Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][N:13]=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([NH:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][N:13]=1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1cc(-c2ccccc2)sn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1cc(-c2ccccc2)sn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
N,N-Dimethylcarbamoyl chloride (1.29 g) and aluminum chloride (1.60 g) are dissolved in toluene (40 ml), and the mixture is stirred at room temperature for 30 minutes. To this mixture is added 3-amino-5-phenylisothiazole (1.76 g), and the resulting mixture is refluxed for 6 hours with stirring. After cooling, the reaction mixture is mixed with water and shaken with toluene. The organic layer is separated, washed with water, dried, and concentrated to dryness to give 1,1-dimethyl-3-(5-phenyl-3-isothiazolyl)urea (2.38 g). Yield is 96.4%. Melting point of the colorless crystals is 129 to 130.5° C. (after recrystallization from benzene/petroleum benzin).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22]CN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCC1CC[N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:24]1[CH2:23][CH2:22][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(4-bromobutyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:27])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: [OH-]
Reactant: C=C1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1g, 4.149 mmol) in THF (25 ml), 0.5 M solution of 9-BBN in THF (9.8 ml, 4.979 mmol) was added at 0° C. and stirred for 2 hrs at room temperature. The reaction mixture was cooled to 0° C., and then 2N NaOH (2.43 ml, 4.979 mmol) and 30% H2O2 (1.6 ml, 14.93 mmol) were added. The reaction mixture was stirred at room temperature for 4 hr and later it was poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, filtered and concentrated under vacuum. Purification by column chromatography offered 4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil (6 g, 56%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([Br:24])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CS(Cl)(=O)=O.[CH:30]([N:33](CC)C(C)C)(C)C.[C-]#N.[K+]>C(#N)C.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:30]#[N:33])=[C:18]([Br:24])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(CO)c(Br)c1)C1(c2ccc3c(c2)OCO3)CC1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: N#CCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reaction time: 336 h
Yield: 46.3 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cyclopropane-carboxamide (1.08 g, 2.78 mmol), methanesulfonyl chloride (0.24 mL, 3.1 mmol), and N,N-diisopropylethylamine (0.72 mL, 4.1 mmol) were dissolved in acetonitrile (27 mL) at 25° C. After complete dissolution, KCN (450 mg, 6.95 mmol) was added and the reaction was stirred for 14 d. The reaction was diluted with dichloromethane (25 mL) and washed with water (25 mL). The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in hexanes) to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclo-propane carboxamide (514 mg, 46%). ESI-MS m/z calc. 398.0, found 399.1 (M+1)+; retention time 3.24 minutes.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[C:8]([F:26])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][C:9]3[CH:24]=[CH:25][C:6]([Cl:5])=[CH:7][C:8]=3[F:26])=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: BrCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
1,2-Dibromoethane (725 mg, 4 mmol) was added by portions of 70 μl every 30 minutes to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (320 mg, 1 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (552 mg, 4 mmol) in DMF (5 ml) heated at 35° C. The mixture was stirred for a further 30 minutes after the completion of the addition and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with petroleum ether/ether, the solid was collected by filtration and dried under vacuum to give 7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (200 mg, 47%).
Reaction SMILES: C[C@@H]([C@@H]1[C@@]2(C)CC[C@@]34C[C@]53C[CH2:24][C@H:25]([O:29][C:30](/[CH:32]=[CH:33]/[C:34]3[CH:35]=[CH:36][C:37]([OH:42])=[C:38]([O:40][CH3:41])[CH:39]=3)=[O:31])C(C)(C)[C@@H]5CC[C@H]4[C@]2(C)CC1)CCC=C(C)C.C(OC(=O)C)(=[O:47])C>N1C=CC=CC=1>[C:30]([O:29][C:25](=[O:47])[CH3:24])(=[O:31])/[CH:32]=[CH:33]/[C:34]1[CH:35]=[CH:36][C:37]([OH:42])=[C:38]([O:40][CH3:41])[CH:39]=1
Reactant: COc1cc(/C=C/C(=O)O[C@H]2CC[C@]34C[C@]35CC[C@]3(C)[C@@H]([C@H](C)CCC=C(C)C)CC[C@@]3(C)[C@@H]5CC[C@H]4C2(C)C)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(/C=C/C(=O)OC(C)=O)ccc1O

