Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:4](=[N:6][OH:7])[NH2:5])O.P(Cl)(Cl)(Cl)(Cl)Cl.O.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[NH2:5][C:4]1[C:3]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:1][O:7][N:6]=1
Reactant: NC(=NO)C(=NO)c1cccnc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: Nc1nonc1-c1cccnc1

Procedure:
Crude alpha-oximino-3-pyridylacetamidoxime (5 g) and phosphorus pentachloride (5 g) was refluxed in dry ether (250 ml) for 6 h. Water and potassium carbonate to alkaline pH was added and the phases separated. The aqueous phase was extracted with ether and the combined ether phases dried. Evaporation of the ether phases gave the title compound in 850 mg yield; M+ : 162.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[C:8](Cl)=[N:9][C:10](Cl)=[N:11][CH:12]=1)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[C:8]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:9][C:10]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1cccnc1
Product: CCOC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cccnc1
Temperature: 120 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester (326 mg, 1.0 mmol) (from Example 10a supra) and aniline (2.0 mL) (Aldrich) was heated at 120° C. for 1 hour. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester as a brown solid which was used in the next step without further purification. (Yield 60 mg, 13.7%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:23])=O.[OH-].[Na+]>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1O
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1Cl
Temperature: 120 °C
Reaction time: 4 h

Procedure:
The mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6-(morpholin-4-yl)quinoline and 3.4 mL of phosphoryl chloride is stirred at 120° C. for 4 hours. The cooled reaction mixture is poured onto 30 g of ice, the pH of the mixture is adjusted to 8 with 10% NaOH solution, and the precipitated material is filtered off. After drying 1.5 g of the title compound is obtained, m.p.: 206° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:13](=[C:15]([C:19]([OH:21])=O)[CH:16]=[CH:17][CH:18]=4)[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.Cl.[NH2:24][C@H:25]1[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[N:27]12[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28]1)[C@H:25]([NH:24][C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:12]3[O:11][C:10]([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)=[N:14][C:13]=13)=[O:21])[CH2:26]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(-c3ccc4c(c3)OCO4)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3ccc4c(c3)OCO4)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
A mixture of 2-benzo[1,3]dioxol-5-yl-benzoxazole-4-carboxylic acid (29 mg, 0.10 mmol), (S)-3-aminoquinuclidine dihydrochloride (24 mg, 0.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.20 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (66 μL, 0.40 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzo[1,3]dioxol-5-yl-benzoxazole-4-carboxamide (17 mg, 42%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.54 (d, J=7.0 Hz, 1H), 8.17 (dd, J=7.5, 1.0 Hz, 1H), 7.82 (dd, J=8.0, 1.5 Hz, 1H), 7.68 (dd, J=8.0, 1.0 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.11 (s, 2H), 4.33-4.29 (m, 1H), 3.56-3.48 (m, 1H), 3.13-2.99 (m, 2H), 2.95-2.88 (m, 2H), 2.85-2.79 (m, 1H), 2.18-2.13 (m, 1H), 1.80-1.59 (m, 4H); MS (ESI+) m/z 392 (M+H); HPLC 97.4% (AUC), tR=12.51 min.