Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O>[O:11]([CH2:3][CH2:2][Br:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCBr
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccccc1
Reaction time: 6 h
Yield: 86.8 %

Procedure:
In a mixed solution consisting of 50 g of 1,2-dibromoethane, 18.5 g of phenol and 100 ml of water was added dropwise 30 ml of water containing therein 7.9 g of sodium hydroxide at a temperature of 130° C. over 30 minutes with stirring, and the reaction solution was further stirred for 6 hours. After completion the reaction, the organic layer was separated from the reaction solution, washed twice with a saturated aqueous potassium carbonate solution, washed twice with water and dried over anhydrous sodium sulfate. The organic layer was separated by filtration and condensed under reduced pressure to give 34.3 g of 2-phenoxyethyl bromide having a boiling point of 105° C. to 107° C. at 6 mmHg in a yield of 85%.
Reaction SMILES: [Cl:1][C:2]([F:19])([F:18])[C:3]([C:14]([F:17])([F:16])[F:15])([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)[OH:4].[O:20]=[C:21](N1C2C(=CC(CO)=CC=2)CC1)[CH2:22][C:23](=O)[CH3:24]>S(=O)(=O)(O)O>[Cl:1][C:2]([F:18])([F:19])[C:3]([C:5]1[CH:13]=[C:12]2[C:11]3=[C:7]([CH2:8][CH2:9][N:10]3[C:21](=[O:20])[CH:22]=[C:23]2[CH3:24])[CH:6]=1)([OH:4])[C:14]([F:17])([F:15])[F:16]
Reactant: OC(c1ccc2c(c1)CCN2)(C(F)(F)F)C(F)(F)Cl
Reactant: CC(=O)CC(=O)N1CCc2cc(CO)ccc21
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)Cl)cc13)CC2

Procedure:
By the method of Example 7, α-(chlorodifluoromethyl)-α-(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol is converted to α-(chlorodifluoromethyl)-α-trifluoromethyl)-1-(1,3-dioxobutyl)-2,3-dihydro-1H-indole-5-methanol, m.p. 160°-164°, which is cyclized by heating in sulfuric acid to give 1,2-dihydro-8 [2-chloro-2,2-difluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl-4H-pyrrolo[3,-2,1-ij]quinolin-4-one, m.p. 294°-295°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[NH:17][C:18]([CH2:23][OH:24])=[C:19](CO)[N:20]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.COC(O)C>O1CCOCC1>[CH2:9]([C:16]1[NH:17][C:18]([CH2:23][OH:24])=[C:19]([Br:1])[N:20]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1nc(Cc2ccccc2)[nH]c1CO
Agent: COC(C)O
Solvent: C1COCCO1
Product: OCc1[nH]c(Cc2ccccc2)nc1Br

Procedure:
3.56 Grams (20 mmol) of the N-bromosuccinimide was added to a solution consisting of 4.86 g (20 mmol) of the 2-benzyl-4,5-bis(hydroxymethyl) imidazole, 80 mol of methoxyethanol and 30 ml of dioxane maintained at a temperature of 45° to 50° C. with stirring. The mixture was further reacted at the same temperature for 24 hours with stirring and, then, the solvent was distilled off under reduced pressure. The obtained reaction product was washed with water and was recrystallized from acetonitrile to obtain a 2-benzyl-4-bromo-5-(hydroxymethyl) imidazole in an amount of 2.1 g (yield, 39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[CH2:20]([N:27]([C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:37]1[CH:36]=[CH:35][C:34]([N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:39][CH:38]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Ic1ccc(N(Cc2ccccc2)c2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccccc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 60.4 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (59.3 mg) was reacted with N-benzyl-N-(4-iodophenyl)pyrimidin-2-amine (67.0 mg) to obtain (E)-5-[4-(benzyl-pyrimidin-2-yl-amino)-phenyl]-2-(2,6-dichlorobenzamido)-pent-4-enoic acid methyl ester (58.7 mg). Column chromatography (silica gel, eluent: chloroform/cyclohexane=2/1→chloroform) and thin layer chromatography (silica gel, developing solvent: cyclohexane/ethyl acetate=2/1) were used for purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:27]1([CH2:33][C:34](O)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][CH:10]2[NH:14][C:34](=[O:35])[CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:4][N:3]=1
