Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([CH3:5])([O-:4])[CH3:3].[Li+].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[O:15][CH:14]2S(C1C=CC=CC=1)(=O)=O.[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[C:2]([C:5]1[CH:11]=[C:10]2[C:9]([C:32](=[O:31])[C:28]3[CH:16]([OH:18])[CH:17]4[C:13](=[C:14]([OH:15])[C:29]=3[CH2:30]2)[CH2:12][CH2:11][CH2:10][CH:9]4[O:8][CH3:7])=[CH:17][CH:16]=1)(=[O:4])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: COc1cccc2c1C(=O)OC2S(=O)(=O)c1ccccc1
Agent: [Li+]
Product: COC1CCCC2=C(O)C3=C(C(=O)c4ccc(C(C)=O)cc4C3)C(O)C21

Procedure:
To a magnetically stirred solution of lithium t-butoxide (8.8 mmol, prepared from 8.8 mmol of n-BuLi and 9.0 mmol of t-BuOH in 100 mL of THF), cooled to -78° C., was slowly added a slurry of 7-methoxy-3-phenylsulfonyl-1-(3H)-isobenzofuranone (6) (0.91 g, 3 mmol) in THF (20 mL).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][CH2:13]3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.CS(O[Na])=O.[C-:25]#[N:26].[K+]>CN(C=O)C>[CH3:18][C:15]1([CH3:19])[CH2:16][CH2:17][CH:12]([C:10]2[S:9][C:4]3[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:25]#[N:26])[C:3]=3[CH:11]=2)[CH2:13][CH2:14]1
Reactant: [C-]#N
Reactant: Cc1nc(Cl)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: CS(=O)O[Na]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C#N)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 70 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
To a mixture of 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (31.1 g) and DMF (220 mL) were added CH3SO2Na (11 g) and KCN (10 g), followed by heating and stirring at 70° C. for 15 hours. The reaction mixture was concentrated to about a half of the amount under reduced pressure, diluted with water (300 mL), and then stirred. The precipitate was collected by filtration. To the precipitate was added chloroform, followed by dissolving therein, and MgSO4, activated carbon (10 g), and silica gel (100 mL) were added thereto, followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (27.4 g).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])=O)(C)(C)C.[CH:17](C1C=CC=CC=1B(O)O)=O.[BH4-].[Na+].C[Si]([Cl:34])(C)C>CO.C(N(CC)CC)C.CO>[ClH:34].[ClH:34].[NH2:8][C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Reactant: O=Cc1ccccc1B(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](N)CCCN
Product: Cl

Procedure:
Nα-tert-Butyloxycarbonyl-ornitine was reacted with 2-formylphenylboronic acid in methanol-triethylamine and subsequently treated with sodium borohydride (Wiskur et al, Org. Letters 2001, 3, 1311). The resulting secondary amine was transformed to the methyl ester by treatment with methanol and trimethylsilyl chloride, 10:1, to give N′-(2-boronobenzyl), methyl ornitinate, dihydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.CCN(CC)CC.[CH3:42][O:43][C:44](=[O:61])[CH2:45][NH:46][C:47](=[O:60])[C@H:48]([CH:55]([CH3:59])[CH:56]=C=O)[NH:49]OC(C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:42][O:43][C:44](=[O:61])[CH2:45][NH:46][C:47](=[O:60])[C@H:48]([CH:55]([CH3:56])[CH3:59])[NH:49][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)CNC(=O)[C@@H](NOC(C)(C)C)C(C)C=C=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(C)C
Reaction time: 0.25 h

