Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO.N(C(OCC)=O)=N[C:15](OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cccnc1Br
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cccnc1Br
Reaction time: 2 h
Yield: 111 %

Procedure:
2-Bromonicotinic acid (7.33 g, 36 mmol) was suspended in dry Et2O (40 mL), and MeOH (2.3 mL) and diethyl azodicarboxylate (5.8 mL, 37 mmol) were added. Triphenylphosphine (9.61 g in 40 mL Et2O, 37 mmol) was added dropwise over 2.5 hours. After stirring an additional two hours, the reaction was filtered and evaporated. The resulting clear liquid was chromatographed on silica gel (10-40% EtOAc/hexanes) to yield a clear oil (8.63 g, 100%). 1H NMR (CDCl13): δ8.49 (dd, 1H, J=4.8, J′=2.2), 8.09 (dd, 1H, J=7.7, J′=1.8), 7.36 (m, 1H), 3.97 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.CN([CH:21]=[O:22])C>C1COCC1>[CH3:12][O:11][C:10]1[C:2]([CH:21]=[O:22])=[CH:3][C:4]2[O:8][CH2:7][CH2:6][C:5]=2[CH:9]=1
Reactant: CN(C)C=O
Reactant: COc1cc2c(cc1Br)OCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1C=O)OCC2
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of 6-bromo-5-methoxy-2,3-dihydrobenzofuran (9.20 g, 40.35 mmol) in THF (50 mL) was dropwise added n-Butyl lithium (24.00 mL, 38.40 mmol) at -78° C. After stirring for 30 min, DMF (5.00 ml, 60.53 mmol) was added and the mixture was allowed to stir at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate (3×150 mL). The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure. Flash chromatography (1:1 ether/hexane) of the residue afforded 5.42 g (76%) of the title compound as a yellow solid: 1H NMR (250 MHz, CDCl3) d 10.32 (s, 1H), 6.90 (s, 1H), 6.82 (s, 1H), 4.57 (t, 2H), 3.91 (s, 3H), 3.25 (t, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][CH:14]=[C:15]([C:21]([O:23]C)=[O:22])[C:16]([C:17]([O:19]C)=[O:18])=[C:11]2[N:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O>[CH2:1]([N:8]1[C:12]2=[CH:13][CH:14]=[C:15]([C:21]([OH:23])=[O:22])[C:16]([C:17]([OH:19])=[O:18])=[C:11]2[N:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(C(=O)O)c(C(=O)O)ccc2n1Cc1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
A mixture of dimethyl 1-benzyl-2-methyl-4,5-benzimidazoledicarboxylate (5.50 g, 16.2 mmol), methanol, 10N sodium hydroxide (13 mL, 130 mmol) and water is stirred for 4 hours at 70° C., cooled, acidified to pH 4 with hydrochloric acid and filtered to afford the title product as an off-white solid (4.94 g, 98.4%), mp 224°-226° C.
Reaction SMILES: [CH:1]1(N)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:8]([C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[N+:26]([O-:28])=[O:27])[C:16](=[O:29])[C:15]=2[CH:14]=[CH:13][CH:12]=1)([O-])=O>[N+](C1C=CC=CC=1)([O-])=O>[N+:26]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[C:23](=[O:25])[C:24]1[C:11]([NH:8][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]2=[O:29])([O-:28])=[O:27]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NC1CCCCC1
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2cccc(NC3CCCCC3)c2C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
175 ml of cyclohexylamine are added over the course of one hour to 300 g of 67% strength 1,8-dinitroanthraquinone in 1,200 ml of nitrobenzene at 175°-180°, the mixture is stirred for a further 15 minutes at the same temperature and then overnight until cold and the product is filtered off and washed with 200 ml of nitrobenzene and finally with a large amount of methanol until free of nitrobenzene. 187 g of 8-nitro-1-cyclohexylamino-anthraquinone of very good quality are obtained.
Reaction SMILES: Br[C:2]1[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][C:18]1[C:22]([C:23]2[CH:24]=[C:25](B3OC(C)(C)C(C)(C)O3)[C:26]3[NH:30][C:29](=[O:31])[NH:28][C:27]=3[CH:32]=2)=[C:21]([CH3:42])[O:20][N:19]=1.N12CCCN=C1CCCCC2.CS(C)=O>O>[CH3:17][C:18]1[C:22]([C:23]2[CH:24]=[C:25]([C:2]3[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[C:26]3[NH:30][C:29](=[O:31])[NH:28][C:27]=3[CH:32]=2)=[C:21]([CH3:42])[O:20][N:19]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Reactant: FC(F)(F)Oc1ccc2ncccc2c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(C)c1-c1cc(-c2c(OC(F)(F)F)ccc3ncccc23)c2[nH]c(=O)[nH]c2c1

