL, 0.83 mol) was added followed by iron (2 g, 0.04 mol) in two portions. The reaction was stirred for 1 hour and poured onto dichloromethane (200 mL) and extracted. the solvent was removed under reduced pressureunder reduced pressure and the residue was purified by flash chromatography to afford the desired product as a light yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[O:9][C:7](=[O:8])[C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].F[C:32]1[CH:46]=[CH:45][C:35]([C:36]([C:38]2[CH:43]=[CH:42][C:41](F)=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1.C1(C)C=CC=CC=1>CN(C)C(=O)C>[CH:1]1[CH:2]=[CH:3][C:4]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])[C:35]1[CH:45]=[CH:46][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Polymerization was carried out similar to the P(BPZ-BNZPH) polymerization, except phenolphthalein (15.0000 g, 47.12 mmol), potassium carbonate (13.02 g, 94.28 mmol), 4,4′-difluorobenzophenone (10.2819 g, 47.12 mmol), toluene (117 g) and N,N-dimethylacetamide 100 g) were used. The yield was about 21.87 g. The number average molecular weight of the polymer was about 40.4 K.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Ic1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a stirred suspension of 4-iodo-1H-pyrazole (1.50 g, 7.73 mmol) and potassium carbonate (2.67 g, 19.3 mmol) in acetone was added benzyl bromide (0.96 mL, 8.07 mmol) and the reaction was refluxed for 3 h. After cooling to room temperature the mixture was concentrated onto silica gel in vacuo and eluted through a short silica plug (sequential elution—hexane, 10% diethyl ether in hexanes) to provide the title compound as a white solid (2.12 g, 97% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=[CH:13][C:14]=1[I:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+2]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[I:15])[CH:16]=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(I)c(OCc2ccccc2)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(I)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.5 %

Procedure:
7.8 g (90 mmol, 5 eq) of manganese oxide are added to a solution of 6.5 g (17.98 mmol, 1 eq) of (3-benzyloxy-4-iodophenyl)methanol in 50 mL of dichloromethane. The reaction medium is stirred for 12 hours at room temperature, and the solid is then filtered off and the solvent is evaporated off. The residual oil is chromatographed on silica gel (8/2 heptane/ethyl acetate). The oil obtained is crystallized from pentane. 3.25 g of 3-benzyloxy-4-iodobenzaldehyde are obtained. Yield=54% for the three steps c, d and e.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[NH2:14]
Reactant: Cc1cccc(-c2ccccc2)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2ccccc2)c1N

Procedure:
During a 45 minute period 3-methyl-2-nitro-[1,1'-biphenyl] (25.4 g, 0.119 mole) was added portionwise at 30° to a stirred solution of stannous chloride (107.5 g, 0.476 mole) and 150 ml of concentrated hydrochloric acid in enough ethanol to produce a solution. After complete addition the mixture was heated at reflux for 17 hours. The mixture was cooled and made basic (pH 9-10) with 4 N aqueous sodium hydroxide, producing a white precipitate. The precipitate was collected by filtration and partitioned between water and methylene chloride. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 3-methyl-[1,1'-biphenyl]-2-amine as a yellow oil.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1>C(O)=O>[CH:1]([NH:3][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1)[CH3:12])=[O:2]
Reactant: NC=O
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: O=CO
Product: CC(NC=O)c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
In the same manner as in Example 3 except that a mixture of formamide, formic acid and 4'-chloroacetophenone was heated with stirring at 160° C. for 6 hours in place of the concurrent addition of 4'-chloroacetophenone and formic acid to formamide for 3 hours and keeping the mass after the addition stirred for 3 hours, the reaction and post treatment were carried out to obtain 144.2 g of crude N-formyl-1-(4-chlorophenyl)ethylamine; the purity: 84.6%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)=[N:5][N:4]=[N:3]1.N1C(C)=CC=CC=1C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].Cl>ClCCl>[C:26]1([O:25][C:23](=[O:24])[NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH:8]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1nnnc1-c1cccc(N)c1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
In a dry flask of 1-methyl-5-(3-aminophenyl)-tetrazole (24.0 g, 137 mmol) was dissolved in dichloromethane (1.4 L) and 2,6-lutidine (44.1 g, 411 mmol) was added. Phenyl chloroformate (21.2 g, 136 mmol) was added in 4 portions over 15 minutes, then the reaction was stirred for 1.5 hours. The reaction was poured into 1N aqueous hydrochloric acid (200 mL) and the mixture was extracted with dichloromethane three times (200 mL). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude brown material was dissolved in hot toluene, filtered, and allowed to precipitate at 0° C. to give 34.1 g of a white solid. The filtrate was concentrated and recrystallized from toluene again to give an additional crop of off-white crystals (3.44 g, 93% total). 1H NMR (300 MHz, CDCl3), δ: 10.51 (bs, 1H), 8.01 (s, 1H), 7.71 (dt, J=7, J′=2, 1H), 7.55 (m, 2H), 7.41 (m, 2H), 7.24 (m, 2H), 4.14 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[Cl-].[NH4+]>C1COCC1>[CH3:21][O:20][C:18]([C:13]1([CH2:26][CH2:25][CH2:24][CH2:23][Br:22])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: BrCCCCBr
Reactant: COC(=O)C1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of diisopropylamine (150 mmol, 21 mL) in THF (100 mL) was added dropwise a solution of n-butyl lithium (145 mmol, 58 mL, 2.5M) in hexanes at −10° C. while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. To this, a solution of methyl cyclopentane carboxylate (100 mmol, 13.1 g) in THF (20 mL) was added dropwise at −70° C. maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 1 h at −50 to −60° C. Then, a solution of 1,4-dibromobutane (100 mmol, 21.59 g) in THF (20 mL) was added dropwise and the light brown suspension was stirred for 1 h at −60 to −70° C. Then, it was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (200 mL) and the organic compound was extracted into ether (2×100 mL). The combined extracts were washed with a saturated brine solution (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was distilled at 120-133° C./2.5 mm Hg to obtain 1-(4-bromobutyl)cyclopentane carboxylic acid methyl ester as a colorless oil (12.8 g, 48%). HR MS (C11H19BrO2): Obs mass, 262.0565. Calcd mass, 262.0568 (M+).
Reaction SMILES: [OH:1][CH:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)[CH2:3][CH3:4].Cl.N1C=CC=CC=1.Cl[O-].[Ca+2].Cl[O-]>ClCCl>[C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)(=[O:1])[CH2:3][CH3:4]
Reactant: CCC(O)c1cc(-c2ccccc2)no1
Agent: Cl
Agent: [Ca+2]
Agent: [O-]Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)c1cc(-c2ccccc2)no1