Procedure:
A solution of N-benzyloxycarbonyl-L-leucine (2.65 g, 10 mmol) in 15 ml CH2Cl2 was cooled in an ice-water bath and stirred with a magnetic stirrer. A solution of dicyclohexylcarbodiimide (2.58 g, 12.5 mmol) in CH2Cl2 was added, and stirring was continued for 15 minutes. Dicyclohexylurea was filtered. The solvent was evaporated in vacuo or at room temperature. The residue was dissolved in 4 ml DMF(1) and cooled in an ice-water bath. CF3CO2H·H-Val-Gly-OMe(1.51 g, 5 mmol) was dissolved in 7 ml DMF, and Et3N (0.25 g =0.34 ml, 2.5 mmol) was added, whereupon the mixture was added to the solution (1) and Et3N (0.34 ml) was again added. Stirring was continued for 24 hours at room temperature. The reaction mixture was filtered, diluted with water and AcOEt and separated. The water layer was extracted twice with AcOEt. Collected organic phases were washed once with water, once with 0.5M NaHCO3, once with water, once with 1N HCl, and twice with water and dried over anhydrous MgSO4. After filtration the solvent was evaporated in vacuo. The solid residue was triturated with petroleum ether, filtered and dried in vacuo.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:4][CH:5]=[C:6](CCC=O)[CH:7]=1.C(C(CCCCCCCC)(C([O-])=O)C([O-])=O)CCCCCCC.C(O)(=O)C.N1CCCCC1>O1CCCC1>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)c1cc(CCC=O)co1
Agent: CCCCCCCCC(CCCCCCCC)(C(=O)[O-])C(=O)[O-]
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: C[Si](C)(C)c1ccco1

Procedure:
3-(2-Trimethylsilyl-4-furyl)propan-1-al is reacted with dioctylmalonate in tetrahydrofuran in the presence of acetic acid and piperidine to give 3-[4,4-di (carbooctanoxy)-3-butenyl]- 5-trimethylsilylfuran which is treated with cold aqueous potassium hydroxide to give 3-(4-carboxy-4-carbooctanoxy-3-butenyl)-5-trimethylsilylfuran.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=O)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:32])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:23][F:32])=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CS(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CF)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CF)[C@@H](c2ccc(SCF)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-5-(4-methanesulfinyl-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g, 2.69 mmol) in DCM (50 mL) is cooled to 0° C. followed by addition of SbCl3 (0.018 g, 0.081 mmol) and DAST (0.6 mL, 4.582 mmol). The resulting reaction mixture is stirred at RT for 16 h. After completion reaction mixture is quenched with aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by combi-flash chromatography (12 g column) using 8% ethyl acetate in n-Hexane as an eluent to afford title compound (564 mg) as colorless oil. 1H-NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.48 (s, 3H), 1.61 (s, 3H), 377-.382 (m, 1H), 4.42-4.53 (m, 1H), 4.76-4.92 (m, 1H), 5.06 (d, J=7.36 Hz, 1H), 5.99 (d, J=52.32 Hz, 2H), 7.46-7.51 (m, 4H). LC-MS (m/z): M+H=374.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([N:10]([CH3:12])[CH3:11])=O)[CH:4]=1.[H-].[Al+3].[H-].[H-].O>O1CCCC1.Cl>[CH3:12][N:10]([CH2:8][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[S:7][CH:6]=1)[CH3:11]
Reactant: CN(C)C(=O)c1csc(CO)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1csc(CO)c1
Reaction time: 2 h

Procedure:
A solution of 5-(hydroxymethyl)-N,N-dimethyl-3-thiophenecarboxamide (1.7 g) in dry tetrahydrofuran (150 ml) was treated with a 0.5 M solution of aluminium hydride in tetrahydrofuran (26 ml). After 2 h at room temperature, water (5 ml) was cautiously added and the mixture was filtered through diatomaceous earth. The filtrate was evaporated to leave an oily residue, which was dissolved in 2 M hydrochloric acid (20 ml). The aqueous solution was washed with diethyl ether, basified with 5 M sodium hydroxide and extracted with ethyl acetate.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=2)=[CH:57][C:56]=1[CH3:68]>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:62]=2)=[CH:57][C:56]=1[CH3:68]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 67 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 65% yield: LCMS (ESI) m/z 470 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15](=O)[O:16]C(C)(C)C)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([NH:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1c(N)cccc1O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1c(O)cccc1NC(=O)OC(C)(C)C
Yield: 69 %