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30]>O1CCCC1.CCCCCC>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[C:24]([O:26][CH3:27])[O:25][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=Cc1ccccc1OCc1ccccc1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a dry ice-acetone bath cooled 1.45M solution of lithium diisopropylamide in a mixture of tetrahydrofuran and n-hexane (1.4 ml) was added methyl (2-benzyloxyphenyl)acetate (256 mg). The mixture was stirred for 30 minutes at the same temperature and then for 30 minutes at 0° C. After cooling the solution to −78° C. chlorotrimethylsilane (0.3 ml) was added and the mixture was allowed to warm to room temperature. The solution was diluted with n-hexane (50 ml), filtered through celite, and concentrated under reduced pressure to afford 2-(2-benzyloxyphenyl)-1-methoxy-1-trimethylsilyloxyethylene. To an ice bath cooled solution of (2S)-3-methyl-2-(p-tolylsulfonylamino)butanol (288 mg) in dichloromethane (10 ml) was added a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (1.0 ml) and the mixture was stirred for 30 minutes at ambient temperature. After cooling the solution to −78° C., cyclohexanecarbaldehyde (112 mg) and a solution of 2-(2-benzyloxyphenyl)-1-methoxy-1-trimethylsilyloxyethylene prepared above in dichloromethane (1 ml) were added. The solution was stirred for one hour at −78° C. and then quenched by an aqueous solution of sodium bicarbonate at 0° C. The mixture was extracted with diethyl ether, dried and evaporated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran (4 ml) and aqueous 1M solution of hydrochloric acid (2 ml), and the resulting solution was allowed to stand for 30 minutes. Aqueous solution of sodium bicarbonate was added thereto and the mixture was extracted with ether. The organic layer was dried and evaporated. Preparative thin layer chromatography [silica gel, ether - hexane (1:4)] afforded methyl (2R,3R)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (187 mg). High pressure liquid chromatography analysis (Daicel AD column eluting with 20% isopropyl alcohol - hexane) indicated an enantiomeric excess of 95% (Rt: major 10.51 minutes, minor 8.60 minutes).
Reaction SMILES: [CH:1]1([NH:6][C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([N:25]([C:35]([O:37]C5C=CC=CC=5)=O)C(=O)OC5C=CC=CC=5)[CH:20]=4)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C)C=O>[CH:1]1([NH:6][C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:35]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[O:37])[CH:20]=4)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc3c(ccn3C(=O)NC3CCCC3)c2)ccn1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCCC3)c2)ccn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
Phenyl N-(4-(1-cyclopentylaminocarbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (200 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (1.5 ml) and morpholine (0.15 ml, 1.73 mmol); and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300; ethyl acetate, ethyl acetate:methanol=10:1 in this order); the obtained colorless oil was crystallized by addition of diethyl ether; and the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound as colorless crystals (140 mg, 0.31 mmol, 90%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:11](=[O:12])[C:10](Br)=[C:9]([CH3:14])[N:8]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH3:16])[CH:7]=1)=[O:5])[CH3:2].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CO>[CH2:1]([NH:3][C:4]([C:6]1[C:11](=[O:12])[C:10]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)=[C:9]([CH3:14])[N:8]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH3:16])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(Br)c1=O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CCNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 75 °C
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid ethylamide (preparation 10, 50 mg, 0.129 mmol), 3-trifluoromethyl-phenylboronic acid (29 mg, 0.155 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 0.012 mmol) in acetonitrile (1 mL) is added 2 M aqueous K2CO3 solution (0.20 mL, 0.40 mmol). After stirring for 24 h at 75° C., the reaction mixture is diluted with methanol and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1% NH4OH, 60° C.). Yield: 56 mg (96% of theory); ESI mass spectrum: [M+H]+=454; Retention time HPLC: 0.93 min (Z011_S03).
Reaction SMILES: [OH-].[Na+].Cl.[CH:4]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[C:11]([F:20])[C:10]([O:21][CH:22]([CH3:24])[CH3:23])=[C:9]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[C:34]([CH3:42])[C:33]4=[O:43])[CH2:28][CH2:27]3)[CH:8]=2)[CH2:6][CH2:5]1.O>CO>[CH:4]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)=[C:11]([F:20])[C:10]([O:21][CH:22]([CH3:24])[CH3:23])=[C:9]([CH2:25][N:26]3[CH2:27][CH2:28][CH:29]([N:32]4[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[C:34]([CH3:42])[C:33]4=[O:43])[CH2:30][CH2:31]3)[CH:8]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC2)c(=O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
2M aqueous sodium hydroxide solution (690 mL) was added to a solution of methyl 1-(1-((6-cyclopropyl-2,4′-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate hydrochloride (270 g) in methanol (1.35 L) at room temperature. The mixture was stirred at 50 C for 2 hours and cooled to room temperature. Water (2.70 L) was added to the reaction mixture. The mixture was concentrated in vacuo to remove methanol and neutralized with 2M hydrochloric acid (460 mL) at room temperature. Crystalline seeds were added to the mixture. The mixture was stirred at room temperature for 17 hours. The precipitate was collected by filtration, washed with water (7.00 L) and dried in vacuo at 65 C for 24 hours to give the title compound (245.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>CC(C)=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][N+:3]=1[O-:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1Cc2ccnc(N)c2C1=O
Solvent: CC(C)=O
Product: CN1Cc2cc[n+]([O-])c(N)c2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
A mixture of 4-amino-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (Compound 310B, 62.5 mg, 0.383 mmol) and m-Chloroperbenzoic acid (145 mg, 0.843 mmol) in Acetone (10.0 mL) was stirred at rt for 90 minutes. The reaction mixture was concentrated under reduced pressure to an off white solid. The crude material was purified by silica gel chromatography on the combi-flash Rf system using DCM/7 N NH3 in MeOH (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (68.3 mg, 99.5%). 1H NMR (DMSO-d6, 400 MHz): δ=8.19 (d, J=6.57 Hz, 1H), 7.02 (br. s., 2H), 6.82 (d, J=6.57 Hz, 1H), 4.41 (s, 2H), 3.01 (s, 3H). MS (ES+): m/z 180.07 [MH+] (TOF, polar).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[NH:26][CH2:25][CH2:24][CH2:23]3)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[NH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])[CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2NCCC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
The mixture of 2-[(1,2,3,4-tetrahydro-quinoline-8-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (63) (259 mg, 0.71 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (15 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl dropwise until precipitate falls out of the water. After the filtration, the solid is washed by water and collected. The filtrate is acidified with conc. HCl carefully again to see if more precipitate comes out or not. The combined solid is dried in vacuo to give a pure product (64) as a yellow solid (205 mg, 86%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:34]1[N:35]=[CH:36][S:37][CH:38]=1)[C:19]([NH:21][CH:22]1[C:32](=[O:33])[N:24]2[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C.C(OC(C)C)(C)C.CCCCCC>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:34]1[N:35]=[CH:36][S:37][CH:38]=1)[C:19]([NH:21][CH:22]1[C:32](=[O:33])[N:24]2[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1cscn1
Solvent: COc1ccccc1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1cscn1
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
Trifluoroacetic acid (5.2 ml) was added to a suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.3 g) in methylene chloride (2 ml) and anisole (1.3 ml) at ambient temperature and the mixture was stirred for 1.5 hours at the same temperature. To the resulting solution was added diisopropyl ether (40 ml) and n-hexane (30 ml) under stirring. The precipitates were collected by filtration, washed with solution of diisopropyl ether and n-hexane (1:1). The precipitates were added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 7.5 with saturated aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 4.0 with 10% hydrochloric acid and the solution was washed with ethyl acetate. The resulting solution was adjusted to pH 1.8 with 10% hydrochloric acid under ice-cooling. The precipitates were collected by filtration, washed with cold water and dried over phosphorus pentoxide in vacuo to give 7-[2-carboxymethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][OH:10].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH:28]([O:30][CH2:31][CH3:32])=[CH2:29].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10][CH:28]([O:30][CH2:31][CH3:32])[CH3:29]
