Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].C(OCCC)CC>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Solvent: CCCOCCC
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 20 ml of ethyl acetate) is slowly added to a solution of maleic acid (0.58 g) in absolute ethanol (5 ml) with stirring at room temperature followed by adding 10 ml of dipropyl ether. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 127.8° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3,5-difluorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 338.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.58 (s, 1H); 8.45 (d, J=5.5 Hz, 1H); 7.98 (br s, 1H); 7.85 (d, J=8.5 Hz, 1H); 7.36 (m, 2H); 6.95 (d, J=6.4 Hz, 2H); 6.89 (d, J=5.4 Hz, 1H); 6.74 (m, 1H); 5.87 (br s, 1H); 4.75 (d, J=6.4 Hz, 2H).
Reaction SMILES: Br[Mg][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH:8]12[O:13][CH:12]1[CH2:11][O:10][CH2:9]2>C1COCC1.[Cu]I>[CH2:3]([C@@H:12]1[CH2:11][O:10][CH2:9][C@H:8]1[OH:13])[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C1OCC2OC12
Reactant: C=CCCC[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CCCC[C@@H]1COC[C@H]1O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a mixture of CuI (1.66 g, 8.71 mmol) in THF (100 mL) at −5° C., a 0.5M solution of bromo(pent-4-en-1-yl)magnesium (116 mL, 5.81 mmol) was added. The solution was stirred for 1 hour and cooled to −20° C. 3,6-Dioxabicyclo[3.1.0]hexane (5.0 g, 58.1 mmol) was added dropwise, and the reaction mixture was slowly warmed to RT and stirred for 15 hours. The reaction mixture was quenched with NH4Cl(aq.) and extracted with Et2O (3×). The combined organics were washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified on SO2 (gradient elution, 10-100% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3) δ 5.83-5.75 (m, 1H); 5.04-4.95 (m, 2H); 4.14-4.07 (m, 3H); 3.85 (m, 1H); 3.70 (m, 1H); 3.44 (m, 1H); 2.07 (m, 3H); 1.45 (m, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:24])[NH:14][C:15]1[CH:16]([O:21][CH2:22][CH3:23])[O:17][C:18](=[O:20])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N.[H][H].ClCCl>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:24])[NH:14][CH:15]1[CH2:19][C:18](=[O:20])[O:17][CH:16]1[O:21][CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: N#N
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC1OC(=O)CC1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
To a solution of (R )-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (X, R1=Et) (0.09 g, 0.27 mmol) in toluene previously degassed with N2 (20 mL) in a high pressure reactor in a nitrogen filled glove bag, was added (−)-1,2-bis((2R,5R)-2,5-diethyl-phospholano)benzene-(cyclooctadiene)rhodium(I) trifluoromethanesulfonate (5-15 mg). The reactor was sealed and pressurized with hydrogen (950 psi, 65 atm) and was let stand at room temperature for 2 d. Solvent was evaporated and the residue was purified by flash chromatography (SiO2) eluted with 1.5:98.5 methanol:dichloromethane to provide (R)-2-(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.092 g, quant yield) as a colorless oil. Chiral HPLC (chiralpak-AD column, eluted with 1:9 ethanol:hexanes): isomer Ib-35.4%, isomer Id-56.4%, (mixture of isomers Ia and Ic)-8.2%. 1H-NMR (500 MHz, CDCl3) δ 7.60 (br s, 0.25H), 7.40 (br s, 0.25H), 6.5 (br m, 0.25H), 5.38 (d, J=5 Hz, 0.5H), 5.27 (s, 0.5H), 4.65 (br, 0.5H), 4.20 (br m, 1.5H), 3.85 (m, 0.5H), 3.77 (m, 0.5H), 3.57 (m, 1H), 3.30 (m, 2H), 2.95 (m, 0.5H), 2.80 (br m, 0,5H), 2.30 (br m, 2H), 1.85 (br s, 3H), 1.37 (s, 9H), 1.20 (t, J=7 Hz, 1.5H), 1.15 (t, J=7 Hz, 1.5H) ppm.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[CH3:7][C:8]1([C:11](Cl)=O)[CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)[O:6][N:5]=1
