Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH3:13])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(C)(C)C>C(O)(C)(C)C.[OH-].[Na+].O>[C:19]([N:1]([CH3:13])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:25]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.6 g of H-MePhe-OH are dissolved in a mixture of tert.-butanol, 25 ml of 10% aqueous KHCO3 solution and 5 ml of 4 N sodium hydroxide. 8 ml of di-tert.-butylcarbonate are added and the mixture stirred for 2 days at room temperature. The reaction mixture is diluted with ca. 100 ml of water and extracted with ether. The aqueous phase is acidified, with stirring to pH 2. The precipitated product is extracted with acetic acid, the extract washed with water and dried over Na2SO4. The liquid is evaporated and the product crystallised from ether/petroleum ether to yield Boc-MePhe-OH. M.P. 87°.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClC(Cl)C.O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH:19]([C:20]([CH:19]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Reaction time: 1 h
Yield: 82 %

Procedure:
120 kg (1.09 kmole) of resorcinol were suspended in 660 l of dichlorethane and 150 kg (1.12 kmole) of anhydrous aluminum chloride were added to the suspension while the temperature raised from 15° C. to 25° C. The complex obtained dissolved in the reaction medium. 171 kg (1.10 kmole) of phenyl-acetyl chloride were added over a period of one hour while the temperature raised to 35°-40° C. The mixture was stirred for one hour thereafter it was admixed with diluted hydrogen chloride (the mixture of 300 l of hydrogen chloride and 600 l of water), and it was treated as described in the preceding Examples. The solvent was removed by distillation, the residue was recrytallized from toluene, the product obtained was centrifuged and dried at 45°-50° C. 205-210 kg of 2,4-dihydroxy-phenyl-benzyl-ketone were obtained, yield 82-84.5%. Calculated amount: 248.5 kg. The physical data are identical with the data given in Example 1.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(N)ccc2o1
Reactant: CS(=O)(=O)Cl
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1

Procedure:
A process for synthesizing dronedarone was described in patent application WO 02/48132, mentioned previously, using 2-n-butyl-5-nitrobenzofuran, which is reduced, under pressure with hydrogen in the presence of platinum oxide as catalyst to form 2-n-butyl-5-aminobenzofuran. This benzofuran derivative is then subjected to the action of methanesulfonyl chloride, which gives 2-n-butyl-5-methanesulfonamidobenzofuran, which is treated with 4-[3-(di-n-butylamino)propoxy]benzoyl chloride to obtain dronedarone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-bromophenol was dissolved in dichloromethane. Triethylamine (1 eq) and acetic anhydride (2 eq) were added and the mixture was stirred at room temperature for 5 hours. The solvent was eliminated by vacuum evaporation. The evaporation residue was taken up in dichloromethane then dried on magnesium sulfate. The solvent was eliminated by vacuum evaporation.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:16])[O:10][B:9]([OH:11])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2>C(Cl)(Cl)(Cl)Cl>[CH3:5][C:6]1([CH3:16])[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=[CH:15][C:7]1=2
Reactant: O=[N+]([O-])O
Reactant: CC1(C)OB(O)c2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To 100% fuming nitric acid (10 mL) at −40° C. was added dropwise a solution of 3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (XCVI) (1.37 g, 0.0085 mol) in carbon tetrachloride (40 mL), maintaining the temperature below −40° C. Stirring was continued for 20 min at −40° C. The yellow solution was poured onto ice and was stirred for 10 min at room temperature. The mixture was extracted with EtOAc. To the organic layer was added 1M aqueous NaOH to pH=7. The organic layer was separated, and washed with water, dried over MgSO4 and filtered, and the solvent was removed in vacuo to give an orange viscous oil. The oily residue was triturated with hexane to give pure 3,3-dimethyl-6-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (XCVII) as a yellow solid (1.20 g, 5.8 mmol, yield 68%). 1H NMR (CDCl3) δ ppm 1.61 (s, 6H), 7.42 (s, 1H), 8.35 (d, J=8 Hz, 1H), 8.56 (d, J=8 Hz. 1H). ESIMS found for C9H10BNO4 m/z 206.3 (M−H).
Reaction SMILES: CC1C=C(C(O)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.Br[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].[CH3:34][C:35]1[C:36](B(O)O)=[CH:37][S:38][CH:39]=1>>[CH3:33][O:32][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:22]=1[C:36]1[C:35]([CH3:34])=[CH:39][S:38][CH:37]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: Cc1cscc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Agent: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Product: COC(=O)c1ccc(-c2cscc2C)c(OC)c1

