Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([N:12]([CH3:38])[CH2:13][CH2:14][N:15]([CH3:37])[C:16]([C:18]1[O:19][C:20]2[C:26](F)=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([CH3:34])=[C:23]([C:35]#[N:36])[C:21]=2[N:22]=1)=[O:17])(=[O:11])[CH3:10].C(N(CC)CC)C>CS(C)=O>[C:9]([N:12]([CH3:38])[CH2:13][CH2:14][N:15]([CH3:37])[C:16]([C:18]1[O:19][C:20]2[C:26]([N:5]3[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24]([CH3:34])=[C:23]([C:35]#[N:36])[C:21]=2[N:22]=1)=[O:17])(=[O:11])[CH3:10]
Reactant: CC(=O)N(C)CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)N(C)CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 0.75 h
Yield: 43.9 %

Procedure:
Under nitrogen atmosphere at 140 to 150° C., a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidin (32 μl, 256 μmol) was added to a dimethyl sulfoxide (3 ml) solution of N-{2-[acetyl(methyl)amino]ethyl}-4-cyano-N,5-dimethyl-7-fluoro-6-phenyl-1,3-benzoxazole-2-carboxamide (I-204) (87 mg, 213 μmol) and triethylamine (39 μl, 277 μmol), followed by stirring at the same temperature for 45 minutes. After cooling, the solvent was evaporated away under reduced pressure, the residue was dissolved in chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave the entitled compound (47 mg, 44%) as an amorphous substance.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([O-:3])=O.C[Si](C)(C)[O:17][C:18]#[C:19][CH3:20].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([C:4]1[CH:20]=[C:19]([CH2:18][OH:17])[O:3][N:1]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC#CO[Si](C)(C)C
Reactant: CCCCCCCCCCC[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: CCCCCCCCCCc1cc(CO)on1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
To a solution of 1-nitroundecane (38.0 g) and O-trimethylsilylpropynol (24.1 g) in dry benzene (300 ml) was added dropwise a solution of freshly distilled phenylisocyanate (44.9 g) and triethylamine (22.4 g) in dry benzene (50 ml) at 40° C., with stirring. The reaction mixture was heated at 60° C. for 3 hrs, cooled, and filtered. To the filtrate was added 1.0 M tetrabutylammonium fluoride (40 ml). After 30 mins, the solution was evaporated, and the residue was flash chromatographed (silica gel, 1% methanol-dichloromethane) to give 15.5 g (34%) of product, mp 55-56° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CO>[Pd].CCO.O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH2:17])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8]
Reactant: COC(=O)c1cc(C(=O)OC(C)(C)C)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(N)cc(C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Yield: 71.2 %

Procedure:
A mixture of 5-nitro-isophthalic acid 1-tert-butyl ester 3-methyl ester (D78) (5.3 g, 19 mmol, 1 equiv), NH4COOH (11.9 g, 190 mmol, 10 equiv) and 10% Palladium on charcoal (50% wet, 0.75 g, 7% w/w) in EtOH (50 ml) and H2O (25 ml) was heated at 50° C. for 30 min. MeOH (20 ml) was added and the resulting solution was heated at 50° C. for another hour then cooled to room temperature, filtered through a pad of celite and concentrated in vacuo. The residue was diluted with saturated aqueous NaHCO3 solution (100 ml) and the aqueous phase was extracted with AcOEt (150 ml). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was triturated with iso-hexane to give of 5-amino-isophthalic acid 1-tert-butyl ester 3-methyl ester (D79) (3.4 g, 71%) as a white solid.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[Cl:26][CH2:27][C:28](OC)(OC)OC.[NH2:35][C:36]1[C:37]([C:55]#[N:56])=[N:38][C:39]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)=[CH:40][C:41]=1[NH:42][CH2:43][CH3:44]>C(#N)C>[Cl:26][CH2:27][C:28]1[N:42]([CH2:43][CH3:44])[C:41]2[CH:40]=[C:39]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:52])[F:53])[CH:46]=3)[N:38]=[C:37]([C:55]#[N:56])[C:36]=2[N:35]=1
Reactant: COC(CCl)(OC)OC
Reactant: CCNc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)c1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CCn1c(CCl)nc2c(C#N)nc(-c3cccc(C(F)(F)F)c3)cc21
Yield: 86.8 %

