Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[Br:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1CCC(c2ccc(N)cc2)CC1
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[4-(4-amino-phenyl)-piperidin-1-yl]-ethanone (as prepared in the previous step, 0.36 g, 1.66 mmol) in CH2Cl2 (10 mL) was cooled to −78° C. and treated with NBS (0.28 g, 1.58 mmol) as a suspension in CH2Cl2 (4 mL). The reaction was allowed to warm to room temperature and stir for 30 min. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was used directly in the next reaction. LC-MS (ESI, m/z): Calcd. for C13H17BrN2O 297.1 (M+H). found 297.1.
Reaction SMILES: Cl.Cl.C([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]4[O:29][CH2:30][O:31][C:23]=34)=[N:16][CH:17]=[N:18]2)=[C:13]([O:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)[CH:12]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[Cl:28][C:27]1[C:22]([NH:21][C:15]2[C:14]3[C:19](=[CH:20][C:11]([OH:10])=[CH:12][C:13]=3[O:32][CH:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[N:18]=[CH:17][N:16]=2)=[C:23]2[O:31][CH2:30][O:29][C:24]2=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(OCc3ccccc3)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 80 °C
Yield: 78.2 %

Procedure:
A mixture of 7-benzyloxy-5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)quinazoline dihydrochloride (2.3 g) and trifluoroacetic acid (28 ml) was stirred and heated to 80° C. for 6 hours. The mixture was evaporated and the residue was dissolved in water and the solution was basified to pH10 by the addition of 1N aqueous sodium hydroxide solution. The mixture was stirred at ambient temperature for 1 hour. The solid was isolated, washed with water and dried under vacuum. There was thus obtained the title compound (1.1 g); NMR Spectrum: (DMSOd6) 1.6-1.8 (m, 2H), 2.0-2.15 (m, 2H), 2.65-2.75 (m, 2H), 2.9-3.05 (m, 2H), 4.8 (m, 1H), 6.1 (s, 2H), 6.62 (s, 1H), 6.7 (s, 1H), 6.92 (d, 1H), 7.05 (d, 1H), 8.25 (s, 1H), 9.2 (s, 1H); Mass Spectrum: M+H+ 415 and 417.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O>[CH:25]1[CH:24]=[C:21]2[C:22]([N:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=1)=[O:23]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCN1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 63.5 %

Procedure:
To a stirred mixture of β-alanine (4.45 g, 50.0 mmol) and sodium carbonate (5.35 g, 50.5 mmol) in 100 mL of water is added N-carbethoxyphthalimide (10.95 g, 50.0 mmol). After 1.5 hour, the reaction slurry is filtered. The filtrate is stirred and the pH adjusted to 1-2 with 4N hydrochloric acid. After 15 minutes, the resulting slurry is filtered and the solid washed with water. The solid is dried in vacuo (60° C., <1 mm) to afford 6.96 g (64%) of N-phthaloyl-β-alanine, which can be alternatively named as 3-phthalimido-3-phenylpropionic acid, as a white powder.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[C:10]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:18]([C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:18]([C@H:22]1[CH2:23][CH2:24][C@H:25]([C:28]([O:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:10]([F:17])[C:11]=2[F:16])=[O:29])[CH2:26][CH2:27]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCCCCCc1ccc(O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OC(=O)[C@H]2CC[C@H](CCCC)CC2)c(F)c1F

Procedure:
0.1 mol of this phenol, 0.1 mol of trans-4-butylcyclohexanecarboxylic acid and 0.01 mol of 4-dimethylaminopyridine are initially introduced into 150 ml of methylene chloride, a solution of 0.1 mol of dicyclohexylcarbodiimide in 30 ml of methylene chloride is added dropwise at 10°, while stirring, and the mixture is then subsequently stirred at room temperature for 15 hours. The mixture is filtered over silica gel with suction and the solvent is evaporated off to give 2,3-difluoro-4-octylphenyl trans-4-butylcyclohexanoate as the residue.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11]OS(=O)(=O)[N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:21][N:22]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH2:11][C@@H:7]([NH:8][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)COS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(C[C@@H](NC(=O)OC(C)(C)C)c1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
