Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]O)=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][O:26][C:25]2[CH:30]=[CH:31][C:22]([Cl:21])=[CH:23][CH:24]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc(Cl)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-chlorophenoxy)ethanol (1.25 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1 ) and crystallized from dichloromethane-hexane to provide 0.815 g of 4-[[2-(4-chlorophenoxy) ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 103°-105° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:14]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:16])([CH3:17])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCCCC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.005 g, 4.00 mmol) in 22 mL THF was treated with 722.8 mg CDI (4.4 mmol) and stirred for 2 h at room temperature. The pale yellow solution was then treated with 450 μL (381 mg, 4.47 mmol) piperidine in 22 mL THF in 1-2 mL portions over 2 h. The reaction was stirred overnight at room temperature. The reaction was concentrated and the residue dissolved in 100 mL CH2Cl2 and sequentially washed with 50 mL 0.25 M HCl, 50 mL 1.0 M NaHCO3, 50 mL saturated NaCl and dried over Na2SO4. The organic phase was concentrated. Flash chromatography yielded 992 mg of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperidin-1-yl)methanone as an off-white solid.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].OS(O)(=O)=O.[CH2:13](O)[CH3:14]>C1C=CC=CC=1>[C:1]([O:7][CH2:13][CH3:14])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: C=CCCC(=O)OCC
Reaction time: 15 h

Procedure:
To a solution containing 4-pentenoic acid (20.73 g, 207 mmol) in ethanol (100 mL) and benzene (200 mL) was added H2SO4 (250 μL). The solution was refluxed and monitored by GC (50° C., 1 min to 250° C. at 10° C./min; DB-5; tR of acid 4.4 min, ester 3.8 min). After 15 h, the reaction was complete; about 1/2 of the solvent was removed under reduced pressure and diluted with 150 mL ether. This was extracted with H2O (1×150 mL), saturated NaHCO3 (2×150 mL), H2O (1×150 mL), and brine (1×100 mL). The organic layer was dried over K2CO3, the solvent was removed under water aspirator vacuum, and the residue was distilled to yield ethyl 4-pentenoate, a compound, having the following structure: ##STR11## (20.79 g, 162 mmol, 78%; bp760 144° C.): 1H-NMR (200 MHz, CDCl3) δ 1.25 (t, J=7.2 Hz 3 H, CH3), 2.36 (m, 4 H, CH2CH2), 4.14 (q, J=7.2 Hz, 2 H, OCH2), 4.95-5.13 (m, 2 H, H2C=). 5.81 (m, 1 H, =CH); 13C-NMR (50 MHz, CDCl3) δ 14.2 (CH3), 28.6, 33.5 (C--H2CH2), 115.3 (H2C=), 136.5 (=CH), 172.8 (C=O).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:12][CH2:13][NH2:14])=[CH:3][CH:2]=1>[Pd].CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:3][CH:2]=1
Reactant: NCC=Cc1ccnc2ccccc12
Agent: [Pd]
Solvent: CO
Product: NCCCc1ccnc2ccccc12
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A catalytic amount of 10% palladium on carbon was added to a solution of 3-(4-quinolyl)-2-propenylamine (Intermediate No. 2-4) (188 mg, 1.02 mmol) obtained in Preparation Example 2 in methanol (3 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered with Celite, the solvent was evaporated under reduced pressure, and the resulting residue was distributed with ethyl acetate (30 ml) and a saturated aqueous ammonium chloride solution (30 ml). A 4 N aqueous sodium hydroxide solution (30 ml) was added to the aqueous layer, the whole was extracted with chloroform (100 ml), and the obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 145 mg (76.3%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:24][CH:23]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1-c1c(F)cnn1C
Yield: 49 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-trifluoromethylphenylisocyanate, in a similar manner as described in Example 1.69, providing 24 mg (49% yield) of Compound 89: LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.56 (s, 1H), 8.29 (s, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.65 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.50 (d, J=2.4 Hz, 1H), 7.38 (d, JH,F=4.4 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −62.80 (s, 3F), −177.39 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:18]3[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:10]([C:37]([OH:39])=[O:38])[CH2:9]1)=O)(C)(C)C.O1CCO[CH2:42][CH2:41]1>Cl>[ClH:29].[CH2:41]([O:39][C:37]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[N:18]2[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)=[O:38])[CH3:42]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C(C(=O)O)C1
Agent: Cl
Product: CCOC(=O)C1CNCCN1c1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
4-[9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-piperazine-1,3-dicarboxylic acid tert-butyl ester I-(8A-1)a was dissolved in 4 M HCl in dioxane (0.5 ml). After 30 minutes, the now heterogeneous reaction was concentrated under reduced pressure and then triturated from ether to afford title compound 8A-1 (38 mg, quantitative): +ESI MS (M+1) 497.2; 1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.51–7.30 (m, 7H), 4.35–4.15 (m, 2H), 4.06 (d, J=13.3 Hz, 1H), 3.73–3.47 (m, 5H), 3.40–3.30 (m, 1H), 1.23 (t, J=7.1 Hz, 3H).
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH2:24]>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:27]([F:28])=[C:20]([F:19])[CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2ccc(F)c(F)c2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 99.8 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.740 mmol), 3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 270 mg of the product 195. 1H NMR (CDCl3) δ 8.60 (s, 1H), 7.40-7.10 (m, 3H), 5.15-4.90 (m, 2H), 4.30-4.10 (m, 2H), 2.70-2.55 (m, 1H), 2.20-2.05 (m, 1H), 1.85-1.10 (m, 15H); MS: m/z 366 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:6])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 2-fluorobenzoic acid (1.00 g, 7.14 mmol), thionyl chloride (3 mL, 41.1 mmol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Chlorobenzene (5 mL, 50 mmol) and aluminum trichloride (1.050 g, 7.85 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc. HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22](O)=[O:23])[C:17]=1[CH3:25].[N:26]1([CH2:32][CH2:33][CH2:34][OH:35])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:29]2[CH2:30][CH2:31][N:26]([CH2:32][CH2:33][CH2:34][OH:35])[CH2:27][CH2:28]2)=[O:23])[C:17]=1[CH3:25]
Reactant: OCCCN1CCNCC1
Reactant: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Product: Cc1c(C(=O)N2CCN(CCCO)CC2)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Yield: 59 %

