Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28](I)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50](B2OC(C)(C)C(C)(C)O2)[C:49]([CH3:62])=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:50]5[C:49]([CH3:62])=[N:48][N:47]([CH2:46][C:45]6[CH:63]=[CH:64][CH:65]=[C:43]([F:42])[CH:44]=6)[C:51]=5[CH3:52])=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(I)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)c(NS(C)(=O)=O)c3)cc12
Yield: 2.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 50) (200 mg, 0.286 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (123 mg, 0.373 mmol) in sodium carbonate (90 mg, 0.858 mmol), Pd(PPh3)2Cl2 (10 mg, 0.0143 mmol), Toluene/ethanol/water (5/5/2.5 ml) to afford 6 mg (2.7% yield) of titled compound. MS: m/z=774.2 (M+1).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=1[C:49]([F:52])([F:51])[F:50]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:44]=[CH:45][C:40]([Cl:39])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:42]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
5-(tert-Butyl)-4′-chloro-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 4-chloro-3-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N+](C1C=CC(S(O[CH:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)(=O)=O)=CC=1)([O-])=O.[F-].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH:40]3[CH2:41][CH2:36][CH2:37][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Dimethylformamide (23 ml) was added to 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline, tert-butyl 3-[(4-nitrophenyl)sulfonyloxy]piperidine-1-carboxylate (1.93 g) and cesium fluoride (2.28 g). The reaction mixture was then stirred at room temperature for 4 days. The reaction mixture was evaporated under vacuum and partitioned between methylene chloride and water. The solutions were filtered to remove insoluble solids and the methylene chloride was washed with water and saturated brine and adsorbed onto silica. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6). The fractions containing the required product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-(1-tert-butoxycarbonylpiperidin-3-yloxy)-7-methoxyquinazoline as a yellow gum (0.67 g); Mass Spectrum: (M+H)+ 503.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].Cl[C:23]1[N:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][N:24]=1>C1COCC1>[CH2:29]([C:26]1[CH:25]=[N:24][C:23]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])=[N:28][CH:27]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCc1cnc(Cl)nc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCc1cnc([Sn](CCCC)(CCCC)CCCC)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Tri-n-butylstannane (ALDRICH, 0.40 ml) was added dropwise, with vigorous stirring, to a solution of lithium diisopropylamide (ALDRICH, 0.75 ml) in dry THF (3 ml) at 0° C. After stirring for 20 minutes a solution of 2-chloro-5-nonylpyrimidine (ALFA, 0.200 g) in THF (3 ml) was added dropwise at −78° C., under argon atmosphere. After 1 hour at −78° C. the cooling bath was removed and the reaction mixture warmed up to 0° C. The mixture was stirring for 3 hours at 0° C., then quenched with saturated NH4Cl (10 ml), diluted, extracted with ethyl acetate (3×10 ml), dried over MgSO4, concentrated under vacuum and purified by column chromatography on silica gel, eluting with hexane to afford 0.5 g of the title compound as a yellow oil. Although the material obtained contained a small amount of 5-nonyl-pyrimidine, it was used for the next step without further purification.
Reaction SMILES: S(O[CH:6]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)(=O)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]3([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[C:36](=[O:43])[NH:35][CH2:34]2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(OC(C)C)(C)C>O.CN(C)C=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]2([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH2:8][CH2:7][CH:6]([N:40]3[CH2:39][CH2:38][C:37]4([N:33]([C:30]5[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=5)[CH2:34][NH:35][C:36]4=[O:43])[CH2:42][CH2:41]3)[CH2:11][CH2:10]2)=[CH:20][CH:21]=1
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Reactant: CS(=O)(=O)OC1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: O=C1NCN(c2ccc(F)cc2)C12CCN(C1CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC1)CC2
Reaction time: 50 h

Procedure:
A mixture of 16 g of 4,4-bis(p-fluorophenyl)cyclohexyl mesylate, 10 g of 1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (m.p. 234°-234.5° C), 6.1 g of potassium carbonate, 7.3 g of potassium iodide and 100 ml of dimethylformamide is stirred at 70°-80° C for 50 hours. The reaction mixture is poured into water, isopropyl ether is added to the aqueous mixture, and the resulting mixture is stirred for some time. The precipitated crystals are collected by filtration and dissolved in a mixture of chloroform and methanol (9:1). The solvent is removed to some degree and cooled in an ice bath. The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(p-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 237°-240° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].O>C(#N)C.C(Cl)Cl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a mixture of thiophenol (0.96 mL, 9.3 mmol) and potassium carbonate (1.4 g, 10.1 mmol) in 16 mL of dry acetonitrile is added 2,5-difluoronitrobenzene (1.0 mL, 9.2 mmol). The mixture is allowed to stir overnight at rt. Water (30 mL) and CH2Cl2 are added and the layers seperated. The aqueous layer is extracted with CH2Cl2 (3×25 mL). The combined organics are dried over MgSO4, filtered, and concentrated. Recrystallization from EtOAc/heptane gives 2.3 g (99%) of the title compound as a solid, mp 66-67° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[N:17]1([CH2:22][CH2:23][O:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[C:11]1([C:10]2[C:5]3[CH:4]=[N:3][C:2]([N:29]4[CH2:30][CH2:31][CH:26]([CH2:25][O:24][CH2:23][CH2:22][N:17]5[CH2:21][CH2:20][CH2:19][CH2:18]5)[CH2:27][CH2:28]4)=[N:7][C:6]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncc2c(-c3ccccc3)csc2n1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc(-c2csc3nc(N4CCC(COCCN5CCCC5)CC4)ncc23)cc1
Temperature: 150 °C
Yield: 26 %

Procedure:
2-Chloro-5-phenyl-thieno[2,3-d]pyrimidine (150 mg, 0.61 mmol), 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (293 mg, 0.92 mmol) and potassium carbonate (253 mg, 1.83 mmol) were combined in acetonitrile (2 mL) and heated in the microwave at 150° C. for 30 minutes. The reaction mixture was diluted with DCM (10 mL), washed with water (10 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by basic prep HPLC to afford 5-phenyl-2-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (67 mg). LCMS [M+H]+=423.2.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([C@H:12]1[N:15](C(CC2C=CC(OC)=CC=2)CC2C=CC(OC)=CC=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])[CH3:11])(C(C)(C)C)(C)C.COC1C=CC=C(OC)C=1.B(F)(F)F.CCOCC>ClCCl>[OH:8][CH2:9][C@@H:10]([C@@H:12]1[NH:15][C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11]
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Agent: COc1cccc(OC)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](CO)[C@@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1

Procedure:
To a solution of (3S,4R)-4-(1-(R)-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) in dry dichloromethane (200 ml) were added 1,3-dimethoxybenzene (7.8 g) and boron trifluoride etherate (23 g) at 10 °-20° C., and the resultant mixture was stirred at room temperature for 3 hours, followed by heating under reflux for 3-5 hours. The reaction mixture was cooled down to 10°-15° C., washed successively with brine (200 ml×2), 2.5% sodium bicarbonate (200 ml) and brine (200 ml) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue which was purified by silica gel chromatography to yield (3S,4S)-4-(1-(R)-hydroxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:23][CH2:22][C:5]2[N:6]=[C:7]([NH:9][C:10]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])=[O:11])[S:8][C:4]=2[CH2:3]1.O.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([CH3:24])[CH2:23][CH2:22][C:5]2[N:6]=[C:7]([NH:9][C:10]([C:12]([OH:14])=[O:13])=[O:11])[S:8][C:4]=2[CH2:3]1
Reactant: CC1(C)CCc2nc(NC(=O)C(=O)OCc3ccccc3)sc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC1(C)CCc2nc(NC(=O)C(=O)O)sc2C1

Procedure:
The acids of Examples 26 to 37 are also prepared by hydrogenolysis of the corresponding benzyl esters, by adaptation of the following specific exemplary method. Benzyl 6,6-dimethyl-4,5,6,7-tetrahydrobenzthiazol-2-ylcarbamoylcarboxylate (1 g.) in 25 ml. of 50:50 water:ethanol in the presence of 5% palladium on carbon (300 mg.) is hydrogenated at atmospheric pressure and room temperature until uptake of hydrogen is complete (in small excess of one equivalent to account for reduction of the catalyst). The catalyst is removed by filtration and the filtrate evaporated to dryness to yield 6,6-dimethyl-4,5,6,7-tetrahydrobenzthiazol-2-ylcarbamoylcarboxylic acid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].N1C=CC=CC=1.[C:15]([O:18][CH2:19][C:20](Cl)=[O:21])(=[O:17])[CH3:16]>C(Cl)Cl>[C:15]([O:18][CH2:19][C:20]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:21])(=[O:17])[CH3:16]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)ON1C(=O)CCC1=O
Reaction time: 2.5 h
Yield: 93 %

Procedure:
A 3-neck round-bottom flask equipped with a mechanical stirrer, thermocouple and addition funnel with nitrogen inlet was charged with N-hydroxysuccinimide (commercially available from Sigma-Aldrich, St. Louis, Mo.) (211 g, 1.83 mol) and DCM (2.25 L) at room temperature, resulting in a suspension. Pyridine (178 mL, 2.2 mol) was added in one portion with no change in the internal temperature. A solution of acetoxyacetyl chloride (commercially available from Sigma-Aldrich, St. Louis, Mo.) (197 mL, 1.83 mol) in DCM (225 mL) was added dropwise over 60 minutes and the temperature rose to 35° C. Stirring was continued at room temperature for 2.5 hours. The reaction mixture was washed with water (1×1 L), 1N HCl (2×1 L) and brine (1×1 L). The organic layer was concentrated under vacuum and azeotroped with toluene (1×1 L) to obtain the product as a white solid (367 g, 93%). 1H NMR (400 MHz, CDCl3) δ 4.96 (2H, s), 2.86 (4H, s), 2.19 (3H, s) ppm; LCMS m/z: 238 (M+Na).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[Si](C=[N+]=[N-])(C)(C)[CH3:14]>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([O:8][CH3:14])=[O:7])#[N:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Solvent: CO
Product: COC(=O)c1cc(F)cc(C#N)c1
Reaction time: 1 h

Procedure:
(Step 1) To a solution of 3-cyano-5-fluorobenzoic acid (1.0 g) in methanol (20 ml) was added TMS diazomethane (2M diethyl ether solution, 5 ml) at 0° C., and the mixture was stirred for 1 hr. The reaction solution was quenched with water and diluted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give methyl 3-cyano-5-fluorobenzoate (0.58 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:5]([NH:7][CH:8]1[C:43](=[O:44])[N:10]2[C:11]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:12]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])[CH2:13][S:14](=O)[C@H:9]12)=[O:6].CC(C)=O.[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:5]([NH:7][CH:8]1[C:43](=[O:44])[N:10]2[C:11]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:28])=[C:12]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS(=O)[C@H]12)c1nsc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1nsc(N)n1

Procedure:
A mixture of benzhydryl 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (syn isomer)(1.25 g) in a mixture of dry acetone (150 ml) and tetrahydrofuran (50 ml) was stirred under ice-water cooling and thereto were added sodium iodide (620 mg) and trifluoroacetic anhydride (0.59 ml) followed by stirring for 4 hours at the same temperature. The reaction mixture was evaporated under reduced pressure and to the residue were added ethyl acetate (60 ml) and water (20 ml). The ethyl acetate layer was separated therefrom, washed with 5% aqueous solution of sodium thiosulfate (20 ml×3), and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then evaporated under reduced pressure. The residue was washed with diethyl ether and dried to give benzhydryl 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate.ditrifluoroacetate (syn isomer)(0.9 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][CH:20]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cccc(OCc3ccccc3)c2)s1
Temperature: 70 °C
Reaction time: 3 h
Yield: 2.8 %