Procedure:
The title compound was prepared following procedure described for Intermediate 5, step 1, but starting from methyl 4-bromo-3-methoxybenzoate (Combi-Blocks, 2.50 g; 10.20 mmol; 1 eq.) and 4-methyl-3-thiopheneboronic acid (1.59 g; 11.22 mmol; 1.10 eq.), and was isolated as a brown oil. It was used in the next step without further purification. LC/MS (Method A): 262.8 (M+H)+. HPLC (Method A) Rt 4.79 min.
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1)=[O:10]>>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccc(CBr)cc1)c1cccs1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCc1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5.9 parts of sodium cyanide in 40 parts of dimethyl sufoxide is heated to 60° C and there are added at once 11.3 parts of α-bromo-p-tolyl 2-thienyl ketone (exothermic reaction: temperature rises to 100° C). The whole is stirred for 2 hours at 60° C. After cooling, the reaction mixture is poured onto water and the product is extracted three times with 450 parts of chloroform. The combined extracts are washed twice with 200 parts of water, dried and evaporated. The dark-coloured residual tar is extracted several times with ether. The combined ether extracts are stirred with activated charcoal, filtered and evaporated. The residue is triturated in petroleumether (solid carbon dioxide) and the whole is evaporated, yielding 2-[-p-(2-thenoyl)-phenyl]acetonitrile as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:12]3[NH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16](=O)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:27]>ClCCCl>[Cl:27][C:16]1[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2c(cnn2Cc2ccc(OC)cc2)c1=O
Solvent: ClCCCl
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl
Temperature: 90 °C
Yield: 86.8 %

Procedure:
To a solution of ethyl 1-(4-methoxybenzyl)-4-oxo-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (4.0 g, 13 mmol) in 1,2-dichloroethane (9.8 mL) was added POCl3 (2.4 mL, 26 mmol). The resulting mixture was heated at 90° C. for 3 h. After cooling, the most volatile were removed by vacuum, and the residue was diluted with EtOAc and washed with aq. Na2CO3 solution. The organic layer was washed water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 10 to 60% EtOAc in hexanes, to give the sub-title compound (3.9 g, 95%). LCMS calc. for C17H17ClN3O3 (M+H)+: m/z=346.1. Found: 346.1.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH2:19].O>CN1CCCC1=O>[CH3:18][NH:19][C:2]1[C:3]([NH2:4])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-fluoro-5-nitroaniline (5 g, 32 mmol) in 40 ml N-methylpyrrolidinone in a sealed reaction vessel was added potassium carbonate (9.0 g, 50.0 mmol) and a solution of methyl amine (32 ml, 2M in THF) and the reaction was heated to 120° C. After 16 h, the reaction mixture was cooled to room temperature and poured into 400 ml of water. The resulting precipitate was filtered and dried to give the title compound as a red solid. 1H NMR (300 MHz, d6-DMSO) δ7.54 (dd, J=8.7 and 2.7 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 6.41 (d, J=8.7 Hz, 1H), 6.13 (s, 1H), 5.08 (s, 2H), 2.83 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C:10]([C:12]1([C:23]#[N:24])[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]1([CH3:22])[CH3:21])=[O:11])C>O.CO>[C:23]([C:12]1([C:10]([OH:11])=[O:9])[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:13]1([CH3:22])[CH3:21])#[N:24]
Reactant: CCOC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)C(c2ccccc2)C1(C#N)C(=O)O
Temperature: 85 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A solution of potassium carbonate (40 g) in water (125 mL) was added to a solution of 1-cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid ethyl ester (64.26 g, 264 mmol) in MeOH (500 mL). The reaction mixture was heated at reflux for 1 hour and then stirred overnight at 85° C. The volatiles where evaporated under reduced pressure, and the residue was diluted with water and washed twice with EtOAc. The phases were separated and the aqueous phase was acidified by addition of HCl (concentrated). Ethyl ether was added and the mixture was carefully extracted. The organic layer was separated, dried over Na2SO4, filtered and evaporated under reduced pressure to give 27.2 g (49% yield) of 1-cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid as an off-white solid.
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[C:29]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccccc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (725 mg, 2.76 mmol), benzoic acid (338 mg, 2.76 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (649 mg, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for two hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give (R)-2-benzoyloxyoctane as a colorless liquid substance (490 mg, yield: 91%/(S)-2-octanol).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[O:15]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([CH3:10])[CH:8]=1)[C:3](=[O:14])[N:27]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][CH:24]=1)[CH2:12]2
Reactant: COC(=O)c1c(C)cc(Br)cc1CBr
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Yield: 67.2 %

