Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=O)[C@@H:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=1[CH3:44])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.[BH4-].[Na+].O>CO.C1COCC1>[CH3:44][C:20]1[CH:21]=[C:22]([C:25]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)([C:26]([F:27])([F:28])[F:29])[C:30]([F:32])([F:33])[F:31])[CH:23]=[CH:24][C:19]=1[O:18][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][OH:8]
Reactant: COc1ccc(COC(c2ccc(O[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)c(C)c2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(COC(c2ccc(O[C@H](CO)Cc3ccccc3)c(C)c2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 67.3 %

Procedure:
1.7 g (2.7 mmol) of (S)-2-{2-methyl-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propionic acid benzyl ester was dissolved in a mixture of 11 mL of methanol and 11 mL of THF and cooled to 0° C. To this solution 1.0 g (26.9 mmol) of NaBH4 were added in portions, and the mixture was slowly warmed to room temperature overnight. Water was added, the phases were separated and the inorganic one was extracted with dichloromethane. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated. Purification by column chromatography with CH2Cl2/MeOH 95:5 yielded 960 mg (68%) (S)-2-{2-methyl-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propan-1-ol as a light yellow oil, MS: 528 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]([CH:13]2[CH2:15][CH2:14]2)=O)[C:9]#[N:10])=[CH:4][CH:3]=1.O.[NH2:17][NH2:18].C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:11]([CH:13]3[CH2:14][CH2:15]3)=[N:17][NH:18][C:9]=2[NH2:10])=[CH:6][CH:7]=1
Reactant: NN
Reactant: N#CC(C(=O)C1CC1)c1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Nc1[nH]nc(C2CC2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Chlorophenyl)-3-cyclopropyl-3-oxopropanenitrile(7.74 g), hydrazine hydrate (3.5 mL) and acetic acid (7.5 mL) are dissolved in a toluene solvent and stirred for 16 hours while heating. Upon completion of reaction, after cooling to room temperature, the solvent is removed by distillation under reduced pressure. The remainder is extracted with water and ethyl acetate. The extracted organic layer is dehydrated and distilled under reduced pressure. The remainder is purified by column chromatography to yield 5.2 g of the target compound. 1H NMR (CDCl3, 300 MHz): δ 7.40 (m, 4H), 3.75 (br, 2H), 1.86 (m, 1H) 0.93 (m, 2H), 0.65 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][N:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:4](=[O:12])[C:3]=1[CH3:13].[N:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C.CCCCCC>[C:8]([N:5]1[C:4](=[O:12])[C:3]([CH3:13])=[C:2]([NH:1][C:20]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)=[O:21])[CH:7]=[N:6]1)([CH3:9])([CH3:11])[CH3:10]
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1c(N)cnn(C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: Cc1c(NC(=O)c2ccncc2)cnn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
0.72 of 5-amino-2-tert-butyl-4-methylpyridazin-3-(2H)-one, 0.57 g of 4-pyridylcarbonyl chloride, 0.55 g of anhydrous potassium carbonate and 30 ml of dry acetone were mixed and vigorously stirred at room temperature for 40 minutes. Acetone was distilled off under reduced pressure, and the residue was extracted with 150 ml of methylene chloride and washed twice with water. Then, It was dried over anhydrous sodium sulfate and concentrated. The residue thereby obtained was subjected to column chromatography, and using an eluent (n-hexane:ethyl acetate=1:2), 0.56 g of the desired product (Compound No. 1) having a melting point of from 206° to 207° C., was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Na+].C(Cl)(Cl)Cl.[CH2:20]([OH:22])C>O>[C:1]1([C:7]2[CH:12]=[C:11]([CH:20]=[O:22])[C:10]([OH:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1cc(-c2ccccc2)ccc1O
Reaction time: 3 h

