Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:35])[C:10](=[C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27]2)[C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21](OCC)=[O:22])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:35])[C:10](=[C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[NH:30]2)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][CH2:21][OH:22])[CH:14]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)C=Cc1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(C(C(=O)c1cccc(C=CCO)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A 25 ml portion of THF solution containing 1.2 g of ethyl 3-{3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}acrylate was cooled to −78° C. in a stream of argon gas, 5.5 ml of 1.0 M diisobutylaluminum hydride-Tol solution was gradually added dropwise thereto, and then the mixture was stirred at 0° C. for about 2 hours. This was again cooled to −78° C. the same amount of the reducing agent was added dropwise thereto, and then the mixture was gradually risen to room temperature and stirred for about 40 minutes. The reaction liquid was cooled to −30° C. or lower, small amount of methanol and purified water were added thereto, and the thus formed insoluble matter was removed by filtration through washing with an appropriate amount of ethyl acetate. The organic layer obtained by layer separation operation of the filtrate was washed with water, dried with anhydrous magnesium sulfate and concentrated, and then the thus obtained residue was purified by a silica gel column chromatography to obtain 0.58 g (53%) of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-[3-(3-hydroxyprop-1-en-1-yl)phenyl]propane-1,3-dione as a yellow foam from a ethyl acetate-hexane (1:1) eluate. FA: 433
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH:32]=O)[NH:24][C:23]=1[CH3:34])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH:32]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:34])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCC(=O)O
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c1CCC(=O)O

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 4-(2-carboxyethyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (56 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:13][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)c1ccccc1
Temperature: 25 °C

Procedure:
A carbon tetrachloride (150 mL) solution of the intermediate from Step A (10.39 g, 66.6 mmol), N-bromosuccinimide (14.22 g, 80 mmol) and AIBN (0.547 g, 3.33 mmol) was heated to reflux. After 4 hours the reaction solution was cooled to room temperature and the mixture filtered. The filtrate was concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (500 MHz, CHCl3-d): δ 7.59-7.53 (m, 2H); 7.37-7.30 (m, 3H); 3.80 (s, 3H); 2.31 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].C(Cl)Cl>C(O)C.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9])[NH2:10]
Reactant: CCc1ccc([N+](=O)[O-])cc1Br
Agent: [Ni]
Solvent: ClCCl
Solvent: CCO
Product: CCc1ccc(N)cc1Br

Procedure:
Hydrogenation of 4.45 g (19 mmol) of 3-bromo-4-ethyl-nitrobenzene (for preparation see Macromolecules 1995, 28, 5618) in 100 ml of ethanol in the presence of 1 g of Raney nickel, followed by filtration, concentration by evaporation and chromatography (SiO2; methylenechloride), yields 3-bromo-4-ethyl-aniline; 1H NMR (CDCl3) δ 6.94 (d, 1H), 6.82 (s, 1H), 6.50 (d, 1H), 3.50 (s, H2N), 2.57 (q, 2H), 1.10 (t, 3H).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[C:26]([C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[CH:30][CH:29]=1)#[N:27].NC1C=NC(C#N)=CC=1.C(N(C(C)C)CC)(C)C.Cl>CS(C)=O.C(OCC)C>[ClH:1].[C:26]([C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:36])=[CH:30][CH:29]=1)#[N:27]
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: N#Cc1ccc(NC(=O)Oc2ccccc2)cn1
Agent: Cl
Agent: N#Cc1ccc(N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#Cc1ccc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 6-cyanopyridin-3-ylcarbamate (0.286 g, 1.00 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-6-cyanopyridine) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and was heated to 50° C. After 3 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to form a residue. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to provide an oil upon concentration of the pure fractions. This oil was dissolved in 20 mL of diethyl ether and treated with 1 mL of 1N HCl in diethyl ether. The resulting solid was collected by filtration to provide the title compound (270 mg, 56%). MS (APCI 10V) AP+ 480.20; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H+DMSO) 3.49 (t, J=5.46 Hz, 2H) 3.56 (t, J=5.46 Hz, 2H) 6.39 (s, 1H) 7.03 (m, 2H) 7.12 (d, J=7.80 Hz, 1H) 7.21 (d, J=8.80 Hz, 1H) 7.4 (dd, J=8.5 Hz, 1 Hz, 1H) 7.84 (d, J=8.75 Hz, 1H) 8.10 (dd, J=8.57 Hz, 2.2 Hz, 1H) 8.20 (dd, J=9.24 Hz, 3 Hz, 1H) 8.55 (s, 1H) 8.8 (d, J=2.3 Hz, 1H) 9.29 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:17]([NH:19][C:20]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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.CO.C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:20]([NH:19][C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:12]=2)=[O:18])=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2ccncc2)c1
Yield: 32.3 %