Procedure:
Commercial available γ-oryzanol (100 g, 24-methylenecycloartanol content 45%) was acetylated with acetic anhydride in pyridine. This acetylated γ-oryzanol was recrystallized repeatedly from chloroform-ethyl acetate-ethanol (4:3:2, V/V), giving acetyl ferulate (18 g) of 24-methylenecycloartanol content 95%. This acetyl ferulate was completely saponified in the solution of 2N NaOH-ethanol, then the obtained alcohol was converted into the benzoate. This benzoate was recrystallized repeatedly, and completely saponified to give 24-methylenecycloartanol (5 g). A portion (2 g, 0.0045 mole) thereof wa converted into 24-methylenecycloartanol-4-acetoxy-3-methoxycinnamate according to following the procedure of Example 65. This ester was then deacetylated according to following the procedure of Example 100-2, giving 24-methylenecycloartanol-4-hydroxy-3-methoxycinnamate (2.58 g), in a 90% yield. m.p. 166°-167° C.
Reaction SMILES: N#N.[N:3]([C@H:6]1[C@H:10]([OH:11])[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[N+:4]=[N-:5].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>N1C=CC=CC=1>[N:3]([C@H:6]1[C@H:10]([O:11][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[N+:4]=[N-:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Agent: N#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of trans-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (J. Med. Chem. 2010, 53, 6730-6746) (320 mg, 1.40 mmol) in pyridine (3 mL) was added TsCl (588 mg, 3.00 mmol). The mixture was stirred at 5° C. overnight. The solvent was removed under reduced pressure and the mixture was partitioned between CH2Cl2 and 10% aq. NaHCO3. The organic layer was washed with water, dried over MgSO4, and the solvent removed under reduced pressure. The residue was purified by FC (Hept/EA, 9.5:0.5→8:2) to afford trans-tert-butyl 3-azido-4-(tosyloxy)pyrrolidine-1-carboxylate as a colorless oil. LC-MS-conditions 08: tR=0.96 min; [M-CH3+H]+=368.10. TLC: rf (Hept/EA, 8:2)=0.22.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].Br[CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:17]([CH3:19])[CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Cl)cc1Cl)C(C)C
Yield: 94 %

Procedure:
To a stirred mixture of 22 parts of methyl 2,4-dichlorobenzeneacetate and 135 parts of N,N-dimethylformamide are added 3.1 parts of a sodium hydride dispersion 78% while nitrogen gas is introduced. After stirring till foaming has ceased, there are added 15 parts of 2-bromopropane and the whole is stirred for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated, yielding 24.5 parts (94%) of methyl 2,4-dichloro-α-(1-methylethyl)benzeneacetate as a residue.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH2:5]1[C:14](=[O:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH2:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][NH:1][C:14]1=[O:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2ccccc2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2CCN1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
While maintaining the temperature of the reaction mixture below 65° C., NaN3 (13.35 g; 205.2 mmol) is added in small portions to a solution, heated beforehand to 55° C., of β-tetralone (25 g; 171 mmol) in a mixture of 150 ml of glacial acetic acid and concentrated sulphuric acid (33.39 g; 342 mmol; 18.25 ml). Stirring is then carried out for 8 hours at 70° C. After returning to ambient temperature, the reaction mixture is poured onto ice and diluted with ethyl acetate. After extracting the organic phase, drying over magnesium sulphate and concentrating, the residue obtained is purified by chromatography on silica gel (eluant ethyl acetate) to yield the expected compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:15]=[CH:14][C:13]=2[NH2:25])=[N:2]1.C(N(CC)CC)C.[CH3:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39](Cl)=[O:40].C(=O)([O-])O.[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH:15]=[CH:14][C:13]=2[NH:25][C:39]([C:35]2[S:36][CH:37]=[CH:38][C:34]=2[CH3:33])=[O:40])=[N:2]1
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CN1CCN(c2ccc(N)c(C=Cc3n[nH]c4ccccc34)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1ccc(N2CCN(C)CC2)cc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
In a similar manner to Example 2, crude 3-{2-[5-(4-methylpiperazin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (262 mg, 0.72 mmol) obtained in Step 1 was dissolved in ethanol (10 mL) and was reacted with tin (0.26 g, 2.2 mmol) and concentrated hydrochloric acid (1.3 mL) at room temperature to obtain 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methylpiperazine-1-yl)phenylamine. In a similar manner to Example 29, 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methylpiperazin-1-yl)phenylamine (0.10 g, 0.30 mmol) was dissolved in THF (5.0 mL) and the solution was added with triethylamine (0.13 ml, 0.90 mmol) and 3-methylthiophenecarbonyl chloride (0.05 g, 0.31 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained crude product was triturated in ethyl acetate to obtain Compound 228 (0.10 g, 73%).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[OH:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[C:10]1=[O:27].C(=O)([O-])[O-].[K+].[K+].C(NCC)C>CN(C=O)C>[CH2:8]([N:9]([CH2:10][CH3:11])[CH2:2][C:3]([OH:5])=[O:4])[CH3:7].[OH:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[C:10]1=[O:27]
Reactant: O=C(O)CBr
Agent: O=C([O-])[O-]
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)CC(=O)O