Procedure:
22 g of phenylphenol was dissolved in 95% ethanol; a solution of 40 g of sodium hydroxide in 80 ml of water was rapidly added. The resulting solution was heated to 75°-80° C. and 20 ml of chloroform was added over a one-hour period, the mixture being gently refluxed. The mixture then was stirred for three hours, cooled and the ethanol and excess chloroform were evaporated under reduced pressure. The resulting residue was cooled and poured into cold water. The resulting mixture was acidified by slow addition of hydrochloric acid and extracted with ether. The solvent was evaporated from the extract under reduced pressure, the residue was poured in twice its volume of saturated sodium metabisulfite solution and the mixture was shaken vigorously for forty-five minutes. The resulting semisolid bisulfite addition compound was allowed to stand for one hour, filtered in the dark and washed with small portions of ethanol and ether to remove the phenol. The bisulfite addition compound was decomposed with dilute sulfuric acid, the mixture being warmed on a water-bath for thirty minutes. The cooled mixture was extracted with ether, dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was treated with activated charcoal and recrystallized from ethanol/water to give 5-phenylsalicylaldehyde (1A), as yellow crystals, mp: 98°-99° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[O:3].C([N-]C(C)C)(C)C.[Li+].[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=O)[CH3:21].C1C[O:31]CC1>>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH2:1][C:25](=[O:26])[C:24]([O:23][CH2:20][CH3:21])=[O:31]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,4-dichloroacetophenone (3.78 g) in THF (20 ml) was cooled to −78° C. under a nitrogen atmosphere. To this stirred solution was added lithium diisopropylamide (LDA) (1.0 M, 22 ml) and the resulting solution was stirred at −78° C. for 15 minutes. Acetoxyacetyl chloride (2.3 ml) was injected and the mixture was stirred for 1 hour and then allowed to warm to room temperature. The reaction was quenched with 1N HCl and the product was extracted with diethyl ether (200 ml). The organic layer was dried, concentrated and recrystallized from ether/hexanes, yielding ethyl 4-(2,4-dichlorophenyl)-2,4-diketobutyrate (intermediate 1).
Reaction SMILES: [C:1]([S:9][C@@H:10]([CH2:26][S:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:11]([NH:13][C@H:14](C(N1CCC[C@H]1C(O)=O)=O)[CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:39]CC)(=[O:38])[CH3:37].[CH:42](Cl)(Cl)Cl>>[C:1]([S:9][C@H:10]([CH2:26][S:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:11]([N:13]1[CH2:14][CH2:15][CH2:42][C@H:37]1[C:36]([OH:39])=[O:38])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)[C@H](CSC(=O)c1ccccc1)SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: ClC(Cl)Cl
Reactant: CCOC(C)=O
Product: O=C(SC[C@@H](SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1

Procedure:
N-[(R)-2,3-Bis-(benzoylthio)-propionyl]-alanylproline, melting point 195°-196° C. (ethyl acetate), Rf=0.40 in system I, [α]D20 =-125° (c=1 in chloroform).
Reaction SMILES: [CH3:1]C(O)=O.[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([N:16]=C=S)=[C:14]([CH3:15])[C:9]=2[N:8]=[CH:7]1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>C(Cl)Cl.CO>[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([NH:16][N:21]3[CH2:20][CH2:19][N:22]=[CH:1]3)=[C:14]([CH3:15])[C:9]=2[N:8]=[CH:7]1
Reactant: Cc1c(N=C=S)ccc2c1ncn2C
Reactant: NCCN
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1c(NN2C=NCC2)ccc2c1ncn2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HOAc. A solution of 1,4-dimethyl-5-benzimidazolylisothiocyanate (210 mg) in methylene chloride (40 mL) is added dropwise over 20 minutes to ethylenediamine (0.35 mL) in solution in methylene chloride (100 mL). The mixture is stirred for 1 hour at room temperature, then rotary evaporated. The residue is dissolved in methanol (70 mL), mercuric acetate (395 mg) is added, and the mixture is stirred at room temperature for 2 hours. The resulting black suspension is filtered on Celite with methanol wash of the solids. The filtrate is rotary evaporated, and the residue is purified by flash chromatography on silica gel, eluting with 10% methanol/chloroform containing 0.1% of ammonium hydroxide. The product-containing fractions are combined and rotary evaporated to yield 1,4-dimethyl-5-(2-imidazolinylamino)benzimidazole.HOAc.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:13]([C:16]1[C:17]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[C:14]=S>ClCCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:14]([NH:13][C:16]3[C:17]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cccc(Oc2ncccc2N=C=S)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Solvent: ClCCCl
Product: CC(C)(C)c1ccc2nc(Nc3cccnc3Oc3cccc(C(F)(F)F)c3)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(tert-butyl)-1,2-diaminobenzene (20 mg, 0.12 mmol) in DCE (1 mL) was slowly added 3c (19 mg, 0.06 mmol). The reaction was stirred 18 h at rt and concentrated. The crude mixture containing 3d and 3d′ was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1.C(N(C(C)C)CC)(C)C.Br[CH2:35]/[CH:36]=[CH:37]/[C:38]([Cl:40])=[O:39].[CH3:41][O:42][CH2:43][CH2:44][NH:45][CH3:46].C(=O)(O)[O-].[Na+]>O1CCCC1>[ClH:24].[ClH:40].[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:38](=[O:39])[CH:37]=[CH:36][CH2:35][N:45]([CH2:44][CH2:43][O:42][CH3:41])[CH3:46])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:14]#[N:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CNCCOC
Reactant: O=C(Cl)/C=C/CBr
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1OC
Product: Cl
Reaction time: 0.75 h

