Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:46])([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)/[CH:15]=[CH:16]/[C@@H:17]1[C@@H:29]2[C@@H:20]([O:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH2:28]2)[CH2:19][C@H:18]1[O:31]C1CCCCO1>CO>[F:46][C:14]([F:13])([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)/[CH:15]=[CH:16]/[C@@H:17]1[C@@H:29]2[C@@H:20]([O:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH2:28]2)[CH2:19][C@H:18]1[OH:31]
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: CO
Solvent: O
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-toluenesulfonic acid monohydrate (10.37 g, 54.5 mmol) was add to a stirred solution of (8aR,9R,10R,11aS,Z)-9-((E)-3,3-difluoro-4-phenoxybut-1-en-1-yl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-4,5,8,8a,9,10,11,11a-octahydrocyclopenta[b]oxecin-2(3H)-one (26.0 g from example 33) in methanol (200 mL). The mixture was stirred for 2 hr at room temperature (TLC monitoring). Then, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (300 mL), and the methanol was removed under reduced pressure. The residue was extracted with ethyl acetate (200 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 30.0 g of crude product. The crude product was purified by column chromatography providing 20.0 g of the titled compound (90.0% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9](B(O)O)[S:8][C:7]=2[CH:14]=1.[C:15]([O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Na+].[Na+].[Al]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:9]2[S:8][C:7]3[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)=[CH:22][CH:21]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1ccc2cc(B(O)O)sc2c1
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3ccc(OC(C)(C)C)cc3)sc2c1
Temperature: 25 °C

Procedure:
A solution of 6-methoxybenzo[b]thiophene-2-boronic acid (8.87 g, 42.6 mmol) and 4-tert-butoxybromobenzene (U.S. Pat. No. 540,851; 10.25 g, 44.7 mmol) in 400 mL of THF was treated with Pd(PPh3)4 (1.9 g, 1.64 mmol) and 45 mL of 2 N aqueous Na2CO3. The reaction vessel was covered with aluminum foil to keep out light, and the mixture was heated at reflux overnight. After cooling to ambient temperature, the layers were separated, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by PrepLC (SiO2; 5% THF in hexanes) to give 8.8 g (28.2 mmol; 66%) of the title product as a white powder.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:21])([CH3:20])[CH2:14][CH2:15][C:16]2=[O:19])=[CH:11][CH:10]=1>C1C=CC=CC=1.[Zn]>[OH:19][C:16]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([Br:8])[CH:18]=2)[C:13]([CH3:21])([CH3:20])[CH2:14][CH2:15]1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: CCOC(=O)CBr
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(Br)cc21
Temperature: 25 °C

Procedure:
To a suspension of Zn (1.20 g, 18.4 mmol) in 10 mL benzene at 100° C. was slowly added a solution of ethyl 2-bromoacetate (658.0 mg, 3.94 mmol) and 3,4-dihydro-4,4-dimethyl-7-bromo-naphthalen-1(2H)-one (Compound G, 500.0 mg, 1.97 mmol) in 20.0 mL benzene. The resulting mixture was heated for 2 h, cooled to room temperature, and the solution decanted from the residual solids. The solids were washed with EtOAc and the combined organic layers were washed with cold 15% H2SO4, saturated aqueous NaHCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents undr reduced pressure and column chromatography (10% EtOAc-hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]([NH:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][C@@:6]([NH:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH2:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@](C)(CCc1ccc(C#CCCCc2ccccc2)o1)COC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@](C)(CCc1ccc(CCCCCc2ccccc2)o1)COC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a suspension of 10% palladium-charcoal (50% wet with water) (25 mg) in methanol (1 ml) was added a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[5-(5-phenylpent-1-ynyl)furan-2-yl]butane (0.1245 g, 0.32 mmol) obtained in Example (1a) in methanol (1.5 ml), and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. After stirring, the internal atmosphere was replaced with nitrogen, and the palladium-charcoal in the reaction mixture was filtered off using celite, which was washed with ethyl acetate. The filtrate and the washings were combined and evaporated to dryness in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:2) as the eluent to afford the title compound (0.1029 g, yield: 82%).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N+:20]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl)([O-:22])=[O:21]>C(O)C>[N+:20]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:19])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CCO
Product: NCCCCCCCCCCCCCCCCCCCc1ccccc1[N+](=O)[O-]
Reaction time: 72 h

