Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:26][CH2:27][NH2:28])=[CH:20][CH:19]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[ClH:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:25][CH2:26][CH2:27][NH:28][C:9](=[O:11])[C@@H:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:20][CH:19]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@H](NC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)C[C@H](NC1CCCCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
A suspension of (S)-2-cyclohexylamino-4-methyl-pentanoic acid (108 mg, 0.51 mmol) and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (151 mg, 0.51 mmol) in dry DMF (4 mL) was treated with Triton® B (0.92 mL, 2.0 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.), then sonicated for a few seconds, a clear solution was obtained. The clear solution was concentrated in vacuo to remove most of the methanol, then cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.19 g, 0.51 mmol) was then added. After stirring at 0° C. for 20 minutes the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (60% EtOAc in hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 150 mg (60%) of the pure titled compound as a white foam; mp 75-85° C. APCI-MS m/z 457.3 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.OCC1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)=[CH:17][CH:16]=1.N1CCCC1>ClCCl>[N:3]1([CH2:6][C:7]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)[CH2:4][CH2:5][CH2:2][CH2:1]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(CO)cc2)C1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(CN3CCCC3)cc2)C1
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 56.3 %

Procedure:
Triethylamine (0.47 g, 3.4 mmol) and methanesulfonyl chloride (0.12 ml, 1.6 mmol) were added to an ice-cooled solution of 3-(4-hydroxymethylphenyl)-1-(tert-butoxycarbonyl)piperidine (0.39 g, 1.34 mmol) in dichloromethane and stirred for 7.5 hr. Pyrrolidine (1.0 ml, 12 mmol) was added to the solution and stirred overnight. Organic solvents were removed under reduced pressure after addition of water and extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure and the residue was purified by silica gel chromatography (eluent; ethyl acetate to ethyl acetate/methanol=1/1, then methanol only) to give 3-(4-(1-pyrrolidinyl)methylphenyl)-1-(tert-butoxycarbonyl)piperidine (0.26 g, 56%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N(C)C=O.[H-].[Na+].CI>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[N:17]([CH3:28])[C:18](=[O:20])[S:19]/2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)/C(=C/c2cn(-c3ccccc3)nc2OCc2ccccc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)S/C(=C\c2cn(-c3ccccc3)nc2OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a mixture of (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-1,3-thiazolidine-2,4-dione (1.30 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.15 g) at 0° C. After stirring the reaction mixture at 0° C. for 30 min, methyl iodide (0.58 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 4 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to give (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-3-methyl-1,3-thiazolidine-2,4-dione as yellow crystals (1.30 g, yield 98%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 226-227° C.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:9][CH:8]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C(N(CC)CC)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:20]2[CH2:21][CH2:22][N:17]([C:14]3[C:15]4[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[CH:16]=4)[CH:11]=[CH:12][N:13]=3)[CH2:18][CH2:19]2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc2ccnc(N3CCNCC3)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc2ccnc(N3CCN(Cc4ccc(F)cc4)CC3)c2c1
Yield: 72 %

Procedure:
Into 10 ml of acetone, 50 mg of 7-methoxy-1-piperazin-1-ylisoquinoline, 100 mg of 4-fluorobenzyl bromide and 100 mg of triethylamine were added and heated under reflux for 5 hours. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (methanol:chloroform=1:19) to provide 52 mg (79%) of 1-[4-(4-fluorobenzyl)piperazin-1-yl]-7-methoxyisoquinoline.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](O)=[C:5]([CH2:7][OH:8])[CH:6]=1.C1([OH:16])C=CC=CC=1>>[OH:16][C:2]1[CH:3]=[CH:4][C:5]([CH2:7][OH:8])=[CH:6][CH:1]=1
Reactant: Oc1ccccc1
Reactant: OCc1ccccc1O
Product: OCc1ccc(O)cc1

Procedure:
The saligenol yield is 90.6% in relation to the phenol consumed.
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH2:23](N)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]CC.C(N(CC)CC)C>C1COCC1.C(OCC)C>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: CCCCCCCCCCCCN
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNC(=O)OCc1ccc(OC(C)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.5 %

