Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][O:17][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:7])[F:8]
Reactant: C1=COCCC1
Reactant: O=C(Nc1ccc(CCO)cc1Cl)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(CCOC2CCCCO2)cc1Cl)C(F)(F)F

Procedure:
To a solution of 2′-chloro-4′-(2-hydroxyethyl)-2,2,2-trifluoroacetanilide (1.4 g) and 3,4-dihydro-2H-pyran (1.4 ml) in dichloromethane (15 ml) was added pyridinium p-toluenesulfonate (14 mg), and the mixture was heated under reflux for 1 hour with stirring. After concentration of the reaction mixture in vacuo, the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=3/1) gave 2′-chloro-4′-[2-((RS) -tetrahydropyran-2-yloxy)ethyl]-2,2,2-trifluoroacetanilide (1.4 g).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:24]([Li])[CH2:25][CH2:26]C.C(Br)C#C>O1CCCC1>[CH2:1]([C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:3])[CH2:26][C:25]#[CH:24]
Reactant: [Li]CCCC
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#CCBr
Solvent: C1CCOC1
Product: C#CCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
20.0 g of methylcarbonylmethylenetriphenyl phosphorane is dissolved in 628 ml of tetrahydrofuran and mixed by instillation at -78° C. with 41.3 ml of butyllithium (1.6 molar solution in hexane). Then,5.0 ml of propargyl bromide is instilled. The reaction mixture is added to an ice/common salt solution after heating to room temperature, and the mixture is extracted with ethyl acetate. After drying the organic phase with sodium sulfate,23.4 g of solid is obtained. Column chromatographic purification (silica gel/ethyl acetate) yields 15.4 g of the title compound with a melting point of 135°-136° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>ClCCl>[Br:8][C:7]1[C:2]([NH:1][C:15]([NH:14][C:12](=[O:13])[O:11][CH2:9][CH3:10])=[S:16])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1Br
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Product: CCOC(=O)NC(=S)Nc1ncccc1Br
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 2-amino-3-bromopyridine (50.0 g, 289 mmol, 1 equiv) in dichloromethane (500 mL) was added dropwise ethoxycarbonyl isothiocyanate (39.0 g, 297 mmol, 1.03 equiv) at room temperature. After 2 h, dichloromethane was removed in vacuo to provide crude ethyl [(3-bromopyridin-2-yl) carbamothioyl]carbamate (88 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[N+]([C:11]1C=CC=CC=1)([O-])=O.C[CH:18]1[CH:24]([CH3:25])[CH2:23][C:22](=[O:26])[O:21][C:19]1=[O:20].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][C:2]1[S:3][C:4]([C:22](=[O:26])[CH2:23][C:24]([CH3:25])([CH3:11])[CH2:18][C:19]([OH:21])=[O:20])=[CH:5][C:6]=1[CH3:7]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Cc1ccsc1C
Reactant: CC1CC(=O)OC(=O)C1C
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)CC(C)(C)CC(=O)O)sc1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 81 %

Procedure:
40 g (0.355 mol) of 2,3-dimethylthiophene, 630 ml of nitrobenzene and 55.5 g (0.390 mol) of 2,3-dimethylglutaric anhydride are introduced into a 2 liter three-necked flask fitted with a mechanical stirrer. The mixture is brought to 0° C. and 71 g (0.532 mol) of aluminum chloride are added in portions while maintaining the temperature below 5° C. After 10 hours' stirring at room temperature, the mixture is hydrolysed with water/ice/concentrated HCl (500 g/500 g/170 ml) for 15 minutes. The nitrobenzene is then stripped off with steam and the residue is extracted 3 times with 100 ml of CH2Cl2 each time. The combined organic phases are washed with dilute HCl and then with H2O, dried over MgSO4, rendered colourless with carbon black and concentrated to yield 73.4 g of 2,3-dimethyl-5-(4-carboxy-3,3-dimethylbutanoyl)thiophene in the form of a pale yellow oil, yield: 81%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[Cl-].C[Zn+].[CH3:28]COC(C)=O.O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[CH3:28]
Reactant: CCOC(C)=O
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To a suspension of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg) and Pd(PPh3)4 (15 mg) in THF (1.0 ml), was added a solution of methylzinc chloride in THF (2.0M, 0.75 ml). The mixture was stirred at 25° C. for 7.5 hours and then heated at 60° C. for 1.5 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was crystallized form MeOH-IPE and dried in vacuo to give 5-(5-amino-6-methyl-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (95 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:22]([C:19]1[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:17][CH:18]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nn1
Yield: 58 %

