Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[I-].[Na+].[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][N:28]1[CH2:29][CH2:30][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(O)CCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2.6 Grams of 6-(1-hydroxy-3-chloropropyl)-3,4-dihydrocarbostyril and 1.8 g of sodium iodide were mixed in 60 ml of dimethylformamide and the mixture was stirred at a room temperature for 7 hours. Then 2.0 g of triethylamine and 2.5 g of 4-phenyl-piperidine were added to the mixture and stirred at a room temperature for 24 hours. The reaction mixture was poured into 200 ml of 1%-sodium hydrogen-carbonate aqueous solution and was extracted with chloroform. The chloroform layer was washed with water and dried, chloroform was removed by distillation. The residue thus obtained was recrystallized from ethanol to obtain 2.5 g of 6-[1-hydroxy-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydro-carbostyril in colorless plate-like crystals.
Reaction SMILES: [OH-:1].[Na+:2].O.[CH3:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10]>>[CH3:4][NH:5][CH2:9][CH2:8][CH2:7][C:6]([O-:10])=[O:1].[Na+:2]
Reactant: CN1CCCC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CNCCCC(=O)[O-]

Procedure:
contacting an aqueous sodium hydroxide and N-methyl-2-pyrrolidone to form a first mixture comprising sodium N-methyl-4-aminobutyrate, water and N-methyl-2-pyrrolidone, and subsequently contacting said first mixture with sodium bisulfide under reaction conditions of time and temperature sufficient to produce a second mixture comprising a polymerizable complex of said sodium N-methyl-4-aminobutyrate and said sodium bisulfide, N-methyl-2-pyrrolidone, water and metal impurities wherein said temperature is about 105° C. to about 205° C. and said time is about 5 minutes to about 6 hours,
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[N:13][S:14][C:10]=2[C:9]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[NH2:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[N:13][S:14][C:10]=2[C:9]=1[NH:26][C:20]1[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:19]=1[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc2cnsc2c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To a solution of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid tert-butyl ester (1.26 g, 5.0 mmol) and 2-fluoro-4-iodo-phenylamine (1.18 g, 5.0 mmol) in anhydrous THF (25 mL) at −78° C. was added a 1.0M solution of LHMDS in hexanes (10.0 mL, 10.0 mmol) under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and then stirred for 30 minutes before being quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was separated and washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, TBME in cyclohexane) to give the title compound as a yellow solid (717 mg, 30%). LCMS (method B): RT=5.14 min, [M+H]+=471.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:28]=[N:29][NH:30][N:25]=3)=[CH:22][CH:23]=2)=[N:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc(NC(=O)c2ccc(C#N)cc2)sc1C(=O)NCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)c2ccc(-c3nn[nH]n3)cc2)sc1C(=O)NCc1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
A mixture of 2-(4-cyanobenzoylamino)-4-methylthiazole-5-carboxylic acid benzylamide (0.080 g, 0.21 mmol), sodium azide (0.028 g, 0.43 mmol) and ammonium chloride (0.006 g, 0.11 mmol) in N,N-dimethylformamide (5 mL) was stirred at 80° C. for 18 hours. The reaction mixture was cooled to ambient temperature, and 1 N hydrochloric acid (0.5 mL) solution was added. Ethyl acetate (10 mL) and brine (10 mL) were added to the reaction mixture. The organic layer was separated and dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrate in vacuo and the residue was purified by column chromatography to afford the title compound as a white solid in 23% yield (0.020 g); m.p.>300° C.; 1H NMR (CD3OD, 300 MHz) δ 8.20-8.09 (m, 4H), 8.45-7.20 (m, 5H), 4.51 (s, 2H), 2.55 (s, 3H); 13C NMR (CD3OD, 75 MHz) δ 163.6, 138.8, 128.4, 128.1, 127.1, 126.8, 126.5, 43.1, 15.8; MS (ES+) m/z 420.5 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:20][CH3:21]>CN(C=O)C.CCOC(C)=O>[CH3:16][O:15][C:13](=[O:14])[CH:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=1)[CH2:20][CH3:21]
Reactant: CCCCOc1ccc(CC(=O)OC)cc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C(CC)C(=O)OC)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