Procedure:
In 10 ml of dichloromethane, 1.0 g (5.0 mmol) of 5-(1-hydroxypropyl)-3-phenylisoxazole was dissolved. To the solution were added 100 mg (0.9 mmol) of pyridine hydrochloride, followed by the further addition of 1.4 g (9.9 mmol) of calcium hypochlorite. They were reacted at room temperature for 5 hours. After completion of the reaction, insoluble matter was filtered off and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was then recrystallized from ethanol, whereby the target compound, namely, 5-propionyl-3-phenylisoxazole was obtained as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.Cl[CH:12]([F:14])[F:13]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:12]([F:14])[F:13])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: FC(F)Cl
Reactant: CSc1nc(O)cc(Cl)n1
Product: CSc1nc(Cl)cc(OC(F)F)n1

Procedure:
On the other hand, in the latter process, 4-chloro-6-hydroxy-2-methylthiopyrimidine as the starting material is first reacted with monochlorodifluoromethane to obtain 4-chloro-6-difluoromethoxy-2-methylthiopyrimidine, then this product was reacted with sodium nitrite in dimethylformamide t obtain 4-hydroxy-6-difluoromethoxy-2-methylthiopyrimidine, which is further reacted with monochlorodifluoromethane in dioxane in the presence of potassium hydroxide to obtain desired 4,6-bis(difluoromethoxy)-2-methylthiopyrimidine at a yield of 50%. However, this process also involves long process steps and is very cumbersome, and as such, it is not suitable as an industrial process.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12](O)=[O:13].ClC(OCC(C)C)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(O)(=O)C.C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:15]=[CH:16][N:17]=1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1ccnc(Br)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
30.2 ml (295 mmol) of triethylamine is added to 56.5 g (280 mmol) of 2-bromo-isonicotinic acid in 1.21 of THF. Then, it is cooled to −10° C. and mixed drop by drop with 38.2 ml (295 mmol) of isobutyl chloroformate. After stirring has been continued for one hour at −10° C., it is cooled to −70° C. and mixed drop by drop with 590 ml (590 mmol) of LiAlH4 solution (1 M in THF). After stirring is continued for one hour at −70° C., it is allowed to reach −40° C. 600 ml of 50% acetic acid is added. It is stirred overnight at room temperature. The insoluble components are suctioned off, and the filtrate is concentrated by evaporation. The residue is purified on silica gel with hexane and hexane/ethyl acetate 1:1. 28.0 g of white solidifying oil accumulates.
Reaction SMILES: C([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1)(O)=O.[O:22]1CCCC1>C1(C)C=CC=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][OH:22])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: C1CCOC1
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Solvent: Cc1ccccc1
Product: CCCSc1ncc(CO)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole (3.74 g, 11.5 mmol) in dry tetrahydrofuran (50 ml) was cooled to 78° C. under argon, and a solution of diisobutyl-alumninum hydride in toluene (30 ml of 1M) was added dropwise. The mixture was stirred at -78° C. for 1.5 hours, then allowed to slowly warm to room temperature. The reation was quenched by pouring onto iced dilute acetic acid, the product was extracted into methylene chloride and the organic extracts were washed with water, 5% sodium carbonate solution and brine. The dried, concentrated product was a light tan solid (3.32 g). Crystallization from ethanol/water gave 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole; mp 98°-101° C. The title compound is prepared by the procedure of Example 1 [(iii) Method A (i-vi)] using 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole in place of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole.