Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=1)=[CH:5]/[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+]>C(O)C>[CH:7]1([CH2:6]/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]([CH3:23])=[N:21][N:20]=[N:19]3)=[C:14]([C:24]([F:25])([F:27])[F:26])[CH:13]=2)/[C:3]([OH:28])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)/C(=C/CC1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 47.5 °C
Yield: 99.3 %

Procedure:
A solution of (E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid methyl ester (359 mg, 0.9 mmol) in ethanol (5 mL) was treated with a 1N aqueous sodium hydroxide solution (3 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (20 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid (340 mg, 98%). as a yellow solid: EI-HRMS m/e calcd for C18H19F3N4O2 (M+) 380.1460, found 380.1460.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[S:12])([O-:3])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[N:13][C:14](=[O:16])[CH3:15])[S:12][CH3:17])([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC(=S)Nc1ccccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=NC(C)=O)Nc1ccccc1[N+](=O)[O-]
Yield: 42 %

Procedure:
6.5 g (0.026 M) of N-(o-nitrophenyl)-N'-acetyl-thiourea, 2.1 g (0.015 M) of potassium carbonate, 1.9 ml (0°-0.29 M) of methyl iodide and 70 ml of acetone are boiled in a reflux for four hours. The acetone is distilled off. Water is added to the residue and it is filtered. After drying 6.6 g (100% of the theoretical yield) of the product are obtained with a melting point of 118°-160°. After recrystallization twice from ethanol and isopropanol N-(o-nitrophenyl)-N'-acetyl-S-methylisothiourea with a melting point of 120°-122° C. and 42% yield of the theoretical one is obtained.
Reaction SMILES: CC1[N:3]([C:8]2[CH:18]=[C:11]3[CH:12]([CH3:17])[N:13]([CH3:16])[CH2:14][CH2:15][N:10]3[N:9]=2)C(C)=CC=1.NO.Cl>C(O)C>[CH3:17][CH:12]1[N:13]([CH3:16])[CH2:14][CH2:15][N:10]2[N:9]=[C:8]([NH2:3])[CH:18]=[C:11]12
Reactant: Cc1ccc(C)n1-c1cc2n(n1)CCN(C)C2C
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC1c2cc(N)nn2CCN1C
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 287h (1.63 g, 1.0 eq., 6.70 mmol), NH2OH.HCl (2.33 g, 5.0 eq., 33.5 mmol), and ethanol (50 mL). The mixture was refluxed for 2 days. It was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 287i as a yellow solid (211 mg, 19%). MS-ESI: [M+H]+ 167.1. 1H NMR (500 MHz, CDCl3) δ 5.36 (s, 1H), 4.04-4.00 (m, 1H), 3.94-3.92 (m, 1H), 3.61 (bs, 2H), 3.30 (q, J=6.5 Hz, 1H), 3.10-3.08 (m, 1H), 2.81-2.75 (m, 1H), 2.43 (s, 3H), 1.38 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>>[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:17]=1[C:22](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]2=[O:20]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c(F)cccc21
Product: CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.25 g, 28%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 3-fluorophthalic anhydride (0.57 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)C.[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27].C(O)(=O)C>N>[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Cl
Agent: N
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Nc1ccc(F)cc1F
Temperature: 75 °C
Yield: 87.9 %

Procedure:
To a 50 mL round bottom flask charged with a magnetic stir bar and ethyl 4-chloro-6,7-dimethoxycinnoline-3-carboxylate (0.200 g, 0.675 mmol) (Method 7) was added anhydrous ethanol (10 mL), 2,4-difluoroaniline (0.087 g, 0.675 mmol), and glacial acetic acid (˜100 μL). The reaction mixture was then heated to 75° C. for 1 h, cooled to rt, and diluted with concentrated aqueous ammonia (˜5 mL). The crude product precipitated from this reaction mixture and was collected via vacuum filtration using a Buchner funnel. The solid was washed water (1×100 mL) and diethyl ether (1×100 mL) to yield the crude product which was purified on 40 g silica using EtOAc as eluent providing 0.231 g (88%) of the title compound as a yellow solid. 1H NMR: 9.25 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.10 (m, 1H), 4.02 (s, 3H), 3.95 (q, 2H), 3.85 (s, 3H), 1.20 (t, 3H); m/z 390.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:25][C:18]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:24]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccccc1
Reactant: Nc1ccccc1N
Solvent: CCO
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Yield: 69.7 %

