Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].OP(O)(O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Na]>[CH3:1][C:2]1([CH3:3])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:6][CH2:5][CH2:4]1
Reactant: CC(C)(O)CCSc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na]
Product: CC1(C)CCSc2ccccc21
Reaction time: 24 h
Yield: 86.2 %

Procedure:
A mixture of 15.00 grams (0.076 mol) of 2-methyl-4-(phenylthio)-2-butanol, 12.75 grams of H3PO4, 27.0 grams (0.190 mol) of P2O5 [this is added in three equal portions every 8 h] and 60 mL of sodium-dried benzene was boiled under N2 for 24 hours in a 250-mL, round-bottom flask equipped with a condenser and nitrogen inlet. The resulting, cooled heterogeneous mixture was separated and the P2O5 layer was extracted with ether. The combined organic layers were washed with H2O, brine, dried with Na2SO4 (4 h). Evaporation and vacuum distillation gave 11.68 grams (86.0%) of 4,4-dimethylthiochroman as a clear colorless liquid: bp 75°-82° C./0.1 mm; 1H NMR (DCCl3) δ1.29 [s, 6H, (CH3)2C] 1.92 [m, 2H, ArSCH2CH2 ] 3.00 [m, 2H, ArSCH2CH2 ] 6.90-7.32 [m, 4H, Ar--H]; 13C NMR (DCCl3) ppm 22.8 [ArSCH2CH2 ], 29.9 [(CH3)2C] 32.6 [(CH3)C], 37.4 [ArSCH2CH2 ], 123.7, 125.7, 126.1, 126.2, 131.5, 141.5. ##STR13##
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[Cl-].[Ca+2].[Cl-].C(O)C>C(OCC)(=O)C.[Fe]>[NH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([NH:6][CH2:7][CH3:8])=[O:5])=[C:2]([Cl:1])[CH:12]=1
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(N)cc1Cl
Temperature: 25 °C
Yield: 89.2 %

Procedure:
2-Chloro-N-ethyl-4-nitrobenzamide (2.00 g) obtained in Example 66a), iron powder (2.43 g) and calcium chloride (0.48 g) were suspended in an aqueous solution (30 ml) of 85% ethanol, and the mixture was refluxed for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 ml), and the insoluble material was removed by filtration through celite. The filtrate was concentrated, and the residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a yellow powder (1.55 g, 90%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]1([CH:13]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:21]Br>ClCCl.II>[Br:21][CH:17]1[CH2:16][CH2:15][CH2:14][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:19][C:18]1=[O:20]
Reactant: O=C1CCCCC(c2ccccc2)N1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClCCl
Product: O=C1NC(c2ccccc2)CCCC1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Phosphorus pentachloride (4.95 g, 23.8 mmol) was added to a solution of 7-phenylazepan-2-one (4.50 g, 23.8 mmol) in dichloromethane (75 mL) at 0° C. After 1 h, iodine (0.060 g, 0.24 mmol) and a solution of bromine (1.22 mL, 23.8 mmol) in dichloromethane (10 mL) were added sequentially and the mixture was allowed to warm to ambient temperature. After 1.5 h, the reaction was quenched with aqueous sodium sulfite. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the title compound (4.91 g). MS 268 (M+1).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6](O)=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.[C:20]1([CH:26]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:27]([NH2:50])[CH:28]=[CH:29][S:30]([CH:33]=[CH:34][C@@H:35]([NH2:49])[CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:32])=[O:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:51]1([CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:27]([NH:50][C:6](=[O:7])[C@H:2]([CH:3]([CH3:5])[CH3:4])[NH:1][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:28]=[CH:29][S:30]([CH:33]=[CH:34][C@@H:35]([NH:49][C:6](=[O:7])[C@H:2]([CH:3]([CH3:4])[CH3:5])[NH:1][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)(=[O:32])=[O:31])[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: N[C@H](C=CS(=O)(=O)C=C[C@@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 98 %

Procedure:
Cbz-Val-Phe-VS-Ph was prepared from Cbz-Val-OH and Phe-VS-Ph.HCl using standard mixed anhydride coupling method, yield 98%. 1H-NMR (CDCl3) δ 0.70-0.84 (2d, 6H, Val-CH3), 2.06 (m, 1H, Val-CH), 2.91 (m, 2H, CH2-Phe), 3.82 (m, 1H, α-H), 4.80-4.90 (m, 1H, α-H), 5.10 (s, 2H, Cbz), 5.96 (d, 1H, NH) 6.34 (d, 1H, CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.4 (m, 10H, 2×Ph), 7.5-7.7 (m, 5H, SO2-Ph). MS (ESI) m/z 521 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(OCC)(=O)C.N1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[F:11])[NH:1][S:13]([CH3:12])(=[O:15])=[O:14])(=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(N)ccc1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)c1cc(NS(C)(=O)=O)ccc1F
Yield: 79.7 %