Procedure:
Ytterbium triflate (1.16 g, 1.8 mmol) and 2-chloro-1,1,1-trimethoxyethane (7.56 mL, 56.0 mmol) was added to a solution of 3-amino-4-ethylamino-6-(3-trifluoromethylphenyl)-pyridine-2-carbonitrile (5.73 g, 18.7 mmol) in acetonitrile (150 mL). The mixture was refluxed for 48 hours, then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered off to afford the title compound (5.92 g, 87%) as a solid. 1H NMR (DMSO-d6) δ: 8.85 (s, 1H); 8.50-8.00 (m, 2H); 7.90-7.70 (m, 2H); 5.26 (s, 2H); 4,55-4.45 (m, 2H); 1.48 (t, J=7 Hz, 3H). MS m/z: 365 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH2:12][CH2:11][Br:10]
Reactant: Oc1c(Br)cccc1Br
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1c(Br)cccc1Br

Procedure:
A mixture of 2,6-dibromophenol (10.2 g, 40 mmol), 1,2-dibromoethane (7.6 g, 40 mmol) and NaOH (1.76 g, 44 mmol) in water was heated at reflux overnight under stirring. The mixture was cooled, extracted with diethyl ether (2×100 mL), the extract washed with aqueous NaOH, brine, dried (MgSO4) and concentrated to give the product as a pale yellow oil. Yield: 10.0 g (70%). 1H NMR (400 MHz, CDCl3) δ 3.73 (t, 2H), 4.31 (t, 2H), 6.88 (t, 1H), 7.50 (d, 2H). *Previously reported in Tetrahedron Lett. 1998, 39, 2219-2222.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 3-(Bocamino)-1-propanol (10.51 g: 60 mmol) and TEA (6.07 g; 60 mmol) in dry DCM (100 mL) kept in an ice bath (0° C.) was slowly added methane sulfonyl chloride (6.87 g; 60 mmol) and the reaction mixture was stirred for 30 min at 0° C. The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 5 h (completion of the reaction was monitored by TLC). Water (50 mL) was added with stirring and the resulting mixture was transferred to a reparatory funnel, the layers were separated, and the aqueous layer was extracted with DCM (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to yield compound 5 as a colorless oil (12.82 g: 100% yield). 1H NMR (CDCl3) δ 4.8 (s, 1H), 4.3 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 1.9 (m, 2H), 1.4 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O>[C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCCCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCc1ccccc1
Yield: 91.1 %

Procedure:
To a stirred solution of 24.0 g (0.131 mole) of 1-chloro-5-phenylpentane (Columbia Organics, Camden, S.C.) in 150 mL of dimethylformamide was added 24.3 g (0.131 mole) of potassium phthalimide (Aldrich) and the reaction mixture was heated at reflux under a nitrogen atmosphere for 15 hr. The solvent was evaporated under reduced pressure to heave a viscous, oily residue. The residue was triturated with 200 mL of water and then the mixture was extracted with four 200-mL portions of methylene chloride. The combined methylene chloride extracts were washed with two 200 mL portions of 2N sodium hydroxide solution, twice with 200 mL portions of water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 35.0 g (91%) of title compound as a viscous oil. A sample of this viscous oil was further purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A, PrepPak® 500 silica gel; ethyl acetate-hexanes, 1:10). Fractions containing title compound were combined and the solvents were evaporated under reduced pressure to give purified title compound as a colorless, viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[O:4][CH:3]=1.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17]>CO>[Cl:13][C:8]1[CH:7]=[CH:6][C:5]2[O:4][CH:3]=[C:2]([NH:1][C:15](=[CH:14][C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:12])[C:10]=2[CH:9]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1coc2ccc(Cl)cc2c1=O
Solvent: CO
Product: COC(=O)C=C(Nc1coc2ccc(Cl)cc2c1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
A mixture of 3-amino-6-chlorochromone (8 g, 0.041 mole) and dimethyl acetylenedicarboxylate (10.5 g, 0.074 mole) in methanol (150 ml) was stirred at room temperature for 2 days. The product was filtered off and washed with methanol. Recrystallization from ethyl acetate gave yellow crystals (11 g, 80%), m.p. 158°-160°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[N:19]=[C:18]([CH2:20][OH:21])[CH:17]=[N:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:21][CH2:20][C:18]1[CH:17]=[N:16][N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[N:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1cnn(C2CCN(c3ncc(C(F)(F)F)cn3)CC2)n1
Reactant: OCc1ccccc1
Product: FC(F)(F)c1cnc(N2CCC(n3ncc(COCc4ccccc4)n3)CC2)nc1

