Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[O:24]1[CH2:27][CH:26](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25]1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:26]3[CH2:27][O:24][CH2:25]3)=[CH:23][C:6]1=2
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OC3COC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and toluene-4-sulfonic acid oxetan-3-yl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]([N:16]3[C@@H:20]([C:21]4[C:22]([O:28]C)=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)[CH2:19][O:18][C:17]3=[O:30])=[N:12][C:11]=12)=[O:6]>Cl.CC(O)C>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]([N:16]3[C@@H:20]([C:21]4[C:22](=[O:28])[NH:23][CH:24]=[C:25]([F:27])[CH:26]=4)[CH2:19][O:18][C:17]3=[O:30])=[N:12][C:11]=12)=[O:6]
Reactant: COc1ncc(F)cc1[C@H]1COC(=O)N1c1ccn2ncc(C(=O)NCCCl)c2n1
Agent: Cl
Solvent: CC(C)O
Product: O=C(NCCCl)c1cnn2ccc(N3C(=O)OC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 90 °C
Yield: 83.2 %

Procedure:
A suspension of (S)-N-(2-chloroethyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (80 mg, 0.18 mmol) in 5-6N HCl/IPA (2.5 mL) was warmed to 90° C. in a sealed tube for 1.5 hours. The cooled mixture was filtered and the filtrate was concentrated. The residue was concentrated twice from Et2O and dried under reduced pressure to afford (S)-N-(2-chloroethyl)-5-(4-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (63 mg, 82% yield) as a beige solid. MS (apci) m/z=421.0 (M+H).
Reaction SMILES: C([SiH](CC)CC)C.[S:8]1[C:12]([CH:13]([C:15]2[CH:24]=[C:23]([Br:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[O:26][CH3:27])O)=[CH:11][C:10]2[CH:28]=[CH:29][CH:30]=[CH:31][C:9]1=2.CO.O>C(Cl)Cl>[Br:25][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:26][CH3:27])=[C:15]([CH2:13][C:12]2[S:8][C:9]3[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=3[CH:11]=2)[CH:24]=1
Reactant: COc1c(C(O)c2cc3ccccc3s2)cc(Br)c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1c(Cc2cc3ccccc3s2)cc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
In a nitrogen stream, triethylsilane (2.48 ml, 15.5 mmol) and a boron trifluoride-diethyl ether complex (1.08 ml, 8.54 mmol) were added dropwise to a solution of benzo[b]thiophen-2-yl-(4-bromo-1-methoxynaphthalen-2-yl)methanol (3.1 g, 7.76 mmol) in methylene chloride (60 ml) at 0° C. and the reaction mixture was stirred at room temperature for two hours, and then a 50% methanol aqueous solution (1 ml) was added and furthermore water (30 ml) was added thereto. The resulting mixture was extracted with methylene chloride, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:50)] to obtain the title compound (2.38 g, 80%).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:4]=1)=O.Cl.[NH2:19][OH:20].C[O-].[Na+]>CO>[OH:20][N:19]=[CH:1][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:4]=1
Reactant: COC(=O)c1cccc(-n2ccc(C=O)c2)c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-n2ccc(C=NO)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Methyl 3-(3-formylpyrrol-1-yl)benzoate (10.2 g) was added to a mixture of hydroxylamine hydrochloride (3.1 g) and 28% methanolic sodium methoxide (8.6 ml) in methanol (100 ml) and the whole was stirred for 3 hours at ambient temperature. The solvent was removed by concentration. To the residue was added a mixture of ethyl acetate, tetrahydrofuran and water, and the mixture was adjusted to pH 2 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 3-[3-(hydroxyiminomethyl)pyrrol-1-yl]benzoate (9.24 g) (oil).
Reaction SMILES: [CH2:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:5]#[N:6])[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:5][NH2:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C#N)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=CCC(CN)c1ccc(OC)cc1
Yield: 89.6 %

