Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[Cl:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[Cl:15].[Al+3].[Cl-].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:12]1[S:11][C:10]([Cl:9])=[C:14]([Cl:15])[CH:13]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Clc1ccsc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)C(=O)c1cc(Cl)c(Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
At 5-10° C., Chloro-oxo-acetic acid ethyl ester (5.43 ml, 48.7 mmol) was added to 2,3-Dichlorothiophene (5 g, 32.6 mmol). A solution of AlCl3 (6.49 g, 48.7 mmol) dissolved in nitromethane (13 ml) was added dropwise such that the internal reaction temperature did not rise above 10° C. After 1 hour, the reaction mixture was poured into ice water and extracted with CH2Cl2 (2×100 ml). The organic layer was washed with 10% NaHCO3 (2×50 ml), water (1×50 ml) and brine (1×50 ml). Drying (Na2SO4) and concentration provided a light orange solid that was purified by silica gel chromatography (EtOAc/hexane-gradient) providing 6.8 g (82%) of the subtitle compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:6]=1.COC(=O)CC1C=CC(C)=C(OC2C=CC(N)=CC=2CSCC(F)(F)F)C=1.[C:57](Cl)(=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])=[CH:15][C:14]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:6]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)Cc1ccc(C)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: COC(=O)Cc1ccc(C)c(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Product: COC(=O)Cc1ccc(C)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CSCC(F)(F)F)c1

Procedure:
Following the procedures described for Example 21, {4-methyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester was reduced to {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methyl-phenyl}-acetic acid methyl ester and then treated with pivaloyl chloride to provide {3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methyl-phenyl}-acetic acid methyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])(=O)C.O.NN.CCOC(C)=O.[Na+].[Cl-]>CO>[OH:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(=O)OCc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of 14.1 g (47.7 mmol, 1.00 eq.) of t-butyl 4-(acetoxymethyl)-3-nitrobenzoate in MeOH (200 mL) was added 27.0 mL (477 mmol, 10.0 eq.) of hydrazine hydrate (55% hydrazine). The resulting yellow solution was stirred at 25° C. for 4 hr. EtOAc (250 mL) and saturated aq. NaCl (85 mL) were added, and the organic layer collected after shaking. The organic layer was washed further with saturated aq. NaCl (2×85 mL, and then dried (MgSO4). Removal of volatiles in vacuo gave the product in 93% yield as yellow crystals. The reaction is represented in Scheme 5.
Reaction SMILES: [CH2:1]([S:3]([O:6][C:7]1[CH:11]=[C:10]([CH2:12][C:13]([OH:15])=O)[O:9][N:8]=1)(=[O:5])=[O:4])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C(Cl)Cl>[CH2:1]([S:3]([O:6][C:7]1[CH:11]=[C:10]([CH2:12][C:13]([Cl:17])=[O:15])[O:9][N:8]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Oc1cc(CC(=O)O)on1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)Oc1cc(CC(=O)Cl)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
650 mg of (3-ethanesulphonyloxyisoxazol-5-yl)acetic acid were dissolved in 7 ml of methylene chloride, 577 mg of phosphorus pentachloride were added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and the residual (3-ethanesulphonyloxyisoxazol-5-yl)acetyl chloride thus obtained was dissolved in 5 ml of methylene chloride. This solution was added to a solution of 300 mg of benzhydryl 7β-amino-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate and 207 mg of N,N-diethylaniline in 4 ml of methylene chloride. The reaction mixture was stirred in an ice bath for 1 hour and then the solvent was distilled off. The residue was dissolved in ethyl acetate and the solution was washed with, in turn, dilute aqueous potassium bisulphate, aqueous sodium chloride, aqueous sodium hydrogen carbonate and aqueous sodium chloride, and then dried over anhydrous magnesium sulphate. The solvent was distilled off and the residue was adsorbed on a silica gel preparative thin layer chromatograph and developed with a 1:1 by volume mixture of benzene and ethyl acetate. The portion having an Rf value of 0.63 was extracted with ethyl acetate. The solvent was distilled under reduced pressure from the extract to give 422 mg (100%) of the benzhydryl ester of the desired Compound No. 15.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([P:8](=[O:19])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.CCCCCC.CCOC(C)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:29][CH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([P:8](=[O:19])([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