Procedure:
To a stirred yellow solution of VII (290.8 mg, 0.852 mmol) in anhydrous THF (10 mL) was added 1-dodecylamine (174 mg, 1.1×0.852 mmol) and then, dropwise, triethylamine (118 mg, 132 μL, 1.1×0.852 mmol). The solution was stirred for 3.5 hours at room temperature. The colorless solution was then diluted with diethylether and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (6:4, v/v) to give 165 mg (48%) of a white solid, 10: mp=54-56° C. (uncorrected); Rf=0.61 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 6.99 (d, 3J=8.0 Hz, 1H), 6.95 (d, 4J=1.55 Hz, 1H), 6.92 (bd, 3J=8.0 Hz, 1H), 5.04 (s, 2H), 4.69 (bs, 1H; NH), 3.82 (s, 3H), 3.17 (apparent quartet, 3J=6.7 Hz, 2H), 2.29 (s, 3H), 1.51-1.43 (m, 2H), 1.32-1.19 (m, 18H), and 0.86 (t, 3J=7 Hz, 3H). Exact mass (FAB+) calculated for C23H38NO5 [M+H] 408.2744. found 408.2749.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:26])[CH2:25][O:24]3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[Li+].[B-](CC)(CC)CC.OO>O1CCCC1.O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:24])([CH3:25])[CH3:26])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(C)CO2)(c2ccccc2)NC1=O
Agent: CC[B-](CC)CC
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of (4S)-1-((S)-1-(4-bromophenyl)ethyl)-4-((2-methyloxiran-2-yl)methyl)-4-phenyltetrahydropyrimidin-2(1H)-one (0.61 g, 1.42 mmol) in anhydrous tetrahydrofuran (5 mL) was added to Super Hydride (2.56 mL, 2.56 mmol) at 0-5° C. The addition is exothermic and addition was controlled to maintain Tint=<8° C. The mixture was stirred for 2 h at 0-5° C. and allowed to warm to 10-15 0° C. over 3 h. A solution of hydrogen peroxide (5 mL of a 30 wt % aqueous solution diluted with 50 mL of water) was added. The temperature was controlled to maintain Tint=<25° C. The resulting solution was diluted with methyl tert-butyl ether (MTBE) (200 mL) and washed with water (200 mL) followed by 30 wt % aq solution of sodium thiosulfate (300 mL). The organic solution was dried over Na2SO4, filtered and then concentrated to dryness. The residue was purified by column to afford (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxy-2-methylpropyl)-4-phenyltetrahydropyrimidin-2(1H)-one (0.5 g, Yield: 82%). 1H NMR (MeOD): 0.58 (s, 3H), 1.17 (s, 3H), 1.44-1.46 (d, 3H), 1.90-1.94 (m, 2H), 2.05-2.08 (m, 1H), 2.16-2.18 (m, 1H), 2.24-2.27 (m, 1H), 2.83-2.86 (m, 1H), 5.65-5.67 (m, 1H), 7.04-7.06 (m, 2H), 7.22-7.23 (m, 1H), 7.27-7.33 (m, 6H). LC-MS Method 2 tR=1.296 min, m/z=433.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])[C:6](=[O:16])[N:5]([CH:17]2[CH2:19][CH2:18]2)[C:4](=[O:20])[CH:3]=1.[CH3:21][N:22]([CH3:25])[CH:23]=O.COC(OC)N(C)C.C(O)(C)C>O>[CH:17]1([N:5]2[C:4](=[O:20])[CH:3]=[C:2]([N:1]=[CH:21][N:22]([CH3:25])[CH3:23])[N:7]([C:8]3[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=3[F:15])[C:6]2=[O:16])[CH2:18][CH2:19]1
Reactant: CN(C)C=O
Reactant: Nc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Agent: COC(OC)N(C)C
Solvent: O
Solvent: CC(C)O
Product: CN(C)C=Nc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Under a nitrogen atmosphere, to 6-amino-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione 75 (178 g) were added N,N-dimethylformamide (356 ml) and N,N-dimethylformamide dimethylacetal (178 ml), and the mixture was stirred at room temperature for 2 hrs. Isopropanol (178 ml) was added with stirring at room temperature, and water (1068 ml) was added dropwise. The mixture was stirred at room temperature for 2 hrs, and the precipitated crystals were collected by filtration and dried to give N′-[1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine 76 (188 g, yield 92%) as yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])=[O:4].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[Cl:12][C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To an ice-cooled solution of 2-bromo-1-(2,5-dichlorophenyl)ethanone (0.10 g, 0.37 mmol) in N,N-dimethylformamide (8 mL) was added potassium phthalimide (76 mg, 0.41 mmol). The mixture was warmed to room temperature for 2 hours. The resultant mixture was then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization with diethyl ether afforded 2-(2-(2,5-dichlorophenyl)-2-oxoethyl)isoindoline-1,3-dione as a white solid. (110 mg, 88% yield). 1H NMR (400 MHz, CDCl3): 7.92-7.94 (m, 2H), 7.78-7.80 (m, 2H), 7.72 (m, 1H), 7.45-7.46 (m, 2H), 5.08 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])[CH:19]=1.[CH3:34][NH:35][CH3:36].Cl.CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.O>[CH3:34][N:35]([CH3:36])[C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:33])([C:25]([F:27])([F:28])[F:26])[C:29]([F:31])([F:30])[F:32])[CH:19]=3)[N:4]=2)=[CH:15][CH:14]=1
Reactant: CNC
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1COc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: Cc1oc(-c2ccc(C(=O)N(C)C)cc2)nc1COc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To 25 mg (0.05 mmol) of 4-{5-methyl-4-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxymethyl]-oxazol-2-yl}-benzoic acid (example 81) in 1.5 ml of CH2Cl2 were added 8.6 mg (0.11 mol) of dimethylamine.HCl and 23 μl (0.11 mmol) of NMM. The solution was cooled to 0° C. and 13.1 mg (0.07 mmol, 1.3 eq) of EDCI and 1.4 mg (0.01 mmol) of HOBT were added. The mixture was stirred at room temperature overnight. Water was added and the inorganic phase was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated. Column chromatography with CH2Cl2/MeOH 98:2 gave 22 mg (83%) N,N-dimethyl-4-{5-methyl-4-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxymethyl]-oxazol-2-yl}-benzamide as a colorless oil, MS: 501 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([O:20][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)(C(=O)O)O1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(NC(=O)OCc2ccccc2)(C(=O)OCc2ccc([N+](=O)[O-])cc2)O1
Yield: 55.3 %

