Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[C:4]([F:13])[CH:3]=1.[O:14]1CCC[CH2:15]1.C([Li])CCC.CN(C)C=O>O>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([CH:15]=[O:14])=[CH:3][C:4]=1[F:13]
Reactant: C1CCOC1
Reactant: COC(OC)c1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1ccc(C=O)cc1F
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of 4-bromo-1-dimethoxymethyl-2-fluorobenzene (4.53 g, 18.2 mmol) in 1 tetrahydrofuran (50 mL) were added n-butyllithium (1.6 mol/L in hexanes; 15 mL) and dimethylformamide (2.1 mL, 27 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 15 min. Water was added, and the mixture was extracted twice with ether. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (6:1 Hexane/ethyl acetate) to afford 4-dimethoxymethyl-3-fluorobenzaldehyde (2.26 g, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 10 mL of acetonitrile. To the stirred solvent were added 4-(benzyloxy)-2-hydroxybenzaldehyde (1.0 g, 4.38 mmol), potassium carbonate (1.21 g, 8.76 mmol). The reaction mixture was brought to 0° C., was added methyl iodide (1.135 g, 8.76 mmol) in acetonitrile (5 mL) drop wise and stirred at room temperature for 16 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (50 mL). The organic layer was washed with water (40 mL) and saturated brine solution (40 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product obtained as a white solid (1.06 g, yield: 100.0%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[NH2:38][CH2:39][CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1.Cl>CS(C)=O.C(OCC)(=O)C.CO>[ClH:1].[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:38][CH2:39][CH2:40][C:41]3[N:45]=[CH:44][NH:43][CH:42]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCc1c[nH]cn1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCc4c[nH]cn4)nc32)[C@H](O)[C@@H]1O
Yield: 79.9 %

Procedure:
A solution of 1-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-1-deoxy-N-ethyl-β-D-ribofuranuronamide (0.155 g,0.296 mmol) and histamine (0.22 g) in dimethylsulphoxide (1.5 ml) was heated at 120° C. for 16h. The mixture was cooled and diluted with ethyl acetate (50 ml) then washed with water (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml) and the combined organic phase was washed with water (50 ml), dried (MgSO4) and evaporated to leave a solid which was treated with 2N hydrochloric acid (2 ml) in methanol (30 ml) and the solution was evaporated to leave the title compound (0.15 g,80%) as a solid. MH+ =598, nmr(δ,DMSO-d6) includes 1.02(t,3H), 3.0(m,2H), 3.13(m,2H), 3.7(m,2H), 4.2(m,2H), 4.85(s,1H), 4.55(m,3H), 5.9(d,1H), 7.1-7.6(m,12H), 8.45(s,1H), 9.05(s,1H), 14.3(m,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:21][CH3:22])[C:15]=3[O:19][CH3:20])[CH2:10]2)=[CH:5][CH:4]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:21][CH3:22])[C:15]=3[O:19][CH3:20])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2Cc3cc(OC)c(OC)c(OC)c3C2=O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(C2Cc3cc(OC)c(OC)c(OC)c3C2)cc1
Yield: 98.9 %

Procedure:
A mixture of the ketone 34 (250 mg, 0.74 mmol) and 10% Pd-C (100 mg) in acetic acid (40 mL) was subjected to hydrogenolysis at 42 psi hydrogen pressure until the absorption of hydrogen ceased. Filtration and evaporation of the reaction solution gave an oil. It was purified by flash chromatography (ether:hexane, 70:30 by volume, silica gel 230-400 mesh) to afford 35 as a colorless oil(230 mg, 96.2%). TLC only showed one spot. 1H NMR (CDCl3, 500 MHz) δ7.22 (d, 2H, J=8 Hz), 6.72 (d, 2H, J=8 Hz), 6.59 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.63 (m, 1H), 3.36 (m, 1H), 3.26 (m, 1H), 2.97 (m, 2H). EIMS m/e 314 (M+, 100). Anal. (C19H22O4) C, H.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[S:3][CH2:4][C:5](=[O:7])[CH3:6].C(O)C.[F:13][C:14]([F:18])([F:17])[S:15]Cl>ClCCl>[F:1][C:2]([F:9])([F:8])[S:3][CH:4]([S:15][C:14]([F:18])([F:17])[F:13])[C:5](=[O:7])[CH3:6].[F:1][C:2]([F:9])([F:8])[S:3][CH2:4][C:5](=[O:7])[CH2:6][S:15][C:14]([F:18])([F:17])[F:13]
Reactant: CC(=O)CSC(F)(F)F
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)C(SC(F)(F)F)SC(F)(F)F
Product: O=C(CSC(F)(F)F)CSC(F)(F)F
Reaction time: 67 h

