Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:7][CH:6]=1.[C:22]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH2:23][C:24]([CH3:26])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:29]([O:28][C:22](=[O:27])[CH2:23][CH:24]([N:13]1[CH2:14][CH2:15][O:16][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:2]=3[CH3:1])=[CH:10][CH:9]=2)[CH2:12]1)[CH3:26])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cccc(Oc2ccc(C3CNCCO3)cc2)c1C
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cccc(Oc2ccc(C3CN(C(C)CC(=O)OC(C)(C)C)CCO3)cc2)c1C

Procedure:
A mixture of 2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholine (1.00 g; 3.13 mmol), tert-butyl acetoacetate (2.07 mL; 12.5 mmol), sodium triacetoxyborohydride (1.86 g; 8.75 mmol), and a drop of acetic acid, in 1,2-dichloroethane (20 mL) was stirred overnight, at RT. The resulting mixture was treated with 5% aqueous NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography (SiO2, Et2O/hexanes 1:3) to afford 3-{2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholin-4-yl}-butyric acid tert-butyl ester (1.17 g
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C([Mg]Br)(C)C.[CH:16]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22])([CH3:18])[CH3:17]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:21]([C:20]2[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:19]=2[CH:16]([CH3:18])[CH3:17])[OH:22])=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: COc1cc(C=O)c(C(C)C)cc1OC
Reactant: CSc1ncc(I)c(Cl)n1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(C(O)c2cnc(SC)nc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 4-chloro-5-iodo-2-methylsulfanyl-pyrimidine (1.10 g, 3.9 mmol) in 20 mL THF at −40° C. was added isopropyl magnesium bromide (2.3 mL, 2 M in THF)) over 5 minutes. After 30 minutes, 2-isopropyl-4,5-dimethoxy-benzaldehyde from step 3 (1.04 g, 4.6 mmol) was added and the solution was warmed to room temperature. The mixture was quenched by the addition of brine, and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (ethyl acetate) afforded (4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-(2-isopropyl-4,5-dimethoxy-phenyl)-methanol (1.168 g, 82%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([NH2:11])[N:3]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc(N)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.5 %

Procedure:
2,6-Diaminopurine (5.00 g, 33.3 mmol) and potassium carbonate (6.91 g, 50.0 mmol) were suspended in DMF (250 ml). Benzyl bromide (8.55 g, 50 mmol) was added thereto and the mixture was stirred at room temperature for 5 hours. After condensing the reaction mixture in vacuo, to the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (5% methanol/chloroform) to give the subject compound (1.56 g, yield 19%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]([Si](C)(C)C)([F:17])([F:16])[F:15].C1COCC1>CCOCC>[F:15][C:14]([F:17])([F:16])[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of methyl 4-acetylbenzoate (5.0 g, 28.1 mmol) and CF3SiMe3 (12.5 mL, 84.2 mmol) in THF (150 mL) TBAF (1.0 M, 78.6 mL, 78.6 mmol) was added dropwise at 0° C. The mixture was then stirred for 2.5 h at room temperature, diluted with Et2O (100 mL). The solution was washed with saturated aqueous NaHCO3, and brine, dried, and concentrated. Flash chromatography of the residue, using 2:8 EtOAc-hexane, gave methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate: 1H NMR (CDCl3) δ 8.07 (d, J=8.5 Hz, 2H), δ 7.67 (d, J=8.5 Hz, 2H), 3.93 (s, 3H), 2.70 (br, 1H), 1.80 (s, 3H); ms 249.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[I:11].[OH-].[Na+]>C(O)(=O)C.O>[I:11][C:4]1[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:7][C:3]=1[CH:2]=[O:1]
Reactant: CCCc1nc(I)c(CO)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc(I)c(C=O)[nH]1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of 35.8 g of 5-hydroxymethyl-4-iodo-2-n-propylimidazole in 325 mL of glacial acetic acid at 20° C. was added dropwise over 1 h 290 mL of 1.0N aqueous ceric ammonium nitrate solution. The resulting mixture was stirred at 20° C. for 1 h. The reaction mixture then was diluted with water, adjusted to pH 5-6 employing aqueous sodium hydroxide solution, and extracted with chloroform. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude solid was recrystallized from 1-chlorobutane to furnish 29.9 g of product as a light yellow solid: mp 141°-142° C. NMR (CDCl3) δ 11.51 (br s,1H); 9.43 (s,1H); 2.81 (t,2H); 1.81 (sext., 2H); 0.97 (t,3H). ##STR84##
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CO[CH2:31][CH2:32]OC>C(O)C.O>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([CH:31]=[CH2:32])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOC
Reactant: C[C@]12CCc3c(Br)cccc3[C@H]1CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=Cc1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Temperature: 160 °C