Reactant: OCc1cc(F)ccc1Br
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(C)OCc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Dissolve commercially available (2-bromo-5-fluoro-phenyl)-methanol (4.8 g, 23.4 mmol) in methylene chloride (100 mL) and cool to 0° C. Add PPTS (590 mg, 2.3 mmol) followed by ethyl vinyl ether (3.4 mL, 35.1 mmol). Warm reaction to room temperature slowly after addition. After 4 hours, pour the reaction into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry with sodium sulfate, filter and concentrate in vacuo to yield 5.4 g (83%) of the title compound as a clear and colorless oil. 1H NMR (CDCl3) 37.47 (dd, J=8.6, 5.0 Hz, 1M), 7.27 (dd, J=9.6, 3.1 Hz, 1H), 6.87 (td, J=8.0, 3.1 Hz, 1H), 4.89 (q, J=5.5 Hz, 1H), 4.65 (d, J=13.8 Hz, 1H), 4.54 (d, J=13.8 Hz, 1H), 3.70 (m, 1H), 3.55 (m, 1H), 1.42 (d, J=5.5 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][C:11]([NH:13][C:14]3[S:15][C:16]([C:20]([NH:22][C@@H:23]([CH2:27][NH:28][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[O:30])[C:24]([OH:26])=[O:25])=[O:21])=[C:17]([CH3:19])[N:18]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39][O:25][C:24](=[O:26])[C@@H:23]([NH:22][C:20]([C:16]1[S:15][C:14]([NH:13][C:11](=[O:12])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[N:2][NH:1]3)=[N:18][C:17]=1[CH3:19])=[O:21])[CH2:27][NH:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30]
Reactant: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Reactant: CC(C)(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OCCC(C)(C)C
Temperature: 100 °C
Yield: 35.9 %

Procedure:
A mixture of the (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (75.3 mg, 0.147 mmole), 3,3-dimethyl-1-butanol (1 mL, 8.054 mmol) and p-toluenesulfonic acid monohydrate (14.1 mg, 0.0741 mmol) was heated at 100° C. for 2½ hours. The reaction is cooled, neutralized and extracted with ethyl acetate (3×15 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (80% EtOAc in hexanes) to give (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]propionic acid 3,3-dimethyl-butyl ester (31.5 mg, 35.9%) as a white solid. MS m/e 597.7 (M+H+).
Reaction SMILES: CO[C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C@H:11]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[OH-:36].[Na+]>C(O)C>[CH:13]1([CH2:12][C@@H:11]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([NH:21][CH2:20][CH2:19][C:11]([OH:10])=[O:36])=[O:35])=[CH:9][CH:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(O[C@@H](CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCNC(=O)c1ccc(O[C@@H](CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1

Procedure:
or (S)-4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-benzoic acid methyl ester (85 mg) is taken into ethanol (2 mL), treated with 5N NaOH (1 mL) for 2 h at 40° C., concentrated, acidified with 5 N HCl, extracted with ethyl acetate, dried over sodium sulfate. Concentration gives 80 mg of (R) or (S)-4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-benzoic acid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].C(Cl)(Cl)Cl>CN(C)C=O>[N:28]([C@@H:11]1[CH2:10][C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:14]2[CH2:15][O:16][C@@H:12]1[O:13]2)=[N+:29]=[N-:30]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](OCc3ccccc3)[C@H]3CO[C@@H]2O3)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Temperature: 150 °C
Reaction time: 72 h
Yield: 89.7 %

Procedure:
To a solution of 1,6-anhydro-4-O-benzyl-3-deoxy-2-O-p-toluenesulphonyl-β-D-arabino-hexopyranose (See Preparative Example 3) (0.50 g) in N,N-dimethylformamide (10 ml) was added sodium azide (0.25 g) and the mixture was heated with stirring at 150° C. for 3 days. Chloroform was added and the mixture was washed with water (×4), dried (MgSO4) and concentrated to a syrup. Purification by flash chromatography gave the title compound (0.30 g), [α]D -14.8°; 13C-nmr data: 100.8 (C-1), 55.8 (C-2), 24.6 (C-3), 71.0 and 70.6 (C-4 and PhCH2O), 74.7 (C-5), 65.7 (C-6), 137.8, 128.4, and 127.7 (aromatic).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1)[C:5]([OH:7])=O.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1)[C:5]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)c1nnc(C)s1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nnc(C)s1
Yield: 42.9 %

Procedure:
2-Methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (syn isomer) (0.21 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (0.41 g.) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.23 g.), mp 175° to 178° C. (dec.).