Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18](N(OC)C)=[O:19])[CH:5]=[CH:6][CH:7]=1.[CH3:24][Mg]Br.CCOCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18](=[O:19])[CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N,3-dimethyl-1H-indole-2-carboxamide (0.27 g, 0.86 mmol) in tetrahydrofuran (5 mL) was added 3.0 M methylmagnesium bromide in ether (2.3 mL, 6.9 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-15% EtOAc/hexane) to give the desired product (0.165 g, 71%). LCMS calculated for C17H15FNO(M+H)+: m/z=268.1. Found: 268.0.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].CCCCCC.C(OCC)(=O)C>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([CH2:20][N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: c1nnn[nH]1
Reactant: COC(=O)c1cc(CCl)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(Cn2cnnn2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine tetrazole (0.45 g, 6.42 mmol) and dimethylformamide (6 mL). Cool in an ice bath and add sodium hydride (0.26 g, 60% i oil, 6.5 mmol). After 30 minutes, warm to ambient temperature. Add a solution of methyl 2-methoxy-5-chloromethylbenzoate (1.13 g, 4.12 mmol) in dimethylformamide (10 (mL). Heat to 75° C. After 5.5 hours, partition the reaction mixture between water and ethyl acetate. Extract the organic layer with water, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 7/3 hexane/ethyl acetate to give methyl 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoate: Rf=0.67 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[O:13][N:12]=2)=[CH:3]1.[ClH:41]>>[ClH:41].[CH3:21][C:20]1[NH:19][CH:18]=[N:17][C:16]=1[C:14]1[O:13][N:12]=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[N:15]=1
Reactant: Cc1c(-c2nc(-c3cn(C)c4ccccc34)no2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: Cc1[nH]cnc1-c1nc(-c2cn(C)c3ccccc23)no1
Reaction time: 0.5 h

Procedure:
3-(1-Methyl-1H-indol-3-yl)-5-(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)-1,2,4-oxadiazole (1.1 g) was suspended in methanolic hydrogen chloride. The mixture was stirred for 30 minutes and was refrigerated for 6 h. The title compound was filtered yielding (0.5 g) as a white powder, m.p. 260°-262° C. Found: C, 57,02; H, 4.58; N, 22.07; C15H13N5O.HCl requires C, 57.06; H, 4.47; N, 22.19%; δH (360 MHz, DMSO-d6) 2.70 (3H, s, CH3), 3.92 (3H, s, N-CH3), 7.27 (1H, t, J=6.2 Hz, CH), 7.32 (1H, t, J=6.1 Hz, CH), 7.59 (1H, d, J=7.5 Hz, CH), 8.10 (1H, d, J=7.5 Hz, CH), 8.17 (1H, s, CH), 8.68 (1 H, s, CH); m/z 279 (M+, 70%).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([F:4])[F:3].O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: Oc1ccc(SC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(SC(F)(F)F)cc2)CC1
Yield: 79.1 %

Procedure:
A solution of 2 g 4-trifluoromethylsulfanyl-phenol, 2.07 g t-butyl 4-hydroxy-1-piperidinecarboxylate, 3.2 g triphenyl phosphine and 5.4 g diethyl azodicarboxylate (40% toluene solution) in anhydrous tetrahydrofuran (40 mL) was heated for 24 hours under reflux in a stream of nitrogen. Water was added thereto, and the reaction solution was extracted with ethyl acetate, dried over sodium sulfate, and purified by NH silica gel chromatography (hexane/ethyl acetate) to give 3.07 g of the title compound.
Reaction SMILES: [C:1]1([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>CO.O>[C:1]1([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCC1CCCCN1S(=O)(=O)c1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCC1CCCCN1S(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a solution of methyl 4-(1-(naphthalene-1-ylsulfonyl)piperidin-2-yl)butanoate (Ester-12) (4.95 g, 13.18 mmol.) in Methanol/Water (54 ml/36 ml) lithiumhydroxide (1.58 g, 65.9 mmol) was added and the reaction mixture was stirred over night at room temperature. The completion of the reaction was controlled via thin-layer chromatography. After completion the methanol was evaporated in vacuum, and the residue was triturated with ethyl acetate. The mixture was made acidic with diluted HCl. The aqueous layer was extracted 2× with ethyl acetate, the combined organic layers were dried over sodium sulfate and were evaporated in vacuum to give the desired product 4-(1-(Naphthalen-1-ylsulfonyl)piperidin-2-yl)butanoic acid (AC-12) (4.38 g, 91%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([NH:10][C:11]1[N:16]=[C:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH:14]=[CH:13][CH:12]=1)=[O:9].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1>>[CH3:7][C:5]1[S:6][C:2]([NH:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[C:3]([C:8]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH:14]=[CH:13][CH:12]=2)=[O:9])[N:4]=1
Reactant: CC(=O)OCc1cccc(NC(=O)c2nc(C)sc2Br)n1
Reactant: Nc1cccnc1
Product: CC(=O)OCc1cccc(NC(=O)c2nc(C)sc2Nc2cccnc2)n1