Procedure:
3-Amino-2-methylphenol (2.0 g; 16 mmol) and di-t-butylcarbonate were dissolved in THF (20 mL) and refluxed overnight. Evaporation of the solvent followed by flash chromatography (SiO2; EtOAc 5–30% in isohexane) afforded 2.48 g (69%) of the sub-title compound.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11][O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[Cl:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>>[Cl:17][CH2:18][CH2:19][NH:20][C:21]([N:15]([CH2:14][CH:13]([O:12][CH3:11])[CH3:16])[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:22]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C=NCCCl
Reactant: COC(C)CN
Product: COC(C)CN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 45.9 %

Procedure:
3.0 g of L-arabinose, 3.6 g of 2-methoxy-n-propyl-amine and 3.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 13-(1). 3.0 g of 1-(2-chloroethyl)-3-(2-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[Li+].[OH-].CO.Cl>O.CCOC(C)=O>[C:18]([O:17][C:15]([N:6]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:5][C:4]([OH:22])=[O:3])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CN(CCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)CC(=O)O

Procedure:
A solution of the ester 14-1 (1.7 g, 5.5 mmol), 11.1 mL 1N LiOH and 11 mL MeOH was stirred at room temperature for 16 h. The mixture was poured into water/EtOAc and acidified with 1N HCl to pH≈3. After extraction with EtOAc (2×), the organic layers were washed with brine, dried (MgSO4) and evaporated to give 14-2 as a foam which was used as such in the next step. ##STR97##
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10](Cl)(=[O:12])=[O:11])#[N:2].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1.O.Cl>C1COCC1>[F:9][C:8]1[C:3]2[C:1](=[NH:2])[N:18]([CH2:17][CH:14]3[CH2:16][CH2:15]3)[S:10](=[O:11])(=[O:12])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(F)cccc1S(=O)(=O)Cl
Reactant: NCC1CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N=C1c2c(F)cccc2S(=O)(=O)N1CC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 mg of 2-cyano-3-fluoro-benzenesulfonyl chloride (EP33984 A1 19810819) is added to a solution of 0.85 ml of cyclopropylmethylamin in 3.5 ml of THF. After stirring for 3 hours at room temperature the reaction mixture is poured into water. The mixture is acidified with hydrochloric acid (˜pH3) and extracted three times with methylenchloride. The combined organic phases are dried (Na2SO4), filtered and concentrated. Preparative HPLC affords 16 mg of 4-fluoro-2-cyclopropylmethyl-1,2-benzisothiazol-3(2H)-imine 1,1-dioxide as an orange solid (m.p. 90-93° C.).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].ClC([O:10][C:11]1[CH:16]=C[C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)=O.Cl.[OH2:21]>CC(C)=O>[OH:10][CH:11]([C@H:12]1[O:2][C:1](=[O:4])[NH:17][CH2:14][CH2:13]1)[CH2:16][OH:21]
Reactant: O
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1NCC[C@@H](C(O)CO)O1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