tert-Butyl (45)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1 g; 3.34 mmol), N-methyl-4-nitrobenzenesulfonamide (722 mg; 3.34 mmol), and Cs2CO3 (0.40 ml; 5.01 mmol) were dissolved in CH3CN (25 ml), and stirred overnight. The reaction mixture was filtered, washed with H2O (50 ml), and dried under vacuum to provide the desired intermediate (1.12 g; 77%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([CH:11]1[O:16][C:15](=[O:17])[CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:32][CH2:31]4)=[C:26]([F:41])[C:25]=3[F:42])=[C:20]([F:43])[C:19]=2[F:44])[CH2:13][CH2:12]1)[CH2:9][CH3:10].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(O)=O>[CH2:8]([CH:11]1[O:16][CH:15]([OH:17])[CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:32][CH2:31]4)=[C:26]([F:41])[C:25]=3[F:42])=[C:20]([F:43])[C:19]=2[F:44])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CCCCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4=O)c(F)c3F)c(F)c2F)CO1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4O)c(F)c3F)c(F)c2F)CO1
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Toluene (10 ml) was added to 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(6-pentyltetrahydro-2H-pyran-3-yl)biphenyl-4-yl)tetrahydro-2H-pyran-2-one (20) (1.2 g) prepared in the first step. A diisobutylaluminum hydride-toluene solution (0.99 M; 3.49 ml) was added dropwise at −50° C. or lower, and the stirring was continued for 3 hours. The reaction mixture was poured into a 10% aqueous solution of formic acid (15 ml) to give two layers. The water layer was extracted with toluene (10 ml) twice, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(6-pentyltetrahydro-2H-pyran-3-yl)biphenyl-4-yl)tetrahydro-2H-pyran-2-ol (21) (1.2 g) in 98% yield.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[S:7][CH:8]=1)([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH2:9][C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:12]=2)(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: CC(C)c1csc(COc2cccc(C=O)c2)n1
Reactant: NCCCCNS(=O)(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: CC(C)c1csc(COc2cccc(CNCCCCNS(=O)(=O)c3ccc(Cl)cc3)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.27 g (8.69 mmol) of 3-[(4-isopropyl-2-thiazolyl)methoxy]benzaldehyde and 2.27 g (8.69 mmol) of 4-(4-chlorophenylsulfonylamino)butanamine were dissolved in 150 ml of ethanol and refluxed together with 4.0 g of molecular sieves 3A for 16 hours. The molecular sieves 3A was filtered out, and the filtrate was stirred together with 873 mg of sodium borohydride at room temperature for 3 hours. The reaction solution was evaporated in vacuo for removal of ethanol as the solvent and mixed with water and ethyl acetate for ethyl acetate extraction. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo for removal of the solvent. The residue was purified by silica gel column chromatography (eluent; chloroform to chloroform:methanol=98:2) to give N-[4-(4-chlorobenzenesulfonylamino)butyl]-3-[(4-isopropyl-2-thiazolyl)methoxy]benzylamine (Compound No.1a).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:9])=[CH:15][CH:14]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CSc2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A mixture of 10.0 g (47 mmol) 4-methylphenacyl bromide, 6.8 g (47 mmol) 4-chlorothiophenol, and 6.5 g (47 mmol) anhydrous potassium carbonate in 100 ml dry DMF was stirred for 3 h at 80° C. It was filtered and the filtrate was concentrated under reduced pressure. The concentrate was stirred in water, and the resulting solid was filtered off, washed with water, and recrystallized from ethanol to give 10.7 g (82%) of the crude title compound.
