Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=S)[CH3:2].[K+].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-])=O.CN(C=O)C>[Cl-].[Na+].O>[C:1]([NH:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:4])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC([O-])=S
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Generally, the procedure is as follows: under nitrogen gas, a stirred mixture of potassium thioacetate (e.g., about 3.71 g, 32.5 mmol), nitrobenzene (e.g., about 1 g, 8.1 mmol) and DMF (e.g., about 2.0 ml) is heated at about 130° C. After two hours, the reaction mixture is cooled to room temperature, brine (e.g., about 2 ml) is added and the resulting mixture is extracted with tert-butyl methyl ether (e.g., about 2×15 ml). The combined organic layer is washed with brine (e.g., about 2×4 ml) to remove residual DMF and filtered through a pad of charcoal and Celite to remove any residual sulfur. Evaporation of the solvent produced about 0.9 g of acetanilide (about 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8]1[N:15]=[CH:16][NH:17][C:18](=[O:19])[C:7]=1[CH2:6]2.[OH-].[Na+].[CH3:22]OS(OC)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8]1[NH:15][CH2:16][N:17]([CH3:22])[C:18](=[O:19])[C:7]=1[CH2:6]2
Reactant: COS(=O)(=O)OC
Reactant: COc1cc2c(cc1OC)Nc1nc[nH]c(=O)c1C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)NC1=C(C2)C(=O)N(C)CN1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To a heated (90° C.), stirred solution of 7,8-dimethoxy4-oxo-3,4,5,10-tetrahydropyrimido[4,5-b]quinoline (0.25 g, 0.96 mmol) and sodium hydroxide (0.05 g, 1.25 mmol) in water (3 mL) was added dimethylsulfate (0.23 mL, 2.4 mmol). After 0.5 hour, the reaction mixture was diluted with water (20 mL), the solids filtered, washed with acetonitrile and dried in vacuo to afford 0.13 g of the title compound; m.p. 225-230° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].O.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C1C=CC=CC=1.C(O)C>[CH2:17]([O:13][C:12](=[O:14])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:15])[CH3:18]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Yield: 563.9 %

Procedure:
A solution of 2-(4-isobutylphenyl)-propionoic acid (Ibuprofen, 9.6 g, 46.5 mmol) and p-toluenesulfonic acid monohydrate (1.52 g, 7.9 mmol) in benzene (100 mL) and ethanol (75 mL) was heated to reflux using a Dean-Stark apparatus for 4 h. The solvent was removed under reduced pressure and the residue was taken up in Et2O (100 mL). The solution was extracted with saturated aqueous NaHCO3 solution (2×100 mL) and water (2×100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated, affording 204 (10.44 g, 96%) as a clear oil. 1H NMR (CDCl3): δ 7.19 (d, 2H, J=8.0), 7.08 (d, 2H, J=8.0), 4.10 (m, 2H), 3.66 (q, 1H, J=7.0), 2.44 (d, 2H, J=7.0), 1.84 (m, 1H), 1.47 (d, 3H, J=7.0), 1.19 (t, 3H, J=7.3), 0.89 (d, 6H, J=7.0). 13C NMR (CDCl3): δ 174.92, 140.59, 138.07, 129.45, 127.29, 60.79, 45.32, 45.21, 30.35, 22.55, 18.78, 14.29. HRMS (LSIMS, nba): Calcd for C15H23O2 (MH+): 235.1698, found: 235.1688.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[O:13][CH:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[N+:23]([O-:28])([N+]([O-])=O)=[O:24]>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[O:13][C:14]=2[N+:23]([O-:28])=[O:24])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(-c2coc3c2ccc2ccccc23)cc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc(-c2c([N+](=O)[O-])oc3c2ccc2ccccc23)cc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a mixture of 4.0 g. of the product of step A in 250 ml. of chloroform is added 4.0 g. of dinitrogen tetraoxide. The mixture is stirred at about 20° C. for 20 hours. The mixture is filtered, and the solid obtained is recrystallized from a mixture of N,N-dimethylformamide and water to provide yellow crystals of 3-(4-carboxyphenyl)-2-nitronaphtho-[1,2-b]furan, m.p. greater than 300° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl[S:23]([C:26]1[CH:38]=[CH:37][C:29]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:28]([CH3:39])[CH:27]=1)(=[O:25])=[O:24].C(N(CC)CC)C.S(Cl)(Cl)(=O)=O>C(Cl)Cl.O>[CH2:1]([N:5]([C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[S:23]([C:26]1[CH:38]=[CH:37][C:29]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:28]([CH3:39])[CH:27]=1)(=[O:25])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a solution of N-butyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (0.128 g, 0.44 mmol) In anhydrous CH2Cl2 (10 mL) was added ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (0.121 g, 0.41 mmol) and triethylamine (0.122 mL, 0.87 mmol). The resultant mixture was stirred for 24 h at room temperature prior to addition of sulfonyl chloride (0.121 mg, 0.41 mmol) and triethylamine (0.122 mL, 0.87 mmol). After a further 18 h stirring at room temperature the reaction was diluted with water (10 mL) and extracted with CH2Cl2 (2×10 mL). The organic solution was dried (Na2SO4) and the solvents removed in vacuo. Purification by SPE (Silica, 10 g) eluting 49:1–19:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (0.182 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:14][C:15]1[C:16]([OH:24])=[C:17]([CH3:23])[C:18]([CH3:22])=[C:19]([CH:21]=1)[OH:20]>ClCCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:21]2[C:19](=[O:20])[C:18]([CH3:22])=[C:17]([CH3:23])[C:16](=[O:24])[C:15]=2[CH3:14])[CH2:11][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CCC(O)c1ccc(C(C)C)cc1
Solvent: ClCCCl
Product: CCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccc(C(C)C)cc1
Reaction time: 3 h
Yield: 62.1 %