Procedure:
A solution of (±)-2-allyl-2-(4-methoxyphenyl)acetonitrile (159.7 g., 0.852 mole) in diethyl ether (200 ml.) was added dropwise during 20 minutes to a stirred, slowly refluxing mixture of lithium aluminum hydride (LiAlH4, 42.2 g., 1.11 moles) in diethyl ether (800 ml.). The mixture was refluxed for an additional 1.25 hours and then cooled in an ice-H2O bath. The excess LiAlH4 was decomposed by the slow dropwise addition of H2O until gaseous evolution ceased, and a granular precipitate formed. The mixture was filtered and the filter cake thoroughly washed with diethyl ether. Concentration of the filtrate gave the title product (146 g., 90%) as a cloudy oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][C:23](OCC)=[O:24])([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C.ClCCl>[CH3:21][C:16]1[CH:15]=[C:14]([C:11]2([CH2:22][CH2:23][OH:24])[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[CH:19]=[C:18]([CH3:20])[CH:17]=1
Reactant: CCOC(=O)CC1(c2cc(C)cc(C)c2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)cc(C2(CCO)CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.4 %

Procedure:
Ethyl 2-(1-benzyl-4-(3,5-dimethylphenyl)piperidin-4-yl)ethanoate (2.0 g) (see Preparation 9) was dissolved in anhydrous diethyl ether (50 ml), cooled in an ice-bath and lithium aluminium hydride (0.21 g) added portionwise. The mixture was stirred at room temperature for 45 minutes, water (0.3 ml) was carefully added, followed by 2N aqueous sodium hydroxide solution (0.3 ml) and fiiter water (0.6 ml). The mixture was stirred for 20 minutes and the resulting granular precipitate removed by filtration and washed with diethyl ether. The solvent was removed from the filtrate under reduced pressure to give a solid which was dissolved in dichloromethane, dried over anhydrous sodium sulphate and the solvent again removed under reduced pressure to yield 4-(3,5-dimethylphenyl)-4-(2-hydroxyethyl)-N-benzylpiperidine (1.67 g) as an oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.CN(C)C=O.[NH2:30][CH:31]1[C:41](=[O:42])[N:33]2[C:34]([C:38]([OH:40])=[O:39])=[CH:35][CH2:36][S:37][C@H:32]12>CC(C)=O.O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([NH:30][CH:31]2[C:41](=[O:42])[N:33]3[C:34]([C:38]([OH:40])=[O:39])=[CH:35][CH2:36][S:37][C@H:32]23)=[O:12])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOC2CCCC2)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=CNc1nc(C(=NOC2CCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 71 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer, 1.5 g.), phosphoryl chloride (974 mg.), N,N-dimethylformamide (464 mg.) and tetrahydrofuran (15 ml.) and a solution of 7-amino-3-cephem-4-carboxylic acid (1.38 g.) in 50% aqueous acetone (14 ml.) were treated in a similar manner to that of Example 15-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-cyclopentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.75 g.).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[Cl:8][C:5]1[S:4][C:3]([NH:2][C:16](=[O:17])[O:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[N:7][CH:6]=1
Reactant: Nc1ncc(Cl)s1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ncc(Cl)s1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
2-Amino-5-chlorothiazole hydrochloride (1.00 g, 5.80 mmol) was dissolved in methylene chloride (50 mL), and the obtained solution was then washed with a saturated aqueous solution of sodium hydrogen carbonate. The resulting solution was dried over anhydrous sodium sulfate and was then filtered. After that, pyridine (0.47 mL, 5.80 mmol) and 4-nitrophenyl chloroformate (1.18 g, 5.80 mmol) were added to the filtrate, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a solid was collected by filtration, was then washed with methylene chloride, and was then dried to obtain 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (980 mg, 56%) in the form of a white solid. t-Butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (65.1 mg, 0.184 mmol) synthesized by a method described in the known method (International Publication WO2009/089454) or a method similar thereto was dissolved in N,N′-dimethylformamide (2 mL). Thereafter, 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (55.2 mg, 0.184 mmol) and triethylamine (13 μL, 0.092 mmol) were added to the above obtained solution, and the obtained mixture was then stirred at 50° C. for 3 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the captioned compound (60.0 mg, 64%) in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.[Na].[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20].[I-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:16]2[C:17](=[O:19])[CH2:18][S:14][C:15]2=[O:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1OCCCCl
Reactant: O=C1CSC(=O)N1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncccc1OCCCN1C(=O)CSC1=O
Temperature: 80 °C