Procedure:
Using the method of Example 3, a mixture of 1-trifluoromethylthio-2-propanone (0.15 mole), dichloromethane (75 ml), ethanol (0.3 g) and trifluoromethanesulfenyl chloride was loaded into a sealed metal reaction vessel. The reaction was carried out for 67 hours at room temperature. Most of the dichloromethane was removed by distillation. Vapor phase chromatography of the residual liquid showed about 55 percent unreacted 1-trifluoromethylthio-2-propanone and two products. The distillation residue was returned to the sealed metal reactor, 11.2 g (0.082 mole) of trifluoromethanesulfenyl chloride and 75 ml of dichloromethane were added, and the reaction was allowed to continue for 12 days at room temperature. The dichloromethane was removed by distillation and the residue was examined by vapor phase chromatography. This analysis showed only 16% unreacted starting material. Fractional distillation of the reaction mixture gave 1,1-bis(trifluoromethylthio)-2-propanone, b.p. 44°C/23 mm Hg and 1,3-bis(trifluoromethylthio)-2-propanone, b.p. 67°C/5 mm Hg. These structures were established by elemental and spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:21]=[CH:22]/[CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(/C=C/CO)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(/C=C/CO)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-(4-Chlorobenzyl)-6-[(1E)-3-hydroxy-1-propenyl]-4-hydroxy-3-quinolinecarboxamide from Preparation No. 12 (0.184 g), K2CO3 (0.276 g) and iodomethane (0.062 mL) in DMF (2 mL) is heated in a stoppered flask at 90° C. for 1 h. Water is added and the mixture is allowed to cool and stir at room temperature for 16 h during which a precipitate formed. The precipitate is filtered and dried in vacuo at 60° C. for 48 h to give 0.164 g of the title compound as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15].Cl>CCCCCCC>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([C:3]1[CH2:4][CH2:5][O:1][CH:2]=1)=[O:15]
Reactant: C1=COCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: O=C(C1=COCC1)C(Cl)(Cl)Cl
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
To a nitrogen-purged, 5000-mL, three-neck, round-bottom flask equipped with a bottom stopcock, thermometer, mechanical stirrer, addition funnel and ice bath was charged 330.0 g (4.70 moles) of 2,3-dihydrofuran, 391 g (4.95 moles) of pyridine, and 1000 mL of n-heptane. The mixture was cooled to 10° C. then trichloroacetyl chloride (500 mL, 815 g, 4.48 moles) was added dropwise from the addition funnel. An ice bath was used to hold the reaction mixture at 11 to 220° C. during the 190 minute addition. The resulting yellow slurry was stirred at 22 to 28° C. for 45 minutes. To the mixture was added 700 mL of 10% aqueous HCl. After stirring to dissolve the solids, the lower (aqueous) layer was separated and discarded. The organic layer was washed sequentially with 500 mL of 10% HCl, 250 mL of 5% aqueous sodium bicarbonate and finally with 250 mL of water. The solution was placed in a 3000-mL, three-neck, round-bottom flask equipped with a magnetic stirrer, thermowell/thermocouple, heating mantle, and 12-inch Vigreux distillation head. The mixture was heated under vacuum (130 mm) to distill off the water/heptane azeotrope then most of the heptane. The mixture was distilled to a pot temperature of 102° C. (head temperature was 50° C.). A total of 1135 mL of distillate was collected. The resulting crude 2,3-dihydro-4-trichloroacetylfuran (881.38 g, theory 965.26 g) was 98.4% assay by nuclear magnetic resonance (NMR) (89.8% assay-yield). The crude product was used directly in the following example.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33]
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)CNCCO[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.1 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (230 mg, 0.57 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(2,2-dimethyl-propyl)-amine (8h) (167 mg, 0.68 mmol) in dimethylformamide (2.2 mL) were added N,N-diisopropylethylamine (0.3 mL, 1.70 mmol) and HATU (324 mg, 0.85 mmol). The reaction was stirred at room temperature for 20 h. Water (75 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(2,2-dimethyl-propyl)-amide (300) (310 mg, 86.27%) as an off-white sticky solid.
Reaction SMILES: [CH3:1]I.[Li+].[BH4-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:20][CH3:21])[C:16]=1[CH:17]([CH3:19])[CH3:18])[C:10]([O:12]C)=O.Cl>CCOCC.O>[CH3:21][O:20][C:15]1[CH:14]=[C:9]([CH:10]([OH:12])[CH3:1])[CH:8]=[C:7]([O:6][CH3:5])[C:16]=1[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Reactant: CI
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1cc(C(C)O)cc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of Mg (2 g, 82.2 mmol) in dry ether (100 mL) was added CH3I (5 mL, 80.4 mmol) in dry ether (100 mL). After the addition was completed, the reaction mixture was refluxed for 1 hour and then cooled to 0° C. LiBH4 (2.0M in THF, 25 mL, 50 mmol) was added followed by addition of methyl 3,5-dimethoxy-4-i-propylbenzoate (10.0 g, 42.0 mmol) in dry ether (300 mL). The reaction was stirred at 0° C. overnight. Water (50 mL) was added dropwise followed by 2N HCl (100 mL). The organic layer was separated and the aqueous extracted with ether (4×200 mL). The extract was dried over anhydrous sodium sulfate. Evaporation of the solution yielded a liquid mixture. This was used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]=[CH:5][CH2:6][C@H:7]1[C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:10]2([CH3:11])[C:9](=[O:35])[CH2:8]1)[C:21]1[CH:20]=[C:19]([O:25][CH3:26])[C:18]([O:27]CC2C=CC=CC=2)=[CH:17][C:16]=1[CH2:15][CH2:14]3>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:10]2([CH3:11])[C:9](=[O:35])[CH2:8]1)[C:21]1[CH:20]=[C:19]([O:25][CH3:26])[C:18]([OH:27])=[CH:17][C:16]=1[CH2:15][CH2:14]3
Reactant: COC(=O)C=CC[C@@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4cc(OC)c(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCC[C@@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4cc(OC)c(O)cc4CC[C@H]3[C@H]12
Yield: 1460 %