(Scheme 2, Compound E) The mixture of methyl 4-butoxyphenylacetate (1.20 g, 5.4 mmol) and NaH (60% in mineral oil, 0.50 g, 12.5 mmol) in DMF (25.0 mL) was stirred at 50° C. for 40 min. Bromoethane (2.0 g, 18.3 mmol) was added and the stirring continued at rt for one hour. The reaction mixture was diluted with EtOAc (300 mL), washed with H2O, and then was dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a yellow oil (0.85 g, 3.4 mmol, 63% yield). 1H NMR (DMSO-d6) δ 7.16 (d, 2H, J=7.0 Hz), 6.87 (d, 2H, J=8.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 3.55 (s, 3H), 3.45 (t, 1H, J=9.0), 1.93 (m, 1H), 1.63 (m, 2H), 1.42 (m, 2H), 0.97 (t, 3H, J=7.2 Hz), 0.79 (t, 3H, J=4.0 Hz).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[CH:10](O)[C:9]=2[CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[Cl:3][CH:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:15]=2[CH:14]=[CH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]1=2
Reactant: OC1c2ccccc2C=Cc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In this preparation 25 ml. of thionyl chloride is added dropwise, with vigorous stirring, to a slurry of 5 g. of 5H-dibenzo[a,d]cyclohepten-5-ol in 50 ml. of anhydrous benzene containing five drops of pydridine, at about 0°C. The resulting mixture is continually stirred and allowed to heat to room temperature and then allowed to stand for 4 hours. The resulting mixture is then evaporated under vacuum to remove solvent and excess reagent affording a crystalline residue of 5-chloro-5H-dibenzo[a,d]cycloheptene which is then further dried under vacuum.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].O[Li].O>C1COCC1.O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(C)cc(-c3cccc(F)c3)c2F)c1F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2F)c(F)c(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]phenoxy]acetate (100 mg, 0.2 mmol, 1.0 eq) in a mixture of THF (20 mL) and water (20 mL) was added LiOH.H2O (38 mg, 0.9 mmol, 4.0 eq). The reaction was stirred at room temperature for 2 h. The THF was then removed in vacuo and the aqueous residue acidified by addition of 1M HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was washed with a mixture of petroleum ether: EtOAc, 10:1 to give the title compound (I(g)) as white solid (30 mg, 32%).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:5]=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:7][C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].C(N(CC)CC)C.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>ClCCl>[C:38]([C:37]1[CH:36]=[CH:35][C:34]([S:31]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:8]3[S:7][C:6]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:5][C:4]=3[CH3:3])=[O:10])[CH2:12][CH2:13]2)(=[O:33])=[O:32])=[CH:42][CH:41]=1)([OH:40])=[O:39]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 1-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]piperazine dihydrochloride (180 mg) and triethylamine (253 mg) in dichloromethane (20 ml) was added 4-chlorosulfonylbenzoic acid (108 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in water and neutralized with 1 N hydrochloric acid. The precipitate was filtered, washed with water and dried to give a colorless solid of the title compound (174 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[NH:12][C:11]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=2)=[CH:6][CH:5]=1.[CH3:27][O:28][CH2:29]Cl.[Cl-].[NH4+]>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]([CH2:27][O:28][CH3:29])[C:11]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=2)=[CH:8][CH:9]=1
Reactant: CSc1nccc(-c2[nH]c3cccnc3c2-c2ccc(F)cc2)n1
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCn1c(-c2ccnc(SC)n2)c(-c2ccc(F)cc2)c2ncccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride (130 mg, 2.8 mmoles 60% in oil) is added to a solution of 850 mg (2.53 mmoles) of 3-(4-Fluoro-phenyl)-2-(2-methylthio-pyrimidin-4-yl)-1H-pyrrolo[3,2-b]pyridine in 30 mL of dimethylformamide at room temperature. After 30 min. at room temperature, 0.23 mL of chloromethyl methyl ether is added to the reaction mixture. After 1 hour at room temperature, the reaction mixture is poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue is purified by chromatography on silica gel (ethyl acetate/hexane 2/1) to give 750 mg of 3-(4-Fluoro-phenyl)-1-methoxymethyl-2-(2-methylthio-pyrimidin-4-yl)-1H-pyrrolo[3,2-b]pyridine as white crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: OCc1ccsc1
Reactant: COc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution containing 3-thiophenemethanol (0.45 g, 0.0033×1.2 mol) and sodium hydride (0.14 g, (ca.60% in mineral oil), 0.033×1.05 mol) in tetrahydrofuran, 2,6- dichloro-4-methoxypyridine (0.59 g, 0.0033 mol) was added and the resultant solution was refluxed for about 2 hours.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH:5]2[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: CN1CCC(=O)CC1
Product: Cc1ccc(CCNC2CCNCC2)cc1