Procedure:
The title compound was synthesized from (2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methanol (Intermediate 27) and benzyl alcohol in a manner similar to that described in Example 29. 1H NMR (CDCl3): δ 8.50 (2H, s), 7.60 (1H, s), 7.36-7.30 (5H, m), 4.86-4.82 (2H, m), 4.79-4.72 (1H, m), 4.62 (2H, s), 4.59 (2H, s), 3.33-3.26 (2H, m), 2.30-2.16 (4H, m).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1)#[N:2]>ClCCl>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Solvent: ClCCl
Product: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a suspension of N-{3-[5-(2-cyano-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (2.12 g, 3.80 mmol) in dichloromethane (DCM) (38.0 ml) at −78° C. was added DI BAL-H (18.98 ml, 18.98 mmol). The yellow suspension was slowly warmed to RT and stirred 1 hr. The reaction was quenched with Rochelle's salts and stirred about 1 hr. 4N HCl was added to clear the emulsion. The HCl solution was extracted with DCM (3×). The aqueous was passed through celite and neutralize with 6N NaOH. Solid formed during neutralizing and was filtered to obtain N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (1.57 g, 73%). MS (ESI): 563 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][CH:9]=[CH:8][CH:7](O[Si](C)(C)C)[C:6]=1[C:16]([O:18][CH3:19])=[O:17])=[O:4].[CH2:20]([O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:34][CH:33]=2)=[C:9]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:34][CH:33]=2)[CH:10]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C1=C(C(=O)OC)C(O[Si](C)(C)C)C=CC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccc(OCc3ccccc3)cc2)c(Nc2ccc(OCc3ccccc3)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-his (trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 4.8 g (24 mmol) of 4-benzyloxyaniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is dissolved while hot in ethyl acetate and filtered, then allowed to crystallize at 0°. The crystalline residue is chromatographed on silica gel with ethyl acetate/hexane 3:2 and the product fractions are concentrated by evaporation and recrystallized from ethyl acetate/hexane, yielding the title compound in the form of beige crystals, FAB-MS: 589 [M+ +H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][CH:31]2[CH2:34][CH2:33][O:32]2)=[CH:27][C:26]=1[F:37]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][CH:31]2[CH2:34][CH2:33][O:32]2)=[CH:27][C:26]=1[F:37])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Fc1cc(OCC2CCO2)ccc1Br
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC2CCO2)cc1F)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-2-(4-bromo-3-fluoro-phenoxymethyl)-oxetane (Intermediate 27) in analogy to Example 1a): colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.C=CCl.OP([O-])(O)=O.[K+].[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39].[K+].[Br-]>C(Cl)(Cl)Cl.C(#N)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH:15][C:38](=[O:39])[CH2:37][O:36][CH3:35])=[CH:5][CH:4]=1
Reactant: COCC(=O)Cl
Reactant: COc1ccc2c(c1)C(CCN)CCC2
Agent: C=CCl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=P([O-])(O)O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COCC(=O)NCCC1CCCc2ccc(OC)cc21

Procedure:
N-[2-(1,2,3,4-tetrahydro-7-methoxy naphthalen-1-yl)ethyl]amine was resolved according to the procedure described using D-tartaric acid and shown to have an enantomeric excess of 92% by HPLC analysis. The HPLC analyses were performed on a Ultron ES-OVM, 150×4.6 mm column using an isocratic mobile phase at 95/5 (A/B) where A is 20 mM KH2PO4, pH=3.0 and B is acetonitrile. This amine was converted into the amide according to General Procedure A using methoxyacetyl chloride. The final product was purified by recrystallization from EtOAc/hexane to give a white solid. m.p.=61°-63° C.; 1H NMR (300 MHz, CDCl3) δ6.96 (d, J=8 Hz, 1H), 6.67 (s, 1H), 6.65 (m, 1H), 6.51 (bs, 1H), 3.86 (s, 2H), 3.75 (s, 3H), 3.42 (m, 2H), 3.38 (s, 3H), 2.78 (m, 1H), 2.66 (bm, 2H), 1.97-1.76 (bm, 4H), 1.68-1.65 (m, 2H); 13C NMR (75 MHz, CDCl3) δ169.42, 157.55, 141.23, 130.01, 129.21, 113.34, 111.80, 71.99, 59.15, 55.28, 36.93, 36.45, 35.64, 28.72, 27.51, 20.00; IR (KBr) 1656 cm-1 ; MS (DCI) m/e 278 (MH); Analysis calc'd for C16H23N1O3 : C, 69.29; H, 8.36; N, 5.05; found: C, 69.15; H, 8.33; N, 4.89; [α] (25° C., 589 nm, CHCl3)=-8.33.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:3][CH:2]=1.[OH:32]O>>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[O:32])=[CH:5][CH:6]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(-c4ccccc4)cc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(-c4ccccc4)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-biphenylylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][NH:12]2)[CH2:9]1)=[O:7].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][N:12]2[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)=[O:7]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CNC2C1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CN(C(=O)c3ccccc3)C2C1
Yield: 84 %

