Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:16]1[C:17]2[C:18]3[C:19](=[N:30][N:31]([CH2:33][C:34]4[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=4)[N:32]=2)[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[C:22]=3[CH2:23][S:24][N:25]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].O1CCCC1.ClC(OCC(C)C)=O>O>[OH:28][CH2:27][CH2:26][C:21]1[C:22]2[CH2:23][S:24][N:25]=[C:16]([N:15]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])[C:17]3=[N:32][N:31]([CH2:33][C:34]4[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=4)[N:30]=[C:19]([C:18]=23)[CH:20]=1
Reactant: COc1c(C)cnc(Cn2nc3cc(CC(=O)O)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2nc3cc(CCO)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
N-Methylmorpholine (22 μl) was added to a mixture composed of the above {4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}acetic acid (60 mg) and tetrahydrofuran (2 ml). Then, isobutyl chloroformate (39 μl) was added and the mixture was stirred at 0° C. for one hour. N-Methylmorpholine (44 μl) and isobutyl chloroformate (39 μl) were added to the reaction mixture, and the mixture was further stirred at 0° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Tetrahydrofuran (2 ml) and water (0.4 ml) were added to the resulting residue. Then, sodium borohydride (15 mg) was added under ice-cooling, and the mixture was stirred at 0° C. for one hour. Methanol (2 ml) was added dropwise to the reaction mixture. Then, the mixture was returned to room temperature and stirred for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (hexane-ethyl acetate) to obtain the title compound (16 mg, 27%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:21])[CH2:10][NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:5]=[N:6][C:7]=1Cl>C(O)(=O)C.O.[Br-].C[N+](C)(C)C.C(OCC)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:21])[CH2:10][NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Oc1ccc(CCNC[C@H](O)c2cnc(Cl)c(Cl)c2)cc1
Agent: C[N+](C)(C)C
Agent: [Br-]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Oc1ccc(CCNC[C@H](O)c2cncc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 65.7 %

Procedure:
To a solution of 4-[2-[[(2R)-2-(5,6-dichloro-3-pyridyl)-2-hydroxyethyl)amino]ethyl]phenol (850 mg) in acetic acid (15 ml) and water (1.0 ml) were added tetramethylammonium bromide (5.2 mg) and zinc dust (509 mg), and the mixture was stirred at 50° C. for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 4-[2-[[(2R)-2-(5-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]phenol (500 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:11]1([NH:14][C:15]2[N:20]3[N:21]=[CH:22][C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/4)=[C:19]3[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH2:13][CH2:12]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:13][CH2:12]2)[N:20]2[N:21]=[CH:22][C:23](/[CH:24]=[C:25]3/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/3)=[C:19]2[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(OCc4ccccc4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (14.2 μL, 0.138 mmol) was dissolved in NMP (0.2 ml). Sodium Hydride (60%, 5.5 mg, 0.138 mmol) was added and the reaction stirred at room temperature for one hour. A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]-triazin-8-yl)methylene)imidazolidine-2,4-dione (10 mg, 0.027 mmol) was added and the mixture was stirred at room temperature for one hour. Water was added and the material was extracted with ethyl acetate. After concentration at the rotary evaporator, addition of methanol formed a precipitate that was filtered and dried. (Z)-5-((2-(benzyloxy)-4-(cyclopropylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione was isolated as a solid (5.6 mg). LCMS (ES):>95% pure, m/z 392 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25][C:26]([CH3:49])=[CH:27][CH2:28][O:29][CH2:30][CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:46]1[CH2:47][CH2:48][CH:43]([C:41]([C:33]2[N:32]([CH2:31][CH2:30][O:29][CH2:28][CH:27]=[C:26]([CH3:49])[CH3:25])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=2)=[O:42])[CH2:44][CH2:45]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Reactant: CC(C)=CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: CC(C)=CCOCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3ccccc3)c3ccccc3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(1-(2-(3,3-dimethylallyloxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: CC([C:5](OOC(C)(C)C)=[O:6])(C)C.[C:13](OOC(=O)CCCCCCC)(=[O:21])CCCCCCC.C(OOC(=O)CCCCCCCCCCC)(=O)CCCCCCCCCCC.[N:61]([C:71]([CH3:78])([CH2:74][CH:75]([CH3:77])[CH3:76])[C:72]#[N:73])=[N:62][C:63]([CH3:70])([CH2:66][CH:67]([CH3:69])[CH3:68])[C:64]#[N:65]>>[N:61]([C:71]([CH3:78])([CH2:74][C:75]([O:21][CH3:13])([CH3:77])[CH3:76])[C:72]#[N:73])=[N:62][C:63]([CH3:70])([CH2:66][C:67]([CH3:68])([O:6][CH3:5])[CH3:69])[C:64]#[N:65]
Reactant: CC(C)(C)OOC(=O)C(C)(C)C
Reactant: CCCCCCCC(=O)OOC(=O)CCCCCCC
Reactant: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Agent: CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC
Product: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC

Procedure:
tert-butyl perpivalate, dioctanoyl peroxide, dilauroyl peroxide, 2,2,-azobis(2,4-dimethylvaleronitrile)
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][CH:6]([NH2:8])[CH3:7].CC1[C:20]([O:21]CC(N)C)=[C:19](C)C=CC=1.C(N)(=O)C.C(Cl)(=O)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][CH:6]([NH:8][C:20](=[O:21])[CH3:19])[CH3:7]
Reactant: Cc1cccc(C)c1OCC(C)N
Agent: CC(N)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)NC(C)COc1c(C)cccc1C

Procedure:
In Step 1, 2-(2,6-dimethylphenoxy)-1-methyl-ethylamine (mexiletine) is converted to mexiletine acetamide. Mexiletine is treated with an acetylating agent, such as an acetyl chloride or acetic anhydride, in the presence of concentrated aqueous alkali and an organic solvent, e.g., ethyl acetate. The reaction temperature is maintained at about 0°-25° C., preferably below 10° C., for about 10 minutes to 3 hours, preferably about 35 minutes. Following completion of the reaction, the resulting N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-acetamide is isolated by conventional techniques, and used as such in Step 2.
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH:5]([F:7])[F:6])[CH2:3]O.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].C(=O)([O-])O.[K+]>C(#N)C>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:2]2([CH:5]([F:7])[F:6])[CH2:3][N:1]2[S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])(=[O:26])=[O:27])[CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC(CO)(c1cc(Br)ccc1F)C(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1(c1cc(Br)ccc1F)C(F)F
Temperature: 80 °C
Yield: 37.2 %

Procedure:
2-Amino-2-(5-bromo-2-fluoro-phenyl)-3,3-difluoro-propan-1-ol (13.04 g, 45.9 mmol) [examples 42 step d)] was dissolved in 261 mL acetonitrile, 2-nitrobenzenesulfonyl chloride (22.38 g, 101 mmol) and potassium hydrogencarbonate (13.79 g, 138 mmol) were added. The mixture was heated to 80° C. and stirred over night. After this period, the reaction mixture was cooled down and partitioned between saturated aqueous NaHCO3 solution and TBME. The layers were separated, washed with brine and TBME. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/dichloromethane 2/1→1/2 to give 7.71 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:20]([CH3:22])[CH3:21])[NH:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:20]([CH3:21])[CH3:22])[N:11]([CH3:25])[C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)N1NC(=O)C(c2ccc(Cl)c(Cl)c2)C1c1ccncc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)N1C(c2ccncc2)C(c2ccc(Cl)c(Cl)c2)C(=O)N1C
Temperature: 0 °C

Procedure:
In a 100 mL round bottom flask, was added 0.1 g 4-(3,4-Dichloro-phenyl)-1-isopropyl-5-pyridin-4-yl-pyrazolidin-3-one and 10 mL THF, stirred at 0° C. under nitrogen. 0.43 mL 1 M LHMDS in THF was added drop wise. After stirred at 0° C. for 30 min 0.026 mL iodomethane was added drop wise. The resulted mixture was stirred from 0° C. to rt for 2 hours, quenched with 20 mL sat. NH4Cl, extracted with dichloromethane 3×25 mL. The organic phase was dried over anhydrous Na2SO4. After purification by flash chromatography, obtained the title compound 80 mg as light solid. MS (ES+): 364 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH:17](O)[CH3:18])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O:30][C:31](=[O:34])[CH:32]=[CH2:33])([CH3:29])([CH3:28])[CH3:27].[OH-:35].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:26]([O:30][C:31](=[O:34])[CH2:32][CH2:33][O:35][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[CH:12]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(O)Oc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: [OH-]
Reactant: C=CC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCOCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 48 h

Procedure:
0.2 g of [(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethan-1-ol was suspended in 1.7 ml of toluene and 0.7 ml of tetrahydrofuran. 60 μl of acrylic acid-tert-butyl ester, 13 mg of tetrabutylammonium hydrogen sulfate, and 1.45 ml of 32% sodium hydroxide solution were added to it, and it was allowed to stir for 48 hours. Another 60 μl of acrylic acid-tert-butyl ester and 13 mg of tetrabutylammonium hydrogen sulfate were added, and the mixture was left for 48 hours in an ultrasound bath. Then, it was diluted with water and extracted three times with toluene. The combined organic phases were washed with water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:20])=[CH:17]/[CH2:18][O:19][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C@H:24]([O:23][CH2:21][CH3:22])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:36][CH:35]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CC(=O)c1cccc(-c2ccc(/C(C)=C/CO)cc2)c1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(C(C)=O)c3)cc2)cc1)OCC
Yield: 65.8 %