Procedure:
4-Bromo-2-bromomethyl-6-methylbenzoic acid methyl ester (762 mg, 2.37 mmol), 4-phenoxy benzylamine (0.543 mL, 3.56 mmol) and K2CO3 (981 mg, 7.10 mmol) were stirred in toluene (10 mL) at 95° C. for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2-SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-25% EtOAc/Hexanes) to afford a yellow oil (650 mg). 1H NMR (300 MHz, CDCl3): δ 7.35-7.38 (m, 4H), 7.32 (s, 1H), 7.26-7.29 (m, 1H), 7.15 (t, 1H), 6.99 (t, 4H), 4.74 (s, 2H), 4.23 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=[O:14])[NH:13][C:7]2=[CH:6][CH:5]=1)=[O:10].[CH3:16]I>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:16])[C:12](=[O:14])[O:11][C:9](=[O:10])[C:8]=2[CH:15]=1
Reactant: CI
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
In a 3 L, 3 neck RBF equipped with mechanical stir, addition funnel, thermocouple and N2 inlet, NaH (30.4 g) was suspended in anhydrous THF (400 mL). While stirring at room temperature, a suspension of 5-chloroisatoic anhydride in THF (400 mL) was added in portion-wise manner over 45 min. The reaction mixture was stirred for 50 min (reaction temperature went up from 18 to 28° C.). To this was added CH3I (285 g, 125 mL) over 15 min. The mixture was then stirred at 42° C. for 16 h. Because TLC showed that some unreacted starting material was still present in the reaction mixture, an additional 30 mL of CH3I was added and the reaction mixture stirred at 42° C. for an additional 3 h. Reaction mixture was cooled (RT) and quenched by the slow (40 min) addition of AcOH (55 mL). Reaction mixture was concentrated to give 275 g thick syrupy product, which was used without any further purification. 1H NMR (300 MHz, CDCl3) δ 3.35 (s, 3H), 7.54 (d, 1H), 7.85 (d, 1H), 7.90 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-hydroxy-4-(2-methylthiophenyl)piperidine (2.89 g) in dichloromethane (80 mL) was treated with 6.2 mL of trifluoroacetic acid followed by 25.7 mL of triethylsilane and stirred for 16 hours. At the end of this period, the volatile material was distilled under reduced pressure and the resulting residue was chromatographed. Elution with 3:1 hexane:ethyl acetate afforded the named material (2.02 g); MS: 342(M+1); NMR: 1.5-1.6 (br, 2), 1.8-1.9 (m, 2), 2.45 (s, 3), 2.8-2.9 (m, 2), 3.1-3.2 (m, 1), 4.3 (br, 2), 5.1 (s, 2), 7.1-7.2 (m, 2), 7.2-7.3 (m, 2), 7.3-7.4 (m, 5).
Reaction SMILES: S[C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1.P(Cl)(Cl)([Cl:18])=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+].Cl[O-].[Na+]>O.ClCCl.ClCCCl.CN(C)C=O>[Cl:18][C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(S)nc(-c2ccncn2)cc1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Temperature: 65 °C
Reaction time: 0.83 h

