Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(OCC)(=O)C>ClCCCl>[C:47]([N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(N[C@H](Cc1ccccc1)CN(C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C(=O)c1ccccc1)OCc1cncs1
Reaction time: 2 h
Yield: 48.2 %

Procedure:
The product from Example 26D (50 mg, 0.088 mmol) in 1,2-dichloroethane (2 mL) was treated with triethylamine (14 μl, 0.097 mmol) and benzoyl chloride (10.3 μl, 0.088 mmol) at ambient temperature. After stirring for two hours, the mixture was treated with ethyl acetate (8 mL), wash with aqueous 10% NaHCO3 (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified on a silica gel cartridge eluting with (chloroform:methanol, 99:1) to provide the title compound (28.4 mg, 48%). 1H NMR (CDCl3) δ 8.78 (d, 2H), 7.83 (s, 2H), 7.40-6.75 (m, 15H), 5.24 (s, 4H), 4.27 (br s, 2H), 3.88 (br s, 2H), 3.28 (m, 3H), 2.91 (br s, 1H), 2.78 (br s, 1H), 2.45 (br s, 2H); MS (ESI+) m/z 670 (M+H)+.
Reaction SMILES: Cl.O1CCOCC1.[F:8][CH:9]([F:56])[C:10]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=2)=[CH:45][CH:44]=1)([OH:42])[CH2:11][C:12]1[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[N:16]=1>CO>[F:56][CH:9]([F:8])[C:10]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=2)=[CH:45][CH:44]=1)([OH:42])[CH2:11][C:12]1[NH:13][CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[N:16]=1
Reactant: CC(C)(CO)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(CO)Cc1c[nH]c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4M Hydrogen chloride in dioxane (1 mL, 0.25 mmol) was added to a solution of 3-(2-{3,3-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-2-hydroxypropyl}-1-trityl-1H-imidazol-4-yl)-2,2-dimethylpropan-1-ol (from previous step) in methanol (1 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. Combined extracts were dried (magnesium sulfate) and concentrated Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. LCMS: 420 (M+H) found.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:21][CH2:22][CH3:23])=[C:8]2[CH:14]=[N:13][N:12](CC3OC=CC=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[Se](=O)=O.O.N>COCCOCCOC.O.CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:21][CH2:22][CH3:23])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1OCC
Agent: N
Agent: O=[Se]=O
Solvent: COCCOCCOC
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Reaction time: 1.5 h
Yield: 67 %

Procedure:
31.5 g of 4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxylic acid ethyl ester (0.1 mol) and 20 g of selenium dioxide (0.18 mol) are suspended in 100 ml diethyleneglycol dimethylether. The mixture is heated with stirring at 160° and a few drops of water are added. The temperature is held steady for 1.5 hours. After cooling, 100 ml of water is added and the mixture is neutralized with a dilute solution of aqueous ammonia. Yellow crystals are formed, which yield on recrystallization from methanol 15.8 g of 4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (67%), m.p. 180°.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
Ethanol (100 ml) and 10%-Pd/C (0.5 g) were added to 1-(tert-butoxycarbonyloxy)-4-benzyloxybenzene (10.0 g:33.3 mmol) of synthesized in the Example 13, and the mixture was subjected to hydrogenolysis under H2 atmosphere with stirring at a room temperature. After completion of the reaction, Pd/C was removed by filtration, and then the solvent was removed. The obtained residue was recrystallized from a mixed solvent of hexane/toluene to give 6.74 g (32.1 mmol) of 4-(tert-butoxycarbonyloxy)phenol.
Reaction SMILES: Cl.Cl[CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[Cl:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([S:26][CH:3]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: ClC(CCc1ccccc1)Cn1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(SC(CCc2ccccc2)Cn2ccnc2)cc1Cl