Procedure:
1-Methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 eq.), 2-(4-methylphenyl)ethylamine (1.0 g, 1.0 eq.).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][CH:3]=1.[H-].[Na+].Cl[CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Brc1cc[nH]c1
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccn(CCN2CCCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
To a solution of 3-bromo-1H-pyrrole (100 mg, 0.68 mmol) in DMF at 0° C. was added NaH (60% oil dispersion, 81 mg, 2.05 mmol). The reaction mixture was stirred for 1 hour, followed by the addition of 1-(2-chloroethyl)pyrrolidine (108 mg, 0.82 mmol). The reaction mixture was for 6 hours at 100° C. After cooling, the reaction mixture was treated with 20 mL of ice cold water, extracted with EtOAc (3×20 mL), washed with brine solution (20 mL), dried (Na2SO4), filtered, and concentrated under vacuum at 48° C. to obtain crude product. Purification by silica gel chromatography yielded 3-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole (50 mg, 31% yield); 1H-NMR (400 MHz, CHCl3): 6.69 (1H, s), 6.59 (1H, s), 6.12 (1H, s), 3.95 (2H, t), 2.80 (2H, t), 2.51 (4H, m), 1.81 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.Cl[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN(C)CCCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCNc1ccc(Cl)c(Cl)c1

Procedure:
In the manner given in Example 5, 3,4-dichloroaniline, 1-chloro-2-dimethylaminoethane hydrochloride and sodium carbonate are heated in toluene to give N,N-dimethyl-N'-(3,4-dichlorophenyl)ethylenediamine.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Cl:12][C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:13]([Cl:12])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCNc1ccccc1
Solvent: ClCCl
Product: CCCCN(C(=O)Cl)c1ccccc1
Reaction time: 27 h
Yield: 191.2 %

Procedure:
To a solution of 6.72 g (45 mmol) of butylphenylamine in 50 ml of methylene chloride cooled to 10° C. was added slowly with stirring 6.67 g (22.5 mmol) of triphosgene in 40 ml of methylene chloride. The reaction was allowed to continue at room temperature for 27 hours. The solvent was evaporated and the residue extracted twice with n-hexane. The organic solution was concentrated in vacuo to yield 9.11 g (43.03 mmol) of a yellow oil (96%). 1H-NMR (CDCl3): δ 0.9 (m, 3H), 1.3 (m, 2H), 1.6 (m, 2H), 3.7 (m, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]1([CH2:32]O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:32][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: BrBr
Reactant: OCc1cccc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a stirring solution of 912 mg (3.48 mmol, 1.2 equiv) of triphenylphosphine in 10 mL of CCl4 at 0° C. is added 180 μL (3.48 mmol, 1.2 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 500 mg (3.16 mmol) of 1-Naphthalenemethanol in 5 mL of CCl4 is added over 2 min. The resulting solution is stirred 1.5 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 10/1 as eluent afforded 670 mg of the title compound as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ8.18 (d, 1H), 7.83 (m, 2H), 7.63-7.38 (m, 4H), 4.98 (s, 2H); Rf =0.65 in hexane/EtOAc 5/1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:23])[NH:14]/[C:15](/[CH3:22])=[CH:16]\[C:17]([O:19]CC)=O)=[C:4]([F:24])[CH:3]=1.[H-].[Na+].S(OC)(O[CH3:31])(=O)=O>CN(C)C=O.C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([N:12]2[C:17](=[O:19])[CH:16]=[C:15]([CH3:22])[N:14]([CH3:31])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: CCOC(=O)/C=C(/C)NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C
Reaction time: 1 h