Procedure:
5'-Amino-2'-fluoroacetophenone (28 g) was dissolved in a mixture of 100 ml of ethyl acetate and 15.9 g of pyridine, a solution of 23 g of methanesulfonyl chloride in 50 ml of ethyl acetate was added with ice-cooling and stirring and the mixture was made to react at room temperature for 3 hours. The reaction mixture was washed with water, dried, the solvent was evaporated therefrom and the residue was purified by silica gel column chromatography (eluting with chloroform) to give 33.7 g of 3'-acetyl-4'-fluoromethanesulfonanilide, m.p. 120°-123° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](O)[C:2]=1[OH:12].C1([OH:23])C2CC=CCC=2C=CC=1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(OCC)C>[O:12]1[CH:2]2[CH:3]1[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:23])[C:10]=1[CH2:1]2
Reactant: Oc1cccc2c1CC=CC2
Reactant: Oc1cc2ccccc2cc1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Oc1cccc2c1CC1OC1C2

Procedure:
Alternatively, the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substituted-amino)propoxy]-2,3-naphthalenediol isomer XXVII can be prepared from a 5,8-dihydro-1-naphthol of the structure ##STR34## prepared as described hereinbefore, by mixing a cooled solution (temperature less than about 30° C.) of 5,8-dihydro-1-naphthol in ethyl acetate with m-chloroperbenzoic acid and mixing the resulting slurry with a mixture of ethyl ether and aqueous sodium bicarbonate, to form 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol ##STR35## and reacting the 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol in tetrahydrofuran with aqueous perchloric acid at a temperature within the range of from about 0° to about 60° C., to form trans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol XXV which can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol XXVI which in turn can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-substituted amino)propoxy]-2,3-naphthalenediol XXVII in a manner similar to that described hereinbefore.
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>CCOC(C)=O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)N1CCC(c2nccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(N)cc2)CC1
Temperature: 80 °C

Procedure:
1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (0.153 g, 0.685 mmol), 4-aminophenol (0.079 g, 0.720 mmol), cesium carbonate (0.246 g, 0.754 mmol), and 1-methyl-2-pyrrolidinone (0.685 mL, 0.685 mmol) were combined in a sealed tube and heated at 80° C. for 20 h. The cooled reaction mixture was diluted with EtOAc and washed with water; the aqueous layer was back-extracted with EtOAc (1×). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification (20% to 80% EtOAc/Hexanes) afforded 1-(4-(3-(4-aminophenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as a light brown oil. MS (ESI, pos. ion) m/z: 313.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:14][N:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28].Cl>CC(O)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][N:13]2[CH2:14][C:11]3([CH2:10][C:9](=[O:28])[C:8]4[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=4)[O:24]3)[CH2:12]2)=[CH:18][CH:19]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccc(F)cc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccc(F)cc3)C1)O2

Procedure:
(E)-3-{1′-[2-(4-Fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-acrylic acid methyl ester (120 mg, 0.30 mmol) was hydrolyzed in AcOH (10 ml) and 20% aqueous HCl solution (10 ml) following the procedure described in Example 31, Step B, giving (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-acrylic acid as a yellow solid. [LC-MS: (ES+) MH+: 382]. The obtained acid was suspended in DCM (5 ml), treated with TEA (0.06 ml, 0.4 mmol) and then with EDC (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol) and NH2OTHP (42 mg, 0.36 mmol) following the procedure described in Example 30, Step B, giving (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (88 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11](=O)[C:12]2[C:17]([CH3:18])=[CH:16][S:15][C:13]=2[N:14]=1.O=P(Cl)(Cl)[Cl:22].CN(C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:22][C:11]1[C:12]2[C:17]([CH3:18])=[CH:16][S:15][C:13]=2[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:10]=1
Reactant: COc1ccccc1-c1nc2scc(C)c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2c(C)csc2n1
Yield: 91.7 %

Procedure:
A solution of 2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.4 g, 1.5 mmol), POCl3 (0.14 mL, 1.5 mmol), and N,N-dimethylaniline (0.29 mL, 2.25 mmol) in benzene (1.7 mL) was heated at 80° C. for 2 h. The reaction was cooled, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum to give 4-chloro-2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine (0.4 g, 91% yield). LC/MS: m/z 291.1 (M+H)+ at 3.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@H:6]([NH:13][C:14](=[O:35])[CH2:15][N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH:23]C(OCC2C=CC=CC=2)=O)[C:17]1=[O:34])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@H:6]([NH:13][C:14](=[O:35])[CH2:15][N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]1=[O:34])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](NC(=O)Cn1c(C)ccc(NC(=O)OCc2ccccc2)c1=O)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H](NC(=O)Cn1c(C)ccc(N)c1=O)c1cccnc1
Reaction time: 3 h