Procedure:
A mixture of 600 mg. of 1-(2-chloro-4-phenylbutyl)imidazole hydrochloride, 1.2 g. of 3,4-dichlorothiophenol and 800 mg. of potassium carbonate in 40 ml. of acetone was stirred and refluxed for 4 hours. The solvent was evaporated under vacuum and 50 ml. of water was added. The resulting mixture was extracted with ether and the ether extract was washed with saturated sodium chloride solution, dried and evaporated to afford 1-[2-(3,4-dichlorophenylthio)-4-phenylbutyl]imidazole as an oil. This material was converted to the oxalate salt by treatment with oxalic acid in ether, which salt was recrystallized from acetone/ethyl acetate as colorless flakes (850 mg.), m.p. 145°-147° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: [H][H]
Reactant: CCOC(=O)CCCC(CCC#N)Oc1cccnc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)CCCC(CCCN)Oc1cccnc1

Procedure:
A solution of crude ethyl 7-cyano-5-[3-pyridyloxy)-heptanoate (1.74 g) in 50 mL of methanol saturated with ammonia is subjected to hydrogenation for 5 hours at 3 atmospheres pressure of hydrogen using Raney Nickel (1.0 ml aqueous suspension) as the catalyst. The catalyst is filtered off and washed with methanol. The filtrate is evaporated and the residue filtered through a plug of silica gel using ether as eluent to remove remaining triphenylphosphine oxide. The compound is eluted from the silica gel using methanol:triethylamine (95:5). The solvent is evaporated to yield ethyl 8-amino-5-(3-pyridyloxy)-octanoate; 1H NMR (CDCl3): delta 8.28 (br,1H), 8.19 (br,1H), 4.39 (m,1H), 4.08 (q,2H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:20])([CH3:1])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:12])=[O:4]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: CCNCCC(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CCC(C)C)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 10.1 mg N-ethyl-iso-amylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.29 min. (m/Z=304.2, 388.2, 410.2).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C(O)(=O)C>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]2[NH:13][CH2:12][C:11]3[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][CH:10]=3)[NH:1]2)[CH:16]=1
Reactant: COC(=O)c1cccc(CN)c1N
Reactant: O=Cc1cccnc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c1NC(c1cccnc1)NC2
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
A mixture of methyl 2-amino-3-(aminomethyl)benzoate (5.0 g, 27.7 mmol), nicotinaldehyde (3.0 g, 27.7 mmol) and acetic acid (2.0 mL) in dioxane (50 mL) was stirred in the microwave for 20 minutes. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (10% methanol in CH2Cl2) to give methyl 2-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-8-carboxylate (4.0 g, 53% yield).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl([O-])(=O)(=O)=O.[Li+]>>[F:19][C:20]1[CH:21]=[C:22]([NH:23][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Reactant: Nc1cccc(F)c1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O=C(OCc1ccccc1)N1CCC(O)(CNc2cccc(F)c2)CC1

Procedure:
The object product (2.53 g, 94%) was obtained in the same manner as in Example 24(1) and using benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.98 g), 3-fluoroaniline (889 mg) and lithium perchlorate (960 mg).
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=O>>[S:2]1[CH2:3][CH2:4][NH:5][CH:7]1[C:6]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C=O
Reactant: NCCS
Agent: Cl
Product: CCOC(=O)C1NCCS1
Yield: 84.2 %

Procedure:
22.6 g of mercaptoethylamine hydrochloride and 20.4 g of ethyl glyoxylate are heated with 100 g of 3A molecular sieves on a water bath for 45 min. The mixture is filtered, the filtrate is evaporated in vacuo, the residue is filtered through silica gel and the product is crystallized from methylene chloride/tert.-butyl methyl ether. 27 g of the thiazolidine derivative are obtained. ##STR17##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([CH3:12])=[CH2:11])[N:5]=[CH:4][N:3]=1.[OH-].[Na+].O.[CH:16]([Cl:19])(Cl)[Cl:17]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([CH3:12])[CH2:11][C:16]2([Cl:19])[Cl:17])[N:5]=[CH:4][N:3]=1
Reactant: ClC(Cl)Cl
Reactant: C=C(C)COc1cc(Cl)ncn1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC1(COc2cc(Cl)ncn2)CC1(Cl)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In 6.5 ml of chloroform was dissolved 0.6 g of 4-chloro-6-(2-methylallyloxy)pyrimidine, to which 0.02 g of benzyltriethylammonium chloride was added at 0° C. and 3.25 ml of a 50% sodium hydroxide solution was further added dropwise at the same temperature, followed by stirring at room temperature for 14 hours. The reaction mixture was then poured into water, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.23 g of 4-chloro-6- [(2,2-dichloro-1-methylcyclopropyl)methoxy]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5](OC)=[O:6].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(C(F)(F)F)c1
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102 %