Procedure:
In analogy to the procedure described in Example 181, 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (Example 16C]) and 1-piperazinepropanol gave after suspending in a small amount of EtOAc and filtration the title compound in 59% yield as light yellow powder. MS: 459.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH3:16])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][C:28](=O)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[CH3:16])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Cc1cc2c(cc1N)N1C(=NNC(=O)C1C)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 32.2 %

Procedure:
A solution of 6-amino-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.1 g, 4.5 mmol) and 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.53 g, 8.9 mmol) in methanol (45 mL) and acetic acid (5 mL) was stirred at rt for 2 h. Sodium cyanoborohydride (0.563 g, 8.9 mmol) was added and the resulting dark solution was stirred at rt for 14 h. The solvent was removed in vacuo to give the crude product, which was purified by column chromatography on silica gel (eluting with 33% EtOAc in petroleum ether) to give 3-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (racemate, 0.580 g, 1.45 mmol, 32%) as an off-white powder. The racemate was further separated by chiral SFC (Table 2, Method 3) to give two enantiomers: 3-(4(R),7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 1, SFC (Table 1, Method 8), Rt=3.090 min, 0.250 g, 14%) and 3-(4(S),7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 2, SFC (Table 1, Method 8), Rt=4.151 min, 0.240 g, 13%). LC/MS (Table 1, Method 2) Rt=1.065 min.; MS m/z: 424 [M+23]+.
Reaction SMILES: C(O[C:4](=[O:25])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.CO.[CH3:28][NH:29][C:30]([NH2:32])=[O:31]>C[O-].[Mg+2].C[O-]>[CH2:21]([S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:4]([NH:32][C:30]([NH:29][CH3:28])=[O:31])=[O:25])=[CH:17][CH:16]=1)(=[O:19])=[O:20])[CH2:22][CH2:23][CH3:24]
Reactant: CNC(N)=O
Reactant: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)OCC)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)NC(=O)NC)cc1
Temperature: 110 °C
Yield: 46.1 %