Reaction SMILES: O[CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:15]1[C:19]2=[N:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:23]=[C:18]2[CH:17]=[C:16]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([CH3:14])([CH3:13])[CH2:2][N:15]1[C:19]2=[N:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:23]=[C:18]2[CH:17]=[C:16]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)(C)CNC(=O)OC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of tert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate (2.13 g, 10.5 mmol), diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 2.50 g, 9.53 mmol), and triphenylphosphine (5.00 g, 19.1 mmol) in THF (15 mL) is added diisopropyl azodicarboxylate (3.95 mL, 19.1 mmol). The reaction is stirred at room temperature for 64 h. The solvent is removed in vacuo and the crude material is purified via silica gel chromatography using a gradient elution of 0-30% ethyl acetate/hexanes to afford the title compound as a yellow oil which crystallized upon standing (4.20 g, 99%). LCMS: 478.86 (M+Na+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][C@H:40]([CH3:44])[CH2:39]1)([CH3:37])[CH3:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][C@H:40]4[CH3:44])[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)N1CCN[C@H](C)C1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)C[C@H]4C)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40.0 mg, 0.077 mmol) was added (R)-1-isopropyl-3-methylpiperazine (33.1 mg, 0.232 mmol) in 1,4-dioxane (1 mL) and triethylamine (15.7 mg, 22 μL, 0.155 mmol). The reaction mixture was stirred at 60° C. for 4 d, after which the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCNCCCCCCCC
Reactant: OCCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCN(CCCO)CCCCCCCC
Yield: 66.8 %

Procedure:
A mixture of 24 g of di-n-octylamine, 10 g of 3-chloro-1-propanol and 11 g of triethylamine in 200 ml of toluene was refluxed for 24 hours. The toluene solution was washed twice with water to remove the triethylamine hydrochloride formed and then evaporated. The residue was distilled and gave 19.9 g of N,N-di-n-octyl-3-amino-1-propanol, b.p. 125°-130° C./0.01 mm Hg, nD22 = 1.4613.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[CH3:21]
Reactant: COC(=O)C(C)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)c1ccc(C2CCNCC2)cc1

Procedure:
The compound is prepared analogously to Example XI.1 using 4-[4-(1-methoxycarbonyl-ethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (VIII.1) as educt and TFA in DCM instead of HCl.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CS(C)=O>[N:1]1[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cn2ccccc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
2-aminopyridine (500 mg, 5.31 mmol) and ethyl chloroacetoacetate (870 mg, 5.31 mmol) were dissolved in DMSO and heated to 100° C. for 1 h under inert atmosphere. After 1 h, water added to reaction mixture followed by Work-up (H2O/AcOEt) and purification on 60-120 mesh silicagel using AcOEt and petroleum ether (30:70) gave the title compound (110 mg) as a brown liquid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.06 (d, J 6.7, 1H), 7.59 (s, 1H), 7.55 (d, J 9.4, 1H), 7.14 (t, J 7.9, 1H), 6.75 (t, J 6.7, 1H), 4.12 (q, J 7.1, 2H), 3.87 (s, 2H), 1.3 (t, J 7.1, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH:13]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:12]3[CH2:16][CH2:15][CH2:14][CH:13]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=CC1=CCCC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/C1=CCCC1
Yield: 30.7 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2.51 g, 15 mmol) (Alfa) was reacted with cyclopent-1-enecarbaldehyde (1.45 g, 15 mmol) (Aldrich) and piperidine (1.49 mL, 15 mmol) in methanol to give E/Z-6-chloro-3-cyclopent-1-enylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.13 g, 30%)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][C:12]2([CH2:18][CH2:19][CH3:20])[O:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:24])C>>[CH3:8][C:7]1[C:2]([CH2:1][OH:24])=[N:3][CH:4]=[CH:5][C:6]=1[O:9][CH2:10][CH2:11][C:12]1([CH2:18][CH2:19][CH3:20])[O:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: CC(=O)OC(C)=O
Reactant: CCCC1(CCOc2cc[n+]([O-])c(C)c2C)OCCCO1
Product: CCCC1(CCOc2ccnc(CO)c2C)OCCCO1
Temperature: 90 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
