Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:11][SiH:12]([CH3:17])[O:13][SiH:14]([CH3:16])[CH3:15]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:5]1([NH:4][CH2:1][CH2:2][CH2:3][Si:12]([CH3:17])([CH3:11])[O:13][Si:14]([CH2:3][CH2:2][CH2:1][NH:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)([CH3:16])[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C=CCNC1CCCCC1
Reactant: C[SiH](C)O[SiH](C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: C[Si](C)(CCCNC1CCCCC1)O[Si](C)(C)CCCNC1CCCCC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Following the technique described in Example 1, N-allylcyclohexylamine (0.173 mole), 1,1,3,3-tetramethyldisiloxane (0.0783 mole), and 0.05 g hexachloroplatinic acid are stirred at 70° C for eight hours at 110° C. under nitrogen. The product, in nearly quantitative yield, is purified by vacuum distillation at <1 torr at a temperature of 207°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([F:16])([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.[CH3:17][Mg]Br>O1CCCC1.C(OCC)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH3:17])([OH:11])[C:6]([F:16])([S:12]([CH3:15])(=[O:13])=[O:14])[CH2:5]2
Reactant: C[Mg]Br
Reactant: CS(=O)(=O)C1(F)Cc2cc(Cl)ccc2C1=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(O)c2ccc(Cl)cc2CC1(F)S(C)(=O)=O

Procedure:
At room temperature, 260 mg (1 mmol) of 5-chloro-2-fluoro-2-methanesulfonylindan-1-one are dissolved in 10 ml of dry tetrahydrofuran, and 0.33 ml of a 3M solution of methylmagnesium bromide in diethyl ether is added dropwise with stirring. The reaction mixture is stirred at 50° C. for 3 h. A further 0.33 ml of the methylmagnesium bromide solution is then added, and the mixture is stirred at room temperature for another hour. After the reaction has ended, the reaction mixture is diluted with ethyl acetate and extracted successively with sat. ammonium chloride solution, sat. sodium bisulfite solution, sat. sodium bicarbonate solution and sat. sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure Chromatographic purification on silica gel (n-heptane/ethyl acetate 60/40) gives 5-chloro-2-fluoro-2-methanesulfonyl-1-methylindan-1-ol of melting point 148° C.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.CC1C=CC(C)=CC=1[CH2:26][C:27]1C=[C:31]([S:33](=S)([O-])=O)[CH:30]=[CH:29][C:28]=1[CH3:37].CCN([CH2:48][CH3:49])CC.C([O-])(O)=O.[Na+]>C(OCC)C.C(O)C>[OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[C:3]=1[S:33][CH2:31][C:30]1[CH:29]=[C:28]([CH3:37])[CH:27]=[CH:26][C:48]=1[CH3:49]
Reactant: Cc1ccc(C)c(Cc2cc(S(=O)([O-])=S)ccc2C)c1
Reactant: CCN(CC)CC
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(C)c(CSC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c1
Temperature: 40 °C