Procedure:
8.2 g (29 mmol) of 1-(4-bromophenyl)-2-phenylethanedione, 3.1 g (31 mmol) of o-phenylenediamine, and 100 mL of ethanol were placed into a 300-mL flask, and the mixture was refluxed for 2 hours. After the reaction, the precipitated solid was collected by suction filtration. The collected solid was washed with ethanol and dried. 7.3 g of a light-yellow solid was obtained as the target substrate in 69% yield.
Reaction SMILES: [OH:1][C@@H:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Si:20]([O:1][C@@H:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: C[C@H](O)C(=O)N1CCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a solution of 108 (41.1 g, 287.0 mmol), imidazole (29.31 g, 430.6 mmol), and DMAP (3.507 g, 28.70 mmol) in DMF (100 mL) was added slowly tert-butylchlorodimethylsilane (54.08 g, 358.8 mmol) and the reaction was stirred at RT for 18 h. Water was added and mixture was extracted with Et2O. The organic layer was dried, filtered, and concentrated. The resulting residue was purified by passing through a SiO2 plug eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 56.93 g (77.04%) of (S)-2-(tert-butyldimethylsilyloxy)-1-(pyrrolidin-1-yl)propan-1-one (110).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH:34]([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-dimethylpropyl]-3-pyridinecarboxamide (Intermediate 19, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-dimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC(C)C)=O.C([N:27](CC)CC)C.N>ClCCl.CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([NH2:27])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-Nitrophenoxy)isobutyric acid (5 g), isobutyl chloroformate (4.36 mL) and triethylamine (8 mL) were stirred in dichloromethane (20 mL) at rt for 1 h. Then 2.0 μM ammonia in methanol (20 mL) was added to the solution. It was stirred at rt for 2 h and evaporated. The mixture was purified by recrystallization from EtOAc and hexanes to give 2-(4-nitrophenoxy)-2-methylpropanamide.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].CN.[CH2:27]([N:29](CC)CC)C>C(O)C>[CH3:21][C:20]([C:7]1[CH:8]=[C:9]([C:11]2[S:12][C:13]([NH:29][CH3:27])=[N:14][N:15]=2)[CH:10]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:6]=1[OH:24])([CH3:22])[CH3:23]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Agent: CN
Solvent: CCO
Product: CNc1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of 2,6-bis(1,1 dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]phenol (2.0 %, 0.0054 mole) in ethanol (10 ml) is added 25% ethanolic methylamine solution (15 ml), followed by triethylamine (0.6 g, 0.006 mole). The resulting mixture is heated to reflux for three hours. An additional amount of 25% ethanolic methylamine (15 ml) solution is added and the mixture is stirred overnight at reflux. The solution is cooled and the volatiles removed under reduced pressure. The residue is purified by flash chromatography (SiO2) using 30% ethyl acetate/hexane eluent. Recrystallize from ethyl acetate/hexane to obtain 0.8 g (1.7 g theor., 48%) of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylamino)-1,3,4-thiadiazol-2-yl]phenol, mp 207.5°-208° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[C:13](=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(C)c1N
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A solution of 60.8 g of 2-amino-3-methylbenzoic acid in 900 ml of dry methanol was saturated with anhydrous hydrogen chloride at 0°-10° C., then allowed to stand at room temperature overnight. Then it was refluxed for one hour, cooled to 5° C., resaturated with anhydrous hydrogen chloride, held overnight at room temperature and stripped of solvent. The residue was made neutral with saturated aqueous sodium bicarbonate solution, and extracted with methylene chloride. The extract phase was washed with saturated aqueous sodium bicarbonate solution, dried (MgSO4), filtered and stripped of solvent. The residue was distilled in a kugelrohr apparatus to give methyl 2-amino-3-methylbenzoate (49A), b.p.: 100°-105° C. (1Torr.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:25]=2[CH3:24])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1cccc(O)c1C
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,3-dimethylphenol: 1H-NMR (CDCl3) δ 8.56 (1H, d, J=3.0 Hz), 8.32 (1H, d, J=7.4 Hz), 8.11 (1H, d, J=2.8 Hz), 8.02–7.99 (2H, m), 7.43 (2H, d, J=8.4 Hz), 7.23–7.13 (2H, m), 6.95 (1H, d, J=7.7 Hz), 5.46–5.36 (1H, m), 3.90 (3H, s), 2.35 (3H, s), 2.05 (3H, s), 1.59 (3H, d, J=6.9 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:18]([CH3:20])[N:19]=2)=[C:11]([O:27][CH3:28])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:18]([CH3:20])[N:19]=2)=[C:11]([O:27][CH3:28])[CH:10]=1
Reactant: [H][H]
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc(C)c(-c2cccnc2)[nH]1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(O)ccc1-c1nc(C)c(-c2cccnc2)[nH]1
Reaction time: 5 h
Yield: 28 %