Procedure:
To a solution of 838 mg of 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylic acid in 5 ml of dimethylformamide was added 120 mg of sodium hydride (60% oil) while stirring under ice-cooling. To the mixture was then added 648 mg of 4-nitrobenzyl bromide, followed by stirring at room temperature for 2.5 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and then dried (MgSO4), followed by distilling off the solvent. The residue was subjected to a silica gel column chromatography, eluting with hexane-ethyl acetate (1:1). Fractions containing the end product were combined and concentrated under reduced pressure to give 687 mg of 4-nitrobenzyl 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylate as colorless crystals, m.p. 127°-127.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].[NH2:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[C:19]([Cl:24])[N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN1C(=O)CCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][C:21]3[CH:20]=[C:19]([Cl:24])[N:18]=[C:17]([NH2:16])[N:22]=3)=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2cc(O)ccc12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1csc2cc(Oc3cc(Cl)nc(N)n3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2.563 g (11.5 mMol) 6-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester, 3.06 g (18.5 mMol) 2-amino-4,6-dichloropyrimidine and 5.15 g (23 mMol) K3PO4 in 87 ml NMP is stirred for 1.5 h at 60° C. Then the mixture is poured into EtOAc and water, the aq. layer separated off and extracted 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Trituration in ether and filtration gives the title compound: m.p.: 178-179° C.; TLC(hexane/EtOAc 2:1): Rf=0.27. More product can be obtained from the filtrate by column chromatography (SiO2; hexane/EtOAc 3:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>CO.CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C=Cc2ccc(O)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(CCc2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A solution of 4,4′-dihydroxystilbene (250 mg, 1.178 mmol) in MeOH (10 mL) and EtOAc (2 mL) containing 5% Pd-C (120 mg) was stirred under an atmosphere of hydrogen for 2 h. The catalyst was removed by filtration and the filtrate was concentrated. Chromatography purification of the crude product on silica gel (hexane-EtOAc 3:1, 2;1) provided 245 mg of 4-[4-Hydroxy-phenethyl]-phenol (97%) as a white solid. MS (ES) m/z: 213.05 (M−1).
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:45]([CH3:47])[CH3:46])[C:11]([N:13]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:14][C:15]([NH:17][C@H](C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)=O)CC(O)=O)=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C(N)[C@H](C(OCC=C)=O)C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)O)(C)(C)C.C([O:83][C:84](=[O:107])[CH:85](N)[C@H:86](C(OCC=C)=O)[CH:87]([C:89]1[O:90][C:91]2[CH:97]=[C:96]([Cl:98])[CH:95]=[C:94]([F:99])[C:92]=2[N:93]=1)[OH:88])(C)(C)C.C(OC(=O)C[C@H](NC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=CC=1)C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)O)(C)(C)C>>[C:1]([NH:9][C@@H:10]([CH:45]([CH3:47])[CH3:46])[C:11]([N:13]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:14][C:15]([NH:17][C@H:86]([C:87]([C:89]1[O:90][C:91]2[CH:97]=[C:96]([Cl:98])[CH:95]=[C:94]([F:99])[C:92]=2[N:93]=1)=[O:88])[CH2:85][C:84]([OH:83])=[O:107])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(F)cc(Cl)cc2o1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Agent: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1
Agent: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc2c(F)cc(Cl)cc2o1)Cc1ccccc1