Procedure:
Octadecylamine (13.5 g, 0.05 mol) was dissolved in warm absolute ethanol (300 ml) and 2-nitrobenzyl chloride was added. After three days at room temperature, the mixture was cooled and the unreacted octadecylamine which crystallized was removed by filtration. The filtrate was evaporated to dryness and the residue dissolved in dilute aqueous hydrochloric acid. Ether extraction of the acidic solution removed unreacted 2-nitrobenzyl chloride. The aqueous layer was made basic with potassium hydroxide solution and the resulting mixture was extracted with ether. The dried ether layer was evaporated to yield an oil which crystallized. Crystallization from methanol gave pure product (0.8 g, m.p. 53°-56° C.).
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH:16]=O)[CH:11]=[C:12]([F:14])[CH:13]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:16]=[C:15]([C:10]2[CH:11]=[C:12]([F:14])[CH:13]=[C:8]([Cl:7])[CH:9]=2)[N:4]=1
Reactant: O=CC(=O)c1cc(F)cc(Cl)c1
Reactant: CSC(=N)NN
Product: CSc1nncc(-c2cc(F)cc(Cl)c2)n1
Yield: 38.6 %

Procedure:
3-(methylsulfanyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16 g, 38.4%) was prepared from methyl hydrazinecarbimidothioate (25.5 g, 243 mmol) and 2-(3-chloro-5-fluorophenyl)-2-oxoacetaldehyde (30 g, 162 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[N+:8]([C:11]1[N:16]=[CH:15][C:14]2[CH:17]=[CH:18][O:19][C:13]=2[C:12]=1[OH:20])([O-:10])=[O:9].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:45])[N:34]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:35]=[CH:36][CH:37]=2)=[O:31])=[CH:25][CH:24]=1>O>[N+:8]([C:11]1[N:16]=[CH:15][C:14]2[CH:17]=[CH:18][O:19][C:13]=2[C:12]=1[O:20][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:45])[N:34]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH:35]=[CH:36][CH:37]=2)=[O:31])=[CH:25][CH:24]=1)([O-:10])=[O:9]
Reactant: O=C(Nc1ccc(CBr)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(COc2c([N+](=O)[O-])ncc3ccoc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Into a DMF (1.5 ml) suspension of NaH (11.0 mg, 60% suspension in oil, 0.275 mmol), which was cooled at 0° C. under an atmosphere of nitrogen, was added the DMF (1.5 ml) solution of 6-nitrofuro[3,2-c]pyridin-7-ol (Intermediate 7) (45.1 mg, 0.248 mmol) dropwise. The mixture was stirred at 0° C. for 5 min and was then raised to rt and stirred at rt for 30 min. Then this reaction mixture was added dropwise into the DMF (4 ml) suspension of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (4-bromomethylphenyl)-amide (0.248 mmol) at rt under an atmosphere of nitrogen. The combined mixture was stirred at rt for 1 h. After that time, the reaction mixture was poured into water. The solid was filtered off and washed with water to give a beige solid. It was triturated with EtOAc (4 ml). The solid was filtered off and the mother liquor was purified by TLC eluting with 2.5% MeOH/DCM 2 times to give the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=5.58 (s, 2H), 6.59 (dd, J=6.8 & 7.2 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.38-7.45 (m, 4H), 7.60 (dd, J=2.0 & 4.8 Hz, 1H), 7.73 (dd, J=2.4 & 6.8 Hz, 2H), 7.88 (d, J=2.0, 1H), 8.44 (s, 1H), 8.73 (dd, J=2.4 & 6.8 Hz, 1H), 11.84 (brs, 1H). MS (ES+): m/z 500.99 [MH+]. HPLC: tR=3.58 min (polar—5 min, ZQ3).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1I.[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:13]=[CH2:14]
Reactant: O=C1OCc2c1ccc(Br)c2I
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1c(Br)ccc2c1COC2=O

Procedure:
A mixture of 5-bromo-4-iodo-2-benzofuran-1(3H)-one (1 g, 2.95 mmol), potassium vinyltrifluoroborate (474 mg, 3.54 mmol) and Pd(dppf)Cl2 (200 mg) in 20 mL of TEA and 20 mL of EtOH was heated to reflux under N2 for 2 hours. TLC showed complete reaction. Most of the solvent was removed, and the residue was dissolved in EtOAc (100 mL). The solution was washed with 0.1 N HCl, sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated to provide 5-bromo-4-vinyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([Cl:18])=[CH:11][C:10]=2[Cl:19])=[C:4]([CH3:20])[N:3]=1>C(O)(=O)C.O=[Pt]=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([Cl:18])=[CH:11][C:10]=2[Cl:19])=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(N)nc(N)c1-c1cc(N)c(Cl)cc1Cl

Procedure:
2,4-diamino-5-(2,4-dichloro-5-nitrophenyl)-6-methylpyrimidine (4.80 g, 15 mmol) was dissolved in glacial acetic acid (18 ml). This solution and 10 mg of Adam's catalyst was stirred under an atmosphere of hydrogen at room temperature for 4 hours. The catalyst was filtered off and the acetic acid was evaporated. The colourless liquid obtained was dissolved in ethyl acetate and washed 3 times with water. After evaporating the ethyl acetate, a white solid was obtained (2.64 g, 9 mmol).
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:4]([O:6][CH3:7])=[O:5].[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>COCCOC>[CH3:15][O:1][CH:2]=[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=CO)c1ccccc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: COCCOC
Product: COC=C(C(=O)OC)c1ccccc1C
Temperature: 25 °C
Yield: 97 %