Procedure:
A solution of 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid ethyl ester (125.3 mg, 0.34 mmol) in magnesium methoxide in methanol (7.4 wt %, 0.98 mL, 0.68 mmol) was treated with methyl urea (38 mg, 0.51 mmol). This mixture was refluxed at 110° C. for 12 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 1-{2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionyl}-3-methyl-urea (61.8 mg, 45.8%) as a white solid: mp 189-191° C.; EI-HRMS m/e calcd for C20H30N2O4S (M+) 395.2005, found 395.2008.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]([NH2:13])=[S:12].Cl[CH:15]([C:20](=O)[CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[S:12][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:20]([CH2:21][CH3:22])[N:13]=1
Reactant: NC(=S)Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CCC(=O)C(Cl)C(=O)OC
Solvent: CCO
Product: CCc1nc(Nc2c(Cl)cc(Cl)cc2Cl)sc1C(=O)OC

Procedure:
A stirred solution of 2,4,6-trichlorophenylthiourea (scheme 1: (B)) (3.25 g, 12.72 mmoles) and methyl 2-chloro-3-oxopentanoate (Scheme 1: (C)) (1.92 mL, 1.1 equiv.) in ethanol (60 mL) was heated at reflux for 16 hours. The solvent was removed in vacuo and the product was recrystallized from methanol (4.49 g, 97%). H1 NMR (CDCl3) δ 1.15 (3H, t), 2.91 (2H, q), 3.75 (3H, s), 7.47 (2H, s), 9.10 (1H, br).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C@H:5]2[S:4][CH2:3]1.[N+](=[CH2:28])=[N-]>O1CCOCC1.CCOCC>[CH3:28][O:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)C1C(=O)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C1=C(OC)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-oxo-7-phthalimidocepham-4-carboxylate (b) thus prepared by above methods is dissolved in dioxane, mixed with a solution of diazomethane in ether, and stirred for 1 hour at room temperature. The reaction mixture is evaporated under reduced pressure to give methyl 3-methoxy-7-phthalimido-3-cephem-4-carboxylate in nearly quantitative yield. Recrystallization from a mixture of acetone and ether gives ure crystals, m.p. 225-227° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:37][CH:36]([C:38]([NH:40][CH3:41])=[O:39])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH:36]([C:38]([NH:40][CH3:41])=[O:39])[CH2:37]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CNC(=O)C1CN(S(=O)(=O)c2ccccc2Br)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CNC(=O)C1CN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)C1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-((2-bromophenyl)sulfonyl)-N-methylazetidine-3-carboxamide. MS (ESI): mass calcd. for C21H20FN5O3S, 441.13; m/z found, 441.9 [M+H]+. 1H NMR (500 MHz, DMSO-δ6) δ 8.52 (s, 2H), 8.02 (d, J=7.9, 1H), 7.84 (d, J=4.8, 1H), 7.79-7.72 (m, 1H), 7.69-7.63 (m, 1H), 7.61-7.55 (m, 1H), 7.45 (d, J=7.5, 1H), 7.33 (d, J=11.7, 1H), 7.27 (d, J=7.8, 1H), 6.89 (s, 2H), 3.70 (t, J=7.0, 2H), 3.63 (t, J=8.0, 2H), 3.19-3.08 (m, 1H), 2.56 (d, J=4.4, 3H).
Reaction SMILES: [OH-].[K+].C([CH2:5][NH:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10](=[O:18])[C:9]([C:19]([O:21]CC)=[O:20])=[CH:8]1)=O>O.C(O)C>[CH3:17][C:14]1[N:15]=[C:16]2[C:11]([C:10](=[O:18])[C:9]([C:19]([OH:21])=[O:20])=[CH:8][N:7]2[NH:6][CH3:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cn(NCC=O)c2nc(C)ccc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Temperature: 0 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
A solution of 85% potassium hydroxide (2.25 g, 0.035 m) in 7.8 ml of water was added to a refluxing solution of 4.5 g (0.016 m) of ethyl 1-(N-formylmethylamino)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate in 141 ml of absolute ethanol. The reaction mixture was heated at reflux for one hour, then allowed to stand at room temperature for three days, and poured into 100 ml of ice-water and filtered. The filtrate while cold was acidified with acetic acid, and the solid product was collected by filtration, washed with water and dried at 50° C. in vacuo to yield 3.3 g of 1,4-dihydro-7-methyl-1-methylamino-4-oxo-1,8-naphthyridine-3-carboxylic acid, beige solid, m.p. 215°-217° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][N:7]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8]([CH3:9])=[O:20])=[N:6][N:7]=1
Reactant: CSc1nnc(N)c(=O)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(S(C)=O)nnc(N)c1=O
Yield: 59.2 %

