Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18][C:17]2=[O:24])=[CH:13][CH:12]=1.OS([O-])(=O)=O.[Na+].O>C1COCC1>[Br:1][CH:18]1[C:19](=[O:23])[CH2:20][CH2:21][CH2:22][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:26][CH:25]=2)[C:17]1=[O:24]
Reactant: COc1ccc(CN2CCCC(=O)CC2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCC(=O)C(Br)C2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 151.7 %

Procedure:
N-Bromosuccinimide (2.88 g, 16.17 mmol) was added portionwise to a stirred solution of 1-(4-methoxy-benzyl)-azepane-2,4-dione (4.0 g, 16.17 mmol) and NaHSO4.H2O (0.67 g, 4.85 mmol) in THF anhydrous (80 mL) at 0° C. The reaction mixture was stirred at room temperature for 2.5 hours and the solvent evaporated in vacuo to yield 3-bromodihydro-1-[(4-methoxyphenyl)methyl]-1H-azepine-2,4(3H,5H)-dione (8 g, 91% yield, 60% pure) as a viscous orange oil which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:11](CC)CC)C.C[Si](C#N)(C)C.[OH-].[Na+]>C(#N)C>[Br:1][C:2]1[C:3]([C:9]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cccc(Br)c1
Agent: C[Si](C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1ncccc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
3-Bromo-pyridine 1-oxide (9.4 g, 54 mmol) is dissolved in acetonitrile (60 mL) and triethylamine (15 mL) is added followed by trimethylsilyl cyanide (21.7 mL, 163 mmol). The mixture is heated to 100° C. and stirred for 16 h. The mixture is cooled to 0° C., poured into 250 mL of 5 M aqueous NaOH, and extracted with dichloromethane. The combined extracts are washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting material is purified using flash chromatography (Biotage® Si65M, 20% ethyl acetate/hexane) to yield 7.8 g (79%) of the title compound as a yellow solid. GCMS m/e 182, 184 [M]−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:41])([F:40])[CH:9]([CH:11]1[C:17](=[O:18])[N:16]2[CH:12]1[CH2:13][C:14](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:15]2[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[OH:10].C(OC(=O)C)C>CN(C=O)C>[F:41][C:8]([F:7])([F:40])[CH:9]([CH:11]1[C:17](=[O:18])[N:16]2[CH:12]1[CH2:13][C:14]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[C:15]2[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[OH:10]
Reactant: C1COCCN1
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)C(F)(F)F)C2C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1=C(N2CCOCC2)CC2C(C(O)C(F)(F)F)C(=O)N12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Morpholine (17.5 μl) is added to an ice-cold, stirring solution of benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (51 mg) in anhydrous DMF (0.5 ml). The resulting solution is allowed to warm to room temperature (25° C.) and then stirred at room temperature for 4 hrs. Ethylacetate (10 ml) is added and the solution is washed with water (5×2 ml), pH 3 phosphate buffer, 5% NaHCO3, brine, dried with MgSO4, and filtered. Evaporation of the solvent in vacuo leaves benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:53])C(=O)C1>C(O)(=O)C.C(Cl)Cl>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[C:32]=2[Cl:53])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(Cl)c(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reaction time: 18 h
Yield: 52.5 %