Procedure:
A solution of 5-bromo-2-methyl-thiazole-4-carboxylic (prepared as described in example 119, steps A to B) (0.13 g, 0.60 mmol) in dichloromethane (5.00 ml) and DMF (0.10 ml) was treated with thionyl chloride (0.08 g, 0.66 mmol) and stirred at room temperature for 4.5 h. After this time, 6-amino-pyridin-2-ylmethyl ester (0.10 g, 0.60 mmol) and DIPEA (0.16 g, 1.20 mmol) were added, and the mixture stirred for 30 min. The solvents were then evaporated and the residue purified by flash chromatography (heptane/ethyl acetate) to yield acetic acid 6-[(5-bromo-2-methyl-thiazole-4-carbonyl)-amino]-pyridin-2-ylmethyl ester (0.17 g, 76%) as a white solid, MS (ISP): m/e=372.0, 370.0 (M+H+). Acetic acid 6-[(5-bromo-2-methyl-thiazole-4-carbonyl)-amino]-pyridin-2-ylmethyl ester was then coupled with pyridin-3-ylamine in step B to yield the title compound.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:19]Br>P(OC)(OC)(OC)=O>[Br:19][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:1]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)c1ccccc1c1ccccc21
Solvent: COP(=O)(OC)OC
Product: Brc1ccc2c3ccccc3c3ccccc3c2c1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
3.2 g (14 mmol) of triphenylene was dissolved in 60 mL of trimethyl phosphate. To the suspension was added 2.23 g (14 mmol) of bromine in 10 mL of trimethyl phosphate at room temperature under N2. The mixture was then heated up to 80° C. The reaction was monitored by HPLC. The reaction was quenched by pouring into ice water, then extracted with dichloromethane and washed with saturated sodium bisulfite solution. After drying with magnesium sulfate, the solvent was evaporated. The crude product was run through a short silica gel plug using dichloromethane. 3.0 g of product was obtained after drying under vacuum. The product contains triphenylene, 1-bromotriphenylene, 2-bromotriphenylene, and a mixture of dibromotriphenylene isomers.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[OH2:30]>>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:30])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4]
Reactant: O
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21

Procedure:
Lovastatin shows poor solubility under the aqueous conditions necessary for enzymatic activity. Alternatively, in one aspect, a suspension of lovastatin in water is raised to pH>12 to effect a rapid hydrolysis of the lactone ring resulting in the in-situ formation of the more soluble lovastatin acid salt. In practice, a suspension of lovastatin in water/MeOH is treated with a solution of 1 mole equivalent of NaOH in water and stirred until dissolution is complete. The pH of the reaction mixture is then readjusted to a range suitable for the enzymatic reaction and the enzyme is added.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:26])[C:13](=[O:14])[O:12][CH2:11][C:10]([CH3:16])([CH3:15])[N:9]1[O:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].[NH4+].[Cl-].CCOC(C)=O>C1COCC1.O>[OH:14][CH2:13][C:8]([N:9]([O:17][CH:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[C:10]([CH3:15])([CH3:16])[CH2:11][OH:12])([CH3:7])[CH3:26]
Reactant: CC(ON1C(C)(C)COC(=O)C1(C)C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(ON(C(C)(C)CO)C(C)(C)CO)c1ccccc1
Reaction time: 5 h
Yield: 93.8 %

Procedure:
To a suspension of 2.93 (75 mmol) LiAlH4 in THF (100 ml) is slowly added at 0-10° C. a solution of 13.9 g (50 mmol) of compound 101 in THF (50 ml). After complete addition, the suspension is heated to reflux and kept at this temperature for 5 h. The mixture is cooled in an ice-bath and saturated NH4Cl-solution (25 ml) is added carefully. EtOAc (500 ml) and water (100 ml) is added, the phases separated and the organic layer washed with water (100 ml) and brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 13.2 g (94%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][N+:11]([O-])=[C:10]([CH3:15])[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:15][O:20][C:17](=[O:19])[CH3:18])[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1cc[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Product: CCCCCCOc1ccnc(COC(C)=O)c1C
Yield: 66.3 %