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione bromoacetate (409 mg) was dissolved in DMF (10 mL). Potassium carbonate powder (800 mg) was added. Diethylamine solution (0.4 mL) was added dropwise while stirring. The reaction mixture was stirred for 24 hrs at room temperature. The solvent and the residual diethylamine were removed by rotary evaporation in vacuo. The resultant solid mixture was subjected to silica gel column chromatography (eluted with acetic ether: petroleum ether=2:1) and then a white solid (128 mg) was obtained. 1H NMR (CDCl3, ppm) δ 7.87-7.90 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.04 (m, 1H), 4.28-4.33 (m, 2H), 4.08-4.16 (m, 2H), 3.30 (s, 2H), 2.97-3.02 (m, 1H), 2.76-2.85 (m, 2H), 2.61-2.68 (m, 4H), 2.10-2.14 (m, 1H), 1.02-1.06 (m, 6H). MS (m/e): 416 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.C[C@H]1CNCCN1>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1
Reactant: C[C@@H]1CN(c2ccccc2F)CCN1
Agent: C[C@H]1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H]1CN(c2ccccc2F)CCN1

Procedure:
The title compound was prepared following the protocol used for the preparation of Intermediate 5, but starting from (S)-2-methylpiperazine (40%). TLC-Chloroform/Methanol (9/1); Rf: 0.25. HPLC purity: 97%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:23])C(=O)C1>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Brc1cccc(NCC2CCOCC2)n1
Solvent: CC#N
Product: Clc1ccc(NCC2CCOCC2)nc1Br
Temperature: 80 °C
Yield: 53.1 %

Procedure:
To a solution of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (20 g, 74 mmol) in acetonitrile (240 mL) was added NCS (9.85 g, 74 mmol). The mixture was heated to 80° C. for 3 hr. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The resulting residue was diluted with brine (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, EtOAc/heptane=0/100 to 50/50] providing 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (12 g) and a mixture of 6-bromo-3,5-dichloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine/6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (5 g, ratio ˜2:3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[K+].F[C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: Sc1ccccc1Br
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Sc1ccccc1Br
Temperature: 25 °C
Yield: 98.6 %

Procedure:
2-Bromobenzenethiol (7.2 ml, 85.9 mmol) was added to a solution of KOH (9.6 g, 172 mmol) in water (50 ml) degassed for 15 minutes. 2-Fluoro-5-nitrobenzoic acid (15.9 g, 85.9 mmol) was added to the reaction mixture, which was refluxed under a nitrogen atmosphere overnight. The reaction was cooled to room temperature and was acidified (pH 1) with conc. HCl. The precipitate formed was filtered and dried overnight in a vacuum oven (50° C.) to give the crude title compound as a pale yellow solid (30 g, 99%). The product was used without further purification. m/z (LC-MS, ESP), RT=4.51min, (M−−1)=352-354, (1:1, bromine isotope ratio present).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].CO.ClC(Cl)C(O)=O>O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Agent: O=C(O)C(Cl)Cl
Solvent: CO
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 136 %

