Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17](Cl)=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:20]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([CH3:20])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2ncc(Cl)cc2Cl)c1C
Reactant: CB(O)O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2ncc(Cl)cc2C)c1C
Temperature: 0 °C
Yield: 57.4 %

Procedure:
A suspension of 1-(3,5-dichloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.0 g) in Reference Example 22 (2), methylboronic acid (419 mg), 1,1′-bis(di-tert-butylphosphino)ferrocene (631 mg), palladium acetate (299 mg) and tripotassium phosphate (2.97 g) in 1,4-dioxane (35 ml) was stirred with reflux for 8 hours. After completion of the reaction, the mixture was allowed to cool, and ice water and a saturated aqueous solution of ammonium chloride were added thereto, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 1-(5-chloro-3-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.07 g) as a yellow solid. MS (ESI) m/z: 230 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([S:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Cc2cc(O)ccc2N1
Reactant: BrCCCCSc1ccccc1
Product: O=C1Cc2cc(OCCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 140 from 5-hydroxy-oxindole (J. Chem. Soc. 1961, 2723) and 4-phenylmercapto- butyl bromide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10].C(N(CC)CC)C.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:22]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1NCCCN1CCO
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCN1CCCNC1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
34.3 g (237 mmol) of 1-(2-hydroxyethyl)tetrahydropyrimidin-2(1H)-one (patent; Chem. Werke Huels; DE 1121617; 1962; Chem. Abstr.; EN; 56; 11601 g; 1962) are dissolved in 612 ml of DMF and admixed with 36.1 g (356 mmol) of triethylamine, 1.45 g (11.9 mmol) of DMAP and 85.0 g (309 mmol) of tert-butyl(chloro)diphenylsilane, and stirred at RT for 18 h. Then the mixture is added to 2000 ml of water and extracted three times with dichloromethane. The combined organic phases are washed twice with water and then dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue is recrystallized from acetonitrile. This affords 71.9 g (78% of theory) of the desired compound.
Reaction SMILES: [NH2+]([O-])(=O)C(N)=S.[OH-].[Na+:8].C=O.S([O-])[O-].[Na+].[Na+].[C:16]([OH:28])(=[O:27])[CH2:17][C:18]([CH2:23][C:24]([OH:26])=[O:25])([C:20]([OH:22])=[O:21])[OH:19]>C(O)(=O)C>[C:16]([O-:28])(=[O:27])[CH2:17][C:18]([CH2:23][C:24]([O-:26])=[O:25])([C:20]([O-:22])=[O:21])[OH:19].[Na+:8].[Na+:8].[Na+:8]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C=O
Agent: [Na+]
Agent: [O-]S[O-]
Solvent: CC(=O)O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
The procedure of Example 1 was followed except that in lieu of 0.75 lbs of thiourea dioxide and the sodium hydroxide there was utilized 3.0 lbs of sodium sulfoxylate formaldehyde and sufficient citric acid to give a pH of 4.0-4.5 (buffered with sodium citrate) or acetic acid (56%) buffered with sodium acetate at a temperature of 180°-185° F.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH3:18][C:19]1([CH3:35])[O:24][CH:23]([C:25]([NH:27][CH2:28][CH2:29][C:30](O)=[O:31])=[O:26])[C:22]([CH3:34])([CH3:33])[CH2:21][O:20]1>>[CH2:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH2:2][NH:1][C:30](=[O:31])[CH2:29][CH2:28][NH:27][C:25]([CH:23]1[C:22]([CH3:33])([CH3:34])[CH2:21][O:20][C:19]([CH3:35])([CH3:18])[O:24]1)=[O:26])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)NC[C@H]2CCCN2C(=O)OCc2ccccc2)O1
Yield: 72.3 %

Procedure:
(R)-2-Aminomethyl-1-benzyloxycarbonylpyrrolidine (750 mg) and 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid (829 mg) were Example reacted in the same manner as in Reference Example 25 to obtain 1.10 g of the ojective compound (yield: 72%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:11]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)(=O)[CH3:12]>CO>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7](=[O:8])[CH:12]=[CH:11][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CO
Product: N#Cc1ccc(C=CC(=O)c2ccc(C#N)cc2)cc1