Procedure:
As described for example 42b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (67 mg, 0.20 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (44 mg, 58%) which was obtained as a white solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:22][CH3:23])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[C:15]([CH3:21])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:36]1(=[O:41])[CH2:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:11][CH3:12])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:36]3([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:15]([CH3:21])[CH:14]=2)[CH2:22][CH3:23])=[CH:6][C:5]=1[CH3:24]
Reactant: O=C1CCCC1
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)OC)c(C)c2)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a −78 C solution of 4-[1-Ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-benzoic acid methyl ester (2.50 g, 7.47 mmol) in THF (80 ml) is added lithium hexamethyldisilazide (8.22 ml, 8.22 mmol, 1.0 M in THF) and stirred at −78 C for 30 min. Cyclopentanone (730 μL, 8.22 mmol) is added and the reaction mixture warmed to room temperature. The reaction is quenched with saturated aqueous NH4Cl (30 ml) and concentrated. The residue is partitioned between EtOAc (300 ml) and 1.0N HCl (50 ml). The aqueous layer is extracted with EtOAc (100 ml). The combined organic layer are washed with water (50 ml), brine (50 ml), dried (MgSO4), concentrated and chromatographed (120 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (2.45 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[C:47]([CH3:49])[N:48]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:43][C:44]2[S:45][CH:46]=[C:47]([CH3:49])[N:48]=2)=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Cc1csc(N)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4nc(C)cs4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 129.6 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (84 mg) was dissolved in chloroform (2.5 ml) and triethylamine (0.25 ml) to prepare a solution. A solution of triphosgene (38 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 2-amino-4-methylthiazole (32 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated and was evaporated to dryness. Next, diethyl ether was added to the solid, and the solid was collected by filtration. Further, the collected solid was washed with methyl alcohol to give the title compound (78.3 mg, yield 68%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][C:15]([O:25]C)=[C:16]([O:23]C)[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].Cl.N1C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][C:15]([OH:25])=[C:16]([OH:23])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: COc1cc2[nH]c3ccc4c(c3c2cc1OC)C(=O)N(CCN(C)C)C4=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4cc(O)c(O)cc4c3c2C1=O
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A mixture of 210 mg of N-(2-dimethylaminoethyl)-6,7-dimethoxycarbazole-3,4-dicarboximide and 1.66 g of pyridine hydrochloride was sealed in a tube and stirred at 200°-210° C. for 2 hours. Then, 150 ml of water and 100 ml of ethyl acetate were added to the reaction mixture to dissolve the mixture. The solution was adjusted to pH 8.5 with potassium carbonate. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent was removed by distillation under reduced pressure. The residue was mixed with 20 ml of diethyl ether, and the mixture was stirred for 10 minutes. The resulting insoluble material was collected by filtration and recrystallized from n-propanol to obtain 58 mg (yield: 31%) of N-(2-dimethylaminoethyl)-6,7-dihydroxycarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([C:23]3[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=3)[CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[K+].[C:34]([C:36]1[N:37]=[C:38]([C:49]([O-])=[O:50])[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=1)#[N:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:49]([C:38]3[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=[C:36]([C:34]#[N:35])[N:37]=3)=[O:50])=[C:18]([C:23]3[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=3)[CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 62 %