Procedure:
To a solution of (2S)-ethyl 2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (40 mg, 0.064 mmol, 1 equiv) in acetic acid (0.64 mL) was added NCS (10 mg, 0.077 mmol, 1.2 equiv). After stirring 18 h, reaction is pale yellow solution. LCMS indicated complete conversion. The reaction was diluted with DCM and washed with saturated aqueous bicarbonate. The DCM layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-10% EtOAc in hexane) to provide desired product as a viscous yellow oil (22 mg, 52% yield). 1H NMR (500 MHz, CDCl3) δ 7.16 (s, 1H), 7.12 (d, J=5.7 Hz, 2H), 6.97 (d, J=9.1 Hz, 1H), 6.83 (d, J=10.6 Hz, 1H), 4.97 (s, 1H), 4.62-4.50 (m, 2H), 4.35 (t, J=5.3 Hz, 2H), 4.19-4.11 (m, 2H), 2.84 (s, 3H), 2.75 (s, 2H), 2.27 (d, J=1.7 Hz, 3H), 2.23-2.13 (m, 2H), 1.80 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.17 (s, 9H); 19F NMR (471 MHz, CDCl3) δ −119.48 (s, 1F), −139.47 (s, 1F); LCMS (ESI, M+1): 655.5.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH:15]3[O:16][CH:12]([CH2:13][CH2:14]3)[CH:11]2[C:17]([OH:19])=O)=[O:9])[CH2:4][CH2:3]1.S(Cl)([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH:15]3[O:16][CH:12]([CH2:13][CH2:14]3)[CH:11]2[C:17]([Cl:22])=[O:19])=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)C2C3CCC(O3)C2C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)C2C3CCC(O3)C2C(=O)Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 3-(4-methylpiperazine-1-carbonyl)-7-oxa-bicyclo[2,2,1]-heptane-2-carboxylic acid (938 mg, 3.5 mmole) in methylene chloride (30 mL) was added thionyl chloride (1 mL) followed by a few drops of DMF. After stirring at ice-cold temperature for 30 min, the ice-bath was removed and stirring continued at room temperature overnight. The excess thionyl chloride was removed using oil-free vacuum pump at −50° C. and to the residue was added methylene chloride (10 mL). The resulted thin slurry of 1 was used as such in the next reaction.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:16][C:17]([OH:19])=[O:18])[N:14]=[N:13][N:12]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][O:18][C:17](=[O:19])[CH2:16][N:15]1[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12][N:13]=[N:14]1
Reactant: O=C(O)Cn1nnnc1-c1ccc2ccccc2c1
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccc2ccccc2c1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 64.4 %

Procedure:
To a solution of 1 g (3.94 mM) of [5-(2-naphthyl)tetrazol-1-yl] acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=9/1) for separation and purification, to give 750 mg (yield 64.4%) of [5-(2-naphthyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:3]=1[NH:19][CH:20]([CH3:22])[CH3:21].Br[C:24]#[N:25]>O.C1COCC1>[NH2:25][C:24]1[N:19]([CH:20]([CH3:21])[CH3:22])[C:3]2=[CH:4][C:5]3[C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]=3[CH:10]=[C:2]2[N:1]=1
Reactant: N#CBr
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(C)C)c(N)cc21
Solvent: C1CCOC1
Solvent: O
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(N)n3C(C)C
Yield: 97.5 %

Procedure:
Analogously to general procedure (III) 6-amino-5-isopropylamino-3,3-dimethyl-1-pentyl-1,3-dihydro-indol-2-one (180 mg) is cyclized using BrCN (3 M; 0.2 ml; 600 μmol) at RT in water (2.5 ml) and THF (1 ml). After aqueous work-up the desired compound (190 mg) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].C1C(=O)[N:14](Br)[C:12](=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[C-]#N.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:12]#[N:14]
Reactant: Cc1c(F)cccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CCc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A suspension of 2-bromo-6-fluorotoluene (5.00 g, 26.45 mmol), NBS (5.18 g, 29.10 mmol), and VAZO (323 mg, 1.32 mmol) in CCl4 (100 mL) was heated to reflux under vigoroue stirring overnight. The reaction mixture was cooled to room temperature, concentrated and the residue was removed by filtration. The filtrate was concentrated and the residue was re-dissolved in ethanol (90 mL), treated with a solution of NaCN (2.59 g, 52.9 mmol) in water (20 mL) and the combined mixture was heated to reflux for 5 hrs. Ethanol was removed under reduced pressure, the aqueous residue was diluted with water and extracted with AcOEt. The organic layer was successively washed with water and brine, concentrated, adsorbed on silica gel and purified by flash column chromatography (eluents AcOEt/hexanes: 10/90 to 20/80) to afford title compound 329 (3.92 g, 69% yield over 2 steps, slightly contaminated) as a pale yellow sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.62-7.57 (m, 1H), 7.45-7.35 (m, 2H), 4.08 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCc2ccccc2)ccc(C(=O)OC)c1O