Procedure:
To a degassed solution of the pyridone 16-5 (243 mg; 0.49 mmol) in EtOH (20 mL) was added 10% Pd on carbon (25 mg) and this was then stirred under an atmosphere of hydrogen gas (balloon) for 3 hours. The mixture was filtered through a pad of celite and the solvent removed to give the title compound (16-6) as a viscous oil which was used as such in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:26][CH2:25]1.O>CS(C)=O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([O:13][CH3:14])=[CH:3][C:2]=1[N:33]1[CH2:32][CH2:31][CH:30]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][F:21])[CH2:29][CH2:28]2)[CH2:35][CH2:34]1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1Cl
Reactant: FCCN1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCN(CCF)CC2)CC1
Temperature: 80 °C
Reaction time: 60 h
Yield: 74.6 %

Procedure:
4-Chloro-2,5-dimethoxynitrobenzene (1.0 g, 4.6 mmol) was dissolved in DMSO (10 mL). K2CO3 (0.953 g, 6.9 mmol) and 1-(2-fluoroethyl)-4-(4-piperidinyl)piperazine (0.989 g, 4.6 mmol) were added and the reaction mixture was heated to 80° C. and allowed to stir for 60 h. The mixture was then poured into H2O and extracted with EtOAc (2×). The combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step E (1.36 g, 75%). MS (M+H, ES+) 397.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[F:10][C:11]([F:31])([C:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=2)=[CH:20][CH:19]=1)([OH:17])[CH3:16])[C:12](=[NH:14])[NH2:13].C([O-])(=O)C.[Na+]>O1CCOCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]1[N:13]=[C:12]([C:11]([F:31])([F:10])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)([OH:17])[CH3:16])[NH:14][CH:2]=1
Reactant: CC(C)(C)CC(=O)CBr
Reactant: CC(O)(c1ccc(-c2ccc(F)cn2)cc1)C(F)(F)C(=N)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)Cc1c[nH]c(C(F)(F)C(C)(O)c2ccc(-c3ccc(F)cn3)cc2)n1

Procedure:
1-bromo-4,4-dimethylpentan-2-one (500 mg, 2.6 mmol) was added to an ambient temperature solution of 2,2-difluoro-3-[4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (365 mg, 1.2 mmol) and sodium acetate (290 mg, 3.5 mmol) in 1,4-dioxane (20 mL). After stirring at reflux for 1 h, volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide. The organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% ethyl acetate/hexane afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.67 (dd, J=4.3, 8.8 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.45 (dt, J=2.8, 8.4, 1H) 6.69 (s, 1H), 2.39 (s, 2H), 1.77 (s, 3H), 0.84 (s, 9H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[C:9]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]2[C:15](=[O:27])[N:14]3[C:28]([CH3:31])=[N:29][N:30]=[C:13]3[N:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]=2[N:10]=1>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:16]3[C:15](=[O:27])[N:14]4[C:28]([CH3:31])=[N:29][N:30]=[C:13]4[N:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]=3[N:10]=[C:9]2[N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:20][CH:21]=1
Reactant: c1nc[nH]n1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1c2nc(-n3cncn3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
Sodium hydride 60% in mineral oil (18 mg, 0.74 mmol) was added to a solution of 1H-1,2,4-Triazole (45 mg, 0.65 mmol) in DMF (10 mL) at room temperature. After stirring for 1 hour at room temperature, 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (200 mg, 0.40 mmol) in DMF was added to above solution and the mixture was stirred overnight. The reaction was quenched with a drop of water and the reaction mixture was purified by pre LC-MS to give the desired product (53 mg, 27.2%) and its region-isomer 6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1H-1,2,4-triazol-1-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (53 mg, 27%). LCMS calculated for C22H26N9O2 (M+H): 448.2. Found 448.2.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=1.I[CH3:26]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9](=[O:11])[N:10]([CH3:26])[C:6]=2[CH:5]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)N1CCC(n2c(=O)n(C)c3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 1.9 parts of sodium hydride dispersion 78% and 100 parts of hexamethylphosphoric triamide are added portionwise 16.2 parts of ethyl 4-(5-chloro-2-oxo-1-benzimidazolinyl)-1-piperidinecarboxylate (exothermic reaction: temperature rises to 40° C.). After stirring for one hour at room temperature, there are added dropwise 10.6 parts of iodomethane (temperature rises to 40° C). Upon completion, stirring is continued overnight at 60° C. The reaction mixture is cooled, poured onto ice-water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding ethyl 4-(5-chloro-1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)-1-piperidinecarboxylate; mp. 121.9° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32](C([O-])=O)[C:31]([CH3:37])([CH3:36])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[NH:32][C:31]([CH3:37])([CH3:36])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1C(=O)[O-]
Reactant: OCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and tert-butyl, 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carbox-ylate.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(Cl)Cl>C(N(CC)CC)C>[CH3:9][S:10]([O:8][CH:4]([CH:5]([CH3:7])[CH3:6])[CH:2]([CH3:3])[CH3:1])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(O)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(OS(C)(=O)=O)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
In a four-neck flask having an inner volume of 100 ml, 5.81 g (50 m.mols) of 2,4-dimethyl-3-pentanol, 6.30 g (55 m.mols) of methane sulfonyl chloride, and 50 ml of methylene chloride were placed and cooled to 0° C. To the cooled mixture, 7.59 g (75 m.mols) of triethyl amine was added dropwise over a period of one hour with the reaction temperature retained meanwhile. The reactants in the resultant reaction mixture were left reacting at 0° C. for one hour. After the reaction, the reaction mass was thrown into 50 ml of ice water to obtain an organic layer by separation. The organic layer thus obtained was washed with 50 ml of a diluted aqueous hydrochloric acid solution, 50 ml of water, 50 ml of a saturated aqueous sodium hydrogen carbonate solution, and 50 ml of a saturated saline solution. Then, by removing the solvent from the organic layer, 8.94 g (46 m.mols) of (2,4-dimethyl-3-pentyl) methanesulfonate was obtained as the product aimed at.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>>[N:14]1([CH2:13][CH2:12][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCc1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCc1ccc(OCCN2CCCCC2)cc1