Procedure:
Boron trifluoride/ethyl ether complex (1.30 g, 9.33 mmol) was dropwise added to a suspension of 1-(4-isopropylphenyl)propan-1-ol (5.00 g, 28.0 mmol) and trimethylhydroquinone (4.30 g, 28.0 mmol) in 1,2-dichloroethane (100 mL) at 60° C. in a nitrogen atmosphere, and the mixture was stirred for 3 hours at the same temperature. After cooling, the reaction mixture was washed with an aqueous solution of iron(III) chloride and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=30/1) to obtain the title compound (5.40 g, yield 62%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]>C(O)C>[OH:1][C@@H:2]([CH2:18][N:19]1[CH2:20][CH2:21][CH:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:23][CH2:24]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1/[CH:7]=[C:8]1\[C:9]([O:11][CH2:12][CH2:13]\1)=[O:10]
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2ccc3ccccc3c2)CC1
Solvent: CCO
Product: O=C1OCC/C1=C/c1ccccc1OC[C@@H](O)CN1CCC(c2ccc3ccccc3c2)CC1
Reaction time: 6 h
Yield: 15 %

Procedure:
(S)-α-(2′-(2-Hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)benzylidene)-γ-butyrolactone (2.0 g) was dissolved in ethanol (300 ml) and exposed to the sunlight for 6 hr. The solvent was concentrated under reduced pressure and the obtained oil was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.3 g).
Reaction SMILES: C(OC([N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:25])([O:22]CC)[O:19]CC)[O:7]C(OCC)=O)=O)C.Cl.N.C>O.CO.C(O)C>[OH:7][NH:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:19])([OH:22])[OH:25]
Reactant: CCOC(=O)ON(CCCCCP(=O)(OCC)OCC)C(=O)OCC
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=P(O)(O)CCCCCNO
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A mixture of diethyl 5-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)pentylphosphonate (90.0 g.) and conc. hydrochloric acid (630 ml.) was refluxed for 14 hours and concentrated under reduced pressure to give a residue, which was dissolved in water (200 ml.). The aqueous solution was washed with ethyl acetate, treated with activated charcoal and then concentrated under reduced pressure to give an oily residue (53.7 g.). The residue was dissolved in a mixture of water and methanol (1:2). The solution was adjusted to pH 4.0 with 28% aqueous ammonia under ice-cooling to give precipitates, which were separated by filtration, washed with methanol and dried to give crude crystals. The crystals were dissolved in 20-fold volume of water under heating, treated with activated charcoal and then cooled to ambient temperature. To the solution was added ethanol (100 ml.) and then allowed to stand overnight at 4° C. to give crystals, which were separated by filtration and dried to give crystalline 5-(N-hydroxyamino)pentylphosphonic acid (18.8 g.). M.p. 184°-185.5° C. (dec.).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:17][C:18]1[CH:25]=[C:24](F)[C:21]([C:22]#[N:23])=[CH:20][N:19]=1>CN1C(=O)CCC1>[NH2:17][C:18]1[CH:25]=[C:24]([O:6][C@@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: O[C@@H]1CCOC1
Reactant: N#Cc1cnc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(N)cc1O[C@@H]1CCOC1
Reaction time: 0.03 h