Procedure:
The title compound was prepared as described in General Method 7 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol), 2,5-dimethylbenzyl-p-toluenethiosulfonate (0.312 g, 1.02 mmol), Et3N (0.230 mL, 1.60 mmol), NaHCO3 (0.071 g, 0.85 mmol), absolute ethanol (3.0 mL). The mixture was heated to 40° C. for 16 h then diluted with diethyl ether (100 mL), and washed with H2O. The solvent was then removed in vacuo and the residue submitted to column chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH2Cl2) to provide a solid (0.116 g, m.p. 54°-56° C.) which was dried in vacuo. 1H NMR (400 MHz, DMSO-d6) δ11.498 (bs, 1H), 7.405-7.380 (m, 4H), 7.327-7.285 (m, 1H), 7.258-7.221 (m, 2H), 7.168-7.128 (m, 1H), 7.090 (d, 2H, J=7.5 Hz), 6.970 (d, 1H, J=8 Hz), 6.890 (d, 1H, J=8 Hz), 6.821 (s, 1H), 3.600 (d, 1H, J=11 Hz), 3.505 (d, 1H, J=11 Hz), 3.250 (d, 1H, J=17 Hz), 3.176 (d, 1H, J=17), 2.619-2.564 (m, 1H), 2.235-2.168 (m, 9H).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>C1C=CC=CC=1>[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][N:18]([C:2]([Cl:1])=[O:4])[CH2:17][CH2:16]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CN(C)C1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
Triphosgene (1.78 g, 6 mmol) was dissolved in benzene (120 ml), followed by the addition of a solution of 4-dimethylaminopiperidine (1.96 g, 15.3 mmol) in benzene and triethylamine (1.82 g, 18 mmol). The resulting mixture was stirred overnight at room temperature. Chloroform was added to the reaction mixture, and the resulting mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was then purified by chromatography on a silica gel (chloroform-acetone mixed solvent [1:2]), whereby 4-dimethylaminopiperidinocarbonyl chloride (465 mg, 16%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH3:15]CN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[CH3:15][O:13][C:12](=[O:14])[CH2:11][O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)COCCc1cccc(F)c1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)COCCc1cccc(F)c1
Yield: 92.6 %

Procedure:
A solution of [2-(3-fluoro-phenyl)-ethoxy]-acetic acid (1.20 g, 6.05 mmol), EDCI (1.28 g, 6.66 mmol), HOBt (0.90 g, 6.66 mmol) and DIPEA (1.56 ml, 9.08 mmol) in methanol (4 ml) was stirred at 0° C. for 2 hours. The reaction mixture was brought to dryness, dissolved in CH2Cl2 and washed twice with 1M NaOH and brine. The organic layers were dried over MgSO4, filtrated, the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/heptane, 1/4) to yield [2-(3-fluoro-phenyl)-ethoxy]-acetic acid methyl ester (1.20 g, 5.6 mmol; 93%) as colorless liquid. MS (m/e): 213.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C1([PH2](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:31]([CH2:38][C:39](=[O:41])[CH3:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:40][C:39](=[O:41])[CH2:38][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)COc1ccccc1
Agent: c1ccc([PH2](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C=CC(=O)COc2ccccc2)ccc1O
Reaction time: 3 h
Yield: 76.5 %