Procedure:
Schemes IX through XII exemplify the synthesis of 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)benzyl]-1H-indol-5-ol utilizing intermediates of the present invention. Scheme IIa, described above, can be considered the first step of Scheme IX or a step prior thereto. In this step 4-hydroxybenzyl alcohol is treated with a desired aryl amino alkyl chloride to afford the corresponding alkoxy benzyl alcohol. In the specific example of Scheme IIa, 4-hydroxybenzyl alcohol is treated with 1-(2-chloroethyl)-piperidine hydrochloride in the presence of K2CO3/Me2CO to yield 4-(2-piperidinylethoxy)benzyl alcohol. Toluene and brine can be added to the resulting alcohol mixture to separate its phases. The toluene phase can then be washed Successively with aqueous alkali and brine. The resulting batch can then be concentrated and ethylene dichloride added to form a solution of the intermediate, 4-(2-piperidinylethoxy)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH2:23][NH:24][S:25](=[O:28])(=[O:27])[NH2:26])[CH:5]=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:23][NH:24][S:25]([NH2:26])(=[O:27])=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNS(N)(=O)=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NS(=O)(=O)NCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.6 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-[(sulfamoylamino)methyl]-1,4-oxazepane-4-carboxylate (202 mg) in ethanol (1 mL) was added 4 N hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 18 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethanol-water to give the title compound (103 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].N1CCCCC1>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][C:15]2=[O:23])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=Cc1ccc(O)c2ncccc12
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1ccc(O)c2ncccc12
Yield: 60 %

Procedure:
A solution of 8-hydroxyquinoline-5-carbaldehyde (346 mg, 2 mmol), 2-oxindole (266 mg, 2 mmol) and piperidine (43 mg, 0.5 mmol) in absolute ethanol (10 ml) was heated for 3 h at 60-70° C. under nitrogen. Then the reaction mixture was chilled and evaporated under vacuum to dryness. The residue was submitted to column chromatography over silica gel using dichloromethane/ethanol 4% as eluant to give pure 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole in 60% yield (365 mg). To a solution of 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole (300 mg, 0.99 mmol) in THF (5 ml) was added at room temperature a solution of 1M tetrabutylammonium fluoride (5 ml) and 2-bromopropionic acid ethylester (0.9 ml, 6.9 mmol). The reaction mixture was stirred at room temperature for another 1 h and then diluted with dichloromethane. The organic layer was washed with 5% NaHCO3 solution and water, dried over sodium sulfate and then evaporated under vacuum. The oily residue was chromatographed on silica gel using ethyl acetate as eluant to give pure title compound in 86% yield (330 mg).