Procedure:
A solution of 4-(3-Benzyloxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15β-yl)-but-2-enoic acid methyl ester (17.3 g, 2.36 mmol) in THF (440 ml) and MeOH (440 ml) was purged with H2 (balloon). Then Pd (10% on carbon, 50% H2O) (1.80 g) was added, and the mixture obtained was stirred under H2 pressure for over night. The reaction mixture was filtered over two filter papers and concentrated in vacuo to yield the desired compound (VIIβ-(C2-B)-3a-1) (13.8 g, 97%), which represents a compound falling under the scope of the present invention.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12](Br)[CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:11]=[C:6]2[C:5]([CH:12]([CH3:13])[N:25]([C@@H:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH3:24])[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H](C)N)cc1
Reactant: COC(=O)c1cc(Br)ccc1C(C)Br
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2C)cc1
Temperature: 67 °C
Yield: 52.6 %

Procedure:
Add solid methyl 5-bromo-2-(1-bromoethyl)benzoate (1724 g, 5.35 mol) to a solution of commercially available (R)-1-(4-methoxyphenyl)ethanamine (BePharm, WZG111219-071; 974 g, 6.44 mol) and triethylamine (1710 mL, 12.26 mol) in methanol (12 L). Heat the mixture for 10 hours at 67° C. then evaporate to dryness under reduced pressure. Partition the residue with ethyl acetate (5 L) and aqueous 1 N HCl (10 L), separate the phases, wash the organic phase again with aqueous 1 N HCl (5 L), saturated sodium bicarbonate, saturated aqueous sodium chloride, then dry over sodium sulfate, filter, and evaporate under reduced pressure. Dissolve the dark red oil in methyl-tert-butyl ether (750 mL) and add petroleum ether (3 L) with vigorous stirring. Filter the solids, wash with methyl-tert-butyl ether/petroleum ether (1:8), petroleum ether, dry in open air to give the title compound as an off-white solid (1014 g, 52%). ES/MS m/z: 360 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH2:16])=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:19][N:20]([CH3:23])C=O>>[C:1]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:8][C:7]=2[N:16]=[C:4]1[C:1]1[CH:3]=[CH:23][N:20]=[CH:19][CH:2]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)Nc1ccc(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)n1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.47 g of N1-tert-butyl-4-trifluoromethylbenzene-1,2-diamine, 0.51 g of isonicotinealdehyde-bisulfite adduct and 5 ml of N,N-dimethylformamide was stirred for 10 minutes at 150° C. The reaction mixture was ice-cooled, then, a 10% sodium hydroxide aqueous solution was poured, and the mixture was extracted with methyl tert-butyl ether. The organic layer was washed with water, dried over sodium sulfate, then, concentrated under reduced pressure to obtain a solid residue. The residue was washed with hexane, to obtain 0.26 g of 1-tert-butyl-2-(pyridin-4-yl)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 220).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35]C5C(=O)CCC=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:7][O:8]2)(=[O:3])[CH3:2].[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[CH2:53]([OH:55])C>C(OC(=O)C)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][C:48]5[C:52](=[N:47][O:55][CH3:53])[CH2:51][CH2:50][CH:49]=5)=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC5=CCCC5=O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: CON=C1CCC=C1Oc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-((5-oxocyclopent-1-en-1-yl)oxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (150 mg, 0.22 mmol) in ethanol (1.14 mL), O-methoxylamine.hydrochloride (35 mg, 0.45 mmol) and pyridine (0.91 mL, 1.14 mmol) were added. The reaction mixture was heated to 100° C. for 1 h. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL) and the mixture was washed with 2% HCl (2×10 mL), water (50 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1.5:8.5 Acetone:hexane) to provide title compound (110 mg, 70.2%) as off-white solid.
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.Cl.Cl[CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([CH3:25])=[CH:19][N:18]=1.[OH-].[Na+]>O>[CH3:24][O:23][C:21]1[C:20]([CH3:25])=[CH:19][N:18]=[C:17]([CH2:16][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)[CH:22]=1
Reactant: COc1cc(CCl)ncc1C
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CSc2nc3cc4c(cc3[nH]2)OCO4)ncc1C

Procedure:
5.82 g of 5H-1,3-dioxolo[4,5-f]benzimidazole-6-thiol were suspended in 200 ml of alcohol and the suspension was treated with 6.3 g of 2-chloromethyl-4-methoxy-5-methylpyridine hydrochloride while cooling. Thereafter, a solution of 2.4 g of sodium hydroxide in 100 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×300 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel using ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 6-[[(4-methoxy-5-methyl-2-pyridyl)-methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 191°-193°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH:28]([C@@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)([CH3:30])[CH3:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:32]3[C@H:31]([CH:28]([CH3:30])[CH3:29])[CH2:35][O:34][C:33]3=[O:36])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 48.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (R)-4-isopropyloxazolidin-2-one (258 mg), the title compound (487 mg) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[Cl:15].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:15][C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCCCBr)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(OCCCN2CCN(c3ccccc3)CC2)c1
Reaction time: 18 h
Yield: 78 %

Procedure:
To the compound 26a (2.1 g, 7.1 mmol) in DMF (9 mL) was added N-phenyl piperazine (1.16 g, 7.1 mmol) and potassium carbonate (1.28 g, 9.23 mmol). The mixture was stirred for 18 hrs. at room temperature. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography to get the title compound 26b in 78% yield as yellow solid.
Reaction SMILES: [I-:1].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[CH:7]=[C:6]([CH2:17]OS(C)(=O)=O)[N:5]=1>C(Cl)Cl>[Cl:3][C:4]1[N:5]=[C:6]([CH2:17][I:1])[CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[N:9]=1
Reactant: [I-]
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Temperature: 40 °C
Yield: 91.7 %

Procedure:
Sodium iodide (1.006 ml, 24.61 mmol) was added to 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidine (1.584 g, 4.92 mmol) in DCM at RT. The resulting solution was refluxed at 40° C. for 18 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried (MgSO4), filtered and evaporated to afford the desired product (1.596 g).