Procedure:
0.67 g (5.4 mmol) of 4-pyridine boronic acid, 1.0 g (2.7 mmol) of methyl 2-{[(3-bromophenyl)carbonyl]amino}-5-chlorobenzoate, 313 mg (0.27 mmol) of tetrakis(triphenylphosphine)palladium(0), and 0.58 g (5.4 mmol) of sodium carbonate were heated under reflux in a mixed solvent of 4 mL of water, 23 mL of toluene, and 6.7 mL of methanol for 7.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. Ethyl acetate was added, and solids were collected by filtration. Subsequently, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 320 mg of methyl 5-chloro-2-({[3-(pyridin-4-yl)phenyl]carbonyl}amino)benzoate (yield: 32%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([NH2:6])[CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])([O-:9])=[O:8].CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1.O>[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:14])([O-:9])=[O:8]
Reactant: NC1CCOC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1CCOC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 88.5 %

Procedure:
Tetrahydrofuran-3-amine (0.1 g, 1.148 mmol) and 3-nitrobenzoic acid (0.192 g, 1.148 mmol) were taken in pyridine (2 ml), to the mixture EDC.HCl (0.220 g, 1.148 mmol) was added, the reaction mixture was stirred under nitrogen for 10 hrs at room temperature. The reaction mixture was diluted with cold water (15 ml), extracted with ethyl acetate (2×10 ml). Combined organic layer was washed with satd. aq. sod bicarbonate and dil HCl, the organic layer was dried over sodium sulfate and concentrated under vacuum to afford the title product (240 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]=1>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:17]=2)[CH2:7]1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: COc1ccccc1OC1CCNC1
Solvent: CC(C)O
Product: COc1ccccc1OC1CCN(c2nc(-c3ccccc3)nc3ccccc23)C1

Procedure:
To a solution containing 150 ml of isopropanol and 4.8 g (0.025 mole) of 3-o-methoxyphenoxypyrrolidine was added, with stirring, 6.15 g (0.025 mole) of 4-chloro-2-phenylquinazoline. The reaction was exothermic and the mixture refluxed for 15 min. The temperature subsided to room temperature and, after standing at room temperature for 11/2 hr, the resulting reaction mixture was filtered. The crystalline solid was recrystallized with isopropanol. Yield of product was 1.9 g, m.p. 142°-144° C.
Reaction SMILES: [CH2:1](S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>C(#N)C>[CH2:1]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccnc1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 90.2 %

Procedure:
39.1 g (0.315 mol) of benzylmercaptan are introduced into 200 ml of acetonitrile, 47.8 g (0.346 mol) of K2CO3 are added, and the mixture is stirred for 40 minutes at 60° C. 50.0 g (0.315 mol) of 2-chloro-3-nitropyridine dissolved in 150 ml of acetonitrile are subsequently added dropwise, and the mixture is refluxed for 4 hours. The acetonitrile is distilled off under reduced pressure, the residue is taken up in dichloromethane, the organic phase is washed once using saturated sodium hydrogen carbonate solution and once using 1N hydrochloric acid and dried over magnesium sulfate, the desiccant is filtered off, and the dichloromethane is removed under reduced pressure. Recrystallization from methanol gives 60.9 g (79% of theory) of 2-benzyl-3-nitropyridine of melting point 72° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12](I)[C:10]([NH2:11])=[N:9][C:7]1=[O:8].[CH2:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:16]#[CH:17].CO>ClCCl>[OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([C:17]#[C:16][CH2:15][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:10]([NH2:11])=[N:9][C:7]1=[O:8]
Reactant: Nc1nc(=O)n(COCCO)cc1I
Reactant: C#CCNC(=O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Nc1nc(=O)n(COCCO)cc1C#CCNC(=O)C(F)(F)F
Yield: 23 %