Procedure:
A solution of 9.00 g of ethyl 3-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]-crotonate in 100 ml of anhydrous dimethylformamide is added dropwise at room temperature while stirring to a solution of 1.10 g of a 55% sodium hydride dispersion in 100 ml of isopropanol/dimethylformamide (1:1) and stirred for 1 hour. The reaction mixture is subsequently treated with 4.70 g of dimethYl sulphate and stirred at room temperature for 2 hours. The solvent is largely distilled off under reduced pressure and the residue is poured into 500 ml of water and extracted twice with 200 ml of ethyl acetate each time. The organic phases are washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,6 -dimethyl-2,4(1H,3H)-pyrimidinedione, m.p. 149°-151° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=2)[C:9](=[O:12])[O:8]1
Reactant: O=C1OCc2ccc(C(F)(F)F)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccc(C(F)(F)F)cc21
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 6-(trifluoromethyl)isobenzofuran-1(3H)-one (prepared as described in the previous step, 5.5 g, 27.23 mmol, 1.00 equiv) in CCl4 (10 mL), NBS (5.8 g, 32.58 mmol, 1.20 equiv) and AIBN (0.45 g, 0.10 equiv). The reaction mixture was stirred for 3 h at 65° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of ethyl acetate, washed with 60 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6]CP(=O)OCC)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CCO[PH](=O)CCc1ccc(N)c(OC)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(N)c(OC)c1)OCC

Procedure:
This material was prepared according to the procedure described above for ethyl (4-amino-3-methoxybenzyl)methylphosphinate using triethylphosphite in the first step. MS (ES+): m/z 274.01 [MH+] (ZQ3, polar 5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[S:31][C:30]([C:32]([NH:14][NH:13][C:11]([N:10]2[CH2:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:12])=[O:33])=[CH:29][CH:28]=1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Product: O=C(NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)c1ccc(-c2ccccn2)s1

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[5-(2-pyridyl)thienylcarbonyl]hydrazide (62) was prepared in the manner described in Example 7 on a 10 mmol scale from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, and 5-(2-pyridyl)thiophene-2-carboxylic acid. The yield of product was 1.33 g (28%). Analysis calculated for C24H17N4O3SCl (M.W. 476.95): C, 60.44; H, 3.59; N, 11.75; Cl, 7.43; S, 6.72. Found: C, 60.18; H, 3.66; N, 11.69; Cl, 7.79; S, 6.63.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[N:6]1)[CH2:2][CH:3]=[CH2:4].B1C2CCCC1CCC2.Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][C:30]2[N:31]=[C:32]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][C:40]([S:43]([C:45]([F:48])([F:47])[F:46])=[O:44])=[CH:39][CH:38]=3)[O:33][CH:34]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[F:48][C:45]([F:46])([F:47])[S:43]([C:40]1[CH:39]=[CH:38][C:37]([CH:36]=[CH:35][C:32]2[O:33][CH:34]=[C:30]([CH2:29][S:26]([C:23]3[CH:22]=[CH:21][C:20]([CH2:4][CH2:3][CH2:2][CH2:1][N:5]4[CH:9]=[CH:8][N:7]=[N:6]4)=[CH:25][CH:24]=3)(=[O:27])=[O:28])[N:31]=2)=[CH:42][CH:41]=1)=[O:44]
Reactant: O=S(c1ccc(C=Cc2nc(CS(=O)(=O)c3ccc(Br)cc3)co2)cc1)C(F)(F)F
Reactant: C=CCCn1ccnn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(c1ccc(C=Cc2nc(CS(=O)(=O)c3ccc(CCCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A solution of 1-but-3-enyl-1H-[1,2,3]triazole (0.14 g, 1.14 mmol) in anhydrous THF (10 ml) was treated with 9-BBN (0.5 M in THF, 5 ml, 2.5 mmol) at 0° C. and stirred for 2 h at room temperature. This mixture was added to a solution of 4-(4-bromo-benzenesulfonylmethyl)-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole (0.6 g, 1.15 mmol), [Pd(dppf)Cl2] (98 mg, 0.12 mmol) and aqueous cesium carbonate (3M, 1.15 ml, 3.45 mmol) in N,N-dimethyl formamide (7 ml) and stirred for 3 h at 70° C. After cooling to room temperature ethyl acetate (100 ml) was added and the solution washed with water (2×50 ml). The organic layer was concentrated and the crude product purified by flash column chromatography (ethyl acetate) and crystallization from diethyl ether to yield 1-[4-(4-{2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazol-4-ylmethanesulfonyl}-phenyl)-butyl]-1H-[1,2,3]triazole as white solid (0.36 g, 55%).