Procedure:
cis-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.421 mmol, 150 mg) was dissolved in DME (1 ml) and ethanol (0.5 ml). 2 N sodium carbonate solution (1 ml), tetrakis(triphenylphosphine)Pd(0) (0.021 mmol, 24.32 mg) and 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane-pyridine complex (0.631 mmol, 152 mg) were added and the reaction mixture was heated at 160° C. for 15 minutes in a microwave reactor. The reaction mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were concentrated in vacuo and then purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford cis-2-benzyl-3a-methyl-6-vinyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (100 mg), m/z: 304.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21]O)[CH:6]=1.P(Br)(Br)[Br:25]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21][Br:25])[CH:6]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CO)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CBr)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 4, using the following starting materials: [3-(5-bromo-2-hydroxymethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and phosphorus tribromide.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:45])[F:44])=[CH:39][CH:38]=3)(=[O:41])=[O:42])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-(trifluoromethyl)benzenesulfonamide: 1H-NMR (CDCl3) δ 8.06 (2H, d, J=7.7 Hz), 7.80 (2H, d, J=8.2 Hz), 7.47-7.21 (9H, m), 6.10 (1H, br.s), 3.50-3.43 (2H, m), 2.86 (2H, t, J=6.3 Hz), 2.32 (3H, s), 2.23 (3H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:9][CH:10]=[N:11][CH:12]1[C:20]2[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1([CH3:23])[CH3:22])#N.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O>[CH3:29][O:28][C:26]([C:25]1[N:11]([CH:12]2[C:20]3[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]2([CH3:23])[CH3:22])[CH:10]=[N:9][CH:7]=1)=[O:27]
Reactant: COC(=O)CBr
Reactant: CC1(C)Cc2c(Cl)cccc2C1N=CNC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncn1C1c2cccc(Cl)c2CC1(C)C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
12.7 g of potassium carbonate are added to a solution of 21 g of N-cyano-N'-(2,2-dimethyl-4-chloroindan-1-yl)formamidine in 80 ml of dimethylformamide. 14.1 g of methyl bromoacetate are added dropwise. After the exothermic reaction has ceased the mixture is agitated for 1.5 hours at +50° C. another portion of 12.7 g of potassium carbonate is added and the mixture is stirred for 18 hours at +100° C. The precipitate is filtered off from the hot solution and washed with 30 g of hot dimethylformamide. The combined filtrates are dropwise added at +60° C. to a solution of 14.2 g of tert. butylnitrite in 30 ml of dimethylformamide. Immediate evolution of nitrogen is observed and the temperature of the mixture rises to +67° C. After 30 minutes the dropwise addition is completed. The mixture is maintained at +70° to +75° C. for 2.5 hours and then poured into ice-water and extracted with ethyl acetate. The organic phase is washed with brine, dried with sodium sulfate and concentrated to dryness. The residue is purified by chromatography at a silica gel column with an ethyl acetate/hexane mixture (1:2 by volume), affording 12.7 g of 1-(2,2-dimethyl-4-chloro-indan-1-yl)-5-imidazolecarboxylic acid methyl ester, having a melting point of 111°-113° C.
Reaction SMILES: [C@@H:1]([NH:5][C:6]1[C:7](=[O:20])[NH:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].N1C=CC=CC=1.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl>[C@@H:1]([NH:5][C:6]1[C:7]([O:20][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of (S)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.10 mmol) in dichloromethane (40 mL) was added pyridine (344 mg, 4.36 mmol). Tf2O (615 mg, 2.18 mmol) was added drop-wise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (S)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (390 mg, crude).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:22].[OH-].[Na+]>C1COCC1.O>[C:3]([O:7][C:8]([N:10]([CH3:22])[C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N(C)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Yield: 45 %