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1SCCN1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-Chloro-5-pyridinylmethyl)-2-iminothiazolidine (132 mg, 0.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.5 mmol) and 4-dimethylaminopyridine (65 mg, 0.54 mmol) in 3 ml of dichloromethane, phenylacetic acid (68 mg, 0.5 mmol) was added in portions, and stirred at room temperature overnight. After distilling the solvent off, the resultant crude crystal was washed with 1% hydrochloric acid, recrystallized from ethyl acetate thereby obtaining the intended substance. Yield: 100 mg (58%). Melting point: 157-158° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[C:11]3[C:6]([CH:5]=2)=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: N#Cc1cccc(B(O)O)c1
Product: COc1cccc2c(-c3cccc(C#N)c3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-cyano-phenylboronic acid to give 3-[3-(5-methyl-1H-pyrazol-3-ylamino)-5-methoxy-isoquinolin-1-yl]-benzonitrile LC-MS m/e 356(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=O>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(CCc1ccccc1N)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CNc1ccccc1CCC(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ethyl 2-t-butyloxycarbonylamino-4-(2-aminophenyl)butyrate (10.0 g) and ethyl glyoxylate (4.2 g) in ethanol (120 ml) is hydrogenated at 80° and 3 atmospheres pressure for 72 hours using 10% palladium on charcoal (3 g) as catalyst. The reaction mixture is cooled to room temperature and the catalyst filtered off. The solvent is removed under reduced pressure and the residue distributed between ethyl acetate (150 ml) and water (75 ml). The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure to give ethyl 2-t-butyloxycarbonylamino-4-[o-(ethoxycarbonylmethylamino)phenyl]butyrate which is used without further purification for the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][C:13]([Br:16])=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[OH-].[K+].[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.O>[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][C:13]([Br:16])=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:33][CH:34]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccc(Br)s3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
The product of Example 241b (1.50 g, 4.34 mmol) was dissolved in DMF to which KOH (469 mg, 8.69 mmol), and (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester (909 mg, 4.34 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water that was then extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound to provide the title compound (2.11 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:8][C:7]=1[CH2:19]Br)=[O:5])[CH3:2].[CH2:21]([O:23][C:24](=[O:38])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:8][C:7]=1[CH2:19][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(-c2cccc(OC)c2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2cccc(OC)c2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
A mixture of 4-bromomethyl-2-(3-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (2.03 g, 5.71 mmole), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (1.45 g, 5.71 mmole) and potassium carbonate (1.18 g, 8.56 mmole) in anhydrous dimethylformamide (18 ml) was stirred at room temperature for 16 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (2.31 g). MS: (+) m/z 551.13 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[C:9]([CH:11]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])C(OCC)=O)=[O:10].[OH-].[Na+]>CO>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:9](=[O:10])[CH2:11][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCC(C(=O)OCC)C(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCCC(=O)O)c1
Reaction time: 14 h

Procedure:
To a solution of Diethyl 2-(3-(2,6-dimethylbenzyloxy)benzoyl)pentanedioate (Step B, 1.66 g, 4.0 mmol) in methanol (50 ml) was added 1N NaOH (17 ml) at the room temperature. The reaction mixture was stirred for 14 hours or until all the starting material is gone, concentrated, diluted in chloroform, and washed with 1M HCl to bring the pH to 3.5 to 4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography eluted with chloroform:methanol (95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1.COC1C=C(C2C(C)(C)C(=O)N(C3CCN(S(C4C=C(OC)C=CC=4OC)(=O)=O)CC3)N=2)C=CC=1OC.[OH-].[Na+]>C(O)C>[CH:37]1([CH2:36][O:30][C:28]2[CH:27]=[CH:26][C:25]([CH3:31])=[C:24]([C:22]([N:19]3[CH2:20][CH2:21][CH:16]([N:14]4[C:13](=[O:32])[C:12]([CH3:34])([CH3:33])[C:11]([C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:15]4)[CH2:17][CH2:18]3)=[O:23])[CH:29]=2)[CH2:39][CH2:38]1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Reactant: BrCC1CC1
Agent: COc1ccc(OC)c(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCC5CC5)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 0.35 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.11 ml (bromomethyl)cyclopropane in 8 ml ethanol is treated with 0.11 ml 10 n aqueous sodium hydroxide solution and stirred under a blanket of nitrogen for about 16 h at 80° C. until the reaction is completed largely according to TLC analysis. The solvent is evaporated under reduced pressure, and the resulting crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]34[CH2:26][CH2:25][C:22]([CH2:27][CH2:28][CH3:29])([CH2:23][CH2:24]3)[CH2:21][CH2:20]4)=[CH:15][CH:14]=2)=[N:11][CH:12]=1)/[CH:2]=[CH:3]/[CH2:4]C.C(OC1C=NC(C2C=CC(C34CCC(CCC)(CC3)CC4)=CC=2)=NC=1)/C=C/CCC.C(OC1C=NC(C2C=CC(C34CCC(CCC)(CC3)CC4)=CC=2)=NC=1)/C=C/CCCC.C(OC1C=NC(C2C=CC(C34CCC(CCC)(CC3)CC4)=CC=2)=NC=1)/C=C/CCCCC.C(OC1C=NC(C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)=NC=1)/C=C/C.C(OC1C=NC(C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)=NC=1)/C=C/CC.C(OC1C=NC(C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)=NC=1)/C=C/CCCC.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)/C=C/CCCCC.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)/C=C/C.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)/C=C/CC.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)/C=C/CCC.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)/C=C/CCCC>>[CH2:1]([O:6][C:7]1[CH:12]=[N:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]34[CH2:24][CH2:23][C:22]([CH2:27][CH2:28][CH3:29])([CH2:21][CH2:20]3)[CH2:25][CH2:26]4)=[CH:17][CH:18]=2)=[N:9][CH:8]=1)/[CH:2]=[CH:3]/[CH3:4]
Reactant: CC/C=C/COc1cnc(-c2ccc(C34CCC(CCC)(CC3)CC4)cc2)nc1
Agent: C/C=C/COc1cnc(-c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)nc1
Agent: C/C=C/COc1cnc(-c2ccc(C34CCC(CCCCCCC)(CC3)CC4)cc2)nc1
Agent: CC/C=C/COc1cnc(-c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)nc1
Product: C/C=C/COc1cnc(-c2ccc(C34CCC(CCC)(CC3)CC4)cc2)nc1

Procedure:
1-[4-(5-[(E)-Pent-2-enyloxy]pyrimidin-2-yl)phenyl]-4-propylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Hex-2-enyloxy]pyrimidin-2-yl)phenyl]-4-propylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Hept-2-enyloxy]pyrimidin-2-yl)phenyl]-4-propylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Oct-2-enyloxy]pyrimidin-2-yl)phenyl]-4-propylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-But-2-enyloxy]pyrimidin-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Pent-2-enyloxy]pyrimidin-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Hept-2-enyloxy]pyrimidin-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Oct-2-enyloxy]pyrimidin-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-But-2-enyloxy]pyrimidin-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Pent-2-enyloxy]pyrimidin-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Hex-2-enyloxy]pyrimidin-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Hept-2-enyloxy]pyrimidin-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane. 1-[4-(5-[(E)-Oct-2-enyloxy]pyrimidin-2-yl)phenyl]-4-heptylbicyclo[2.2.2]octane.