Procedure:
To a stirred solution of methyl 3-chloro-5-(trifluoromethyl)benzoate (Reference Example 29, 2.20 g, 9.22 mmol) in THF (100.0 mL) at −78° C. was added disobutylaluminum hydride solution (28.00 mL, 1.0 M in methylene chloride, 28.00 mmol) and the resulting reaction mixture was stirred at this temperature for 4 h. After this time, the reaction was quenched with 1.0 M hydrochloric acid (100 mL) and warmed to room temperature. The reaction mixture was diluted with ethyl acetate, washed with aqueous 1.0 M hydrochloric acid, water, and saturated sodium chloride, dried (Na2SO4), filtered, concentrated under reduced pressure to provide (3-chloro-5-(trifluoromethyl)phenyl)methanol (1.98 g, >99%) as a brown oil, which was used without further purification or characterization.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]2([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]2)/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:69][C@@H:70]1[C:88](=[O:89])[N:72]2[C:73]([C:85]([OH:87])=[O:86])=[C:74]([CH2:77][S:78][C:79]3[N:83]([NH2:84])[N:82]=[N:81][N:80]=3)[CH2:75][S:76][C@H:71]12.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]2([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]2)/[C:27]([NH:69][C@@H:70]2[C:88](=[O:89])[N:72]3[C:73]([C:85]([OH:87])=[O:86])=[C:74]([CH2:77][S:78][C:79]4[N:83]([NH2:84])[N:82]=[N:81][N:80]=4)[CH2:75][S:76][C@H:71]23)=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nnnn4N)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.2 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(1-tert-butoxycarbonylcyclopentyloxyimino)acetic acid (2.80 g, 4.7 mmol), 1-hydroxybenzotriazole (0.73 g, 5.4 mmol) and N,N'-dicyclohexylcarbodiimide (1.07 g, 5.17 mmol) in dimethylacetamide (26 ml) was stirred at room temperature for 2.5 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.70 g, 5.17 mmol) and triethylamine (1.05 g, 10.3 mmol) in dimethylacetamide (13 ml) and water (1.7 ml), and the mixture was stirred at room temperature for 17 hours. The mixture was acidified with citric acid to pH 3.5 and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated. The residue was treated with isopropyl ether to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(1-tert-butoxycarbonylcyclopentyloxyimino)acetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=O)=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:11])[C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[C:14]([O:13][CH3:12])=[O:15])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNCc1ccc(F)c(Br)c1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 67.6 %

Procedure:
To a solution of [(3-bromo-4-fluorophenyl)methyl]methylamine (0.355 g, 1.63 mmol) in THF (16 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.294 g, 1.63 mmol), HBTU (0.929 g, 2.45 mmol), Et3N (0.458 mL, 3.26 mmol) and stirred at room temperature for 65 h, and then quenched with H2O. The organic layer was loaded onto silica gel cartridge and purified by CombiFlash chromatograph to afford the title compound 0.419 g (68%). LC-MS m/z 380 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:21])[C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:13][CH:14]=3)=[CH:4][C:3]=1[C:22]([OH:24])=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[CH2:35][CH2:34][NH:33][C:30]2=[CH:31][N:32]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:21])[C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:13][CH:14]=3)=[CH:4][C:3]=1[C:22]([N:33]1[C:30]2=[CH:31][N:32]=[C:27]([O:26][CH3:25])[CH:28]=[C:29]2[CH2:35][CH2:34]1)=[O:24]
Reactant: O=C(O)c1cc2[nH]c(=O)c3cnc(C4CCOCC4)n3c2cc1F
Reactant: COc1cc2c(cn1)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cn1)N(C(=O)c1cc3[nH]c(=O)c4cnc(C5CCOCC5)n4c3cc1F)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
To a mixture of 106 mg of 8-fluoro-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid, 53 mg of 5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 0.22 mL of N,N-diisopropylethylamine, and 2 mL of N,N-dimethyl formamide was added 146 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 5.9 mg of 8-fluoro-7-[(5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)carbonyl]-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-4(5H)-one as a pale brown solid.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH3:13])C.[OH-].[Na+]>CCO>[CH3:13][O:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C)c1C(=O)O
Yield: 82.2 %