Procedure:
4-Hydroxy-3-methoxybenzaldehyde (2.1 g, 13.8 mMol) and 3-phenoxypropane-2-one triphenylphosphorane (2.8 g, 6.9 mMol) (prepared as described by LeCorre: C. R. Acad. Sci. Paris, 273 81 (1971)) are dissolved in 100 ml of toluene and warmed to reflux. After three hours, the solvent is evaporated and the residue is taken up in tHF. Sodium bisulfite (10.0 g) is dissolved in 100 ml of water and stirred with the solution for one hour. The THF is evaporated and the water is extracted with chloroform. Drying over magnesium sulfate and evaporation of the chloroform gives a yellow oil. Flash chromatography in ethyl acetate on silica gel gives 1.5 g (65%) of 1-(4'-hydroxy,3'-methoxyphenyl)-4-phenoxy-1-butene-3-one; mp=85°-87° C. C, H analysis Calcd for C17H16O4 (71.81, 5.68); Found (71.85, 5.50).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=[CH:33][CH:32]=[CH:31][C:30]=1C.[Si:37](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)([CH3:39])[CH3:38].[Cl-].[NH4+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[N:5]([C:6]([O:8][SiH:37]([CH3:39])[CH3:38])=[O:7])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1cccc(C)n1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCCCN(C(=O)O[SiH](C)C)[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a dichloromethane solution (1.0 ml) of Nα-t-butoxycarbonyl-Nε-benzyloxycarbonyllysine methyl ester (191.0 mg, 0.48 mmol) were added 2.6-lutidine (113 μl, 0.97 mmol) and t-butyldimethylsilyltrifluoromethane sulfonate (167 μl, 0.73 mmol). The mixture was stirred for 15 minutes in an argon atmosphere at room temperature. After addition of a saturated aqueous solution of ammonium chloride, the reaction mixture was extracted with ether and the ether layer was dried over anhydrous magnesium sulfate and filtered. After removal of the solvent in vacuo, Nα-butyldimethylsilyloxycarbonyl-Nε-benzyloxycarbonyllysine methyl ester was obtained (238 mg; yield, 100%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:13].[C:14]([OH:18])(=[O:17])[CH:15]=O>C(#N)C.O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([OH:13])[CH2:12][CH:15]1[C:14]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(=O)O
Reactant: C=CCCNCc1ccccc1
Reactant: O
Solvent: CC#N
Product: O=C(O)C1CC(O)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
The product of step A (24.5 g, 0.15 mol) was dissolved in acetonitrile/water (1:1, 500 mL) and treated with glyoxylic acid monohydrate (15.3 g, 0.17 mol). The resulting solution was allowed to stir at ambient temperature for 12 h. The reaction mixture was concentrated in vacuo, made basic via addition of 1 M NaOH (500 mL) and extracted with dichloromethane (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford crude 1-benzyl-4-hydroxypiperidine-2-carboxylic acid (24 g, 69%) as a colorless oil which was used without further purification: 1H NMR (CDCl3, 400 MHz) δ 7.38-7.27 (m, 5H), 4.82 (t, J=5.2 Hz, 1H), 3.73-3.59 (m, 2H), 3.30 (d, J=4.8 Hz, 1H), 3.03 (dd, J=12.0, 6.4 Hz, 1H), 2.50-2.43 (m, 1H), 2.29-2.19 (m 1H), 2.08-1.98 (m, 1H), 1.97-1.88 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:39])(=[O:38])[C@@H:31]([C@H:33]([C:35]([OH:37])=[O:36])[OH:34])[OH:32]>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:35]([C@@H:33]([C@H:31]([C:30]([O-:39])=[O:38])[OH:32])[OH:34])([O-:37])=[O:36]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Sunitinib (2.15, 5.40 mmol) was suspended in methanol (100 ml). 0.81 g of L-tartaric acid was added. Mixture was heated until all material was dissolved, then left to cool to room temperature to form crystalline sunitinib L-tartrate, 2.1 g. Melting point: 189-193° C. (form II)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:27]([C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=1[C:6]([C:5]1[CH:9]=[C:10]([CH2:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:8])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCc1cc(C(=O)O)cc(CC)c1OC
Reactant: Cc1cc(Cc2ccccc2)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OC

Procedure:
The title compound was prepared according to the procedure in Example 1, step 4, using 3,5-diethyl-4-methoxybenzoic acid (10.66 g, 51.3 mmol), oxalyl chloride (4.90 mL, 56.3 mmol), N,N-DMF (2 drops), tin(IV) chloride (6.60 mL, 56.3 mmol) and 2-benzyl-4,5-dimethylfuran (11.4 g, 61.3 mmol) to give 22.0 g, of the title compound. 1H NMR δ1.13 (t, 6 H), 1.83 (s, 3 H), 2.19 (s, 3 H), 2.61 (q, 4 H), 3.74 (s, 3 H), 3.82 (s, 2 H), 7.05 (d, 2 H), 7.23-7.27 (m, 3 H), 7.42 (s, 2 H). mass spectrum (EI) m/z 376 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[C-:13]#[N:14].[K+].[Cl-].[NH4+:17]>C(O)C.O>[NH2:17][C:9]1([C:13]#[N:14])[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: O=C1CCc2cccc(Cl)c2C1
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CC1(N)CCc2cccc(Cl)c2C1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a vigorously stirred solution, maintained under nitrogen, containing 43 mmol of 8-chloro-3,4-dihydro-2(1H)-naphthalenone in 60 ml of ethanol and 30 ml of water are successively added 44 mmol of potassium cyanide and 44 mmol of ammonium chloride. After stirring for 20 hours at 20° C., the mixture is concentrated under vacuum and the residue is taken up in 80 ml of ethyl acetate. This organic phase is washed with water and is then extracted with 1N hydrochloric acid. The aqueous phase is basified with 35% sodium hydroxide and extracted with ethyl acetate. The expected product is obtained after drying and evaporation of the organic phase as a solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:15][CH2:16][CH2:17][NH2:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCO>[NH2:18][CH2:17][CH2:16][CH2:15][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: NCCCN1CCN(c2ccccc2)CC1
Yield: 56.3 %