Reactant: N=C(CCl)NO
Reactant: CC1(C(=O)Cl)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(c2nc(CCl)no2)CC1
Temperature: 130 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
2.75 g of 2-chloro-N-hydroxyacetoamidine and 3.0 g of 1-methylcyclopropanecarbonyl chloride were dissolved in 50 ml of N,N-dimethylformamide, and 2.8 g of triethylamine was added dropwise under ice-cooling. After completion of the addition, the mixture was heated to 130° C., stirred for 6 hours and then cooled to room temperature. After aqueous saturated sodium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.97 g of 3-(chloromethyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH3:10])=[N:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:4].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][Br:26])=[N:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(C)nc1-c1ccc(OC)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)nc1-c1ccc(OC)cc1
Temperature: 100 °C
Yield: 24.2 %

Procedure:
To the solution of 4-(4-Methoxy-phenyl)-2-methyl-thiazole-5-carboxylic acid methyl ester (0.25 g, 0.94 mmol) in the 20 ml of CCl4 was added NBS (0.16 g, 0.94 mmol) and AIBN (0.015 g, 0.094 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 10% ethyl acetate/hexane as a eluent to give the desired product (0.078 g, 24%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:26][CH2:27][CH3:28]>>[CH2:26]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:27][CH3:28]
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Reactant: CCCI
Product: CCCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 97.3 %

Procedure:
In a similar manner to Example 10(b), by reaction of 2 g (6.2 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)benzaldehyde [prepared in Example 16(a)] with 670 μl (6.8 mmol) of 1-iodopropane, 2.2 g (88%) of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: [I:1][C:2]1[C:10]([NH2:11])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5].C1(=O)[N:18]([CH2:19][CH2:20][C:21](Cl)=[O:22])C(=O)C2=CC=CC=C12>>[I:1][C:2]1[C:10]([NH:11][C:21](=[O:22])[CH2:20][CH2:19][NH2:18])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(I)cc(I)c(C(=O)O)c1I
Reactant: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Product: NCCC(=O)Nc1c(I)cc(I)c(C(=O)O)c1I

Procedure:
The same procedure is used as for Compound I, using 2,4,6-triiodo-3-amino-benzoic acid as iodo starting material and β-phthalimidopropionic acid chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](CC)=[CH:4][CH:3]=1.CCCCC.C([Li])(C)(C)C.C([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=O)=[CH:24][C:23]=1O)=O.[Cl-].[NH4+]>O1CCCC1.O>[C:2]1([CH:26]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:31][CH:30]=2)[OH:28])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Reactant: CCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-bromo-4-ethylbenzene (0.41 mL) in tetrahydrofuran (15 mL) was added 1.45 mol/L tert-butyllithium n-pentane solution (2.3 mL) under an argon atmosphere at −78° C. After the mixture was stirred at −78° C. for 10 minutes, a solution of methyl 4-formyl-3-hydroxybenzoate (0.18 g) in tetrahydrofuran (5 mL) was added to the reaction mixture. After the mixture was stirred under ice-cooling for 45 minutes, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give a diphenylmethanol compound (0.27 g). The obtained diphenylmethanol compound (0.27 g) was dissolved in methanol (5 mL), and concentrated hydrochloric acid (0.08 mL) and 10% palladium-carbon powder (54 mg) were added to the solution. After the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (0.20 g).
