Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(C)(C)C)(=O)C.Cl(O)(=O)(=O)=O>[C:2]([O:19][C:18](=[O:20])[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:7])([CH3:3])[CH3:1]
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
Nα -(Benzyl-oxycarbonyl)-L-lysine (5.0g m, 17.84 mmol) was dissolved in 268 ml of tert-butyl acetate containing 2.80 ml of perchloric acid (69-72% aqueous solution). The solution was stirred for 2 days at room temperature and then was extracted with water (3×200 ml). The combined aqueous layers were adjusted to pH 10 with 50% sodium hydroxide. The aqueous solution was then extracted with ethyl acetate (3×200 ml) and the organic layers dried over MgSO4. After filtration to remove MgSO4, the solvent was removed by evaporation at reduced pressure to provide Nα -(benzyloxycarbonyl)-L-lysine tert-butyl ester as a clear oil (2.16 gm, 36%). 1H NMR (CDCl3) 1.35 (s,9H), 1.40-2.0 (m,6H), 2.60 (t,2H), 4.10 (m,1H), 4.98 (s,2H), 5.29 (bs,1H), 7.35 (s,5H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][C:4]1[NH:5][CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1.[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>>[F:15][C:2]([F:1])([F:14])[CH2:3][C:4]1[N:5]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c[nH]c(CC(F)(F)F)n1
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c(CC(F)(F)F)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(b) starting from ethyl 2-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxylate (3.6 mmol, 0.8 g) and SEM-Cl (4.3 mmol, 0.8 ml). Yield 602 mg. 1H-NMR (400 MHz; CDCl3): δ 0.01 (s, 9H), 0.91 (t, 2H), 1.39 (t, 3H), 3.48 (t, 2H), 3.75 (q, 2H), 4.39 (q, 2H), 5.33 (s, 2H), 7.69 (s, 1H).
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:16][O:17][NH3+:18].[Cl-].C(N(CC)CC)C>C(O)C(C)C>[CH3:16][O:17][N:18]=[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][N+:5]([O-:7])=[O:6]
Reactant: CO[NH3+]
Reactant: CSC(=C[N+](=O)[O-])NCc1cccnc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC(C)CO
Product: CON=C(C[N+](=O)[O-])NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To 3 ml of isobutyl alcohol was added 0.75 g (0.0033 mole) of 1-methylthio-1-(3-pyridylmethyl)amino-2-nitroethylene, followed by addition of 0.56 g of 0-methylhydroxylamine hydrochloride at 100-110° C. Then, a solution of 0.93 ml of triethylamine in 1 ml of isobutyl alcohol was added dropwise at the same temperature with stirring over a period of 30 minutes. After completion of dropwise addition, the reaction mixture was allowed to cool to room temperature and the solvent was distilled off. The residue was purified by silica gel column chromatography [eluents: MeOH—CHCl3 (1:3) in the first run and MeOH—CHCl3 (1:10) in the second run] to give 0.23 g of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:43])[CH3:42])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([NH:40][C:41](=[O:43])[CH3:42])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: CC(=O)NC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and N-(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)acetamide. MS (ESI): mass calcd. for C23H24FN5O3S, 469.16; m/z found, 470.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.41-8.38 (m, 1H), 8.08 (d, J=1.4, 1H), 8.01-7.97 (m, 1H), 7.90 (m, 1H), 7.80 (d, J=7.6, 1H), 7.77-7.72 (m, 1H), 7.68-7.63 (m, 1H), 7.46-7.42 (m, 1H), 7.33-7.24 (m, 2H), 3.61-3.50 (m, 1H), 3.26-3.18 (m, 2H), 2.59-2.52 (m, 2H), 1.76 (s, 3H), 1.67-1.59 (m, 2H), 1.27-1.15 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:28]([F:31])([F:30])[F:29])=[N:15][N:16]([C:17]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=4[C:19](O)=[O:20])[C:10]=3[C:9]2=[O:32])=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:28]([F:31])([F:30])[F:29])=[N:15][N:16]([C:17]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=4[C:19]([Cl:35])=[O:20])[C:10]=3[C:9]2=[O:32])=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)Cl)c1

Procedure:
2-[6-(4-Iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid (186 mg, 0.334 mmol) was dissolved in dry chloroform (10 mL) to which was added thionyl chloride (243 μL, 3.34 mmol), and the reaction heated to reflux. The solvent was evaporated, and the residue dried under vacuum to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoyl chloride as a pale yellow foam. This material was dissolved in dry methylene chloride (10 mL) to which were added pyridine (0.14 mL, 1.67 mmol), N,N-dimethylaminopyridine (4 mg, 0.033 mmol), and lastly C-(1H-imidazol-2-yl)-methylamine bis-hydrochloride (114 mg, 0.668 mmol). Upon completion of the reaction the solvent was evaporated, and the residue was purified by preparative HPLC to give the title compound (69 mg, 24%) as a colorless solid. MS (ES+) 636.9 (M+H)+(100%).
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:39][CH:40]([CH2:44][CH2:45][CH3:46])[C:41](Cl)=[O:42].N1C=CC=CC=1.O>ClCCCl.C(OCC)(=O)C>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:41](=[O:42])[CH:40]([CH3:39])[CH2:44][CH2:45][CH3:46])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reactant: CCCC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(C)C(=O)N1CC(NC(=O)Nc2cccc(C(=O)OCC)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 95.6 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) obtained from Step 1of Example 93 was suspended in 1,2-dichloroethane (10 ml), 2-methyl-n-pentanoyl chloride (144 mg) and pyridine (87 μl) were added, the mixture was refluxed for 3 hours. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture, separated, the organic layer was washed with 1N hydrochloric acid, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 569 mg of the titled compound (Yield: 95.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].[Mg].BrCCBr.[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>O1CCCC1.C(OCC)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(F)ccc1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccc(F)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A solution of 2-bromo-5-fluoroanisole (11.8 g, 57.6 mmol) in tetrahydrofuran (60 ml) was dropped into the magnesium (1.40 g, 57.6 mmol) in refluxed tetrahydrofuran (32 ml) containing small amount of 1,2-dibromoethane and refluxed for 15 min. After addition of tetrahydrofuran (50 ml), the solution was cooled to −78° C. and diethyl oxalate (7.41 g; 50.7 mmol) in diethyl ether (50 ml) was dropped into the solution. After stirring at the same temperature for 30 min, the solution was warmed to −10° C. and 1N aqueous hydrogen chloride (50 ml) and water were added. Organic layer was extracted with diethyl ether, washed with brine and dried over magnesium sulfate. After removal of the solvent under reduced pressure, purification of the residue by silica gel column chromatography (eluent: hexane/ethyl acetate=5/2) gave ethyl 2-(4-fluoro-2-methoxyphenyl)-2-oxoacetate (6.80 g, 59%)
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([CH3:9])=[C:7]([N+]([O-])=O)[C:6]([CH3:13])=[CH:5][N+:4]=1[O-:14].Cl.[CH2:16]([OH:18])[CH3:17]>C(OCC)(=O)C>[CH2:16]([O:18][C:7]1[C:6]([CH3:13])=[CH:5][N+:4]([O-:14])=[C:3]([CH3:2])[C:8]=1[CH3:9])[CH3:17]
Reactant: CCO
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCOc1c(C)c[n+]([O-])c(C)c1C

Procedure:
4.2 g of sodium were dissolved in 780 ml of ethanol under argon. 22.3 g of 2,3,5-trimethyl-4-nitropyridine 1-oxide were then added portionwise thereto and the solution was left to boil under reflux overnight. The pH was adjusted to 7 by means of 5N hydrogen chloride in ethyl acetate while cooling and the mixture was then evaporated in vacuo. The residue was taken up in 0.5 l of methylene chloride, the solution was filtered through silica gel, which was rinsed with 200 ml of methylene chloride, the combined filtrates were evaporated in vacuo and the residue was crystallized from petroleum ether. There was obtained 4-ethoxy-2,3,5-trimethylpyridine 1-oxide of melting point 59°-61°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:24])=[C:18](F)[C:19]=3[O:21][CH3:22])[C:14](=[O:25])[C:13]([C:26]([OH:28])=[O:27])=[CH:12]2)[CH2:10][CH2:9]1>CS(C)=O>[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:24])=[C:18]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[C:19]=3[O:21][CH3:22])[C:14](=[O:25])[C:13]([C:26]([OH:28])=[O:27])=[CH:12]2)[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Product: COc1c(N2CCN(C)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 70 °C