Procedure:
A solution of methyl 2,4-dihydroxy-3-propylbenzoate (3.00 grams) in 2-butanone (30 mL) was treated with benzyl bromide (1.70 mL) and potassium carbonate (1.972 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was chromatographed over silica gel to afford the title compound.
Reaction SMILES: [SH-:1].[Na+].[CH2:3]([N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13](Cl)[NH:12][C:11]1=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CN(C)C=O>[CH2:3]([N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([SH:1])[NH:12][C:11]1=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(Cl)[nH]c(=O)n(Cc2ccccc2)c1=O
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(S)[nH]c(=O)n(Cc2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sodium hydrosulfide (119.8 g, 2,14 mole) was added to a cloudy solution of 3-benzyl-6-chloro-5-methyl-1H-pyrimidine-2,4-dione (178 g, 0.71 mole) in dimethylformamide (1 L) and heated to 60° C. 18 hours to give a dark green solution. The reaction solution was cooled and poured into 1 M HCl (6 L) and stirred at room temperature for 1 hour. The solid was collected by filtration and washed with water, dried under vacuum with P2O5 at 45° C. overnight to give 177.4 g. 1H-NMR (CDCl3) δ 10.45 (s, 1H), 7.41 (d, 2H), 7.23–7.30 (m, 3H), 5.07 (s, 2H), 3.59 (s, 1H), 1.96 (s, 3H).
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([NH:19]C(OCC)=O)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([NH2:19])[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NN1CCN(CCCCC(=O)c2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NN1CCN(CCCCC(=O)c2ccccc2)CC1

Procedure:
21.4 g of the resulting 4-(4-benzoylbutyl)-1-(ethoxycarbonylamino)piperazine was dissolved in 180 ml of ethanol, and a solution of 36.2 g of potassium hydroxide in 36 ml of water was added. The mixture was heated under reflux for 3 hours. The reaction mixture was cooled, and 136 ml of 4N hydrochloric acid was added to form a 4-(4-benzoylbutyl)-1-aminopiperazine solution.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=[O:3].[CH2:21](O)[CH2:22][OH:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[CH2:21]1[CH2:22][O:23][CH2:4][CH:2]([CH2:1][C:5]2[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[O:3]1
Reactant: OCCO
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc(C2=C(CC3COCCO3)C(=O)NCCC2)c1

Procedure:
The starting material is prepared as follows: The solution of 27.2 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 31 g of ethylene glycol and 0.2 g of p-toluene-sulfonic acid hydrate in 200 ml of benzene is refluxed with a water separator for 7 hours. It is cooled to 0°, 100 ml of 5% aqueous sodium bicarbonate are added and the benzene layer separated. It is washed with water, dried, evaporated and the residue crystallized from diethyl ether to give the 3-(2-ethylenedioxypropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 132°-134°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=3)=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1

Procedure:
Palladium tetrakis(triphenylphosphine) (221 mg, 0.19 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 11) (900 mg, 1.9 mmol), 2-bromo-5-fluoropyridine (336 mg, 1.9 mmol) and hexamethylditin (626 mg, 1.9 mmol) in 1,4-dioxane (20 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH2:10].[C:11]([CH:13]=[C:14](OCC)[NH:15][C:16]#[C:17][CH3:18])#[N:12].C(N)C#C.C(C=C(OCC)OCC)#N>>[C:11]([CH:13]=[C:14]([NH:15][CH2:16][C:17]#[CH:18])[NH:10][CH2:9][CH2:8][S:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)#[N:12]
Reactant: CC#CNC(=CC#N)OCC
Reactant: NCCSCc1nccs1
Agent: C#CCN
Agent: CCOC(=CC#N)OCC
Product: C#CCNC(=CC#N)NCCSCc1nccs1