Procedure:
The synthesis employed for the 2,4-substituted dicationic furans 1-6 used 2,4-bis(4-cyanophenyl)furan as the key intermediate and is outlined in scheme 1. This key compound was obtained through a four step approach. A base catalyzed Aldol condensation between 4-cyanobenzaldehyde and 4-acetylbenzonitrile in methanol gave 1,3-bis(4-cyanophenyl)prop-2-en-1-one. Bromination of the double bond of the chalcone (i) in CHCl3 yielded 1,3-bis(4-cyanophenyl)-2,3-dibromopropan-1-one (ii), which was reacted with 2.5 equivalent of MeONa in MeOH to form 1,3-bis(4-cyanophenyl)-3-methoxyprop-2-en-1-one (iii) (Weygand, C.; Bauer, E.; Hennig, H., Ueber Beziehungen zwischen Polymorphismus und Ethylen-Stereomerie. B. 1929, 62, 562-573). The reaction of dimethylsulfonium methylide with the enolether (iii) gave 2,4-disubstituted furan (iv) (Harris, C. M. et al., J. Org. Chem. 1974, 39, 72-77).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]([CH3:10])[CH:8]=[N:9][C:5]=2[CH:4]=1.C([Li])(C)(C)C.C1C(=O)N([I:25])C(=O)C1>C1COCC1>[I:25][C:8]1[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=1
Reactant: COc1ccc2c(c1)ncn2C
Reactant: O=C1CCC(=O)N1I
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)nc(I)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 0.500 g (1.75 mmol) of 5-methoxy-1-methylbenzimidazole in 10 mL of dry THF is cooled to −78° C. 2.47 mL (4.20 mmol) of 1.7 M t-butyllithium in hexanes is added and the reaction mixture is stirred at −78° C. for 1 h. 0.472 g (2.1 mmol) of NIS in 10 mL of dry tetrahydrofuran is added. Reaction is removed from bath and stirred at room temperature for 1 hour, quenched with saturated aqueous solution of ammonium chloride, and diluted with dichloromethane. The layers are separated, the aqueous is extracted 3×50 mL dichloromethane, dried (MgSO4), and concentrated. The crude mixture is purified by chromatography using hexanes:ethyl acetate as a solvent system. The product containing fractions are combined to obtain 0.125 g of the title compound, 25% yield. MS, ES+=289.0 (M+1); 1H NMR (DMSO-d6) δ 7.439-7.417 (d, 1H); 7.147-7.141 (m, 1H); 6.771-6.743 (m, 1H); 3.794 (s, 3H); 3.707 (s, 3H) ppm.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH3:34][O:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:19]([N:18]([C:26]1[N:31]=[CH:30][C:29]([N:38]2[CH2:39][CH2:40][CH:36]([O:35][CH3:34])[CH2:37]2)=[CH:28][N:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC1CCNC1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCC(OC)C2)cn1

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and 3-methoxypyrrolidine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH2:18])=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[Cl-].[Na+].[OH-].[Na+]>ClCCCl>[C:1]1([CH:7]=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[N:18])[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C1CCN(CC=Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: N#CC1CCN(CC=Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 99.4 g of the 1-(3-phenyl-2-propenyl)-4-piperidinecarboxamide, 25 ml of phosphorus oxychloride and 30 g of sodium chloride are suspended in 750 ml of 1,2-dichloroethane and heated to its reflux temperature with vigorous stirring for a period of 2 hours. After several minutes at the reflux temperature a white precipitate separates. The reaction mixture is cooled, a 10% sodium hydroxide solution is added and the mixture extracted with diethyl ether. The combined extracts are washed with water, followed by a solution of sodium chloride, dried (MgSO4) and concentrated in vacuo. The residual oil is distilled under reduced pressure to yield the desired 1-(3-phenyl-2-propenyl)-4-piperidinecarbonitrile as a viscous, colorless oil, b.p. 169°-76° C./0.35-0.70 mm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[S:6]1(=[O:18])=[O:17].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:11][CH2:10][C:9](=[O:12])[C:8]4[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=4[S:6]3(=[O:18])=[O:17])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Cn1ccc2c1C(=O)CCN(CCCCl)S2(=O)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc2c1C(=O)CCN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 99.5 %

Procedure:
A suspension of 116 mg (0.4 mmol) of Compound 18, 108 mg (0.6 mmol) of 1-(4-fluorophenyl)piperazine, 83 mg (0.6 mmol) of potassium carbonate and 120 mg (0.8 mmol) of sodium iodide in 6 ml of acetonitrile was refluxed for 19 hours. The reaction mixture was concentrated under reduced pressure, a half-saturated aqueous solution of potassium carbonate was added to the residue, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: methanol/chloroform=3/97), whereby 173 mg of the title compound were obtained (yield: 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(O)C.O.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21](=O)[O:22]C2C=CC([N+]([O-])=O)=CC=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(N(CC)CC)C>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][C:21]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:22])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: O=C(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
One and one half grams of glycine is slurried in 235 ml of a 80/20 mixture of ethyl alcohol/water. To this is added 5.6 ml of triethylamine, solution occurs, followed by 6.36 g of product from Example 254. A precipitate forms and the reaction is stirred overnight at room temperature. The reaction mixture is concentrated in vacuo. The resulting oil is dissolved in water and ethyl alcohol, the pH is adjusted to 1.5 with concentrated hydrochloric acid and the volume is reduced. The reaction mixture is extracted with methylene chloride, the organic layer is washed with water and concentrated in vacuo. The residue is purified by chromatography (Silica gel: ethyl acetate) to give 2.83 g of the desired product.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([F:22])=[CH:17][N+:16]=1[O-:23].C(=O)([O-])[O-].[NH4+].[NH4+]>S(=O)(=O)(O)O>[CH3:14][C:15]1[C:20]([CH3:21])=[C:19]([N+:10]([O-:13])=[O:11])[C:18]([F:22])=[CH:17][N+:16]=1[O-:23]
Reactant: Cc1cc(F)c[n+]([O-])c1C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cc1c([N+](=O)[O-])c(F)c[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A nitration mixture of 30% oleum (24 ml) and fuming nitric acid (40 ml) was added dropwise with cooling to a solution of 2,3-dimethyl-5-fluoropyridine-N-oxide (6.64 g) in concentrated sulphuric acid (24 ml) at 10°-15°. The solution was stirred at room temperature for 1.5 hours and then 2 hours at 80°-90°. After cooling, the mixture was poured onto ice, basified (ammonium carbonate) and extracted with dichloromethane. After drying (K2CO3), the extracts were evaporated to dryness to give 2,3-dimethyl-4-nitro-5-fluoro-pyridine-N-oxide (5.88 g) m.p. 80°-83°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[F:34][C:35]1[C:40]([F:41])=[C:39]([O:42][CH3:43])[CH:38]=[CH:37][C:36]=1B(O)O>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:34][C:35]1[C:40]([F:41])=[C:39]([O:42][CH3:43])[CH:38]=[CH:37][C:36]=1[C:2]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[C:4]([CH2:5][O:6][CH2:7][C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reactant: COc1ccc(B(O)O)c(F)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)c2)c(F)c1F
Temperature: 120 °C

Procedure:
tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (150 mg, 0.28 mmol), 2,3-difluoro-4-methoxyphenylboronic acid (139 mg, 0.84 mmol), and tetrakis(triphenylphosphine) palladium(0) (33 mg, 0.03 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. After flushing with nitrogen, 1.0 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 45 mg (33%). 1H-NMR (CDCl3, 500 MHz) δ 7.57 (s, 1H), 7.26-7.38 (m, 6H), 7.13-7.17 (m, 1H), 7.00-7.06 (m, 1H), 6.77-6.83 (m, 1H), 4.41 (s, 2H), 3.93 (s, 3H), 3.44 (s, 2H), 2.84-2.92 (m, 2H), 2.68-2.77 (m, 2H), 2.13-2.18 (m, 2H), 1.83-1.92 (m, 2H). Mass spec.: 492.01 (MH)+. Accurate mass spec.: m/z 492.1978 [MH]+, Δ=3.3 ppm.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>O1CCCC1.[Pd]>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([C:32]5[CH:33]=[CH:34][C:35]([C:38]6[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[CH:42][CH:43]=6)=[CH:36][CH:37]=5)[CH2:30][CH2:31]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=C[C@H]4CC[C@H](c5ccc(-c6ccc(C#N)cc6)cc5)CC4)cc3)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(CC[C@H]4CC[C@H](c5ccc(-c6ccc(C#N)cc6)cc5)CC4)cc3)cc2)CC1