Procedure:
To a solution of 2-(4-benzyloxy-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.18 g) in methanol (12 ml) and tetrahydrofuran (6 ml) was added 10% palladium on carbon (wet ca. 50%, 0.30 g), and the mixture was stirred for 7 hours at ambient temperature under atmospheric pressure of hydrogen gas. The mixture was filtered, and the filtrate was evaporated. The residue was dissolved in methanol (20 ml), and hydrogenated again on palladium on carbon (wet, 0.50 g) for 5 hours. After the filtration, the filtrate was evaporated, and the residue was triturated in a mixture of diisopropyl ether and isopropanol (1:1 V/V) to give 2-(4-hydroxy-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.25 g).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[NH2:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1ccco1
Reaction time: 2 h

Procedure:
0.082 mL of triethylamine, 44 mg of 2-furoyl chloride and 2.0 mL of methylene chloride were added to 1.0 mL of methylene chloride solution containing 50 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 2 hours. 380 mg of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(furan-2-carboxamido)-4-phenethylbenzoate.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([NH:12][C@H:13]2[C@@H:19]([OH:20])[CH2:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([NH:12][C@H:13]2[C@H:19]([O:20][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:43][CH:42]=3)[CH2:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(OC(C)(C)C)cc2)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
262 mg of diethyl azadicarboxylate in 2 ml of tetrahydrofuran were added while stirring to 407 mg of the compound prepared in Example 16, 253 mg of 4-(tert-butoxy)-benzoic acid and 394 g of triphenylphosphine in 8 ml of tetrahydrofuran. After stirring at 50° C. for 4hours, the solvent was removed under reduced pressure and the residue was taken up in 20 ml of cyclohexane and washed once with 20 ml of water and twice with 10 ml of 70% methanol/water each time. The aqueous-alcoholic phase was extracted twice with 10 ml of cyclohexane each time. The combined cyclohexane phases were dried over sodium sulphate and the solvent was removed under reduced pressure. The residual viscous oil was dissolved in 10 ml of hot heptane, seeded with pure end product and left to crystallize at room temperature for 18 hours and yielded 241 mg of tert-butyl (3R,4R)-3-(4-tert-butoxy-benzoylamino)-4-(4-tert-butoxy-benzoyloxy)-azepan-1-carboxylate of melting point 126-128° C. This compound can be reacted further as in Example 12b.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[S:6][CH:7]=1>C(Cl)(Cl)Cl.CO.O=[Mn]=O>[O:13]=[C:9]1[N:8]([C:5]2[S:6][CH:7]=[C:3]([CH:2]=[O:1])[N:4]=2)[CH2:12][CH2:11][O:10]1
Reactant: O=C1OCCN1c1nc(CO)cs1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=Cc1csc(N2CCOC2=O)n1

Procedure:
MnO2 (7.2 g; 83.6 mmol) was added to a solution of 3-(4-hydroxymethylthiazole-2-yl)oxazolidin-2-one (0.56 g; 2.8 mmol), prepared as described in the above step, in chloroform (60 ml) and methanol (6 ml).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:23]([O:25][CH:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:23]([O:25][CH:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Temperature: 35 °C
Yield: 91 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methylthiomethyl-3-cephem-4-carboxylate (syn isomer) (8.0 g) in methanol (160 ml) was added conc. hydrochloric acid (5.6 ml), and the mixture was stirred at 35° C. for an hour. The resultant solution was adjusted to pH 5.0 with a saturated aqueous sodium bicarbonate. After distilling methanol under reduced pressure, the residue was dissolved in water (100 ml) and ethyl acetate (200 ml). The ethyl acetate layer was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was removed by filtration to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methylthiomethyl-3-cephem-4-carboxylate (syn isomer) (7.0 g), mp 140°-145° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:16])=[C:6]([CH:12]=[CH:13][C:14]=1[F:15])[O:7][CH2:8][C:9]([OH:11])=[O:10])=[O:3].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]([C:4]1[C:5]([F:16])=[C:6]([CH:12]=[CH:13][C:14]=1[F:15])[O:7][CH2:8][C:9]([O:11][CH2:6][CH2:5][CH2:4][CH2:14][CH2:13][CH3:12])=[O:10])=[O:3]
Reactant: NC(=O)c1c(F)ccc(OCC(=O)O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOC(=O)COc1ccc(F)c(C(N)=O)c1F
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 120.8 %

Procedure:
n-Bromohexane (0.077 ml, 0.55 mmol, 1.05 equiv.) was added to a suspension of 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetic acid (120 mg, 0.52 mmol, 1 equiv.) and K2CO3 (215 mg, 1.56 mmol, 3 equiv.) in DMF (3 ml) and the mixture was stirred at 70° C. for 1.5 h. After cooling at r.t., the mixture was poured into water (25 ml) and the precipitant solid was filtered and washed with water (2×20 ml). After drying, the crude solid was triturated by stirring in hexane (10 ml), filtered and washed with hexane (3×10 ml), to give the desired compound as a white solid (99 mg, 60%), mp 108° C. HPLC-MS: m/z 316 [M+H]+, Rt=4.09 min.