Procedure:
To 32.6 g (0.1 mol, 1.0 eq.) of 4-hexyloxy-2,3-dimethylpyridine-N-oxide, 40.8 g (0.4 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 5 hours at 87 to 93° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 17.6 g of 4-hexyloxy-2-acetoxymethyl-3-methylpyridine as an oily matter (yield 74.3%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[NH:13]C(=O)C.O1CCOCC1.[ClH:23]>CO>[ClH:23].[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[NH2:13]
Reactant: COc1cc(C)c(NC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C)c(N)cc1[N+](=O)[O-]

Procedure:
A slurry of N-[2-methyl-4-(methyloxy)-5-nitrophenyl]acetamide (1 g, 4.46 mmol) in methanol (20 ml) and 4M HCl in dioxane (8.92 ml, 35.7 mmol) was heated at 60° C. for 18 h. The reaction mixture was cooled in an ice bath and solids were filtered and washed with cold methanol to afford 2-methyl-4-(methyloxy)-5-nitroaniline HCl salt (0.516 g, 2.36 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3 H) 3.91 (s, 3 H) 7.31 (s, 1 H) 7.87 (s, 1 H) 9.39 (br. s., 2 H)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.F[C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39])[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C(#N)C>[OH:34][C:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][C:23]2[CH:35]=[CH:36][C:37]([N+:38]([O-:40])=[O:39])=[C:21]([NH:1][C@@H:2]3[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]3)[CH:22]=2)[CH2:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@@H](C(=O)O)CC3)c2)CC1
Temperature: 75 °C
Reaction time: 48 h
Yield: 143.2 %

Procedure:
To a suspension of cis-4-aminocyclohexanecarboxylic acid (0.199 g, 1.392 mmol) and DIPEA (0.553 mL, 3.16 mmol) in ACN (5 mL) was added 2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol (0.375 g, 1.265 mmol). The reaction was stirred at 75° C. After 48 hours, the reaction mixture was concentrated, diluted with water (10 mL), and extracted with DCM and EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide cis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylic acid as an orange powder (0.76 g, 143% yield).
Reaction SMILES: O[C:2]1[C:7]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[C:6](O)[C:5](O)=[C:4](O)[C:3]=1O.P(O)(O)([O-])=[O:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Na+]>O>[CH:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[C:9]2/[C:10]([C:12]3[C:17]([O:23]/2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])=[CH:2][CH:3]=1
Reactant: O=C(C=Cc1c(O)c(O)c(O)c(O)c1O)c1ccccc1
Reactant: O=P([O-])(O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Product: O=C1/C(=C/c2ccccc2)Oc2ccccc21