The product from (A), (1 g.), was dissolved in water (20 ml.) and sodium carbonate (2 g.) and a solution of p-nitrophenyl chloroformate (3 g.) in acetone (10 ml.) were added with stirring at 0° C. The solution was kept at 3° C. for 16 hours, then acidified with 5N hydrochloric acid and washed several times with ethyl acetate. The aqueous solution was evaporated and the residue was extracted with ethanol and chromatographed on a column of silica eluting with a gradient of chloroform/ethanol to give 6-(S)-(1',2'-dihydroxyethyl)tetrahydro-1,3-oxazin-2-one (0.65 g., 55%).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]([O:19]C)=[O:18])=[CH:6][CH:5]=1.Cl>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:21])[CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]([OH:19])=[O:18])=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Cn1cccc1C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
Lithium hydroxide (116.73 mg, 2.15 mmol) was added to a solution of methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (515 mg, 1.85 mmol) in THF (9 mL) water (1 mL) and stirred at room temperature overnight. The mixture was acidified to pH 2 with aqueous HCl (1M) and extracted with EtOAc (3×10 mL). The organic layers were combined and dried (MgSO4), filtered, concentrated in vacuo to give a cream white solid. The solid was triturated with cold CH2Cl2 to give 1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid as a white solid (310 mg, 64%). 1H NMR (400 MHz, d6-DMSO): δ 5.86 (s, 2H), 6.16 (dd, 1H, J 3.9, 2.6 hz), 6.86 (dd, 1H, J 3.9, 1.8 Hz), 7.08 (t, 1H, J 2.1 Hz), 7.65-7.70 (m, 2H), 8.02-8.08 (m, 2H), 12.07 (br s, 1H).
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.C(N(CC)CC)C.[F:19][C:20]([F:60])([F:59])[C:21]1[CH:22]=[C:23]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[CH2:24][N:25]1[C:29]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:28]([C:36]([C:38]2[C:39]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])=[N:40][O:41][C:42]=2[CH2:43]O)=[O:37])[N:27]=[N:26]1>ClCCl.C1COCC1>[F:56][C:55]([F:58])([F:57])[C:53]1[CH:52]=[C:23]([CH:22]=[C:21]([C:20]([F:59])([F:60])[F:19])[CH:54]=1)[CH2:24][N:25]1[C:29]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:28]([C:36]([C:38]2[C:39]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])=[N:40][O:41][C:42]=2[CH2:43][Cl:10])=[O:37])[N:27]=[N:26]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Add N,N-dimethylaminopyridine (119 mg, 0.974 mmol), p-toluenesulfonyl chloride (465 mg, 2.44 mmol) and triethylamine into an ice-cold solution of [1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chlorophenyl)-5-hydroxymethyl-isoxazol-4-yl]-methanone (1.0 g, 1.62 mmol) in dichloromethane (5.0 mL) and THF (5.0 mL). Warm the mixture to RT. After 1 h., concentrate in vacuo. Dilute the mixture with dichloromethane (50 mL) and wash with water (3×40 mL). Dry (MgSO4), filter, and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to provide the title compound (59% yield) as a brown oil. MS (ES) 634.1 (M++1); TLC Rf=0.5 (50% EtOAc in hexanes).
Reaction SMILES: C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[N:28]=1.[CH3:39][O:40][C:41]1[C:49]2[O:48][CH2:47][CH2:46][C:45]=2[CH:44]=[C:43]([CH:50]=O)[CH:42]=1.FC(F)(F)C(O)=O.[C:59](C1C=CC(NC(C2C=C(OC)C(OC)=CC=2F)C2NC(=O)N(C3C=CC=CC=3C(O)=O)N=2)=CC=1)(=N)[NH2:60].C[Si](C#N)(C)C>C1COCC1>[CH3:39][O:40][C:41]1[C:49]2[O:48][CH2:47][CH2:46][C:45]=2[CH:44]=[C:43]([CH:50]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([C:29]3[N:28]=[C:27]([CH3:26])[O:31][N:30]=3)=[CH:33][CH:34]=2)[C:59]#[N:60])[CH:42]=1
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: COc1cc(C=O)cc2c1OCC2
Reactant: COc1cc(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Agent: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc2c1OCC2