Procedure:
A solution of 4-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-ylmethyl}-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine (as prepared in the previous step, 233 mg, 0.590 mmol) in CH2Cl2 (10 mL) was treated with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d), 188 mg, 0.610 mmol), PyBroP (332 mg, 0.713 mmol), and DIEA (177 μL, 10.2 mmol) at RT for 1 h. The mixture was diluted with CH2Cl2 (40 mL) and washed with water (1×30 mL) and satd aq NaHCO3 (1×30 mL). The combined aqueous layers were extracted with CH2Cl2 (1×30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 20-g Isolute SPE column on a FlashMaster system with 10-25% EtOAc-hexane afforded the title compound (223 mg, 62%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C38H62N6O3Si2, 707.4 (M+H). found 707.4.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O1CC[CH2:19][CH2:18]1>>[C:12]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:11][O:5][CH2:4][C:3]([O:7][CH2:8][CH3:9])=[O:6].[CH2:18]([CH:4]([O:5][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([O:7][CH2:8][CH3:9])=[O:6])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: C1CCOC1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COC(CC)C(=O)OCC
Product: CCOC(=O)COCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl diglycolate is prepared by slurrying 270 parts sodium hydride in 2800 parts tetrahydrofuran and adding 705 parts ethyl glycolate to the mixture while maintaining the temperature between 10° to 15°C. The mixture is stirred for 1 hour at 25°C, cooled to 15°C and 894 parts ethyl bromoacetate is added. The mixture is stirred for 12 hours at 25°C; solvent evaporated; residue washed with water to remove salts; dried and purified diethyl digylcolate recovered by distillation under reduced pressure. (Note: Diethyl methylglycolate or diethyl ethyldiglycolate are prepared by similar procedures wherein ethyl lactate (800 parts) or ethyl-2-hydroxybutyrate (895 parts) are, respectively, substituted for the ethyl glycolate.)
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Br:20][C:21]1[S:25][C:24]([CH2:26]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>O1CCCC1.C(OCC)(=O)C>[Br:20][C:21]1[S:25][C:24]([CH2:26][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:23][CH:22]=1
Reactant: OCc1ccc(Br)s1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(Br)s4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (5-bromothiophen-2-yl)methanol (76 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (13 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20].Cl.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>ClCCl.C(#N)C.N1C=CC=CC=1>[ClH:16].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([C:19](=[O:20])[CH2:18][CH3:17])[CH2:24]3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C(Cl)CCCl
Reactant: C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCC(=O)C1CCCN(N2CCC(c3c[nH]c4ccccc34)CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To a suspended solution of 4-(3-indolyl)piperidine (200 mg, 1.0 mmol) in dichloromethane (15 mL) was added pyridine (5 mL), and the resulting mixture was cooled to 0° C. Subsequently, 3-chloropropionyl chloride (0.25 mL, 2.6 mmol) was then added dropwise to the mixture, and the resulting mixture was stirred at 0° C. for 2 hours. After the reaction mixture was poured into hydrochloric acid and then extracted with ethyl acetate, the ethyl acetate layer was washed with 1 N hydrochloric acid and a saturated aqueous sodium chloride and was dried over anhydrous sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated to afford a crude product (100 mg). After identifying the structure of the crude product by 1H NMR and IR, piperidine (350 mg, 4.0 mmol) was added to a solution of the crude product in acetonitrile (10 mL), and the mixture was stirred at 80° C. for 3 hours. After concentrating the reaction mixture, water (10 mL) was added thereto, and the resulting mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated, and the resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=1:2) to afford a free form (97 mg, yield: 29%) of the title compound as a colorless amorphous solid. After adding hydrochloric acid/methanol to a solution of the free form (67 mg) in methanol, the mixture was concentrated and was then reprecipitated from ethanol/ether to afford the title compound (50 mg) as a pale yellow amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+]>CN(C)C=O.O>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C#N)c1ccc(OCc2ccccc2)cc1
Yield: 76 %

Procedure:
4-Hydroxyphenylacetonitrile (15.3 g, 114.9 mmol) was dissolved in dimethylformamide (120 mL) and to this was added potassium carbonate (23.78 g, 172.4 mmol), benzyl bromide (20.64 g, 120.6 mmol) and potassium iodide (3.81 g, 30.0 mmol). The solution was stirred at ambient temperature for 6 hours after which water was added. 4-Benzyloxyphenyl-acetonitrile precipitated out of solution. The suspension was filtered and the precipitate washed with water (3×). Yield 24.8 g (97%) as yellow crystals. The title product was prepared from 4-benzyloxyphenyl-acetonitrile as described in Preparation 7. Yield 76%.
Reaction SMILES: [NH2:1][CH:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]([C:9]3[C:12](=[O:13])[C:11](=[O:14])[C:10]=3[CH3:15])[CH2:7][S:8][C@H:3]12.[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:50]/[O:51][CH3:52])/[C:41](N2C(=S)N(C)N=N2)=[O:42])[N:39]=1.CN(C)C=O>O1CCCC1.C(OCC)(=O)C>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:50]/[O:51][CH3:52])/[C:41]([NH:1][CH:2]2[C:32](=[O:33])[N:4]3[C:5]([C:16]([O:18][CH:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])=[C:6]([C:9]4[C:12](=[O:13])[C:11](=[O:14])[C:10]=4[CH3:15])[CH2:7][S:8][C@H:3]23)=[O:42])[N:39]=1
Reactant: CO/N=C(\C(=O)n1nnn(C)c1=S)c1csc(N)n1
Reactant: Cc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
A mixture of diphenylmethyl 7-amino-3-(3,4-dioxo-2-methyl-1-cyclobutenyl)-3-cephem-4-carboxylate (100 mg, 0.217 mmol) and 1-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl]-4-methyltetrazole-5-thione (65 mg, 0.217 mmol) in tetrahydrofuran (1 mL) was stirred at 5° C. for 0.25 hr and then for 1 hr at 22° C. when N,N-dimethylformamide (0.05 mL) was added. The solution was diluted with ethyl acetate. The solution was sequentially washed with dilute aqueous NaHCO3 (2×), H2O, and saturated NaCl and then was dried over Na2SO4. Removal of the solvent left a yellow solid which was chromatographed on SiO2 (6 g) with methylene chloride/2-propanol (96:4) to afford the title compound (120 mg, 86% yield) as a yellow powder.