Procedure:
The title compound (0.16 g, 65% yield) was prepared from (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol (0.133 g, 0.50 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.125 g, 0.525 mmol) by a procedure analogous to that described in example 52 c.
Reaction SMILES: [F:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[OH-:10].[Na+].S(O)(O)(=O)=O.[NH2:17]O>O.CCO>[F:1][C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[O:10][N:17]=1)([CH3:9])[CH3:8]
Reactant: [OH-]
Reactant: NO
Reactant: CC(C)(F)C(=O)CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(F)c1cc(N)on1
Temperature: 80 °C
Yield: 34.7 %

Procedure:
To a stirred solution of 4-fluoro-4-methyl-3-oxopentanenitrile from Step 1 (12.9 g, 0.1 mol) and sodium hydroxide (8.20 g, 0.11 mol) in 1:1 water/EtOH (184 mL) was added hydroxylamine sulfate (17.23 g, 0.11 mol). The mixture was adjusted to pH 7.5 with 1N NaOH, then heated at 80° C. for 15 h. After cooling to rt, the mixture was concentrated to dryness under reduced pressure. The resulting solid was partitioned between water and dichloromethane, and the separated organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc in petroleum ether to afford 3-(2-fluoropropan-2-yl)isoxazol-5-amine as a yellow solid (5 g, 35%). LC-MS (ESI) m/z 145 (M+H)+.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=12.[CH2:12]1[C:17](=O)[CH2:16][C:14](=[O:15])[CH2:13]1.[NH2:19][C:20]1[N:24]([CH3:25])[NH:23][C:22](=[O:26])[CH:21]=1>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH:10]3[C:21]4[C:22](=[O:26])[NH:23][N:24]([CH3:25])[C:20]=4[NH:19][C:17]4[CH2:12][CH2:13][C:14](=[O:15])[C:16]3=4)[CH:7]=[CH:6][C:5]=12
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=C1CCC(=O)C1
Reactant: O=Cc1ccc2nonc2c1
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc2nonc2c1
Yield: 52.6 %

Procedure:
2,1,3-Benzoxadiazole-5-carboxaldehyde (0.15 g, 1.0 mmol), prepared as described in (Gasco, A. M., Ermondi, G. Eur. J. Med. Chem., (1996) 31, 3), 1,3cyclopentadione (0.1 g, 1.0 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.11 g, 1.0 mmol) were processed as described in Example 1 to provide 0.17 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.32 (m, 2H), 2.71 (m, 2H), 3.51 (s, 3H), 4.87 (s, 1H), 7.5 (dd, 1H), 7.6 (s, 1H), 7.9 (d, 1H), 9.61 (bs, 1H), 10.52 (s, 1H);
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[Br:13][C:14]1[C:18]2[CH:19]=[C:20]([CH2:23][N:24]3[C:28]([C:29]([OH:31])=O)=[C:27]([CH3:32])[N:26]=[C:25]3[CH3:33])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40][S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42]>C1COCC1>[Br:13][C:14]1[C:18]2[CH:19]=[C:20]([CH2:23][N:24]3[C:28]([C:29]([NH:3][CH3:1])=[O:31])=[C:27]([CH3:32])[N:26]=[C:25]3[CH3:33])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40][S:41]([C:44]([F:46])([F:45])[F:47])(=[O:42])=[O:43]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(C)n(Cc2ccc3oc(-c4ccccc4NS(=O)(=O)C(F)(F)F)c(Br)c3c2)c1C(=O)O
Solvent: C1CCOC1
Product: CNC(=O)c1c(C)nc(C)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.8 %