Procedure:
A flask is charged with a suspension of sodium hydride (60% in mineral oil) (0.109 g, 2.72 mmol) in THF (5 mL). The ethyl 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylate (0.735 g, 2.70 mmol) is added, followed by iodomethane (175 μL, 2.70 mmol) and the resulting suspension is heated to reflux for 3 hours, then cooled to room temperature. Water is added, followed by 1.0 N NaOH. The basic phase is extracted with 3 portions of EtOAc. The combined organic phases are washed with brine, dried over Na2SO4, filtered, and concentrated to give a clear oil purified with flash chromatography. Yield 45%. HRMS (FAB) calculated for C12H18N2O4S+H 287.1065, found 287.1068.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]([CH2:15][NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[OH:14])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:16]([CH2:15][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1)[OH:14])[C:17]([CH3:20])([CH3:18])[CH3:19])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)NCC(O)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N(CC(O)c1cccc(Cl)c1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (0.21 g, 0.15 ml) in dichloromethane (5 ml) was added dropwise, under nitrogen to a stirred, ice-cooled solution of 3-chloro-α-[[[1,1-dimethylethyl]amino]methyl]benzenemethanol (0.5 g) and triethylamine (0.38 g, 0.53 ml) in dichloromethane (40 ml). The reaction mixture was stirred at ambient temperature for 2 h., washed with hydrochloric acid (2N), brine, dried (MgSO4), evaporated and chromatographed on silica. Elution with chloroform gave α-chloro-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[1,1-dimethylethyl]acetamide as a colourless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:4]3[CH:3]=[CH:2][S:6][C:5]=3[S:7]([NH2:10])(=[O:9])=[O:8])=[CH:18][C:17]1=2
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccsc3S(N)(=O)=O)cc21

Procedure:
Prepared according to procedure B from 5-bromothiophene-2-sulphonamide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 258-260° C., 1H-NMR (DMSO-d6) δ10.41 (s, 1H), 7.71 (s, 2H), 7.58 (m, 2H), 7.52 (d, 1H, J=3.9 Hz), 7.48 (d, 1H J=8.16 Hz), 6.95(d, 1H J=8.16), 1.66 (s, 6H); MS m/z 337 (M−H). Anal. Calc. For C14H14N2O4S2: C, 49.69; H, 4.17; N, 8.28. Found: C, 49.90; H, 4.28; N, 8.12.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@@H:21]([OH:23])[CH3:22])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C@@H:21]([OH:23])[CH3:22])(=[O:14])=[O:13])[CH:6]=[CH:5]3)=[CH:27][CH:26]=1
Reactant: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc(F)cc1
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Yield: 83.5 %

Procedure:
The title compound was prepared from (1S)-1-{2-[(6-bromo-2-naphthyl)sulfonyl]phenyl}ethanol (2.0 g, 5.1 mmol) and 4-fluorobenzeneboronic acid (1.1 g, 7.6 mmol) according to the methods of Example 2 Step 1. Crude product was first purified by flash column chromatography eluting with a 20-80% diethyl ether/isohexane gradient then a second flash column chromatography eluting with 10% diethyl ether/dichloromethane. Crystallisation from methanol/H2O gave (1S)-1-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}phenyl)ethanol (1.73 g, 83%). 1H NMR (500 MHz, CDCl3) δ 8.55 (1H, s), 8.17 (1H, d, J 8.0 Hz), 8.05 (1H, d, J 8.6 Hz), 8.02 (1H, s), 7.97 (1H, d, J 8.7 Hz), 7.84 (1H, dd, J 1.5, 8.5 Hz), 7.76 (2H, d, J 8.4 Hz), 7.69-7.63 (3H, m), 7.49 (1H, t, J 7.2 Hz), 7.19 (2H, t, 8.6 Hz), 5.68-5.62 (1H, m), 2.49 (1H, d, J 3.1 Hz), 1.35 (3H, d, J 6.3 Hz); m/z (ES+) 389 [(M-OH)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:28])=[O:29])=[C:23]([F:31])[CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:28](=[O:29])[N:6]2[CH:7]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8](=C)[CH2:9][S:10][C@H:5]12)[CH3:3].C(Cl)Cl.[O:33]=[O+][O-].CSC>O=O>[OH:1][CH:2]([CH:4]1[C:28](=[O:29])[N:6]2[C:7]([C:12]([O:14][CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[C:8]([OH:33])[CH2:9][S:10][C@H:5]12)[CH3:3]
Reactant: C=C1CS[C@@H]2C(C(C)O)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CSC
Solvent: ClCCl
Product: CC(O)C1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reaction time: 0.33 h