Procedure:
To a flask (1000 mL), 48 g of methyl 3-hydroxy-2-o-tolylacrylate, 54.4 g of potassium carbonate, and 500 mL of ethylene glycol dimethyl ether were added. The mixture was stirred at room temperature for an hour, and then 36 mL of dimethyl sulfate was added. The mixture was allowed to react for between 6 and 8 hrs with stiffing at room temperature. The reaction was monitored with thin layer chromatography (TLC) until the reactants were basically consumed. Subsequently, the mixture was filtered, the solvent was removed by vacuum distillation, the residue was washed with water (1000 mL), extracted with ethyl acetate (2×300 mL), dried with anhydrous sodium sulfate and concentrated under reduced pressure to yield a light yellow oily product with a yield of 97%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Cl:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[C:20](Cl)(=[O:22])[CH3:21].CN(C=O)C.CC(C)([O-])C.[K+]>O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:20](=[O:22])[CH3:21])[C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Cl:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.1 g of 3-acetoxy-4-chloro-10H-phenothiazine (see Example 4) was added acetyl chloride (7 ml), DMF (5 ml) and potassium tert-butoxide (0.42 g). The reaction mixture was stirred at ambient temperature for 1 hour and then, poured in water. The resulting precipitate was filtered and purified by chromatography on silica gel to give (1.08 g) 3-acetoxy-10-acetyl-4-chloro-10H-phenothiazine (m.p. 155° C.).
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C:5]3[C:10]([C@H:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3.S(=O)(=O)(O)O.C(#[N:18])C>>[NH2:18][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:1]
Reactant: CC#N
Reactant: c1ccc2c(c1)C[C@H]1O[C@@H]21
Agent: O=S(=O)(O)O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
Into a 200 ml four-neck flask, 9.24 g (70 mmol) of cis-(±)-1,2-epoxyindan (IV) and 35 ml of acetonitrile were introduced. While the mixture was stirred in cool, 10.62 g of 97% sulfuric acid was dropwise added thereto at 20°-25° C. in a period of 30 minutes. The reaction mixture was further stirred at room temperature for 1 hour. Then, acetonitrile was distilled off under reduced pressure. The remaining mixture was further stirred at 60° C. for 1 hour and then cooled to room temperature. Impurities were extracted off from the mixture with 20 ml and 10 ml of methylene chloride. An aqueous solution of 25% sodium hydroxide was added to the water phase to attain a pH of 11. The crystal deposited thereby was filtered off and then dried in vacuo to yield 4.76 g (raw yield: 45.7%) of cis-(±)-1-aminoindan-2-ol (V) as a grayish white crystal. From thus obtained crystal, 2 g was taken out and washed with 6 ml of acetonitrile at 10° C. The washed crystal was filtered off and then dried in vacuo to yield 1.68 g of the aimed product (V) as a white crystal. Its purity determined by a liquid chromatography was 98.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35]([OH:37])=O)([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1.CCN=C=NCCCN(C)C.[C:51]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35]([NH:60][S:57]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)(=[O:59])=[O:58])=[O:37])([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1
Reactant: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)c5ccccc5)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
Compound 7e (60 mg, 0.112 mmol) was dissolved in DCM (5 ml). EDAC (26 mg, 0.135 mmol) was added and the reaction mixture was stirred at RT over night. benzensulfonamide (19 mg, 0.123 mmol) and DBU (35 μl, 0.235 mmol) were added and the reaction mixture was stirred at RT for 2 h. Citric acid (5%) was added, the organic layer was separated, washed with brine, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound. (36 mg, 48%), MS (M+H)+674.
Reaction SMILES: CN(C)CC[C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[N:10]([CH2:16][O:17][CH3:18])[C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=3[C:7]=2[N:6]=1>C(O)C.ClCCl.[Pd]>[CH3:11][N:10]([CH3:16])[CH2:9][CH2:8][C:21]1[CH:20]=[CH:19][C:9]2[N:10]([CH2:16][O:17][CH3:18])[C:11](=[O:15])[C:12]3[CH2:13][CH2:14][CH2:5][NH:6][C:7]=3[C:8]=2[CH:22]=1
Reactant: COCn1c(=O)c2ccc(CCN(C)C)nc2c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COCn1c(=O)c2c(c3cc(CCN(C)C)ccc31)NCCC2
Reaction time: 24 h
Yield: 181.2 %