Procedure:
(R)-tetrahydrofuran-3-ol (161 mg, 1.82 mmol) was treated at room temperature with KHMDS (1 M in THF, 1.09 ml, 1.09 mmol). The reaction mixture was stirred for 2 min. Then, the mixture was added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol) in NMP (0.5 ml). The resulting dark brown solution was stirred at room temperature for 1 h 50 min. The reaction mixture was quenched with sat. aq. NH4Cl and extracted 2× with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(1 M NH3 in MeOH) 9/1) 100:0 to 0:100) to give the title compound as a brown solid. (UPLC-MS 3) tR 0.48 min; ESI-MS 206.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:1][C:2]2[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)=[CH:39][CH:38]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (464 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (767 mg, yield 75%) was obtained as colorless crystals from a fraction eluted with ethyl-acetate. The crystals were recrystallized from ethyl acetate-hexane. melting point: 113–114° C.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][CH:45]([S:47](Cl)(=[O:49])=[O:48])[CH3:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([S:47]([CH:45]([CH3:46])[CH3:44])(=[O:49])=[O:48])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(S(=O)(=O)C(C)C)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (47 mg, 0.091 mmol) in DCM (908 μL) at 0° C. was treated with triethylamine (38.0 μL, 0.272 mmol), followed by propane-2-sulfonyl chloride (15.3 μL, 0.136 mmol). The reaction mixture was allowed to stir for 45 min, gradually warming to room temperature. The reaction mixture was concentrated under reduced pressure and was purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 60% to 95% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (16.4 mg, 29.0%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.29 (d, J=6.6 Hz, 6H), 1.35 (d, J=6.8 Hz, 6H), 1.95 (m, 2H), 2.13 (m, 2H), 2.82 (t, J=5.9 Hz, 2H), 3.07 (m, 2H), 3.42 (m, 3H), 3.67 (t, J=5.8 Hz, 2H), 4.12 (septet, J=6.5 Hz, 1H), 4.41 (s, 2H), 4.48 (dt, J=7.5, 3.6 Hz, 1H) 6.87 (m, 1H), 6.98 (ddd, J=11.3, 8.5, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 510.5.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:1][C:2]1[C:6]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:4][N:3]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1noc(-c2ccccc2)c1C1CCCC1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C1CCCC1
Yield: 82.8 %

Procedure:
3-Hydroxy-4-cyclopentyl-5-phenylisoxazole (229 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example I (a) to obtain the title compound (308 mg, 83%) as colorless crystals.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]([O:18]C2C=CC=CC=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCc1ccccc1Oc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of phenyl 3-(2-phenyloxyphenyl)propionate (0.45 g, 1.30 mmol), 2N NaOH (20 ml) and MeOH (10 ml) was stirred at room temperature overnight, which was then neutralized to pH˜2 with concentrated HCl and extracted with EtOAc (100 ml). The organic phase was washed with brine and dried over sodium sulfate and concentrated in vacuo to yield 3-(2-phenyloxyphenyl)propionic acid as an oil. This was used for next step without further purification.
Reaction SMILES: [CH:1]1([N:8]([C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:9](=[O:24])[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=2[OH:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([O:41][C:42]([NH:44][CH2:45][C:46](O)=[O:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:41][C:42]([NH:44][CH2:45][C:46]([O:23][C:12]1[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[NH:10][C:9]([N:8]([CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1)=[O:24])=[O:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(O)c(C(C)(C)C)c1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(OC(=O)CNC(=O)OCc2ccccc2)c(C(C)(C)C)c1

Procedure:
2-[3-Cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol and N-benzyloxycarbonylglycine were treated in the same manner as described in Example 172 (1) to give O-(N-benzyloxycarbonylglycyl)-2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol.
Reaction SMILES: [Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:21]([O:25][C:26](=[O:38])[N:27](C[C@H]1CC[C@H](C=O)CC1)[CH3:28])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(O)(CC)C>[C:21]([O:25][C:26](=[O:38])[NH:27][CH3:28])([CH3:24])([CH3:23])[CH3:22]
Reactant: CN(C[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
0.700 g (1.42 mmol) of 3-benzyloxypropyl)triphenylphosphonium bromide, 0.305 g (1.18 mmol) of trans-(4-formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester (example 1.2) and 0.662 g of finely milled potassium carbonate were suspended in 10.0 ml of 2-methyl-2-butanol and the reaction mixture intensively stirred at 100° C. for 2 hours. It was then evaporated, poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of ethylacetate. The combined ethylacetate phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 95:5 v/v mixture of dichloromethane and ether as the eluent giving 0.364 g (78.6%) trans-[4-(4-benzyloxy-[E/Z 1:9]but-1-enyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester as colorless viscous oil, MS: 331 [M−C4H8)+].
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([O:21]COCC[Si](C)(C)C)[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[Li+].C(#N)C>>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([OH:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2cn(Cc3ccccc3)nn2)cc(OCOCC[Si](C)(C)C)c1=O
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: Cn1cc(-c2cn(Cc3ccccc3)nn2)cc(O)c1=O
Yield: 42.9 %