Procedure:
15.4 g. of Acetonine was dissolved in a mixed solvent comprising 169.8 g. of acetone and 56.6 g. of methanol. The solution was ice-cooled, added with 12.9 g. of dichloroacetic acid and 1.8 g. of water under stirring. The mixture was stirred at room temperature for 24 hours to effect the reaction. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, added with 40% aqueous potassium carbonate solution and extracted with ether. The extract was dried over anhydrous potassium carbonate, then ether was distilled off and the resulting residue was purified by distillation under reduced pressure to obtain triacetonamine in a yield of 136%.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[NH2:54][C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[C:58]([O:65][CH:66]([CH3:71])[CH2:67][CH2:68][CH2:69]O)[CH:59]=[CH:60][CH:61]=2)[N:56]=1>C1COCC1>[CH3:71][CH:66]([O:65][C:58]1[CH:59]=[CH:60][CH:61]=[C:62]2[C:57]=1[N:56]=[C:55]([NH2:54])[CH:64]=[CH:63]2)[CH2:67][CH2:68][CH2:69][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CC(CCCO)Oc1cccc2ccc(N)nc12
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2cccc(OCCCC(C)Oc3cccc4ccc(N)nc34)c2n1
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial with a septum cap was charged with PS-PPh3 resin (Aldrich Chemical Co., Inc, 90 mg, 4.4 equiv), 8-hydroxyquinaldine (1.5 equiv) and DBAD (22 mg, 1.6 equiv) and purged by passing a stream of N2 for 45 seconds. Anhydr. THF (3 mL) was added and the contents of the vial were shaken for 5 min. Then, a solution of 4-((2-aminoquinolin-8-yl)oxy)pentan-1-ol (15.0 mg/mL; 1.0 mL, 0.061 mmol)) in anhydr. THF (1 mL) was added and the resulting suspension was agitated at room temperature for 6 h. Following this, DBAD (22 mg, 1.6 equiv) was added and the mixture was agitated at room temperature for additional 12 h. The suspension was filtered, and the resin washed with THF (3×3.0 mL). The filtrate and washings were combined and evaporated in vacuo. The residue was then treated with 6.0 mL of 4 M HCl in dioxane at room temperature for 6 h. The resulting solution was evaporated in vacuo. The residue was dissolved in 1.5 mL of a 1:1 mixture of DMSO/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (500 MHz, CDCl3) δ ppm 8.61 (d, 1H), 7.89 (d, 1H), 7.66 (m, 2H), 7.52 (d, 1H), 7.29 (m, 3H), 7.15 (m, 2H), 4.74 (m, 1H), 4.31 (m, 2H), 3.09 (s, 3H), 2.36 (m, 2H), 2.05 (m, 2H), 1.44 (d, 3H); MS (DCI/NH3) m/z 388 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Sn](CCCC)(CCCC)CCCC.I[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1.[Cu]Cl>[CH2:28]([O:27][P:25]([C:24]1[CH:23]=[CH:22][S:21][C:20]=1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([O:30][CH2:31][CH3:32])=[O:26])[CH3:29]
Reactant: CCOP(=O)(OCC)c1ccsc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccsc1-c1cccs1

Procedure:
Copper(I) chloride (2.5 equivalents) was charged into a reaction container, to which 2-thienyltributyl tin (2.5 equivalents) and 2-iodo-3-diethoxyphosphorylthiophene were added under nitrogen atmosphere while being dissolved in tetrahydrofuran, followed by heating under reflux for 20 hours. After completion of the reaction, the reaction solution was filtered through celite and the resulting residue was washed with ethyl acetate. The filtrate was washed three times with a 1N hydrochloric acid aqueous solution and a 10% saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was purified with a silica gel column (hexane:ethyl acetate=1:3) to obtain a colorless liquid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[CH3:14]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:15][C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([CH3:7])[CH:9]=1
Reactant: BrCCCCBr
Reactant: Cc1ccc(O)cc1C
Product: Cc1ccc(OCCCCBr)cc1C
Yield: 86 %

Procedure:
1,4-Dibromobutane, condensed with 3,4-dimethylphenol according to Ismaïel et al. (J. Med. Chem., 1993, 36, 2519-25), gives 1-[4-bromobutoxy]-3,4-dimethylbenzene with a yield of 86%. The condensation of this compound (according to the same authors) with 1,4-dioxa-8-azaspiro[4.5]decane gives, after deprotection, 1-[4-(3,4-dimethylphenoxy)butyl]-4-piperidone in the form of an orangey oil with a yield of 61%. The reductive amination of this ketone (4.33 g or 15.7 mmol) with methylamine hydrochloride (1.06 g; 15.7 mmol) in the presence of sodium triacetoxyborohydride (4.33 g; 20.5 mmol) according to the protocol of Example 3.1 makes it possible to prepare 5.95 g (Yd: 63%) of the compound of formula 10:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.C([CH2:18][S:19]([CH2:22][S:23]([CH2:26][C:27](O)=O)(=[O:25])=[O:24])(=[O:21])=[O:20])(O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])/[CH:6]=[CH:18]/[S:19]([CH2:22][S:23](/[CH:26]=[CH:27]/[C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:24])=[O:25])(=[O:20])=[O:21]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: COc1cc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Yield: 62 %

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 62% yield. m.p. 127-129° C.