Procedure:
To a solution of 426 mg of Yb(OTf)3 in 30 ml of THF there were added 1.2 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 1.22 g of 7-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde [CAS No. 363185-46-0], 1g of MS3A and 1.9 ml of trimethylsilyl cyanide under a nitrogen atmosphere, and the mixture was stirred at room temperature. The reaction mixture was filtered through celite, and the celite was washed with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of (7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[C:6]#[N:7].Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[C:6](=[N:15][OH:16])[NH2:7]
Reactant: N#Cc1c(F)cccc1OC(F)F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1c(F)cccc1OC(F)F
Temperature: 75 °C
Reaction time: 20 h

Procedure:
A mixture of 6.4 g of 2-difluoromethoxy-6-fluorobenzonitrile and 3.1 g of hydroxylamine hydrochloride, 2.6 g of sodium carbonate, 7 ml of water and 35 ml of ethanol was stirred for 20 hours at 75° C.
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[OH:6][C@H:7]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)[CH2:8][C:9](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=[O:10]>>[OH:6][CH:7]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)[CH2:8][C:9]([OH:10])=[O:2]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCc1ccc(F)cc1
Reactant: O=P([O-])([O-])[O-]
Product: O=C(O)CC(O)CCc1ccc(F)cc1

Procedure:
Then 10 parts of the above described immobilized enzyme was suspended in 480 parts of a 0.1M phosphate buffer (pH 7.0), then 10 parts of (R)-3-hydroxy-5-(4-fluorophenyl)valeryl CoA (prepared by a method described in Eur. J. Biochem., 250, 432–439 (1997) after obtaining 3-hydroxy-5-(4-fluorophenyl)valeric acid by hydrolyzing 3-hydroxyphenyl valeric acid ester obtained by a Reformatsky reaction) and one part of bovine serum albumin (Sigma) were added to the suspension, and this suspension was moderately shaken for two hours at 30° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([O-:20])=[O:19])=[C:14]([CH3:17])[CH2:15][S:16][C@H:11]12)=[O:8].C1([O:29]C)C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:29][CH:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:7]([NH:9][CH:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[C:14]([CH3:17])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: COc1ccccc1
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3ccco3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3ccco3)[C@H]2SC1
Yield: 57.3 %

Procedure:
Diphenylmethyl (6R,7R,2'R and S)-7-(2'-[fur-2-yl]-acetamido)-3-methylceph-3-em-4-carboxylate (463mg, 1.365 mmole) was treated with anisole and trifluoroacetic acid in the manner described previously [see Example 10 (b)] to give (6R,7R,2'R and S)-7-[2'-hydroxy-2'-(fur-2-yl)acetamido]-3-methylceph-3-em-4-carboxylic acid as a foam (368mg, 1.09 mmole, 57.3%). The title compound was obtained from the acid (368mg, 1.1 mole) by treatment with sodium 2-ethylhexanoate in acetone and ether, as a pale-brown solid containing 21/2mole-equivalents of water (i.r. and microanalysis), (221mg, 0.545 mmole, 50%); λmax (pH6 buffer) 220 and 258nm (ε10,780 and 8,000 respectively); νmax (Nujol) 3370 (OH,NH, and H2O), 1755 (azetidin-2-one), 1675 and 1518 (CONH), and 1590 cm-1 (CO2-); τ(Me2SO-D6) 1.57 and 1.63 (total 1H,2d, J9Hz, NH), 2.37 (1H,s) and 3.59 (2H,m) (furyl protons), 4.44 (1H,m, C7 -H), 4.81 and 4.83 (total 1H, 2s, -CHOH), 4.97 (1H,d,J5Hz, C6 -H), 6.47 and 6.86 (2H,ABq, J18Hz, C2 -H2), 8.00 (3H,s, C3 -CH3). (Found: C, 41.2, 41.5; H,3.4, 3.6; N,6.4, 6.5; S,7.8; Na,5.9. C14H13N2NaO6S.2.5 H2O (405.3) requires: C, 41.6; H,4.5; N,6.9; S,7.9; Na,5.7%).
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH3:39][S:40]([O-])(=[O:42])=[O:41]>CN(C=O)C.O>[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1)NC1CC1
Reactant: CS(=O)(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 23.2 %

Procedure:
To a stirred suspension of compound 271 (150 mg, 0.302 mmol) and K2CO3 (180 mg, 1.302 mmol) in DMF (10 mL) was added 2,5,8,11-tetraoxamidecan-13-yl methanesulfonate (112 mg, 0.39 mmol, K. Fukase, et al., SynLett., 2005, 2342-2346). The reaction mixture was stirred at RT for 2.5 days, diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; MeOH/DCM: 0/100 to 15/85 over 20 CV) tp produce a material that upon trituration with Et2O/hexane afforded an unexpected compound 275 (35 mg, 0.07 mmol, 21% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.45 (d, J-5.6 Hz, 1H), 7.71 (dd, J=2.8 and 13.6 Hz, 1H), 7.57 (s, 1H), 7.35 (t, J=8.8 Hz, 1H), 7.22-7.16 (m, 1H), 6.02-5.95 (m, 2H), 6.44 (t, J=3.2 Hz, 1H), 3.95-3.90 (m, 2H), 3.42 (t, J=6.4 Hz, 2H), 2.96 (s, 3H), 2.58-2.50 (m, 1H), 0.68-0.62 (m, 2H), 0.44-0.41 (m, 2H). MS (m/z): 503.3 (M+H).