Procedure:
A solution of 5-bromo-6-(trifluoromethoxy)quinoline (obtained by bromination of 6-trifluoromethoxyquinoline) (50 mg, 0.17 mmol), 6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (91 mg, 0.26 mmol), dichloro 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (12.7 mg, 0.02 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL, 1.37 mmol), DMSO (0.2 mL) and water (0.2 mL) under nitrogen was heated at 120° C. for 1 h. The reaction mixture was filtered and purified by reverse-phase HPLC to give 6-(3,5-dimethylisoxazol-4-yl)-4-(6-(trifluoromethoxy)quinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[N+:59]([C:62]1[CH:76]=[CH:75][C:65]([C:66]([O:68][CH2:69][CH2:70][CH2:71]CC=C)=[O:67])=[CH:64][CH:63]=1)([O-:61])=[O:60].[C:77]([OH:81])(C)([CH3:79])[CH3:78].O>CC(=O)OCC>[N+:59]([C:62]1[CH:76]=[CH:75][C:65]([C:66]([O:68][CH2:69][CH2:70][CH2:71][CH2:78][C@@H:77]([OH:81])[CH2:79][OH:22])=[O:67])=[CH:64][CH:63]=1)([O-:61])=[O:60]
Reactant: CC(C)(C)O
Reactant: C=CCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCCCC[C@@H](O)CO)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of AD-mix-beta (34 g) in t-BuOH—H2O (1:1, 0.077 M) at 0° C., was added hex-5-en-1-yl 4-nitrobenzoate (6 g, 24.07 mmol). The reaction was stirred at 0° C. overnight. The reaction mixture was diluted with 250 mL of EA, quenched by addition of 10 g of sodium metabisulfite and stirred 30 min at 0° C. The mixture was allowed to stir at rt for 1 h then was extracted 3 times with EtOAc, washed with brine, dried over Na2SO4, filtered and evaporated. The compound was recrystallized with ether and stirred in the cold room overnight for twice to afford 3.3 g of the titled compound as a white solid (greater than 99% in e.e. by Mosher derivatives analysis). 1H NMR (500 MHz, acetone-d6): δ 8.36 (d, 2H), 8.27 (d, 2H), 4.38 (t, 2H), 3.62-3.54 (m, 3H), 3.49-3.45 (m, 1H), 3.41-3.35 (m, 1H), 1.87-1.77 (m, 2H), 1.69-1.62 (m, 1H), 1.59-1.49 (m, 2H), 1.46-1.40 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1c[nH]nn1
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2nccn2)cc1
Yield: 66.4 %