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[OH:24][CH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:30]3[CH:31]=[C:26]([CH2:25][OH:24])[CH:27]=[CH:28][CH:29]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CO)c3)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (500 mg, 1.52 mmol), 3-(hydroxymethyl)phenylboronic acid (350 mg, 2.28 mmol), Pd2dba3 (100 mg, 0.15 mmol), X-phos (300 mg, 0.61 mmol) and K2CO3 (625 mg, 4.56 mmol) was dissolved in dioxane/water (50 mL/5 mL). The reaction mixture was degassed with bubbling nitrogen for 5 minutes then heated at 100° C. with stirring for 3 h, the solvent removed in vacuo, The residue purified by chromatography (silica gel, 200-300 mesh, dichloromethane/methanol=40:1) to give (3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanol (300 mg, 81%) as a white solid. 1H NMR (300 MHz, DMSO): δ 9.62 (s, 1H), 8.77 (s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.81-7.78 (m, 1H), 7.63 (s, 1H), 7.49-7.39 (m, 3H), 6.71 (d, 1H, J=7.8 Hz), 6.05 (d, 1H, J=7.8 Hz), 5.31 (t, 1H, J=5.7 Hz), 4.59 (d, 2H, J=5.7 Hz), 4.25-4.20 (m, 1H), 3.58-3.50 (m, 1H), 3.42-3.38 (m, 1H), 2.08-1.97 (m, 3H), 1.70 (brs, 1H), 1.11 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 401, tR=1.679 min, HPLC: 99.87% at 214 nm, 99.85% at 254 nm, tR=5.87 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([S:39]([NH:1][C:2]2[CH:10]=[C:9]3[C:5](/[C:6](=[C:12](/[NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]5)=[CH:22][CH:21]=4)\[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)/[C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: O=C1Nc2cc(NS(=O)(=O)c3ccccc3)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and benzenesulphonyl chloride
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH2:20][CH2:21][CH:22]([CH3:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH2:20][CH2:21][CH:22]([CH3:29])[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(CCc1cc2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O)c1ccncc1
Agent: [Pd]
Product: CC(CCc1cc2cccnc2n(-c2cccc(N)c2)c1=O)c1ccncc1
Yield: 68.8 %

Procedure:
The procedure of Example 7(2) was repeated using 1-(3-nitrophenyl)-3-[3-methyl-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (1.19 g, 2.97 mmol; prepared in Example 11) and 10% palladium on carbon (200 mg) to obtain 1-(3-aminophenyl)-3-[3-methyl-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (757 mg, 89%). The product was purified through flash column chromatography (mp 83–91° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH2:26]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:15][N:14]3[CH2:13][CH2:12][CH:11]([C:6]1=2)[CH2:17][CH2:16]3
Reactant: C=Cc1ccccc1F
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2F)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (158 mg, 0.70 mmol; Example 2B) and 1-fluoro-2-vinylbenzene (171 mg, 1.40 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.63-1.76 (m, 2H), 1.87-2.01 (m, 2H), 2.39 (s, 3H), 2.88-3.22 (m, 7H), 4.16 (s, 2H), 4.33 (t, J=7 Hz, 2H), 6.86-7.26 (m, 7H); MS (DCI/NH3) m/z 349 (M+H)+.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:14]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:13][CH:11]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O:58][C:59](=[O:62])[CH2:60]Br)C1C=CC=CC=1.COC(C)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[C:1]([O:9][C@H:10]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:14]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:13][CH:11]1[O:12][CH2:60][C:59]([OH:62])=[O:58])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(OC[C@H]1OC(O)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: COC(C)(C)C
Solvent: COCCOC
Product: O=C(O)COC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 59.66 g (100 mmol) of 2,3,4,6-tetra-O-benzoyl-mannopyranose, 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 63.59 g (600 mmol) of fine-powder sodium carbonate in 350 ml of 1,2-dimethoxyethane is cooled to 0° C. At 0° C., 34.36 g (150 mmol) of bromoacetic acid benzyl ester is added in drops over 10 minutes while being stirred vigorously. It is stirred for one hour at 0° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is dissolved in 500 ml of ethanol. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Then, catalyst is filtered out, rewashed with ethanol, and the combined solutions are evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.