Procedure:
A solution of 0.214 g of 4'-[trans-4-[2-(4'-(trans-4-pentylcyclohexyl)-4-biphenylyl)vinyl]cyclohexyl]-4-biphenylcarbonitrile in 200 ml of tetrahydrofuran was treated with 52.5 mg of palladium/carbon (5%) and hydrogenated at room temperature until the hydrogen uptake came to a stand-still (1.75 hours). The reaction mixture was subsequently gassed with nitrogen and suction filtered (rinsing with hot tetrahydrofuran). After concentrating the filtrate in vacuo and drying at 50° C. under a water-jet vacuum there was obtained 0.310 g of colourless, solid 4'-[trans-4-[2-(4'-(trans-4-pentylcyclohexyl)-4-biphenylyl)ethyl]cyclohexyl]-4-biphenylcarbonitrile which still contained solvent. Recrystallization from tetrahydrofuran gave colourless needles with (S-N) 194.5° C. and cl.p. (N-I) 440° C.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].O[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=O)[CH3:39]>O1CCCC1>[CH3:39]/[C:38](/[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29])=[CH:8]/[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: CC(=O)CCCCCCCCCO
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCCCCC/C(C)=C\CCCC(=O)O
Yield: 107 %

Procedure:
164.6 g (0.37 mol) of (4-carboxybutyl)triphenylphosphonium bromide were suspended in 700 ml of tetrahydrofuran. 101 g (0.9 mol) of potassium t-butylate in 150 ml of tetrahydrofuran were added and then 68 g (0.36 mol) of 11-hydroxy-2-undecanone in 50 ml of tetrahydrofuran were added After usual working up there were obtained 98 g of crude 5Z-6-methylpentadec-5-enoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15].CCN(CC)CC>C1COCC1>[CH2:13]([NH:16][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:12])[CH:14]=[CH2:15]
Reactant: CC(C(=O)O)c1ccc(O)cc1
Reactant: C=CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCNC(=O)C(C)c1ccc(O)cc1
Reaction time: 3 h

Procedure:
N,N′-Carbonyldiimidazole (22.65 g, 140 mmol) was added to commercially available 2-(4-hydroxyphenyl)propionic acid (21 g, 127 mmol) in THF (100 mL). Gentle warming and gas evolution was observed. The resulting mixture was stirred for 3 h. Allylamine (10.9 g, 190.5 mmol) and Et3N (19.2 mL, 190.5 mmol) were added dropwise, and the mixture was stirred overnight. The reaction was quenched with water (200 mL) and the organic phase was extracted with ethyl acetate (50 mL×3). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (elution with ethyl acetate). Phenol 49.1 was obtained as a white solid. MS ESI m/e: 206 (M−H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[Na+:13]>C1COCC1.CO>[NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O-:9])=[O:8])[N:6]=1.[Na+:13]
Reactant: CCOC(=O)c1coc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=O)[O-])co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-aminooxazole-4-carboxylate (1.56 g, 9.99 mmol) in THF (4 mL) and MeOH (4 mL), was added sodium hydroxide (8.0 g, 20 mmol, 10%) aq solution. The reaction was stirred at rt for 18 h then quenched with 4N HCl to pH=3. The aqueous solution was concentrated to give a yellow solid as a mixed acid and salts. The mixture was washed with EtOAc and MeOH, and the filtrate was collected and concentrated to give sodium 2-aminooxazole-4-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:46][O:47][CH:48]2[CH2:50][CH2:49]2)[C:8]([NH:10][C@@H:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C.C(=O)(O)[O-].[Na+:77]>C(Cl)Cl.C(OCC)(=O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:46][O:47][CH:48]2[CH2:50][CH2:49]2)[C:8]([NH:10][C@@H:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O-:30])=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:77]
Reactant: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CS/C=C\c4cccnc4)CS[C@H]23)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(CS/C=C\c4cccnc4)CS[C@H]23)cs1

Procedure:
A solution of benzhydryl 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (0.69 g), anisole (0.69 ml), and trifluoroacetic acid (2.07 ml) in methylene chloride (1.38 ml) was stirred under ice-cooling for 40 minutes. The mixture was poured into diisopropyl ether to give a precipitate. The precipitate was dissolved into a mixture of water (30 ml) and ethyl acetate (15 ml) and the solution was adjusted to pH 7.1 with saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 5.6 with 1N hydrochloric acid. The solution was subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (12 ml). After the column was washed with water, the elution was carried out with 20% isopropyl alcohol. The fractions containing the object compound were combined, concentrated in vacuo to about 20 ml and lyophylized to give sodium 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (0.30 g).