Procedure:
To a stirring solution of 1.2 g (3.5 mmol) of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile and 0.52 g (4.0 mmol) of diisopropylethylamine in 40 ml of tetrahydrofuran at 0° C. was added a solution of 4-bromo crotonyl chloride in 10 ml of tetrahydrofuran. After 45 min, 1.87 (21 mmol) of 2-methoxyethyl methyl amine was added. After 1 hr at room temperature, the mixture was poured into a solution of sodium bicarbonate and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solvent was removed and the residue was purified by chromatography on silica gel. Product eluted with ethyl acetate-methanol-triethylamine 40:8:1 giving 0.87 g of the free base. This was dissolved in 20 ml of ethyl acetate and 10 ml of a solution of hydrogen chloride in ether was added. The solid was collected giving 1.02 g of the title compound as a yellow powder: mass spectrum (electrospray, m/e): M+H 498.0, (M+2H)+2248.5.
Reaction SMILES: C[Li].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]2=[O:25])[CH:7]=[CH:8][C:9]=1[Cl:10].I[CH2:27]I.O>C(OCC)C.C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13][C:12]32[O:25][CH2:27]3)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: ICI
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(=O)C1
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C2(CO2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
A solution (3 M, 0.56 mL) of methyllithium in diethyl ether was added to a solution of tert-butyl (7RS)-7-(3,4-dichlorophenyl)-6-oxo-1,4-oxazepane-4-carboxylate (300 mg) and diiodomethane (335 mg) in THF (3 mL), and the mixture was stirred at 0° C. for 30 min, and at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and HPLC to give the title compound (59 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O.C(O[Na])(C)=O.Cl>O>[CH2:19]([O:18][C:12]([C:13]1[C:4]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:3][NH:2][C:14]=1[CH3:16])=[O:17])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: NCC(=O)CCCC(=O)O
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: O
Product: CCOC(=O)c1c(CCCC(=O)O)c[nH]c1C
Temperature: 25 °C
Yield: 70.6 %

Procedure:
6-amino-5-oxohexanoic acid hydrochloride (9.73 g, 49.8 mmol) was dissolved in H2O (35 mL), and ethyl acetoacetate (5.51 g, 42.34 mmol) and AcONa (20.3 g, 14.95 mmol) were added to the above-mentioned solution. The reaction solution was refluxed for 1 h, cooled to room temperature and 0.5N HCl was added until a pH of about 5 was reached. The combined organic layers were anidrified on Na2SO4, filtered and concentred to give 7.15 g (yield: 60%) of the title compound as brown solid.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[F:22])C1C=CC=CC=1.Cl>CCO.[Pd]>[NH2:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][C@@H:10]1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](F)C1
Reaction time: 14 h
Yield: 53 %