Procedure:
When 2-[(thiazol-2-yl)methylthio]ethylamine is reacted in an inert solvent with about an equimolar amount of 1-cyano-2-ethoxy-2-propynylaminoethylene [prepared from propargylamine and 1-cyano-2,2-bis(ethoxy)ethylene, which is itself prepared according to the procedure described in J. Am. Chem. Soc., 71, 47 (1949)], the title product is produced.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([CH:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:22]2[C@@H:27]([NH2:28])[CH:26]3[CH2:29][CH2:30][N:23]2[CH2:24][CH2:25]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:37]([P:39]([C:43]1[CH:44]=[CH:45][C:46]([O:51][CH3:52])=[C:47]([CH:50]=1)[CH:48]=O)([CH2:41][CH3:42])=[O:40])[CH3:38].S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)CCl>[C:31]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:22]2[C@@H:27]([NH:28][CH2:48][C:47]3[CH:50]=[C:43]([P:39]([CH2:41][CH3:42])([CH2:37][CH3:38])=[O:40])[CH:44]=[CH:45][C:46]=3[O:51][CH3:52])[CH:26]3[CH2:29][CH2:30][N:23]2[CH2:24][CH2:25]3)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Reactant: CCP(=O)(CC)c1ccc(OC)c(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCP(=O)(CC)c1ccc(OC)c(CN[C@H]2C3CCN(CC3)[C@H]2C(c2ccccc2)c2ccccc2)c1
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (202 mg, 0.95 mmol) was added to a solution of (2S,3S)-2-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-amine (150 mg, 0.51 mmol) and 5-diethylphosphoryl-2-methoxybenzaldehyde (150 mg, 0.55 mmol) dissolved in methylene chloride (5 ml) at rt, and the resulting solution was stirred for 16 h. Ethylene chloride and 1N sodium bisulfate were added to the reaction mixture. After 5 min the organic layer was washed with aq. sodium bicarbonate solution and brine. The extracts were dried over magnesium sulfate, and concentrated by evaporation. The residual oil was purified by following process: (1) silica-gel chromatography (4-14% methanol-methylene chloride), (2) Merck Lobar Li Chroprep NH2 (25-70%), (3) crystallization from diisopropyl ether. The title compound was obtained in a pure form (11 mg). IR (CH2Cl2) 1270 cm-1 1 H NMR δ: 7.66 (ddd, J=13, 8, 2 Hz, 1H), 7.39 (dd, J=13, 2 Hz, 1H), 7.31-7.03 (m, 10H), 6.75 (dd, J=8, 3.5 Hz, 1H), 4.47 (d, 12.2 Hz, 1H), 4.10 (m, 4H), 3.69-3.57 (m, 2H), 3.54 (s, 3H), 3.25-3.10 (m, 1H), 3.19 (d, J=13 Hz, 1H), 1H), 2.87 (dd Hz, 1H), 2.75 (m, 2H), 2.60 (m, 1H), 2.05 (m, 1H), 1.88 (m, 1H), 1.70-1.20 (m, 3H), 1.35 (t, J=7 Hz, 3H), 1.34 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:33])(=[O:32])[NH2:34])=[O:14])=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2cccc(C(=O)O)c2)cc1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (15.5 mmol) of 3-(4-methoxybenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.93 g (17.0 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained residue was purified by a silica gel chromatography to obtain 1.5 g (yield: 31.0%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[C:37]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:9])=[O:10])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(C(=O)c3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a stirred solution of 2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (example 4, step 2, 60 mg) in dichloromethane (0.5 mL) were added N,N-diisopropyl ethyl amine (21 mg) and benzoyl chloride (20 mg) at 0° C. The mixture was stirred at r.t. overnight. Ice cold water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give N-benzoyl-2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (76 mg) as a colorless solid. MS: 568.2 ([M+Na]+)
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([C@@H:13]2[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([Cl:44])=[N:24][C:25]=4[NH:29][CH2:30][CH:31](C3C=CC=CC=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@@H](CC1C=CC=CC=1)[CH2:47][OH:48]>>[CH2:31]([C@H:30]([NH:29][C:25]1[N:24]=[C:23]([Cl:44])[N:22]=[C:21]2[C:26]=1[N:27]=[CH:28][N:20]2[C@H:15]1[C@H:16]([OH:19])[C@H:17]([OH:18])[C@@H:13]([C:10]2[N:11]=[N:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=2)[O:14]1)[CH2:47][OH:48])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O[C@@H]1[C@H](O)[C@@H](c2nnn(Cc3ccccc3)n2)O[C@H]1n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(Cl)nc21
Product: OC[C@H](Cc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](c2nnn(Cc3ccccc3)n2)[C@@H](O)[C@H]1O

Procedure:
The title compound is prepared in an analogous fashion to (2R,3S,4R,5R)-2-(2-benzyl-2H-tetrazol-5-yl)-5-[2-chloro-6-(2,2-diphenylethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol (WO 99/38877) by replacing 2,2-diphenylethylamine with (S)-2-amino-3-phenyl-propan-1-ol