Procedure:
Benzhydryl 7-(1-hydroxyethyl)-3-methylene-cepham-4-carboxylate (4.6 g.) is dissolved in 500 ml. of CH2Cl2, cooled to -78° and treated with a stream of ozone in oxygen until a blue color persists in the reaction mixture. After 1 minute at -78° the reaction mixture is treated with 5 ml. of dimethyl sulfide and the reaction mixture is allowed to stand at -78° for 20 min. followed by 1 hour at 25° C. The solvent is removed under reduced pressure to give the crude benzhydryl 7-(1-hydroxyethyl)-3-hydroxy-3-cephem-4carboxylate.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])[CH2:16][CH2:15]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC1)C(F)(F)F
Yield: 64.9 %

Procedure:
A solution of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (438 mg, 2.07 mmol), (R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide (438 mg, 2.07 mmol) and DIPEA (1 mL) in EtOH (4 mL) was heated at 155° C. in the microwave for 5 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale orange gum (518 mg). A portion of this gum (39 mg, 0.10 mmol) in dry THF (2 mL) was treated with sodium hydride (60% in mineral oil, 5 mg, 0.12 mmol). After stirring at room temperature for 10 min, iodomethane (0.01 mL, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 2 hr. The reaction was repeated on the remaining (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide. Water (50 mL) was added carefully and the mixture was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (518 mg). This gum (514 mg, 1.29 mmol) was dissolved in MeOH (20 mL) and treated with ammonium formate (325 mg, 6.15 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85° C. for 2 hr. After cooling to room temperature the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (50 mL) and water (30 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford (R)—N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (348 mg, 46% over three steps). 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 6.19 (tq, J=55.4, 4.4 Hz, 1H), 4.65-4.15 (m, 3H), 3.40-3.10 (m, 4H), 3.10 and 2.97 (2s, 3H), 2.80 (br s, 2H), 2.10-1.70 (m, 6H).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8]O)([CH2:6][OH:7])[CH2:4][OH:5].[Br:10]C(C(C)(C(Br)O)C)O.BrCC(CO)(CBr)CBr>>[CH2:4]([OH:5])[C:3]([CH2:2][Br:1])([CH2:8][Br:10])[CH2:6][OH:7]
Reactant: CC(C)(C(O)Br)C(O)Br
Reactant: OCC(CO)(CO)CBr
Agent: OCC(CBr)(CBr)CBr
Product: OCC(CO)(CBr)CBr

Procedure:
The compounds which constitute one of the starting reagents according to the present invention, consist of dibromoneopentyl glycol 2-bromomethyl-2-hydroxymethylpropane-1,3-diol, 2-bromomethyl-2-hydroxymethyl-1,3-dibromopropane, or mixtures thereof. As known, commercial DBNPG is obtained by the bromination of pentaerythritols. Depending on the method of operation, the product may be a relatively pure DBNPG or mixtures of 2-bromomethyl-2-hydroxymethylpropane-1,3-diol, 2,2-bis(bromomethyl)propane-1,3-diol, and 2-bromomethyl-2-hydroxymethyl-1,3-dibromopropane, wherein an average of 1.7 to 2.5 of the hydroxyls per molecule have been replaced by bromine. This represents a mixture of 2-bromomethyl-2-hydroxymethylpropane-1,3-diol,2,2-bis(bromomethyl)propane-1,3-diol and 2-bromomethyl-2-hydroxymethyl-1,3-dibromopropane whose concentration ranges vary from 5% 2-bromomethyl-2-hydroxymethylpropane-1,3-diol, 80% 2,2-bis(bromomethyl)propane-1,3-diol and 15% 2-bromomethyl-2-hydroxymethyl -1,3-dibromopane to 15% 2-bromomethyl-2-hydroxymethylpropane-1,3-diol, 80% 2,2-bis(bromomethyl)propane-1,3-diol, and 5% 2-bromomethyl-2-hydroxymethyl-1,3-dibromopropane. The residual hydroxyl groups of this mixture of compounds can also be readily hydroxymethylated. Therefore instead of utilizing pure DBNPG, the latter can be successfully replaced by the less expensive mixtures.