Reaction SMILES: CN1CCOCC1.[C:8]1([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCCc1ccccc1
Temperature: -25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
N-Methylmorpholine (3.4 ml) and 4-phenylbutyric acid (5.02 g) were added to L-proline benzyl ester hydrochloride (7.37 g) in dichloromethane (80 ml) under ice-cooling. The mixture was cooled to -25° C., added with DCC (6.31 g) and stirred at room temperature for 16 hours. The resultant dicyclohexylurea was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 9.42 g of N-(4-phenylbutyryl)-L-proline benzyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[Sn](CCCC)(CCCC)CCCC.[ClH:20].[CH2:21]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH:37][C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[C:45](I)[CH:46]=4)[N:41]=[CH:40][N:39]=3)=[CH:34][CH:35]=2)[CH:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl>O1CCOCC1.CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:20].[CH2:21]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH:37][C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[C:45]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=5)[CH:46]=4)[N:41]=[CH:40][N:39]=3)=[CH:34][CH:35]=2)[CH:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Ic1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cccc1-c1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Yield: 28.6 %

Procedure:
A stirred solution of 1-methyl-2-(tri-n-butylstannyl)pyrrole (prepared as described in H. M. R. Hoffmann et al. Synthesis, 1996, 164) (1.07 g, 2.89 mmol), (1-benzylindazol-5-yl)-(6-iodoquinazolin-4-yl)-amine hydrochloride (1.0 g, 1.95 mmol), triethylamine (0.4 ml, 0.29 g, 2.87 mmol) and 1,4-bis(diphenylphosphino)-butane palladium (II) chloride (0.9 g, catalytic) in dioxane (10 ml) was heated to reflux under a nitrogen atmosphere for 18 hours. The mixture was concentrated in vacuo and purified by silica gel chromatography, eluting with 2:1 i-hexane/EtOAc. Concentration of the appropriate fractions gave a yellow solid which was dissolved in EtOAc and treated with a solution of HCl in dioxane. The precipitate was collected by filtration, washed with EtOAc and dried at 60C in vacuo to give the product as a green-yellow solid (0.26 g, 0.557 mmol, 29%); δH [2H6]DMSO 11.95 (1H,s), 8.86-8.96 (2H,m), 8.18-8.27 (2H,m), 8.07 (1H,s), 7.99 (1H,d),7.83 (1H,d), 7.65 (1H,dd), 7.22-7.40 (5H,m), 7.01 (1H,t), 6.49 (1H,dd), 6.19 (1H,t), 5.71 (2H,s), 3.82 (3H,s); m/z (M+1+) 4.31.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([C:36](O)=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[C:39]([O:47][CH2:48][CH3:49])(=[O:46])[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)[CH:17]([C:36]([N:43]3[CH2:44][CH2:45][CH:40]([C:39]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:42]3)=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CCOC(=O)c1ccncc1
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)C2CN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC(=O)N2N(C)C2CCN(c3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazine carboxylic acid (0.18 g) obtained in Example 110, ethyl isonicotinate (0.068 ml) and 1-hydroxy-1H-benzotriazole monohydrate (0.068 g) in DMF (4.4 ml) was combined with WSC (0.096 g) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain ethyl 1-[[4-[(6-chloro-2-naphthyl)sulfonyl]-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinyl]carbonyl]-4-piperidinecarboxylate as a colorless powder. Then a mixture of this material with 1N sodium hydroxide (1.14 ml) and methanol (4.0 ml) was stirred at 40° C. for 30 minutes. The reaction mixture was cooled, and the reaction system was adjusted at pH 5 with 1N hydrochloric acid, and concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% conc. aqueous ammonia-containing 25% aqueous solution of acetonitrile) to obtain the title compound (0.07 g) as a colorless powder.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12]#[N:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C>CS(C)=O>[O:1]=[C:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12]#[N:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1cnc2c(c1)CCCC2O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cnc2c(c1)CCCC2=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (555 mg, 3.19 mmol) in DMSO (15 ml) at 23° C. was added triethylamine (1.93 g, 2.66 ml, 19.1 mmol) and sulphur trioxide-pyridine complex (1.52 g, 9.56 mmol). The brown solution was stirred at 23° C. for 2 hours. The reaction mixture was poured on water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give of a light brown solid, which was purified by silica gel flash chromatography with dichloromethane/methanol to give the 8-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile (286 mg, 1.66 mmol, 52.1% yield) as a light yellow solid. MS (ISP): m/z=173.1 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.C([Li])(C)(C)C.[Br:17][C:18]1[CH:19]=[C:20](/[C:26](/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[C:41]#[N:42])=[N:27]\S(C(C)(C)C)=O)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].Cl.CO>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:26]2([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[C:34]3[C:35](=[C:36]([F:40])[CH:37]=[CH:38][CH:39]=3)[C:41]([NH2:42])=[N:27]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(/C(=N\S(=O)C(C)(C)C)c2cccc(F)c2C#N)cc1Br