Procedure:
Compound 719 was prepared by a method similar to the method used to prepare compound 710, except compound 707 was replaced with compound 714 in the preparation of 708: 1H NMR (500 MHz, CD3OD) δ 8.70-8.54 (m), 8.48-8.35 (m), 8.34-8.08 (m), 7.98-7.87 (m), 7 .75-7.67 (m), 7.63 (m), 7.58 (m), 7.51-7.44 (m), 7.43-7.29 (m), 7.28-7.03 (m), 6.97 (m), 5.51 (m), 4.99-4.66 (m), 4.65-4.26 (m), 4.25-3.61 (m), 3.42 (m), 3.13-2.83 (m), 2.68-2.42 (m), 2.23-2.00 (m), 1.02-0.69 (m). ##STR98##
Reaction SMILES: [CH:1]([Li])(CC)C.[CH2:6]([C:8]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[C:15]2[C:9]=1[C:10](=[O:23])[NH:11][S:12]2(=[O:14])=[O:13])[CH3:7].CI>O1CCCC1>[CH2:6]([C:8]1[C:18]([O:19][CH3:20])=[C:17]([CH3:1])[C:16]([O:21][CH3:22])=[C:15]2[C:9]=1[C:10](=[O:23])[NH:11][S:12]2(=[O:13])=[O:14])[CH3:7]
Reactant: [Li]C(C)CC
Reactant: CCc1c(OC)cc(OC)c2c1C(=O)NS2(=O)=O
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(OC)c(C)c(OC)c2c1C(=O)NS2(=O)=O
Reaction time: 0.25 h
Yield: 32 %

Procedure:
s-Butyllithium (0.87M in cyclohexane, 20.4 mL) was added dropwise during one hour with stirring at -78° C. to a solution of 4-ethyl-5,7-dimethoxysaccharin (Example 22L, 2.2 g) in tetrahydrofuran (100 mL). After continued stirring at -78° C. for one hour methyl iodide (1.5 mL) was added. Stirring was continued at -78° C. for 15 minutes, the temperature was allowed to rise to room temperature, and the mixture was quenched in water. Aqueous sodium hydroxide (0.5%, 200 mL) was added. The mixture was washed with ethyl acetate (200 mL), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (200 mL). The ethyl acetate extract was washed with aqueous sodium thiosulfate (10%, 50 mL) and saturated aqueous sodium chloride (50 mL), dried over sodium sulfate and stripped of ethyl acetate affording 4-ethyl-5,7-dimethoxy-6-methylsaccharin (0.73 g, 32% yield).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[F:9][C:10]([F:24])([F:23])[O:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=[CH:16][CH:17]=1>>[F:23][C:10]([F:9])([F:24])[O:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[C:20](=[O:22])[CH2:19][CH2:18]2
Reactant: O=C(O)CCc1cccc(OC(F)(F)F)c1
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1CCc2cc(OC(F)(F)F)ccc21
Reaction time: 18 h

Procedure:
About 37 ml of trifluoromethanesulfonic acid were added at about 5° C., with stirring, to 12.4 g of the product from step 1, and stirring was then carried out for 18 hours at room temperature. Crushed ice was then added, followed by extraction with diethyl ether. The combined organic phases were washed with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, and dried over magnesium sulfate, filtered and concentrated in vacuo at from 25 to 40° C. (yield 10.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:18][C:19]([Cl:23])([Cl:22])[C:20]#[N:21]>CCOCC>[Cl:18][C:19]([Cl:23])([Cl:22])[C:20](=[NH:21])[O:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: OC(c1ccccc1)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N=C(OC(c1ccccc1)c1ccc(Br)cc1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(4-bromophenyl)(phenyl)methanol from example 67 step 2 (175 g, 0.665 mol) was dissolved in Et2O (700 mL) and sodium hydride (2.66 g of 60% dispension in oil, 0.067 mol, 0.1 eg) was added. Reaction mixture was cooled to 0° C. and trichloroacetonitrile (96 g, 0.665 mol, 1 eg) was added dropwise over 15 min. Reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. Mixture was evaporated to dryness and solid was stirred in hexane for 18 hours. The solid was filtered to give the product.