Procedure:
Ethyl-2-methoxy-6-methylbenzoate (30.4 g, 0.157 mol) was added to 100 mL 3.2 M NaOH (2 equiv) and 150 mL hot EtOH. The mixture was refluxed overnight after which EtOH was removed in vacuo. The aqueous mixture was acidified with 5 M HCl to pH 3. CH2Cl2 (200 mL) was added, and the layers were separated. The water layer was extracted two times with 200 mL CH2Cl2, and the organic layers were combined and dried over Na2SO4. Filtering the Na2SO4 and concentrating the CH2Cl2 to dryness yielded 21.4 g (0.129 mol, 82.3%) of 2-methoxy-6-methyl-benzoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:41][C:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][C:44]([OH:52])([CH2:45]3)[CH2:43]1)[CH2:49]2>CN(C=O)C>[OH:52][C:44]12[CH2:50][CH:48]3[CH2:47][CH:46]([CH2:51][C:42]([NH:41][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:9])([CH2:49]3)[CH2:43]1)[CH2:45]2
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC12CC3CC(CC(O)(C3)C1)C2)c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
To a 40 ml vial was added picolinic acid (0.68 g, 5.5 mmol), DMF (15 ml), triethylamine (0.90 mL, 6.4 mmol), and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 2.3 g, 6.0 mmol). The mixture was stirred at rt for 5 minutes to get a clear solution. 3-Amino-adamantanol (0.84 g, 5.0 mmol; AK Scientific, 897-4G Independence Ave., Mountain View, Calif. 94043) was added to the above solution and stirred at rt for 2 hours. DMF was removed in Genevac and the residue was dissolved in DCM (20 mL), washed with 1N aqueous NaOH, water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford 1.32 g (97%) of crude title compound, pyridine-2-carboxylic acid (3-hydroxy-adamantan-1-yl)-amide, as an oil, which became a colorless solid upon standing at room temperature. LC/MS (Gradient: acetonitrile in water, 20-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column: Inertsil® ODS-3, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time: 0.79 min; purity (UV254): 100%; ESI-MS m/z: 273 (M+H)+. It was used in the next step without further purification.
Reaction SMILES: C([O:8]C1C=CC(C(O)=O)=CC=1)CCCCCC.ON1C2C=CC=CC=2N=N1.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.NC1C=CC=CC=1O>O1CCCC1>[CH:37]1([NH:36][C:35]([NH:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:8])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: Nc1ccccc1O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4.7 g of p-heptyloxybenzoic acid, 2.7 g of 1-hydroxybenztriazole (HOBT) and 50 ml of tetrahydrofuran was added 4.2 g of dicyclohexylcarbodiimide (DCC) under ice cooling. After stirring at room temperature for 1 hour, 9 g of o-aminophenol was added to the mixture. The resulting mixture was stirred at room temperature overnight. Dicyclohexyl urea formed was filtered off and the filtrate was concentrated. The residue was dissolved in 500 ml of ethyl acetate. The solution was washed subsequently with diluted hydrochloric acid, a diluted sodium hydrogen carbonate solution and then water, dried over anhydrous magensium sulfate and the concentrated under reduced pressure. The residue was applied to silica gel column chromatography (using 500 ml of silica gel), eluted with a toluene-ethyl acetate (1:1) mixture and further recrystallized from ethanol to obtain 5.6 g of p-heptyloxy-N-(o-hydroxyphenyl)benzamide.