Procedure:
4-Fluoronitrobenzene (21 g) was reacted with 1H-1,2,3-triazole (12.4 g) in the same manner as in Reference Example 9. The resultant was cooled and poured into water. The precipitated crystals were collected by filtration and purified by silica gel chromatography (eluent:dichloromethane to dichloromethane/acetone=8/1). The first eluted fraction was recrystallized from dichloromethane-diisopropyl ether to give 2-(4-nitrophenyl)-2H-1,2,3-triazole (18.8 g) as pale yellow prisms.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: O=Cc1ccco1
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
3-(4-Amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.229 mmol), 2-furaldehyde (0.027 mL, 0.321 mmol), sodium triacetoxyborohydride (193 mg, 0.916 mmol) and glacial acetic acid (55 mg, 0.916 mmol) were mixed with 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol/ammonium hydroxide (95:5:0.2) as mobile phase to give 3-{4-[(2-furylmethyl)amino]-3-methoxyphenyl}-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (57 mg, 48%). 1H NMR (DMSO-d6) 6 1.45 (m, 2H), 1.71 (m, 2H), 1.87 (m, 4H), 2.14 (s, 3H), 2.28 (m, 5H), 2.80 (m, 2H), 3.01 (m, 2H), 3.86 (s, 1H), 4.37 (d, J=3.13, 1H), 6.76 (d, J=8.62, 1H), 7.07 (m, 2H), 7.57 (s, 1H), 8.19 (s, 1H). LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+ 517.3, Rt=2.28 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2C(=C[CH:12]=1)[C:9](=O)[CH2:8][CH2:7]2)([O-:3])=[O:2].[BrH:14].BrBr.[C:17]([OH:20])(=O)[CH3:18]>>[Br:14][CH:9]1[CH2:8][C:7]2[C:18](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:17]1=[O:20]
Reactant: Br
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)O
Agent: BrBr
Product: O=C1c2cc([N+](=O)[O-])ccc2CC1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.1 g (0.04 mol) of 5-nitroindan-1-one are dissolved in 135 ml of glacial acetic acid, and 1.12 ml of 48 percent hydrobromic acid solution are added. Then 2.06 ml of bromine in 40 ml of glacial acetic acid are added dropwise at room temperature to the solution, which is then stirred for 2 h. The reaction mixture is poured into ice-water and extracted with dichloromethane and, after drying, the solvent is removed from the organic phase in vacuo. The residue is purified by column filtration (silica gel; dichloromethane). 2-Bromo-6-nitroindan-1-one is obtained with a melting point of 113° C.
Reaction SMILES: [CH3:1][C:2]1(O)[S:12][C:5]2=[N:6][CH:7]=[C:8]([CH3:11])[C:9](=[O:10])[N:4]2[CH:3]1[CH3:13].[C:15](=[O:18])([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31](CBr)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:15][O:18][C:7]3[N:6]=[C:5]4[S:12][C:2]([CH3:1])=[C:3]([CH3:13])[N:4]4[C:9](=[O:10])[C:8]=3[CH3:11])=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1cnc2n(c1=O)C(C)C(C)(O)S2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1sc2nc(OCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c(C)c(=O)n2c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
To a solution of 2,3,6-trimethyl-2-hydroxy-5H-thiazolo [3,2-a]pyrimidin-5-one (382 mg) and potassium carbonate (357 mg) in DMF (10 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (581 mg) and the mixture was stirred at 80° C. for 2 hours. This reaction mixture was concentrated and the residue was diluted with water-ethyl acetate and extracted with ethyl acetate. Recrystallization from ethyl acetate gave the title compound as colorless solid (266 mg).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23](O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Br:1][C:2]1[C:11]([CH2:12][O:13][C:21]2[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=2[CH3:26])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1O
Reactant: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CO)c21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A mixture of 7-bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1, 805 mg, 2.69 mmol), 5-fluoro-2-methylphenol (382 μL, 3.50 mmol), and tri-n-butylphosphine (874 μL, 3.50 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), 1,1′-(azodicarbonyl)dipiperidine (883 mg, 3.50 mmol) was added thereto, and then the mixture was stirred at room temperature for 1 hour. 5-Fluoro-2-methylphenol (382 μL, 3.50 mmol), tri-n-butylphosphine (874 μL, 3.50 mmol), and 1,1′-(azodicarbonyl)dipiperidine (890 mg, 3.53 mmol) were added thereto and it was furthermore stirred for 20 minutes. After hexane (15 mL) was added to the reaction mixture and the precipitated solids were filtered out, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (900 mg) as a colorless solid. (Yield 82%)
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH:33]C(=O)C(F)(F)F)[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[OH-].[Na+].O.Cl>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Yield: 47.5 %

Procedure:
A solution of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g.) in a 0.1N aqueous solution of sodium hydroxide (10.5 ml.) was warmed at 45° C. for 6 hours. Water (15 ml.) and ethyl acetate (30 ml.) were added to the reaction mixture and the resulting mixture was adjusted to pH 3.5 with 10% hydrochloric acid. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 5.0 with an aqueous solution of sodium bicarbonate. The aqueous solution was subjected to column chromatography on Amberlite XAD-2 (20 ml.)(prepared by Rohm & Haas Co.) using 10% ethanol as developing solvent. The eluate containing object compound was collected and lyophilized to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.12 g.).
Reaction SMILES: [CH:1]1([C:6]([OH:34])([CH2:24][C:25]2[O:26]C(C)(C)O[C:29](=[O:31])[CH:30]=2)[C:7]#[C:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17]#[N:18])=[C:11]([F:23])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17]#[N:18])=[C:11]([F:23])[CH:10]=3)[CH2:24][C:25](=[O:26])[CH2:30][C:29](=[O:31])[O:34]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(C#N)(CC)c1c(F)cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: CCC(C#N)(CC)c1c(F)cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F