A mixture of di(tert-butyl) (4-methylbenzoyl)phosphonate (10 g), NBS (8.3 g), NaHCO3 (10 g) and benzoyl peroxide (0.1 g) in 200 mL of CCl4 was heated to reflux for 20 min. The mixture was cooled to room temperature, diluted with 200 mL of 10:1 hexane/EtOAc and filtered through a pad of silca gel. The filtrate was concentrated and the residue was swished from hexane to give 2.8 g of the title compound as a beige solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:9]([O:16][CH2:17][CH3:18])(=[O:15])[C:10]([O:12]CC)=O>CCOCC>[C:1]1([NH:8][C:10](=[O:12])[C:9]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:10](=[O:12])[C:9]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=1
Reactant: Nc1cccc(N)c1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)Nc1cccc(NC(=O)C(=O)OCC)c1

Procedure:
A mixture of m-phenylenediamine (10.8 grams) 0.10 ml.) and diethyl oxalate (50 ml.) is refluxed for 2.5 hours. The cooled reaction mixture is diluted with ether (200 ml.) and the crude product collected (19.2 grams, M.P. 150° C.). Two recrystallizations from methanol give off white crystals (6.65 grams, 155°-160°).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][C:6]=2[CH3:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22]/[CH:23]=[CH:24]/[CH2:25][CH3:26]>CN(C)C=O>[CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH2:22]/[CH:23]=[CH:24]/[CH2:25][CH3:26])[CH:8]=[CH:7][C:6]=2[CH3:13]
Reactant: CC/C=C/CBr
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC/C=C/COc1ccc(C)c2[nH]c(=O)c(C)cc12
Yield: 25.6 %

Procedure:
3,8-Dimethyl-5-hydroxycarbostyril (1.72 g, 9.1 mmol), potassium carbonate (2.51 g, 18.1 mmol), E-1-Bromo-2-pentene (2.0 g, 13.4 mmol) and dimethylformamide (30 ml) were allowed to react at 60° C. for 1 hour. After the completion of the reaction, the procedure described in Reference Example 31 was followed to obtain 0.60 g of the title compound as a colorless solid (25.6%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]([CH3:22])[CH3:21])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[O:44][CH3:45])[N:40]=[CH:39][N:38]=[C:37]2[O:46][C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:50][C:49]2[CH:51]=[CH:52][CH:53]=[C:47]([O:46][C:37]3[C:36]4[C:41](=[CH:42][C:43]([O:44][CH3:45])=[C:34]([O:33][CH3:32])[CH:35]=4)[N:40]=[CH:39][N:38]=3)[CH:48]=2)=[O:19])[N:7]([CH:20]([CH3:21])[CH3:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C(C)C)c3)c2cc1OC
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.50 mmol), N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isopropyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (62 mg, 40%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 7.55-7.59 (m, 2H), 7.37-7.40 (m, 2H), 7.24 (m, 1H), 6.93 (m, 1H), 6.00 (s, 1H), 4.35 (m, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 1.34 (d, J=6.4 Hz, 6H), 1.24 (s, 9H); LC-MS (ESI) m/z 505 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]1.[Cl:10][C:11]1[C:16]([CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[C:15](Cl)[N:14]=[CH:13][N:12]=1.C(N(CC)CC)C>C(O)CCC>[Cl:10][C:11]1[N:12]=[CH:13][N:14]=[C:15]([NH:1][C@H:2]2[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]2)[C:16]=1[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOC(Cc1c(Cl)ncnc1Cl)OCC
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)C1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCOC(Cc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)C1)OCC
Yield: 85.2 %

Procedure:
A solution of (1S,2R,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (0.485 g, 3.69 mmol) (Ho, J. Z.; Mohareb, R. M.; Anh, J. H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003, 68, 109-114), 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (0.392 g, 1.48 mmol) (Montgomery, J. A.; Hewson, K. J. Med. Chem. 1967, 10, 665-667) and triethylamine (0.30 mL, 2.22 mmol) in butanol (4 mL) was microwave irradiated at 150° C. for 450 seconds. The solution was concentrated and purified by flash chromatography (100% EtOAc) to give the title compound (0.454 g, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([CH3:30])=[C:19]([CH2:25][C:26]([O:28]C)=[O:27])[C:20](=[O:24])[O:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].Cl>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([CH3:30])=[C:19]([CH2:25][C:26]([OH:28])=[O:27])[C:20](=[O:24])[O:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)Cc1c(C)c2ccc(NS(=O)(=O)c3ccc([N+](=O)[O-])cn3)cc2oc1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c(=O)oc2cc(NS(=O)(=O)c3ccc([N+](=O)[O-])cn3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 2b was dissolved in THF (4 ml), lithium hydroxide•monohydrate (24.4 mg, 0.58 mmol, 7.4 equivalents) dissolved in H2O (4 ml) was added under cooling on ice, and the mixture was stirred. After 30 min, the reaction mixture was warmed to room temperature and further stirred. After 3 hr, the disappearance of the starting materials was confirmed by TLC and the reaction mixture was acidified with 5% HCl and extracted with CHCl3. The organic layer was washed with saturated brine, and dried over Na2SO4. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluate: 1% acetic acid-containing CHCl3:MeOH=20:1) (compound 3b: 29.9 mg, 0.07 mmol, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:35][C@@H:34]([OH:36])[C:33]([CH3:38])([CH3:37])[CH2:32]2)[N:3]=1>CC(O)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:35][C@@H:34]([OH:36])[C:33]([CH3:38])([CH3:37])[CH2:32]2)[N:3]=1
Reactant: CC1(C)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)C[C@H]1O
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1294 g, 0.232 mmol) in 4:1 HOAc-water (5 mL) was heated at 30° C. and stirred overnight. The solution was cooled to room temperature, concentrated in vacuo, and purified directly by Gilson RPLC to give [(2R)-3-(2-{2-chloro-5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (69.1 mg, 63% yield) as a yellow solid. LCMS: (M+H)+: 473.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8](=[O:13])[CH2:9][C@@H:10]([OH:12])[CH:11]=1)=[O:5])[CH3:2].N1C=CN=C1.[CH2:19]([Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])Cl)[CH3:20]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8](=[O:13])[CH2:9][C@@H:10]([O:12][Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:19][CH3:20])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CC1=C[C@H](O)CC1=O
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1=C[C@H](O[Si](CC)(CC)CC)CC1=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
25 g of (R)-2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-1-one (5 g, 98% e.e.) was dissolved in ethyl acetate and the solution was placed in a nitrogen purged flask. Imidazole (13.87 g, 204 mmol) was added. The solution was cooled to 0° C. and triethylchlorosilane (26.6 g, 176 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for another 15 hours. After filtration, the filtrate was washed with a saturated sodium bicarbonate solution and a brine solution, respectively, dried over anhydrous magnesium sulfate, and concentrated to obtain the titled compound (38.5 g, 95%). [α]D: +27.8° (c 1.0, CH3CN).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:18][C:19]([O:21][CH2:22][C@H:23]1[O:28][C@H:27](Br)[C@H:26]([O:30][C:31]([CH3:33])=[O:32])[C@@H:25]([O:34][C:35]([CH3:37])=[O:36])[C@@H:24]1[O:38][C:39]([CH3:41])=[O:40])=[O:20].[OH-].[Na+]>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[C:31]([O:30][C@@H:26]1[C@@H:25]([O:34][C:35](=[O:36])[CH3:37])[C@H:24]([O:38][C:39](=[O:40])[CH3:41])[C@@H:23]([CH2:22][O:21][C:19](=[O:20])[CH3:18])[O:28][C@H:27]1[O:17][C:10]1[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[C:13]([CH:14]([CH3:15])[CH3:16])[NH:12][N:11]=1)(=[O:32])[CH3:33]
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(Br)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a suspension of 4-[(4-bromophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (5.0 g) in dichloromethane (50 mL) were added acetobromo-α-D-glucose (7.0 g), benzyltri(n-butyl)ammonium chloride (5.3 g) and 5 mol/L aqueous sodium hydroxide solution (8.5 mL), and the mixture was stirred at room temperature overnight. The organic layer was separated, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (4.12 g).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O-:19])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2].[Na+].[C:28]([O:34][CH2:35]I)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O:19][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 1.5 h