Procedure:
Iodide 68 (311 mg, 1.00 mmol) was coupled to N-propargyltrifluoroacetamide (43) according to the general procedure described in Example 1C. Flash chromatography on silica gel (3×20 cm) with 5%, 10% and 20% methanol in dichlormethane afforded alkynylamino nucleotide 69 as a pale yellow foam (77.4 mg, 23%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>N1C=CC=CC=1.O>[C:26]([N:8]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N(c1cccc(C(=O)O)c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5.6 g of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid (from Example 13) and 15 ml of acetic anhydride was heated under a nitrogen atmosphere at 70°-120° C. for about 90 minutes. The mixture was cooled to 80° C., 5 drops of pyridine were added and the reaction was reheated to 120° C. for 10 minutes. An additional 0.25 ml of pyridine was added at about 80° C., followed by the gradual addition of 10 ml of water to hydrolyze the excess acetic anhydride and the mixed anhydride of the product. Heating was continued until a precipitate formed. The reaction mixture was allowed to cool to room temperature, and the precipitate was then collected, rinsed with a cold mixture of methanol and water, and dried to give 4.3 g of off-white solid m.p. 204°-205.5° C. This material was recrystallized first from a mixture of 30 ml of ethanol and 5 ml of water, and then from a mixture of 30 ml of isopropanol and 5 ml of hexane to give 3.3 g of white solid N-acetyl-3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid m.p. 214.5°-215.5° C. Analysis: Calculated for: C23H29NO4 ·1/2(CH3)2CHOH: % C, 71.2; % H, 8.0; % N 3.4. Found: % C, 71.4; % H, 8.1; % N, 3.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](F)[CH:23]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:30]N1C(=O)CCC1=O>>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([Br:30])=[CH:15][N:16]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(CCOc1cccc2c1ccn2Cc1cccc(F)c1)C(=O)OC(C)(C)C
Product: CN(CCOc1cccc2c1c(Br)cn2Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
{2-[1-(3-Fluoro-benzyl)-1H-indol-4-yloxy]-ethyl}-methyl-carbamic acid tert-butyl ester was treated with N-bromosuccinimide using the procedure of step 3 of Example 6 to provide [2-(1-benzyl-3-bromo-1H-indol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:18])[NH:4][C:3]1=[O:19]>CO.CC#N.C(NCC)C>[CH3:1][N:2]1[C@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:18])[NH:4][C:3]1=[O:19]
Reactant: CN1C(=O)NC(=O)C12Cc1ccc([N+](=O)[O-])cc1C2
Solvent: CO
Solvent: CC#N
Solvent: CCNCC
Product: CN1C(=O)NC(=O)[C@]12Cc1ccc([N+](=O)[O-])cc1C2

Procedure:
(±)-3-Methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (described in Intermediate 7) was dissolved in a mixture of MeOH, CH3CN and diethylamine and the enantiomers were resolved by HPLC, utilizing a ChiralPak AD column and eluting with CH3CN:MeOH—90:10. The first major peak to elute was (S)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione and the second major peak to elute was (R)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione, the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:19][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: OCCc1ccccn1
Reactant: COc1cc(O)ccc1C=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(OCCc2ccccn2)ccc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.1 %