Procedure:
1.7 g of 6-amino-4-methyl-3-methylthio-1,2,4-triazin-5-one are dispersed in 200 ml of methylene chloride, and 1.8 g of 3-chloroperbenzoic acid are added in portions at 15°-20° C. A clear yellow solution is thereby formed and is evaporated at 40° C. in vacuo. The solid residue is treated with ethyl acetate, whereupon the 3-chlorobenzoic acid formed in the reaction dissolves completely. The undissolved pure product is filtered off to give 1.1 g of 6-amino-4-methyl-3-methylsulfinyl-1,2,4-triazin-5-one with a melting point of 189° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH2:25]([CH:27]1[NH:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]1=[O:34])[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH:27]([CH2:25][CH3:26])[C:28](=[O:34])[N:29]([CH3:33])[C:30]4=[O:32])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CCC1NC(=O)N(C)C1=O
Product: CCC1C(=O)N(C)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Yield: 62.8 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 5-ethyl-3-methylimidazolidine-2,4-dione (63 mg) described in Preparation Example 215 and by the reaction and treatment in the same manner as in Example 536, the title compound (114 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14]>C(NCC)C.ClCCl.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15]
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: C#CCCCO
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: OCCCC#Cc1cc(Cl)ccc1Cl

Procedure:
A solution of 1,4-dichloro-2-iodobenzene (20.0 g, 73.3 mmol), 4-pentyn-1-ol (6.17 g, 73.3 mmol), bistriphenylphosphine(Pd II) chloride (1.03 g, 1.47 mmol), and copper(I) iodide (0.14 g, 0.733 mmol) in 400 ml of diethylamine was stirred under nitrogen for three days. This was diluted with dichloromethane and the oily layer was adsorbed onto silica gel and eluted with hexanes-ethyl acetate (5:1) to give 5-(2,5-dichlorophenyl)pent-4-yn-1-ol, 13.7 g (82%); NMR (CDCl3) δ 1.9 (m, 2H), 2.6 (t, 2H), 3.85 (t, 2H), 7.2 (dd, 1H), 7.28 (m, 1H), 7.4 (d, 2H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[CH:9][CH:10]=1>CO>[CH3:1][O:2][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[CH:9][CH:10]=1
Reactant: C[O-]
Reactant: Clc1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1

Procedure:
A solution of sodium methoxide in methanol (28%, 411 mg) was added to a mixture of 3-(3-chloropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (436 mg) and methanol (4 ml) at room temperature. The reaction mixture was heated under reflux for 3 hours. After evaporating the solvent in vacuo, a saturated aqueous solution of sodium chloride (20 ml) was added to the residue and extracted with chloroform (20 ml×3). The combined extract was washed with a saturated aqueous solution of sodium chloride (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (10 g) using chloroform as an eluent and recrystallized from 95% EtOH to give 3-(3-methoxypyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (165 mg).
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]=[O:21])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(=O)C>[CH2:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:20]=2[OH:21])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CNN=CC(C)=O
Reactant: CCCCCc1ccc(C(=O)C=O)cc1
Solvent: CC(=O)O
Product: CCCCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 10.3 %

Procedure:
2-Oxopropanal methylhydrazone (8.6 mmol, 861 mg) synthesized in Reference Synthetic Example 1 and (4-n-pentylphenyl)(oxo)acetaldehyde (8.6 mmol, 1.757 g) synthesized in Reference Synthetic Example 6 were dissolved in acetic acid (30 mL) and stirred at 100° C. for about 5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/AcOEt=2/1, and 4/1) to give the desired product as an orange solid (252.5 mg, yield 10.3%, crude).