Procedure:
In addition, the reaction was carried out under the same conditions using pentahydroxychalcone (PHC) instead of THC as a substrate, and using 0.116 M sodium citrate phosphate buffer (pH 5.4) as a buffer. Similarly, water was used instead of tyrosinase as a control.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>O1CCCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: O=S(=O)(c1c[nH]cn1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A dry round botton flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with a filtered solution of 8.33 g of imidazole-4-sulfonylchloride in 300 ml of tetrahydrofuran (THF). The clear solution was treated with 7.0 g of imidazole in one portion and allowed to stir overnight at room temperature. The reaction mixture was filtered and the filtrate concentrated to dryness. All the solids were triturated with water, filtered, rinsed with water and dried at high vacuum over NaOH. Recrystallization from ethanol gave 5.35 g of white crystals of 1-(4-imidazolylsulfonyl)imidazole mp 208°-10°, λmaxnujol 3.21 (HH), 7.29 (SO2N) and 8.52 μ (SO2N). NMR (DMSO, d6) 570-510 Hz, M, 1H; 497 Hz, t, J ~ 1 Hz, 2H; 481 Hz, d J ~ 1 Hz, 1H; 457 Hz, t, J ~ 1 Hz, 1H; 429 Hz, t, J ~ 1 Hz, 1 H.
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][O:14][C:15]2([C:19]([F:22])([F:21])[F:20])O)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)Cl.O.[NH4+].[Cl-]>[F:22][C:19]([F:20])([F:21])[CH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:17]=2)[CH2:13][O:14]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(O)(C(F)(F)F)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)C(C(F)(F)F)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 6-[tert-butyl(dimethyl)silyl]oxy-1-(trifluoromethyl)-3H-isobenzofuran-1-ol (Intermediate 26, 1.2 g, 3.59 mmol) in DCM (20 mL) 2,2,2-trifluoroacetic acid (5.5 ml, 71.77 mmol) and then triethylsilane (2.86 ml, 17.94 mmol) were added and the reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with DCM (50 ml) and water (30 ml) and two phases were separated. The organic layer was washed with brine (2×20 ml), dried (Na2SO4), filtered and evaporated. The residue was dissolved in THF (20 mL) and tetrabutylammonium fluoride 1M in THF (3.6 ml, 3.6 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with an aqueous saturated solution of NH4Cl (30 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 25 g as column and cyclohexane/ethyl acetate from 100:0 to 70:30 as eluent affording the title compound (550 mg) as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@H:14]2[C@@H:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C@@H:17]3[C@@H:16]([O:24][CH2:25][CH2:26][OH:27])[CH2:15]2)=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].C(O)(=O)C.[N:32]([O-])=O.[Na+]>O.C(OCC)(=O)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:32][N:13]([C@H:14]3[C@@H:18]4[O:19][C:20]([CH3:22])([CH3:23])[O:21][C@@H:17]4[C@@H:16]([O:24][CH2:25][CH2:26][OH:27])[CH2:15]3)[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Temperature: 2.5 °C

Procedure:
A flask was charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol (50 g), acetic acid (265 mL) and water (50 mL). The mixture was stirred and cooled to 0-5° C. followed by addition of aqueous sodium nitrite solution (8.65 g in 50 mL) over a period of about 1 hour. The mixture was stirred at the same temperature for about 2 hours followed by addition of ethyl acetate (250 mL) and water (250 mL). The mixture was further stirred at room temperature for about 45 minutes at which point water (250 mL) was added. The mixture was stirred and layers were separated, aqueous layer was extracted with ethyl acetate (250 mL). Total organic layer was separated and washed with aqueous potassium carbonate solution (20%, 2×250 mL). The organic layer (˜500 mL) was used for subsequent step.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:25])([O:23][CH3:24])[CH3:22])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:62][CH:63](Br)[CH3:64])(=[O:61])[CH3:60].Cl>O.CN(C)C=O>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:22])([O:23][CH3:24])[CH3:25])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([O:13][CH:63]([O:62][C:59](=[O:61])[CH3:60])[CH3:64])=[O:12])=[N+:2]=[N-:3]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A mixture of 739 mg of 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid, 76 mg of potassium carbonate and 3 ml of dimethylformamide was stirred at 20° C. for 10 minutes and after cooling the mixture to 0° to 50° C., 0.6 g of 1-bromoethyl acetate was slowly added thereto. The mixture was stirred for 20 minutes at 0° to 5° C. and for one hour at 20° C. and then a mixture of 40 ml of iced water and 1.5 ml of N hydrochloric acid were added thereto. The mixture was vacuum filtered and the product was rinsed with water and dried to obtain 761 mg of the syn isomer of 1-acetoxyethyl 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.N(OCCC(C)C)=O.[ClH:40]>C(#N)C.[Cu](Cl)Cl>[Cl:40][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
9 g (19.762 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrile are initially charged in 200 ml of acetonitrile, 7.98 ml (59.285 mmol) of isoamyl nitrite and 7.97 g (59.285 mmol) of copper(II) chloride are added and the mixture is stirred at 60° C. for 4 hours. 1N Hydrochloric acid is added to the mixture, and the precipitated solid is filtered off. It is purified on a silica gel column (mobile phase: toluene). This gives 5.98 g (63% of theory) of the target compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.O[C:24]1[CH:25]=[CH:26][C:27]([N+:34]([O-:36])=[O:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1>>[CH:20]([O:19][C:10]1[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=1[C:7]([N:4]1[CH2:5][CH2:6][CH:2]([O:1][C:24]2[CH:25]=[CH:26][C:27]([N+:34]([O-:36])=[O:35])=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:29]=2)[CH2:3]1)=[O:8])([CH3:22])[CH3:21]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1
Yield: 56 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and 5-hydroxy-2-nitrobenzotrifluoride. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 56%). MS (m/e): 517.5 (M+H+, 100%).