Procedure:
To a solution of the enantiomeric mixture of cis-4-benzylamino-1-tert-butoxycarbonyl-3-fluoropiperidine (prepared according to the procedures of J. Med. Chem. 1999, 42, 2087-2104, 1.0 g, 3.2 mmole) in EtOH (40 mL) was added 3 N HCl (2.5 mL) and 10% Pd/C (50 mg). The reaction was shaken under H2 (40 psi) on a Parr aparatus for 14 h, then was filtered through celites. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3) to afford the title compound (370 mg, 53%) as a white solid: MS (ES) m/e 219 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][N:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: COC(=O)c1c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(CNC(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred brown solution of 2-(di-tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl ester (51.53 g, 126 mmol) in methylene chloride (600 mL), was added trifluoroacetic acid (18.2 mL, 245 mmol), and the mixture was stirred at room temp overnight. Sat. sodium bicarbonate (400 mL) was added to the solution, and the mixture was stirred for 10 minutes. The organic layer was separated, dried over magnesium sulfate and evaporated to give 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl ester as a brown oil (41.4 g, 106% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:28][C:29]1[CH:30]=[C:31]([N+:36]([O-:38])=[O:37])[CH:32]=[CH:33][C:34]=1F>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:34]3[CH:33]=[CH:32][C:31]([N+:36]([O-:38])=[O:37])=[CH:30][C:29]=3[F:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 7-(benzyloxy)-6-methoxyquinolin-4-ol (4.0 g, 14.2 mmol) and Cs2CO3 (11.5 g, 35.5 mmol) in DMF (40 mL) at 40° C. under N2 was added 3,4-difluoronitrobenzene (1.6 mL, 14.2 mmol). The suspension stirred at 40° C. for 45 min. Solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (150 mL) and 1 N NaOH (50 mL). The organic layer was washed with water (50 mL) and brine (25 mL) and purified on silica gel yielding the title compound. Calc'd Mass for C23H17FN2O5, 420, MS (M+1) 421.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:15]([C:18]1[CH:19]=[C:20]([C@H:36]2[CH2:40][CH2:39][C@H:38]([C:41]3[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=3)[O:37]2)[CH:21]=[C:22]([O:34][CH3:35])[C:23]=1[O:24][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:17])=[O:16])[CH2:13][CH3:14]>ClCCl>[CH2:12]([S:15]([C:18]1[CH:19]=[C:20]([C@H:36]2[CH2:40][CH2:39][C@H:38]([C:41]3[CH:42]=[C:43]([O:51][CH3:52])[C:44]([O:49][CH3:50])=[C:45]([O:47][CH3:48])[CH:46]=3)[O:37]2)[CH:21]=[C:22]([O:34][CH3:35])[C:23]=1[O:24][CH2:25][CH2:26][S:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:9])(=[O:16])=[O:17])[CH2:13][CH3:14]
Reactant: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCSc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
m-Chloroperbenzoic acid (50 mg, 1.1 eq) was added to a solution of trans-2-[3-propylsulfonyl-4-{2-(phenylthio)ethoxy}-5-methoxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (300 mg) in dichloromethane (3 mL), and the mixture was stirred at room temperature for 1 h. The solid was filtered off and the filtrate was washed with 1N NaOH, dried, and concentrated to a residue. Purification by flash column chromatography (hexane-ethyl acetate 1:2) afforded the title compound.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OB(O)O)c(Cl)c1
Reactant: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nn2c(-c3ccc(OC)cc3Cl)cccc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
After dissolving 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (100 mg) in 1,2-dimethoxyethane (6 mL) and water (1 mL), 2-chloro-4-methoxyphenylboric acid (138 mg), tetrakis(triphenylphosphine)palladium(0) complex (86 mg) and barium hydroxide octahydrate (233 mg) were added and the mixture was heated and stirred at 80° C. for 3 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract washed with saturated aqueous sodium hydrogencarbonate and brine, in that order. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([CH2:25][O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:23][N:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][CH:20]2[CH2:42][OH:43])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([CH2:25][O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:23][N:22]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:21][CH:20]2[CH:42]=[O:43])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(COCCN2CCOCC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(COCCN2CCOCC2)C1

Procedure:
In an analogous manner to that described in Example 74 (f), from tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(2-morpholin4-yl-ethoxymethyl)-piperidine-1-carboxylate by oxidation with dimethyl sulphoxide/oxalyl chloride in methylene chloride there was obtained tert-butyl (3RS,4SR,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-formyl-5-(2-morpholin-4-yl-ethoxymethyl)-piperidine-1-carboxylate as a yellow oil; MS: 597 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH:9]([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH2:10][CH2:11][OH:12])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH2:46][CH2:47][O:48][CH:49]=[O:50])[C:41](O)=[O:42])[N:39]=1)=[O:33].P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH2:46][CH2:47][O:48][CH:49]=[O:50])[C:41]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH:9]([S:13][C:14]4[NH:15][N:16]=[N:17][N:18]=4)[CH2:10][CH2:11][OH:12])[CH2:7][S:8][C@H:3]23)=[O:42])[N:39]=1)=[O:33]
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=CNc1nc(C(=NOCCOC=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(C(CCO)Sc4nnn[nH]4)CS[C@H]23)cs1
Yield: 31.4 %

Procedure:
A solution of 7-amino-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (2.0 g) and trimethylsilylacetamide (5.9 g) in dry ethyl acetate (40 ml) and a solution of 2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetic acid (syn isomer, 1.8 g), dry dimethylformamide (0.5 g) and phosphoryl chloride (1.0 g) in dry ethyl acetate (22.0 ml) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 1.10 g).