Procedure:
To a solution of 38.1 mg of sodium (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 3 ml of DMF was added 0.021 ml of pivaloyloxymethyl iodide under the atmosphere of argon at −30° C., and the mixture was stirred for 1.5 hours. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with 20 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 3 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) and on Sephadex LH-20 (chloroform:methanol=1:1) in this sequence to give 35.8 mg of the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][C:4]1[CH:3]=[N:2][N:1]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:5]=1
Reactant: BrBr
Reactant: O=C(O)Cc1ccc(-n2cccn2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1ccc(-n2cc(Br)cn2)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
20.2 g (100 mmoles) of 4-(pyrazol-1-yl)phenylacetic acid are dissolved in 400 ml of carbon tetrachloride. 16 g of bromine (200 mmoles) in 400 ml of carbon tetrachloride are added dropwise, with ice cooling, to the resulting solution. After subsequent stirring for half an hour at room temperature, washing with sodium dithionite solution is effected; this is followed by drying with sodium sulfate and, finally, by evaporation to dryness to obtain 27.5 g (98% of theory) of 4-(4-bromo-pyrazol-1-yl)phenylacetic acid, m.p. 187° C. (from acetonitrile).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[C:11]([CH2:30][CH2:31][CH2:32][CH3:33])[N:10]=[C:9]1[CH2:34]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:46])CCOC.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[C:11]([CH2:30][CH2:31][CH2:32][CH3:33])[N:10]=[C:9]1[CH2:34][F:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCCCc1nc(CO)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nc(CF)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
4′-{[1-Benzyl-4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.86 g) was dissolved in dichloromethane (20 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (0.34 mL) was added −78° C. The mixture was stirred at 0° C. for 3 hr, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.35 g, 41%) as a colorless liquid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:35]([C:34]3[CH:38]=[CH:39][C:31]([C:30]([O:29][CH3:28])=[O:40])=[CH:32][CH:33]=3)=[O:36])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)c(-c2ccccc2)nn3C(C)=O)cc1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a flask containing 1-acetyl-5-amino-3-phenyl-1H-indazole (300 mg, 1.2 mmol) was added dichloromethane (10 mL), 4-(dimethylamino)pyridine (75 mg, 0.6 mmol) and triethylamine (180 mg, 1.8 mmol). The mixture was allowed to stir for ten minutes. Terephthalic acid monomethyl ester hydrochloride (285 mg, 1.44 mmol) was then added and stirring continued for 18 hours. The mixture was quenched with 5% sodium bicarbonate and extracted with dichloromethane. The extracts were dried using sodium sulfate, filtered and condensed to give a solid. The solid was recrystallized in ethanol to give the title compound (368 mg, 75% yield). ES-MS (m/z) 414 [M+1]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C[O-].[Na+].[I-].[K+].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>CO.C1C=CC=CC=1.O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccc(NC(C)=O)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 3.78 g of p-acetamidophenol, 1.1 g of sodium methoxide, and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 15 ml of benzene. The mixture is refluxed for 20 hours, poured into ice and water and extracted with chloroform. The chloroform extracts are washed with 10% potassium carbonate and with water. The extract is dried over magnesium sulfate and concentrated to a gum under vacuum. Petroleum ether is added to the residue and several ml of acetone. Scratching the flask gives crystals which are filtered to give the product as pink crystals, mp 152°-157° C. The crystals are dissolved in a minimum amount of hot acetone, the solution chilled and diluted with petroleum ether. Chilling and filtering gives pale pink crystals mp 157°-160° C.