Procedure:
The desired product was prepared analogously to Example A (97), step 4, substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluorophenyl}-2-ethyl-butyronitrile (3.11 g, 6.55 mmol) from Step 2 below in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. Yield: 1.52 g, 56%. 1H NMR (CDCl3) δ: 1.03 (t, J=3.65 Hz, 6H), 1.18-1.29 (m, 2H), 1.38-1 42 (m, 1H), 1.60-1.82 (m, 4H), 1.92-2.09 (m, 5H), 2.23-2.29 (m, 3H), 2.63-2.80 (m, 4H), 3.45 (d, J=3.6 Hz, 2H) 6.73 (d, J=10.8 Hz, 2H). MS (ESI): 416 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:35]2[CH2:34][CH2:33][N:32]([C:25]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:37][CH2:36]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c(N2CCNCC2)c1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(N2CCN(CC(O)COc3ccc(OCc4ccccc4)cc3)CC2)c1
Yield: 33.9 %

Procedure:
2.56 g of 1-(4-benzyloxyphenoxy)-2,3-epoxypropane was dissolved in 100 ml of dioxane, and to this were added 2.95 g of 1-(2,5-dimethoxyphenyl)piperazine dihydrochloride and 3.5 ml of triethylamine and reaction and workup were carried out as in Example 1-A. The residue obtained was purified by column chromatography (silica gel, elution with ethyl acetate:hexane=1:1) to give 1.62 g of brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:14]([O:21][C:22]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:34][C:23]=1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.COCCOC>[CH2:14]([O:21][C:22]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:35]=[CH:34][C:23]=1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: O=C(OCc1ccccc1)c1ccc(-c2ccccn2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Water (1.1 mL), 2-bromopyridine (0.11 mL), sodium carbonate (0.21 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg) were added to a solution of ethylene glycol dimethyl ether (3.5 mL) of the obtained benzyl 2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, 2-bromopyridine (0.11 mL), sodium carbonate (0.21 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.18 g of benzyl 2-(benzyloxy)-4-(pyridin-2-yl)benzoate.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[N:31]=[C:32]=[O:33]>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[NH:31][C:32]([NH:10][C:9]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)=[O:33]
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2c(Cl)cccc2Cl)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyaniline (1 g) and triethylamine (0.69 mL) in dry dichloromethane (20 mL) is treated dropwise at 0-5° C. with a solution of 2,6-dichlorophenyl isocyanate (0.9 g) in dry dichloromethane (10 mL). The resulting mixture is stirred for 30 minutes at this temperature and then for 6 hours at room temperature. The precipitate which forms is collected and stirred with isopropanol (50 mL), with ice cooling. The resulting solid is collected and dried, to give N-(2,6-dichlorophenyl)-N'-(3-cyclopentyloxy-4-methoxyphenyl)urea (1.06 g), m.p. 203-204° C. [Elemental analysis: C,57.2; H,5.0; N,7.0; Cl,18.2%; calculated: C,57.7; H,5.1; N,7.1; Cl,18.0%].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([Cl:15])[C:11]=1[O:12][CH2:13][CH3:14])[NH2:8].[C:16](Cl)(Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([N:8]=[C:16]=[O:17])[CH:9]=[C:10]([Cl:15])[C:11]=1[O:12][CH2:13][CH3:14]
Reactant: O=C(Cl)Cl
Reactant: CCOc1c(Cl)cc(N)cc1OCCCl
Solvent: Cc1ccccc1
Product: CCOc1c(Cl)cc(N=C=O)cc1OCCCl
Temperature: 25 °C

Procedure:
3-(2-Chloroethoxy)-4-ethoxy-5-chloroaniline (2.50 g) in toluene (20 ml) was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-(2-chloroethoxy)-4-ethoxy-5-chlorophenyl isocyanate. The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and 1-butyn-3-ol (0.75 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give 1-methyl-2-propynyl N-[3-(2-chloroethoxy)-4-ethoxy-5-chlorophenyl]-carbamate (Compound No. 31) (3.27 g) in a yield of 91.6%.