Procedure:
Carbonyldiimidazole (0.17 g) was added to a solution of the product of Example 101 (0.2 g) in dry THF (15 ml) under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 4 h, concentrated in vacuo to ~5 ml and then poured into an autoclave with 20 ml of liquid methylamine. The autoclave was heated to 60° C. for 1.5 h and then cooled to -40° C. before opening. The solution was diluted with cold methanol (-35° C.; 50 ml). The resulting solution was concentrated in vacuo and the residue was purified by flash chromatography eluting with chloroform-methanol (10:3) followed by another column eluted with 10-20% methanol in ethyl acetate to give the title compound as a white solid (104 mg), m.p. 208°-210° C.
Reaction SMILES: [F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O-:27])=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3].[Na+].[C:31]([O:34][CH2:35]Br)(=[O:33])[CH3:32]>CN(C=O)C.O>[F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O:27][CH2:35][O:34][C:31](=[O:33])[CH3:32])=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3]
Reactant: CC(=O)OCBr
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)[O-])N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCOC(=O)C1=C(C(C)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CSC(F)(F)F)C(=O)N12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cold solution of sodium 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate (738 mg, 1.5 mmol) in dry DMF (10 ml) is added a solution of bromomethyl acetate (253 mg, 1.65 mmol) in DMF (1 ml). The reaction is stirred for 30 minutes at 0°C and 90 minutes at room temperature. The reaction is diluted with water and the aqueous mixture is extracted with ethyl acetate. The extracts are washed with water, dried and evaporated to give acetoxymethyl 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. The product is dissolved in ethyl acetate and is precipitated by the addition of petroleum ether.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]Br>CN(C)C=O.C(OCC)C.O>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][N:9]1[CH:8]=[C:7]2[C:11]([CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6]2)=[N:10]1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(Cn1cc2ccc([N+](=O)[O-])cc2n1)OC

Procedure:
To a stirred suspension of 6-nitroindazole (10 g, 61 mmol) and K2CO3 (9.31 g, 67.5 mmol) in N,N-dimethylformamide (60 mL) at room temperature was added bromoacetaldehyde dimethylacetal (8.0 mL, 67.5 mmol) and the reaction was heated to 55 C for 18 ours. The mixture was allowed to cool and was diluted with diethyl ether (30 mL) and H2O (60 mL). The layers were separated and the aqueous was extracted with additional diethyl ether (3×30 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to an orange oil. The residue was purified by MPLC (SiO2, 9:1 Hx:Ethyl acetateto 4:1 Hx:EtoAc) to yield the titled product as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.31 (m, 6 H), 4.67 (d, J=5.42 Hz, 2 H), 4.91 (t, J=5.42 Hz, 1H), 7.82 (m1 H), 7.99 (m, 1 H) and 8.63 (s, 2 H); MS (ESI) 252 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])=[CH:15][C:14]=3[F:28])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.N1C=CC=CC=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])=[CH:15][C:14]=3[F:28])=[O:9])=[CH:29][CH:30]=1
Reactant: N#CCCCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#CCCCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a suspension of the title compound of Example 89 (0.11 g) in 25 mL EtOAc is added triethylamine (0.08 mL) and pyridine (5 mL) to aid dissolution. After 10% Pd/C (50 mg) is added, the reaction is placed under a hydrogen balloon. After 2 hours, the reaction is complete and subsequently filtered over Celite. The filter cake is washed with ethyl acetate. The filtrate is concentrated to give a tan solid which is further dried on the vacuum pump to afford the desired product (0.088 g).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([OH:33])[CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:26]([O:25][C:23]1[CH:24]=[C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:20]=[C:21]([OH:33])[C:22]=1[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OCC=Cc1ccccc1
Reactant: Oc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: Oc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C/C=C/c1ccccc1
Yield: 62 %

Procedure:
Following the procedure in the literature (Li, L.; Chan, T. H. Org. Lett. 2001, 5, 739), cinnamyl alcohol was reacted with 3,5-dibenzyloxyphenol to yield (#a) as a white solid (62% yield); mp 76-78° C.; 1H NMR. (CDCl3, 400 MHz) δ 7.40-7.24 (m, 15H), 6.48 (A of AB, J=15.9 Hz, 1H), 6.35 (B of ABt, J=15.9, 5.5 HZ, 1H), 6.27 (d, j=2.1 Hz, 1H), 6.16 (d, J=2.1 Hz, 1H), 5.07 (s, 1H), 5.02 (s, 2H), 4.99 (s, 2H), 3.59-3.57 (d, J=5.5 Hz, 2H); 13C NMR (CDCl3, 400 MHz) δ 158.5, 157.6, 155.4, 137.0, 136.8, 136.6, 130.2, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6, 127.3, 127.0, 126.8, 125.8, 106.6, 94.8, 93.4, 70.1, 69.9, 26.2; HRMS (ESI) calcd for C29H26O3Na (M+Na) 445.1780. found 445.1793.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[N:9]=[C:8]2SC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:23]=1[NH2:24]>>[F:20][C:21]([F:33])([F:34])[C:22]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][C:23]=1[NH:24][C:8]1[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12](=[O:13])[CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[N:9]=1
Reactant: CSc1nc(C(F)(F)F)cc(=O)n1C1CCCCC1
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: O=c1cc(C(F)(F)F)nc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)n1C1CCCCC1
Yield: 60 %

Procedure:
3-Cyclohexyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone which had been synthesized in accordance with the method of Example 24 was allowed to react with 2,5-bis(trifluoromethyl)aniline, thereby obtaining white solid of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-cyclohexyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 64].