Procedure:
To a suspension of 9.33 g (50 mmol) of 2-amino-3-(3-chloropropyloxy)pyridine and 6.97 g (50 mmol) of thiazolidine-2,4-dione sodium salt in 200 ml of N,N-dimethylformamide, 7.49 g (50 mmol) of sodium iodide was added, followed by refluxing at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 8.14 g (60.9%, yellow solid) of the desired product.
Reaction SMILES: [C:1]([C:5]1([CH:8]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[F:9])[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[K]>COCCOCCOC>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:7][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([OH:6])[CH:8]([F:9])[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)C1(C(F)n2cncn2)CO1
Reactant: Oc1ccc(F)cc1
Agent: [K]
Solvent: COCCOCCOC
Product: CC(C)(C)C(O)(COc1ccc(F)cc1)C(F)n1cncn1
Temperature: 0 °C
Yield: 49.1 %

Procedure:
3.0 g of 2-tert.-butyl-2-[(1H-1,2,4-triazol-1-yl)fluoromethyl]-oxirane, 1.7 g of 4-fluorophenol and 0.3 g of potassium p-fluorophenate in 10 ml of diethylene glycol dimethyl ether are stirred at 140° C. for 5 hours. After cooling, the mixture is taken up in ice water and extracted with ethyl acetate. The combined organic phases are washed with water, saturated sodium chloride solution and 2N sodium hydroxide solution and again with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystallisation from a 1:4 ether/hexane mixture gives 2.3 g of 1-(4-fluorophenoxy)-2-tert.-butyl-2-hydroxy-3-fluoro-3-(1H-1,2,4-triazol-1-yl)-propane, melting point 89°-90° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][CH:21]([CH3:38])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:26]=1)=[O:23]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:27]3[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:38])[CH:30]=[CH:29][C:28]=3[CH3:31])[CH2:33][CH2:34]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Prepared by Procedure G and Scheme AI using 1-[4-chloro-1-(4-fluorophenyl)butyl]-4-fluorobenzene and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 505.0 (M+H)+.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH3:20])[O:13][C:12]([CH3:22])([CH3:21])[CH:11]=[C:10]2[CH:23]([CH3:25])[CH3:24])\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1>>[F:1]/[C:2](=[C:5](/[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH3:20])[O:13][C:12]([CH3:22])([CH3:21])[CH:11]=[C:10]2[CH:23]([CH3:24])[CH3:25])\[CH3:6])/[CH:3]=[O:4]
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CC(C)(C)O2
Agent: C[N+]1([O-])CCOCC1
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure M, (2E)-2-fluoro-3-(4-isopropyl-2,2-dimethyl-7-propoxy-2H-chromen-6-yl)-but-2-en-1-ol (Compound 86, 100 mg, 0.27 mmol) and 4-methylmorpholine N-oxide (75 mg, 0.57 mmol) were reacted to give the title compound as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].CCN(CC)CC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OCC1CCCCO1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC1CCCCO1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A CH2Cl2 solution of (tetrahydro-2H-pyran-2-yl)methanol (7.91 g, 68.1 mmol), Et3N (14 mL, 102 mmol), and catalytic DMAP was treated with 4-bromobenzenesulfonyl chloride (14.3 g, 74.9 mmol). After 2 h, the reaction was quenched with water. The organic layer was washed with 1M HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography on silica gel (EtOAc/Hex) to afford ((tetrahydro-2H-pyran-2-yl)methyl 4-bromobenzenesulfonate as an oil (16 g).
Reaction SMILES: IC1C=CC(C)=CC=1S(O)(=O)=[O:10].OOS([O-])=O.[K+].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[N+](C)([O-])=O>[C:19]1([CH2:25][CH2:26][CH2:27][C:28]([OH:10])=[O:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCCc1ccccc1
Reactant: Cc1ccc(I)c(S(=O)(=O)O)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C[N+](=O)[O-]
Product: O=C(O)CCCc1ccccc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
8.9 mg (0.03 mmol) of 2-iodo-5-methylbenzenesulfonic acid prepared by Preparation Example 2, 2.04 g (3.3 mmol) of powdered Oxone (registered trademark) were added to 3.75 ml of nitromethane, and 450 mg (3 mmol) of 4-phenylbutanol was added dropwise for two hours, and the mixture was heated at 70° C. while being stirred for six hours. The later treatment was carried out in the same way as in Example 1, and then 4-phenylbutanoic acid was obtained. The yield of the obtained 4-phenylbutanoic acid was determined and the result is shown in Table 1.
Reaction SMILES: [Cl-:1].[NH:2]=[C:3]1[NH:9][CH:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][N+:15](C)=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>>[ClH:1].[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH:8]2[NH:9][C:3](=[NH:2])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: C[n+]1ccc(CCC2CCCCC(=N)N2)cc1
Reactant: [Cl-]
Agent: Cl
Product: N=C1CCCCC(CCc2ccncc2)N1