Procedure:
A suspension of 2-mercapto-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (intermediate 7, 8.8 g, 40 mmol) in a mixed solvent of dimethylformamide (30 ml) and 1,2-dichloroethane (30 ml) was added to phosphorus oxychloride (11.2 ml, 120 mmol), and the mixture was stirred at 65° C. for 50 minutes. The solution was poured into ice-cooled dichloromethane (300 ml), water was added to the solution, and the mixture was vigorously stirred for 5 minutes. Aqueous sodium carbonate solution (25.4 g, 240 mmol, in water (100 ml)) was added and the pH was adjusted to 8 with saturated aqueous sodium hydrogen carbonate solution. Aqueous sodium hypochlorite solution (5% in water, 120 ml) was added. After filtration with celite, the organic layer was extracted twice with dichloromethane, and washed with saturated aqueous sodium bicarbonate solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate/hexane=1/1) and washed with diethyl ether to give 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (intermediate 1) as a pale-yellow solid (2.2 g, 62%, purity 98.7%).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([NH2:13])=[S:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[K].[O-]CC.[Na+]>C(O)C>[C:2]1([C:1]2[N:9]=[N:10][C:11](=[S:12])[N:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)NNC(=O)c1ccccc1
Agent: CC[O-]
Agent: [K+]
Agent: [K]
Solvent: CCO
Product: S=C1N=NC(c2ccccc2)=N1

Procedure:
3-Phenyl-1,2,4-triazole-5-thione (E. Hogarth, J. Chem. Soc. (1949) 1163) was prepared by first reacting benzoyl chloride with thiosemicarbazide in pyridine at 0° C. to give benzoyl thiosemicarbazide. Benzoyl thiosemicarbazide was treated with potassium hydroxide or potassium or sodium ethoxide in ethanol to give 3-phenyl-1,2,4-triazole-5-thione. 3-Phenyl-1,2,4-triazole-5-thione (1.77 g) was then dissolved in 50 mL of methanol and treated with 0.57 g of 95% sodium methoxide, and then with 2-bromo-5-nitrothiazole (2.09 g). The mixture was stirred at room temperature for 2 hours and the precipitated sodium bromide was removed by filtration. The methanol was evaporated and the product crystallized from ethanol and water to give 1.5 g of 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole as colorless crystals, MP 155-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:14]N1C(=O)CCC1=O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1cc(CBr)ccc1OC
Temperature: 25 °C
Yield: 44 %

Procedure:
Under a nitrogen atmosphere, methyl 2-methoxy-5-methylbenzoate (901 mg, 5 mmol) was dissolved in acetonitrile, and N-bromosuccinimide (890 mg, 5 mmol) and benzoyl peroxide (24 mg, 0.1 mmol) were added thereto. The mixture was refluxed for one hour. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature, and the solvent was distilled off. Thereafter, the residue was dissolved in ethyl acetate. The organic layer was washed with water 3 times and then with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, and then the resulting residue was purified by flash column chromatography (Yamazen, Hi-Flash column, silica gel, hexane/ethyl acetate (volume ratio)=10:1) to give the title compound (570 mg, 44.0%) as an oily substance.
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.[CH3:40][CH2:41][CH2:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46]>O1CCCC1.C1CCCCC1>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:6]1[CH2:7][CH2:8][CH2:9][C:10]2=[C:2]([C:43]([OH:47])([CH2:44][CH2:45][CH3:46])[CH2:42][CH2:41][CH3:40])[N:3]([CH3:20])[N:4]=[C:5]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Reactant: CCCC(=O)CCC
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (122 mg) and a crystal of 1,10-phenanthroline were dissolved in 3 mL of dry tetrahydrofuran and the solution was chilled to −78° C. under an atmosphere of argon. Then nbutyllithium (2.0 M in cyclohexane) was added until the dark color of the organolithium/phenanthroline complex persisted. An additional 0.17 mL of the butyllithium solution then was added. After 10 min, a solution of 4-heptanone (42.6 mg) in 1 mL tetrahydrofuran was added via syringe. The reaction mixture was allowed to stir at −78° C. for 15 min, then was allowed to warm to 0° C. After quenching with aqueous ammonium chloride, the reaction mixture was partitioned between ethyl acetate and brine. The ethyl acetate was dried with magnesium sulfate and concentrated on the rotary evaporator. The residue was chromatographed on silica gel eluting with 9:1 hexane/acetone to provide 76.0 mg of 4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-b]pyridin-3-yl]heptan-4-ol, which was recrystallized from hexane, mp 129–130 ° C.