Procedure:
In analogy to the experimental procedure of example 1c) rac-3-(2,4-Dichloro-benzylcarbamoyl)-3,6-diaza-bicyclo[3.2.0]heptane instead of 6-(2,4-dichloro-benzylcarbamoyl)-2,6-diaza-spiro[3.3]heptane using benzoyl chloride was converted into the title compound (92 mg, 84%) which was obtained as a white solid. MS (EI) m/e: 404.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:14]([CH2:15][CH2:16][OH:17])[CH3:13])(=[O:11])=[O:10]
Reactant: CNCCO
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO)S(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
2,4-Difluorobenzenesulfonyl chloride (CAS no. 13918-92-8) (4.0 g, 19 mmol) in DCM (10 mL) was added slowly to a solution of 2-(methylamino)ethanol (1.66 mL, 20.7 mmol) in DCM (200 mL) and 10% sodium hydroxide solution (200 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 20 hours. The DCM layer was separated and the aqueous re-extracted into DCM (2×50 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSO4), filtered and evaporated under reduced pressure to afford the product (4.7 g, 98%). 1H NMR δ (400 MHz, CDCl3): 1.98 (t, 1H), 2.94 (s, 3H), 3.32 (t, 2H), 3.79 (q, 2H), 6.94-7.03 (m, 2H), 7.89-7.95 (m, 1H).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=[O:8])=[O:7])(C)C.Br>CO>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccccn1
Agent: Br
Solvent: CO
Product: NS(=O)(=O)c1ccccc1-c1ccccn1
Yield: 50.2 %

Procedure:
A solution of 14.8 g of the sulfonamide from Example 1 and 10 ml of 48% hydrobromic acid in 100 ml of methanol was heated at 40°-45° for 16 hours, concentrated, and neutralized with aqueous sodium bicarbonate. The solid was filtered, washed with ice-water, and air-dried to afford 6.0 g of product, m.p. 186°-190°. NMR(CDCl3 /DMSO-d6)δ: 7.5 (m, 7), 8.1 (m, 2), 8.6 (d, 1). IR(Nujol) 3300, 3260 cm-1. m/e M+ 234.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[C:19]1([C:25]2[CH2:29][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[C:19]1([C:25]2[CH2:29][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([C:36]3[CH:37]=[CH:38][C:39]([CH:40]=[CH:1][C:2]4[O:3][C:4]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=4)=[CH:42][CH:43]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(N2N=C(c3ccccc3)CC2c2ccccc2)cc1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(C#N)=C1C=C(C=Cc2ccc(N3N=C(c4ccccc4)CC3c3ccccc3)cc2)OC(c2ccccc2)=C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 4, 0.4 g (1.7 mmol) of 2-(2-methyl-6phenyl-pyran-4-ylidene)-malononitrile and 0.55 g (1.7 mmol) of 4-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-benzaldehyde} were added into 40 ml of ethanol, and 0.17 g (2.0 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(CN2CCC(O)CC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2CCC(OC(=O)c3ccccc3)CC2)cc1
Yield: 63.6 %

Procedure:
0.31 g (0.0015 mol) of 1-(4-methyl-benzyl)-piperidin-4-ol and 0.52 ml (0.00375 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.25 ml (0.00215 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:4). 0.295 g (64%) of 1-(4-methyl-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH:20]=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:36])[C:32]([NH2:35])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[CH:33][C:32]3[N:35]=[C:20]([C:14]4[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([O:10][C:7]6[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=6)[CH:12]=5)[NH:16][N:15]=4)[NH:36][C:31]=3[CH:30]=2)[CH2:27][CH2:28]1
Reactant: O=Cc1n[nH]c2ccc(Oc3ccc([N+](=O)[O-])cn3)cc12
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5ccc(Oc6ccc([N+](=O)[O-])cn6)cc45)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from 5-(5-nitro-pyridin-2-yloxy)-1H-indazole-3-carbaldehyde and 4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine using the method described above in Example 4. LC/MS (m/z) 471.3 (MH+), Rt 2.94 minutes.