Procedure:
To a solution of the resulting 3-benzyloxy-phenol (2.6 g, 13.0 mmol) and a 5-nitrothiophene-2-carbonitrile (2.0 g, 13.0 mmol) in dimethylsulfoxide (25 mL) was added potassium carbonate (1.98 g, 14.0 mmol), and the solution was stirred at 70° C. for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile (110 mg, 2.8%) was obtained as a pale brown solid.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([CH2:12][CH3:13])([CH:8]([OH:11])[CH2:9][CH3:10])[CH2:4][O:3]1.O>CO>[CH2:12]([C:5]([CH2:6][OH:7])([CH:8]([OH:11])[CH2:9][CH3:10])[CH2:4][OH:3])[CH3:13]
Reactant: CCC(O)C1(CC)COC(C)(C)OC1
Solvent: O
Solvent: CO
Product: CCC(O)C(CC)(CO)CO
Reaction time: 3 h
Yield: 74.8 %

Procedure:
2,2-Dimethyl-5-ethyl-5-(1-hydroxypropyl)-1,3-dioxane (10 g.) and Dowex 50×8-200 ion exchange resin (H+ form) (1.0 g.) in methanol (200ml) containing water (40 ml) was refluxed with stirring for three hours. The mixture was filtered and the filtrate was evaporated in vacuo. 2-Ethyl-2-hydroxymethyl-pentan-1,3-diol (6.0 g.) was obtained as a colourless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:18][C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[O:31][CH3:32])=[N:21][C:20]=1[CH3:33]>N1C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:23][C:19]([NH:18][C:9](=[O:11])[CH:8]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=3)=[C:20]([CH3:33])[N:21]=2)=[C:25]([O:31][CH3:32])[CH:26]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: COc1cc(Cl)ccc1-c1nc(C)c(N)s1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C=CC(=O)Nc2sc(-c3ccc(Cl)cc3OC)nc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
4-Methoxycinnamic acid (178 mg, 1.0 mmol) and thionyl chloride (480 mg, 4.0 mmol) were heated under reflux for 2 hours. The excess thionyl chloride was distilled off. The resulting residue was dissolved in pyridine (1 ml). Under an ice cooling, the resulting solution was added to a solution of 5-amino-2-(4-chloro-2-methoxyphenyl)-4-methylthiazole (254 mg, 1.0 mmol) prepared in the Step 28-1-2 in pyridine (4 ml). After the removal of the ice bath, the mixture was stirred for 16 hours at a room temperature. To the mixture, 3.5% hydrochloric acid was added, and the resulting mixture was subjected to extraction with chloroform. The extract was washed with water. The washed product was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give the title compound (54 mg, 13%).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)C>[CH3:21][N:22]([CH3:24])[CH:23]=[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCCCCCc1ccc(CC(=O)OCC)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCc1ccc(C(=CN(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
0.50 g (2.0 mmol) of ethyl 2-(4-hexylphenyl)acetate was dissolved in 7 mL of N,N-dimethylformamide, mixed with 0.31 mL (2.3 mmol) of N,N-dimethylformamide dimethyl acetal and stirred at 60° C. for 18 hours. After the stirring, the reaction mixture was further mixed with 0.65 mL (4.9 mmol) of N,N-dimethylformamide dimethyl acetal and stirred at 60° C. for 24 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether and washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product as a brown liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(O)(=O)[CH2:18][C:19](CC(O)=O)(C(O)=O)[OH:20]>N1C=CC=CC=1>[C:10]([O:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([O:8][C:19](=[O:20])[CH3:18])[CH:7]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Oc1cc(O)cc(I)c1
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(I)cc(OC(C)=O)c1
Reaction time: 1 h

Procedure:
NMR (CDCl3) δ: 5.22 (2H, s), 6.31 (1H, t, J=2.5), 6.79 (2H, d, J=2.5) (3) 3,5-Dihydroxyiodobenzene (1.02 g) is dissolved in pyridine (2.8 ml), and thereto is added acetic anhydride (1.53 g) at room temperature. The mixture is stirred for one hour, and the reaction mixture is poured into 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure to give 3,5-diacetoxyiodobenzene (1.37 g).