Procedure:
To a solution of containing 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-methyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridin-2(1H)-one (148 mg, 0.359 mmol) in 1 mL THE was added 1.1 mL of a 1 M solution of lithium tetrafluoroborate in acetonitrile (1.1 mmol). This mixture was microwaved in a sealed vial at 100° C. for 10 minutes. After cooling, the mixture was evaporated under reduced pressure and purified by reversed-phase HPLC to afford 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-hydroxy-1-methylpyridin-2(1H)-one (43.5 mg, 0.154 mmol, 43% yield). 1H NMR δ (ppm) (DMSO-d6): 9.28 (1 H, s), 8.38 (1 H, s), 7.75 (1 H, d, J=2.20 Hz), 7.42-7.31 (5 H, m), 5.61 (2 H, s), 3.53 (3 H, s). High resolution mass spec (ESI) calc (M+H)+=283.1190 found 283.1188.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])=[CH:5][CH:4]=1.[CH:27](Br)([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+].Cl>C(#N)C.C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH:13]2[CH2:18][CH2:17][N:16]([CH:27]([CH3:29])[CH3:28])[CH2:15][CH2:14]2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(Cl)cc2)C2CCNCC2)cc1
Reactant: CC(C)Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)N(Cc2ccc(Cl)cc2)C2CCN(C(C)C)CC2)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
42ELH89 (0.25 g, 0.67 mmol, 1.0 eq) was transferred to a 4 ml vial and dissolved in acetonitrile (2 ml). Isopropyl bromide (0.25 g, 3.0 eq.) was added along with Hünigs base (0.87 g, 10.0 eq.). The vial was sealed and shaken for 4 days at 60° C. The reaction mixture was transferred to a separatory funnel with distilled water and CH2Cl2. The aqueous phase was made basic with sodium hydrogen carbonate and extracted with dichloromethane (3 times). The organic layers were collected and dried with sodium sulfate and concentrated, this resulted in a yellow oil. The product was purified by flash chromatography (3% MeOH in CH2Cl2). The resulting product was dissolved in dichloromethane (1 ml) and HCl (1 eq. 2 M HCl in ether) was added under stirring. The salt precipitated by addition of the dichloromethane solution into heptane. Concentration on the rotary evaporator returned the product as white crystals. Yield 101.2 mg (63%), UV/MS 94/96 (M+ 415), Rf 0.25 (3% MeOH/CH2Cl2).
Reaction SMILES: I[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[Na+].[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[C@H:25]([NH:26][C:27](=[O:36])/[C:28](/[C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)=[N:29]\[OH:30])[C:24](=[O:37])[N:19]2[C:20]=1[C:21]([O-:23])=[O:22])(=[O:12])[CH3:11].CCO.C([O-])(=O)C>CS(C)=O>[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[C@H:25]([NH:26][C:27](=[O:36])/[C:28](/[C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)=[N:29]\[O:30][CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])[C:24](=[O:37])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Reactant: NC(=O)NC(=O)CI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)NC(N)=O)c3ccco3)[C@H]2SC1
Yield: 34 %

Procedure:
This compound was prepared from iodoacetylurea and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt by the method described in Example 1. λmax (EtOH) 274 nm (ε 17,300), νmax (Nujol) 3420, 3260 (--NH--, --NH2), 3700-2100 (bonded OH), 1780 (β-lactam), 1720(--CO2H, acetate), 1700, 1570, 1545 cm-1 (CONH, CONH2), τ (DMSO d6) 2.11, 3.3, 3.18 (furyl), 5.28 (--O--CH2 --), 0.09 (--CONHCO--), 2.5 (CONH2), 0.11 (CONH), 4.1 (7 H), 4.78 (6 H), 6.29, 6.51 (2--CH2), 4.95, 5.28 (3 --CH2), 7.93 (CH3CO--). Yield: 34%.