The 2,3-dimethyl-4-(2-(2-propyl-1,3-dioxan-2-yl)ethoxy)pyridine 1-oxide (3.9 g, 13.2 mmol) obtained in the step (8c) was mixed with acetic anhydride (16 ml). The mixture was stirred at 90° C. for 2 hours. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue, methanol (20 ml) and a 5N aqueous sodium hydroxide solution (10 ml) were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was separated by use of a saturated saline solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain the title compound (1.69 g, yield: 43.3%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:9])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Product: COc1ccc(NC(=O)c2cnc(Cl)c(Cl)c2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 5,6-dichloronicotinic acid and 4-methoxy-2-nitroaniline and was obtained as a yellow solid as described in Example 15. 1H NMR (DMSO-d6): 10.85 (bs, 1H), 8.88 (d, J=2.4, 1H), 8.59 (d, J=2.4, 1H), 7.58-7.54 (m, 2H), 7.39-7.35 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH2:17][N:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:15][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH:32]([CH3:34])[CH3:33]>C1COCC1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH2:17][N:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:32]([CH3:34])[CH3:33])[CH:25]=1)[CH2:15][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cccc(O)c1)C2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cccc(OC(C)C)c1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
Sodium hydride (48 mg, 1.2 mmol) was added to a solution of 30 (300 mg, 0.8 mmol) in THF (10 ml) and the reaction mixture was stirred at rt for 20 min. 2-Iodopropane (0.12 ml, 1.2 mmol) was added and the reaction mixture was stirred at rt for 26 h. Further 2-iodopropane (0.36 ml, 3.6 mmol) was added and the reaction mixture was heated at 60° C. 24 h. The solution was concentrated in vacuo, water was added and the aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 50 g, 100% hex-100% EtOAc over 35 min) afforded the title compound (259 mg, 77%) as a colourless oil; 1H NMR (270 MHz; CDCl3) 1.31 (6H, d, J=6.2 Hz, 2×CH3), 2.66-2.75 (4H, m, 2×CH2), 3.54 (2H, s, CH2), 3.62 (2H, s, CH2), 3.80 (3H, s, OCH3), 4.54 (1H, septet, J=6.2 Hz, CH), 5.09 (2H, s, CH2Ph), 6.50 (1H, s, CH), 6.61 (1H, s, CH), 6.77-6.81 (1H, m, CH), 6.91-6.94 (2H, m, 2×CH), 7.16-7.47 (6H, m, 5×CH, phenyl). 13C NMR (67.5 MHz; CDCl3) 22.18 (CH3), 28.77 (CH2), 50.80 (CH2), 55.85 (CH2), 56.16 (OCH3), 62.85 (CH2), 69.75 (CH), 71.18 (CH2), 110.13 (CH), 114.30 (CH), 114.59 (CH), 116.47 (CH), 126.31 (C), 127.35 (CH), 127.55 (C), 127.82 (CH), 128.58 (CH), 129.32 (CH), 137.40 (C), 140.16 (C), 146.69 (C), 147.91 (C), 158.02 (C). LC/MS (APCI−) tr=7.47 min, m/z 416.35 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Mg]Br)C.Br[C:15]1[C:16]([N:18]([CH3:32])[C:19](=[O:31])[C:20]=1[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH3:30])[CH:22]=1)=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:15]2[C:16](=[O:17])[N:18]([CH3:32])[C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN1C(=O)C(Br)=C(c2cn(C)c3ccccc23)C1=O
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: CN1C(=O)C(c2c[nH]c3ccccc23)=C(c2cn(C)c3ccccc23)C1=O
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
To a solution of indole (66 mg, 0.21 mmol) dissolved in toluene (1 mL) was added 0.95M ethylmagnesium bromide (0.5 mL, 0.47 mmol) at 40 ° C., and the whole was stirred at 40° C. for 45 minutes. Successively, a solution of 2-bromo-3-(1-methyl-1H-indol-3-yl)-N-methylmaleimide (66 mg, 0.21 mmol) dissolved in toluene (3 mL) was added thereto, followed by stirring under heating and refluxing for 2 hours. After 20% aqueous citric acid solution (1 mL) was added thereto under ice cooling and the whole was stirred, toluene was removed by concentration under reduced pressure and the resulting concentrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:1) to obtain 3-(1H-indol-3-yl)-2-(1-methyl-1H-indol-3-yl)-N-methylmaleimide (71 mg, 96.8%) as red solids.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[NH:18][C:17](=[O:26])[C:16]=1[C:27]#[N:28]>C1(C)C=CC=CC=1>[CH3:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:26])[C:16]([C:27]#[N:28])=[C:15]2[N:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(Cl)c2c1
Reactant: O=C(c1cccs1)N1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Temperature: 110 °C
Yield: 92.1 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (8.73 g, 41.16 mmol) was added to a solution of Compound 106 (4.5 g, 20.08 mmol) in toluene (50 mL) and heated overnight at 110° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0–2% methanol in dichloromethane gradient to yield 7.0 g (92%) of white solids. M.P. 269° C. 1H NMR (DMSO-d6): δ 2.34 (s, 3H), 3.65 (m, 4H), 3.92 (m, 4H), 7.14 (m, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.49 (d, J=3.5 Hz, 1H), 7.51 (s, 1H), 7.81 (d, J=4.8 Hz, 1H). EIMS m/z 379 (M+1).