Procedure:
4-[2-(hexahydro-7-imino-1H-azepin-2-yl)ethyl]-1-methylpyridinium chloride, monohydrochloride salt;
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:11][N:12]=[C:13]=[S:14]>C(N(CC)CC)C>[CH3:11][NH:12][C:13]([NH:10][C:8]1[O:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1)=[S:14]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: CN=C=S
Solvent: CCN(CC)CC
Product: CNC(=S)Nc1cc(C(C)(C)C)no1
Temperature: 75 °C
Yield: 52.7 %

Procedure:
A mixture of 3-t-butyl-5-aminoisoxazole (2.07 g), methyl isothiocyanate (1.40 g) and triethylamine (3 drops) is heated at 75° C. for 72 hours. The reaction mixture is chromatographed on a column of silica gel, whereby 1-methyl-3-(3-t-butyl-5-isoxazolyl)thiourea (1.66 g) is obtained as an oil. IR: 1622 cm-1 (CC14).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:16](=[O:31])[N:17]([CH2:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)[N:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>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].C1COCC1>[CH3:30][C:21]1[C:20]([CH2:19][N:17]2[C:16](=[O:31])[N:4]3[CH:5]=[CH:6][C:7]([C:8]4[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=4)=[C:2]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:3]3=[N:18]2)=[CH:25][CH:24]=[C:23]([C:26]([F:27])([F:29])[F:28])[N:22]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(C#N)cc3)ccn2c1=O
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccccc3)c(-c3ccc(C#N)cc3)ccn2c1=O
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 90 %

Procedure:
Into a flame-dried reaction vessel under argon was placed 4-(8-bromo-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile (49 mg, 0.1 mmol), phenylboronic acid (37 mg, 0.3 mmol), K3PO4 (64 mg, 0.3 mmol), Pd(dppf)Cl2.CH2Cl2 (8.0 mg, 0.01 mmol) and anhydrous THF (1.5 mL). The suspension was degassed with argon bubbling, and the reaction vessel was sealed and stirred at 90° C. for 4.5 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional palladium catalyst (3 mg) and THF (0.5 mL) was added, and the suspension was degassed again. The reaction mixture was stirred at 90° C. for 16 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-70%) in hexanes to afford the desired product (90% pure). The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 70% to 100% B over 10 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue obtained was dissolved in acetonitrile, frozen and lyophilized to afford 19.5 mg of the title compound as a light yellow powder. HPLC/MS: retention time=3.69 min, [M+H]+=486.7.
Reaction SMILES: Br[CH:2]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]1[CH2:29][C:30](=[S:32])[NH2:31].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:5]1([C:3]2[N:31]=[C:30]([CH2:29][N:20]3[C:19](=[O:18])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:28])[S:32][C:2]=2[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)C(Br)Sc1ccccc1
Reactant: NC(=S)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)c(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a solution of 2-bromo-1-phenyl-2-(phenylthio)ethanone (3.2 g) in N,N-dimethylformamide (25 mL) was added 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanethioamide (2.3 g), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as white crystals (yield 3.0 g, 71%).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].C(OCC)C.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[Mg]I>C1(C)C=CC=CC=1>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9]([OH:10])([C:33]2[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][C:34]=2[Cl:36])[C:7]1=[O:8])[CH3:23]
Reactant: Clc1ccc([Mg]I)c(Cl)c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc(Cl)cc2Cl)c2c1cc(I)cc2C(F)(F)F
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (150 mg, 0.341 mmol) in a mixed solvent of diethyl ether (2 mL) and toluene (1 mL) was added dropwise a freshly prepared 0.794 N 2,4-dichlorophenyl magnesium iodide in ether (0.45 mL, 0.387 mmol) at room temperature. The mixture was stirred for 1 h at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 80:1 to 50:1 chloroform/methanol to give the title compound (111 mg, 55%).