Reaction time: 6 h
Yield: 26.6 %

Procedure:
0.12 g (0.0012 mole) of N-methylpiperazine was added to a solution of 0.09 g (0.0003 mole) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IIc) (prepared as described in Preparation 6) in 0.5 ml of dimethyl sulfoxide, and the mixture was stirred at 70° C. for 6 hours. At the end of this time, the solvent and the excess N-methylpiperazine were removed by evaporation under reduced pressure at the same temperature, and the residue was washed with ethyl acetate and subjected to silica gel column chromatography, eluted with methanol, to afford 0.03 g of 1-cyclopropyl-6-fluoro-8-methoxy-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless powdery crystals, melting at 211°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:15]([Cl:16])=[N:14][C:13](Cl)=[CH:12][N:11]=1)=[O:9].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[OH:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:15]1[C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:9])=[N:11][CH:12]=[C:13]([O:26][C:20]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=2[F:18])[N:14]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(c1ccccc1Cl)c1ncc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Cl)c1ncc(Oc2ccc(F)cc2F)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a dimethylformamide, i.e., DMF, (25 mL) solution of (2-chlorophenyl)-(3,5-dichloropyrazin-2-yl)methanone (2.1 g, 7.3 mmol, 1.0 eq) under nitrogen was added 2,4-difluorophenol (0.7 mL, 7.3 mmol, 1.0 eq) and potassium carbonate (1.21 g, 8.76 mmol, 1.2 eq). The resulting mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude oil which was purified via a chromatography using dichloromethane/hexanes (1:1) as the eluent to give [3-chloro-5-(2,4-difluorophenoxyl)pyrazin-2-yl]-(2-chlorophenyl)methanone (2.46 g, 6.45 mmol, 88% yield). Mass spec. M+1=382.
Reaction SMILES: I[C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:17]([C@@H:24]1[C@@H:33]([OH:34])[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[O:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+].C(O)C>[Pd].C(OC(C)C)(C)C.C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=1[C:29]1[CH:28]=[C:27]2[C:32]([C@H:33]([OH:34])[C@@H:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][O:26]2)=[CH:31][CH:30]=1)[CH3:8]
Reactant: OB(O)c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1I
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Yield: 93.6 %

Procedure:
A mixture of ethyl 2-iodo-4-trifluoromethyl-benzoate (723 g, 2.1 mol), (3S, 4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid (627 g, 2.2 mol), potassium fluoride (366 g, 6.3 mol), 10% palladium on carbon (157 g, 50% water wet), and anhydrous ethanol (6.27 L) was heated at reflux for 3 hours at which point thin layer chromatography (toluene/acetic acid, 5:1) indicated the reaction to be complete. The reaction mixture was diluted with isopropyl ether (8 L), filtered through Celite® and washed with 10% aqueous sodium bicarbonate (1.5 L). The aqueous layer was separated and extracted with isopropyl ether (3 L). The combined organic layers were washed with water (6 L), dried over magnesium sulfate, and treated with Darco®G-60 (1.0 kg) and silica gel (1 kg, 70-230 mesh) at ambient temperature. This mixture was filtered-through a pad of silica gel (70-230 mesh) and concentrated in