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cccc32)cc1Br
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
A solution of 4-bromo-2-trifluoromethylpyridine (1.76 g, 7.80 mmol) in THF (2 mL) was added dropwise at −100° C. to t-butyllithium (9.17 mL, 15.59 mmol) in THF (15 mL) followed by the addition of (E)-N-((3-bromo-4-methoxyphenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (3.1 g, 7.09 mmol) in THF (10 mL). The reaction mixture was left on a thawing cooling bath for 1 hour and then allowed to reach room temperature and stirred for 2.5 hours. Hydrochloric acid in methanol (1.25 M, 28.4 mL, 35.4 mmol) was added and the reaction was stirred for 1 hour. Silica powder was added and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% 0.1M NH3 in methanol in DCM) to afford the title compound (3.04 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH2:15][OH:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClS([N:24]=[C:25]=[O:26])(=O)=O.O.Cl>C(#N)C>[C:25](=[O:26])([O:16][CH2:15][C:13]1[NH:14][C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:17]([CH3:19])[CH3:18])[N:12]=1)[NH2:24]
Reactant: CC(C)c1nc(CO)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC(C)c1nc(COC(N)=O)[nH]c1Sc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
The compound 2 40 g (126 mmol) obtained in the step 1 was suspended in acetonitrile 400 ml, and the suspension was cooled down under nitrogen atmosphere. To the suspension was added dropwise chlorosulfonyl isocyanate 24.3 g (171 mmol) at -20 to -25° C. for 1 hour. To the mixture was added water 400 ml under 10° C. To the mixture was added concentrated hydrochloric acid 40 ml, and the mixture was stirred at 50° C. for 2 hours. The mixture was cooled down to -10° C. and crystallized at the same temperature for 1 hour. The obtained slurry was filtered, washed with cooled acetonitrile, and dried to yield the compound 3 43.2 g. Yield 83%
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O.N1(O)C2C=CC=C[C:31]=2N=N1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:63][C:64]([F:75])([F:74])[CH2:65][NH:66][C:67]([CH:69]([NH2:73])[CH:70](C)C)=[O:68].C(N(C(C)C)CC)(C)C>CC#N>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:15])([F:16])[F:17])[CH:8]=[CH:7][C:3]=1[C:4]([NH:73][C:69]([CH3:70])([CH3:31])[C:67](=[O:68])[NH:66][CH2:65][C:64]([F:63])([F:74])[F:75])=[O:6]
Reactant: CC(C)C(N)C(=O)NCC(F)(F)F
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)C(=O)NCC(F)(F)F
Yield: 54.9 %

Procedure:
To (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (200 mg, 0.409 mmol) in MeCN (5 mL) was added 1H-benzo[d][1,2,3]-triazol-1-ol hydrate (63 mg, 0.411 mmol), HBTU (155 mg, 0.409 mmol), N-(2,2,2-trifluoroethyl) 1-amino-2-methyl-propanecarboxamide hydrochloride (180 mg, 0.816 mmol) and diisopropylethylamine (0.24 mL, 1.38 mmol). After 24 h the material was concentrated in vacuo. The crude product was purified by passing the crude reaction mixture through a silica frit and eluting with EtOAc/hexane (1:2). The recovered material was further purified by medium pressure chromatography on silica with EtOAc/hexane as the eluent to afford the title as a white foam (147 mg, 55%). Characterization data for this molecule is listed in Table 2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][NH:17][C:18]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.S(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:18]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:17][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(NNC(=O)C3CCOCC3)c(Cl)nc2c1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1nnc(C3CCOCC3)n12
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
To a mixture of 1.20 g of methyl 3-chloro-2-[2-(tetrahydro-2H-pyran-4-ylcarbonyl)hydrazino]quinoxaline-6-carboxylate and 36 mL of acetonitrile was added 0.5 mL of thionyl chloride, followed by stirring at 90° C. for 4.5 hours. The solvent was evaporated under reduced pressure, to the obtained residue was added water, and the solid was collected by filtration and dried under reduced pressure to obtain 1.13 g of methyl 4-chloro-1-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C.[OH-].[Na+]>Cl.C(OCC)(=O)C>[C:1]1([C:12]2[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Nc1ccccc1
Product: Nc1ccc(C2=CCCCC2)cc1
Temperature: 110 °C

Procedure:
A mixture of cyclohexanone (50 g, 0.325 mol), and aniline (95 g, 1 mol) in 12 M HCl (100 mL), and ethanol (15 mL) was refluxed at 110° C. for four days. The solution was cooled and diluted with ethyl acetate. The aqueous layer was basified with 6 M NaOH. The organic layer was separate and washed with brine (3×), dried over MgSO4, and concentrated to give a brown oil. Approximately half of the crude product was introduced into a silica gel column and eluted with 5% ethyl acetate/hexane to obtain the desired product along with aniline. The combined organic fractions were extracted with 1 N HCl and separated. Addition of brine to the aqueous layer precipitated the 4-cyclohex-1-enylaniline as a cream colored solid (9 g).