Procedure:
To a stirring ice-cooled mixture of 5.0 g of 4-hydroxy-2-methoxybenzaldehyde, 4.5 g of 2-(2-pyridyl)ethanol and 10.3 g of triphenylphosphine was added dropwise 15.8 g of a 40% solution of diethyl azodicarboxylate in toluene. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, purified by silica gel column chromatography (hexane/acetone system) and further purified by silica gel column chromatography (hexane/AcOEt system) to give 5.84 g of the title compound (69% yield).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]=[C:5]([C:21](OCC)([O:24]CC)[CH2:22][Cl:23])[C:6]([NH:8][CH:9]1[C:19](=[O:20])[N:11]2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7]>C(Cl)Cl>[CH3:2][O:3][N:4]=[C:5]([C:21](=[O:24])[CH2:22][Cl:23])[C:6]([NH:8][CH:9]1[C:19](=[O:20])[N:11]2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7]
Reactant: CCOC(CCl)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: Cl
Solvent: ClCCl
Product: CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 44.1 %

Procedure:
6N Hydrochloric acid (2.4 ml), 7-(2-methoxyimino-3,3-diethoxy-4-chlorobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 301.5 mg) and methlene chloride (3 ml) were treated in a similar manner to that of Example 48 to give 7-(2-methoxyimino-3-oxo-4-chlorobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 110.4 mg).
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12](CC)[N:13]=2)[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C)N=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:8][C:9]3[N:10]([CH3:5])[N:13]=[N:12][N:11]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(C(C)(C)C)nc(N3CC(F)(F)C(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as light yellow solid. MS (m/e): 415.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11]([NH:14][C:15]1[C:16]([F:25])=[CH:17][C:18]2[CH2:22][O:21][B:20]([OH:23])[C:19]=2[CH:24]=1)(=[O:13])=[O:12]>CC(O)=O.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:11]([NH:14][C:15]2[C:16]([F:25])=[CH:17][C:18]3[CH2:22][O:21][B:20]([OH:23])[C:19]=3[CH:24]=2)(=[O:12])=[O:13])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(Cl)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(Cl)c1
Temperature: 50 °C
Yield: 7.8 %

Procedure:
A mixture of 2-chloro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzenesulfonamide (0.5 g, 1.3 mmol), iron powder (0.36 g, 6.5 mmol) in AcOH (10 mL) was heated to 50° C. over night and monitored by LC/MS. The mixture was filtered, washed with EtOAc then AcOH, and evaporated under vacuum. Preparative HPLC was applied for the purification and give title product as yellow powder yield 36.3 mg (2%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.71 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.20 (d, J=10 Hz, 1H), 6.65 (d, J=2 Hz, 1H), 6.41 (dd, J=8.8, 2.4 Hz, 1H), 4.88 (s, 2H); MS (ESI): m/z=355.0 (M−H, negative).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:55])[NH:41][C:42]([C:45]([O:47]CC3C=CC=CC=3)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:56])=[C:28]([CH:57]([CH3:59])[CH3:58])[NH:27][N:26]=1)(=[O:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:55])[NH:41][C:42]([C:45]([OH:47])=[O:46])([CH3:43])[CH3:44])=[CH:33][C:32]=2[CH3:56])=[C:28]([CH:57]([CH3:59])[CH3:58])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl)ethylcarbamoyl]-ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.15 g) was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.13 g).
Reaction SMILES: S(=O)(=O)(O)O.[I:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:13]=[C:14]([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>O1CCOCC1>[I:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][C:14]([CH3:16])([CH3:15])[CH3:13])=[O:11]
Reactant: O=C(O)CCCI
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCI
Temperature: 25 °C
Reaction time: 72 h
Yield: 61 %

Procedure:
To a solution of concentrated sulfuric acid (2 ml) and 1,4-dioxane (20 ml) in a pressure bottle at 0° C. were added 4-iodobutanoic acid (5.5 g, 25.7 mmol) and isobutene (30 ml). The mixture was stirred at room temperature for 3 days, cooled to 0° C. and poured slowly into an aqueous solution (120 ml) of sodium bicarbonate (10 g). The mixture was stirred at room temperature for 15 minutes and extracted with diethyl ether. The organic phase was washed three times with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane:dichloromethane=1:1) to give the title compound (4.24 g, 61%) as a pale yellow liquid.