vacuo to 922 g of dark oil. This oil was diluted with ethyl acetate (1 L) and filtered through a column of silica gel (2 kg) eluting with ethyl acetate giving a light amber solution which was concentrated to afford 897 g (92%) of (3S, 4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid ethyl ester as a light amber oil: 1H NMR (400 MHz, CDCl3) 67 7.89 (d, J=8.1 Hz, 1H), 7.63-7.67 (m, 2H), 7.18-7.38 (m, 6H), 6.91 (dd, J=1.8, 7.8 Hz, 1 H), 6.86 (d, J =1.7 Hz, 1H), 4.55 (bs, 1H), 4.25 (dd, J=2.7, 11.2 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.00 (ddd, J=1.0, 4.5, 11.2 Hz, 1 H), 2.75 (dd, J=6.4, 13.9 Hz, 1 H), 2.56 (dd, J=9.3, 13.8 Hz, 1 H), 2.26 (m, 1 H), 1.93 (d, J=4.3 Hz, 1 H), 1.09 (t, J=7.2 Hz, 3H); IR 3307 (br), 3216 (br), 1734, 1339, 1298, 1247, 1191, 1175, 1118, 1097, 1050 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.C([Mg]Cl)CCC.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:45]OS(O)(=O)=O>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:45])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To a clear solution of 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole from Example 2 (40,0 mg, 1 mmol) in tetrahydrofuran (THF) (8 mL) at 0° C., n-BuMgCl (2M solution in THF, 2 mL, 4 mmol) was added over 10 minutes. After stirring for additional 10 minutes, ice bath was removed and solution stirred for 1 hour. The reaction mixture was re-cooled to 0° C. and triethylborane (1M solution in THF, 5 mL, 5 mmol) was added. After stirring for 2 hours, the reaction was heated to reflux for 48 hours. The reaction mixture was cooled to room temperature and treated with aqueous sodium acetate (1 g in 4 mL water). After stirring for 5 minutes, solid hydroxylamine-O-sulfonic acid (1 g) was added and the mixture stirred for 20 hours. The reaction mixture was diluted with water and extracted with ether (2×250).The ethereal layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid (568 mg) was purified by chromatography [silica gel, ethyl acetate/toluene (3/7)] to give 4-[2-(4-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (260 mg, 65%): mp (DSC) 225° C. Anal. Calc'd. for C16H11N3SO2F3Cl: C, 47.83; H, 2.76; N, 10.46; S, 7.98. Found: C, 48.00; H, 2.83; N, 10.14; S, 7.94.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])(O)=[O:2].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ncn(-c2ccccc2)n1)C(=O)O
Solvent: Cc1ccccc1
Product: CC(Oc1ncn(-c2ccccc2)n1)C(=O)Cl

Procedure:
A 22.8 g portion of the compound of Example 22 was suspended in 150 ml of toluene, and 49 ml of thionyl chloride was added. The mixture was heated under reflux for 2 hours, and was then cooled and evaporated under vacuum. One hundred ml of additional toluene was added and was removed under vacuum, and the residue was recrystallized from toluene.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1.ClC(Cl)(Cl)C(=N)O[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:12]([O:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: O=C1CC(O)CO1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: O=C1CC(OCc2ccccc2)CO1
Temperature: 0 °C
Reaction time: 48 h
Yield: 75.5 %

Procedure:
To a stirred solution of 4-hydroxydihydrofuran-2(3H)-one (25 g, 245 mmol) and benzyl 2,2,2-trichloroacetimidate (68.6 mL, 367 mmol) in CH2Cl2 (500 mL) and cyclohexane (500 mL) at 0° C. was added, dropwise, trifluoromethanesulfonic acid (2.175 mL, 24.49 mmol) over 10 min. The reaction mixture was stirred for 2 h at 0° C. and 48 h at room temperature. After this, it was diluted with hexanes (0.75 L), filtered and the filtrate washed with sat. aq. NaHCO3 (150 mL), dried (Na2SO4), filtered and concentrated. The resulting yellow oil was purified by flash column chromatography on silica gel column using 5-40% ethyl acetate/hexane (5% increment for every liter) to afford 4-(benzyloxy)dihydrofuran-2(3H)-one (35.52 g, 185 mmol, 75% yield) as a clear yellow oil. 1H NMR (500 MHz, CDCl3) δ: 7.34-7.39 (2 H, m), 7.29-7.34 (3 H, m), 4.53 (1 H, d, JAB=11.9 Hz), 4.52 (1 H, d, JAB=11.90 Hz), 4.34-4.41 (3 H, m), 2.64-2.68 (2 H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[C:28]3[F:50])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])[NH:1][C:58](=[O:59])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][CH:33]=2)[C:28]([F:50])=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C(C)C)ccc1[C@@H](C)CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23 %

Procedure:
To a solution of 8C (228 mg, 0.282 mmol) in acetonitrile (10 mL) and dichloromethane (5 mL) at 0° C., was added phosgene solution (20% in toluene) (0.178 mL, 0.339 mmol) dropwise. The mixture was stirred at 0° C. for 20 min, then at rt for 15 min. The extra phosgene was removed by bubbling Ar though the reaction mixture (15 min). The resulting solution was added dropwise via syringe pump into a stirred solution of TEA (0.315 mL, 2.258 mmol) in dichloromethane (80 ml) at rt over 3.0 h. The reaction was quenched by 0.5 N HCl and extracted with CH2Cl2. The organic layer was collected, washed with water and dried over sodium sulfate, then concentrated. The crude product was purified by flash chromatography to give a mixture of diastereoisomers (235 mg). The diastereomers (165 mg) were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 8D (54 mg, 0.065 mmol, 32.7% yield). MS (ESI) m/z: 883 [M+1]+. 1H NMR (400 MHz, chloroform-d) δ ppm 1.26 (d, J=6.59 Hz, 3H) 1.28-1.37 (m, 21H) 1.42 (d, J=6.59 Hz, 3H) 2.09 (s, 3H) 3.27-3.42 (m, 5H) 3.90 (dd, J=10.77, 3.73 Hz, 1H) 4.30 (d, J=17.58 Hz, 1H) 4.63 (t, J=10.99 Hz, 1H) 5.43 (d, J=5.71 Hz, 1H) 5.68 (d, J=18.02 Hz, 1H) 6.36 (s, 1H) 6.55 (d, J=5.71 Hz, 1H) 6.75 (d, J=8.35 Hz, 1H) 6.86 (s, 1H) 7.01 (d, J=9.23 Hz, 1H) 7.04-7.12 (m, 2H) 7.45-7.54 (m, 2H) 7.61 (d, J=7.91 Hz, 1H) 7.77 (d, J=8.35 Hz, 1H) 8.03 (s, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −141.12 (br. s., 1F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][N:18]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[CH:24]=[CH:23][CH:22]=[C:21]3[NH:20][C:19]1=[O:31].C(=O)(O)[O-].[Na+].O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][N:18]3[C:29]4=[C:30]5[C:25](=[CH:26][CH:27]=[CH:28]4)[CH:24]=[CH:23][CH:22]=[C:21]5[NH:20][C:19]3=[O:31])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cccc3cccc(c23)N1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3cccc(c23)N1CCCN1CCN(c2ccc(F)cc2)CC1
Yield: 22.8 %

Procedure:
1.35 g of 4-(4-fluorophenyl)piperazine, 1.84 g of 1-(3-chloropropyl)-2-perimidinone and 0.66 g of sodium bicarbonate, in 25 cm3 of dry N,N-dimethylformamide are stirred at the reflux temperature of the solvent for 2 hours. The reaction mixture is cooled and poured into a mixture of 20 cm3 of water and 25 cm3 of dichloro-methane. The organic phase is decanted, washed with water (3×15 cm3), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column under a pressure of 0.7 bar of nitrogen, eluting with ethyl acetate. 0.65 g of 1-{3-[4-(4-fluorophenyl)-1-piperazinyl]-propyl }-2-perimidinone is thus obtained; melting point =206° C.