Procedure:
The compound (22 mg, 0.07 mmol) prepared in step 6 was dissolved in ethanol (4 ml)/dichloromethane (2 ml), added with 10%-palladium (Pd) (5 mg) at room temperature. The resulting mixture was stirred for one day under hydrogen gas and filtered using celite to remove 10%-palladium (Pd). The filtrate was then concentrated under reduced pressure to obtain the title compound (20 mg, yield: 90%, white solid).
Reaction SMILES: Br[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1B(O)O>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:13]([C:3]1[C:2]([C:24]2[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=2[OH:22])=[CH:6][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:4]=1)([O-:15])=[O:14]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1O
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(C(F)(F)F)ccc1O
Temperature: 75 °C
Yield: 53.8 %

Procedure:
To a solution of 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 869, 18.95 g, 0.06864 mol) in 1,2-dimethoxyethane (175 mL) was added aqueous potassium carbonate (2M in water, 68.0 mL, 0.123 mol) and tetrakis(triphenylphosphine)palladium(0) (6.34 g, 0.00549 mol). The reaction was sparged 3 times with Argon and heated to 75° C. To this, [2-hydroxy-5-(trifluoromethyl)phenyl]boronic acid (Preparation 871, 21.22 g, 0.103 mol) was added in four portions over six hours. The reaction solution was heated for an additional 12 hours and then allowed to cool. The mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by automated flash column chromatography using a 0-50% ethyl acetate/hexanes gradient and a 80 g column gave the title compound (13.2 g, 54%) as a yellow oil.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C:27](=[O:28])[N:5]2[C:6]([C:24]([O-:26])=[O:25])=[C:7]([CH2:10][N+:11]3[N:12]([CH2:19][CH2:20][O:21]C=O)[C:13]([NH:16]C=O)=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12.C(OCC)(=O)C>CO>[ClH:1].[ClH:1].[ClH:1].[NH2:2][C@@H:3]1[C:27](=[O:28])[N:5]2[C:6]([C:24]([O-:26])=[O:25])=[C:7]([CH2:10][N+:11]3[N:12]([CH2:19][CH2:20][OH:21])[C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC=O)n3CCOC=O)CS[C@H]12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCO
Reaction time: 3 h

Procedure:
Concentrated hydrochloric acid (5.67 ml) was added to a mixture of bis(trifluoroacetic acid salts) of 7β-amino-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (10 g) in methanol (50 ml) at ambient temperature. After being stirred at the same temperature for 3 hours, the mixture was added dropwise to ethyl acetate (500 ml). The resultant precipitate was collected by filtration to give 7β-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4carboxylate trihydrochloride (6.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([N+:18]([O-:20])=[O:19])[C:7]=1[O:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[N:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1COCC1>[CH2:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH:9]1[O:8][C:7]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:5][C:4]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]=1[C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([CH3:27])[N:29]=[CH:30]2
Reactant: COC(=O)CCc1cc(Br)c(OC2Cc3ccccc3C2)c([N+](=O)[O-])c1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC2Cc3ccccc3C2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
THF (40 ml) was added to methyl 3-[3-bromo-4-(indan-2-yloxy)-5-nitrophenyl]propionate (14.00 g, prepared according to the method of International Patent Publication No. WO 03/70686), 1-methyl-1H-indazol-5-boronic acid (7.62 g, prepared according to the method of International Patent Publication No. WO 03/70686), palladium acetate (75 mg, Wako Pure Chemical Industries, Ltd.) and triphenylphosphine (0.17 g, Wako Pure Chemical Industries, Ltd.), and the mixture solution was stirred. Then, a solution having tripotassium phosphate (16.97 g, Wako Pure Chemical Industries, Ltd.) dissolved in water (27 ml) was added to the above mixture, and the mixture solution was purged with nitrogen. Then, this mixture solution was stirred for 4 hours at 60° C. to react. After confirming the completion of the reaction, the reaction solution was partitioned to obtain the upper layer. The upper layer was cooled to room temperature, ethyl acetate (40 ml) and activated carbon (2.8 g, Japan Envirochemicals, Ltd.) were added thereto, and the mixture solution was further stirred for 1 hour at room temperature. The suspension was filtered to obtain a filtrate, and the residue was washed on the filter with ethyl acetate (20 ml) to obtain the wash solution. The filtrate and the wash solution were combined and concentrated under reduced pressure to obtain a concentrate (44 g). Then, acetone (140 ml) was added to the concentrate. The mixture solution was stirred and water (140 ml) was added thereto over 1 hour while stirring. The mixture solution was further stirred for another 1 hour at room temperature. Then, this mixture solution was filtered, the solids were washed on the filter with water (70 ml), and wet solids were obtained. These wet solids were dried under reduced pressure at 50° C. to obtain crystals of the title compound (15.7 g).