Procedure:
4-Phenylpiperazine (5.00 g, 30.8 mmol, 1.00 equiv, Aldrich), 3-bromopropylamine hydrobromide (8.09 g, 37.0 mmol, 1.20 equiv) and potassium carbonate (8.51 g, 61.6 mmol, 2.00 equiv) were stirred in refluxing acetone (200 mL) and EtOH (40 mL) for 14 hours. After removal of the solvents, water (250 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH2Cl2 (4×250 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3—MeOH—NH3 (2 M in MeOH) 100:10:5 to 100:20:10) to give 3.80 g (56%) of yellow oil, which was characterized spectroscopically.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])=[N:6][CH:7]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc(N)nc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1

Procedure:
A mixture containing 5-methylpyridin-2-amine (5.4 g, 50 mmol), phthalic anhydride (8.88 g, 60 mmol) and DIEA (19 ml, 110 mmol) in toluene (30 ml) is refluxed for 18 hours, and cooled. The solvent is removed by rotary evaporation. The crude product is purified by silica gel flash chromatography to afford 2-(5-methylpyridin-2-yl)isoindoline-1,3-dione as a dark brown oil. LC-MS m/z: 239.1 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[CH:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17]>>[ClH:1].[ClH:1].[CH:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:2][CH:3]2[O:8][CH2:7][CH2:6][NH:5][CH2:4]2)[CH2:20][CH2:19]1)=[O:17]
Reactant: O=CN1CCNCC1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: Cl
Product: O=CN1CCN(CC2CNCCO2)CC1

Procedure:
By the use of 2-chloromethyl-4-benzylmorpholine and N-formylpiperazine, the reaction is similarly carried out as Reference example 2 to give 2-(4-formyl-1-piperazinylmethyl) morpholine.dihydrochloride as white crystals, melting at 243°-245° C. with decomposition.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:30])[CH3:29])[CH:23]=2)=[O:20])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:30][N:28]([CH3:29])[C:24]1[CH:23]=[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:16]([NH:15][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:36][CH:35]=3)[CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
Using an analogous procedure to that described in the last paragraph of the portion of Example 1 which is concerned with the preparation of starting materials, a mixture of 3-(4-benzyloxybenzamido)-N-(3-dimethylaminophenyl)4-methylbenzamide (0.227 g), 10% palladium-on-carbon (0.028 g), ammonium formate (0.37 g) and methanol (20 ml) was stirred and heated to reflux for 1.5 hours. The mixture was cooled to ambient temperature and filtered through diatomaceous earth. The filtrate was evaporated and the residue was triturated under water. The resultant solid was washed with a 100:1:0.12 mixture of methylene chloride, methanol and a saturated aqueous ammonium hydroxide solution and dried under vacuum at 55° C. There was thus obtained the title compound as a solid (0.104 g); NMR Spectrum: (DMSOd6) 2.26 (s, 3H), 2.84 (s, 6H), 6.44 (d, 1H), 6.84 (d, 2H), 7.13 (m, 3H), 7.39 (d, 1H), 7.76 (d, 1H), 7.86 (d, 2H), 7.92 (s, 1H), 9.73 (s, 1H), 9.91 (s, 1H); Mass Spectrum: M+H+ 391.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]([F:15])([F:14])[F:13])=O.[CH3:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20].C(O)(=O)C.N1CCCCC1>ClCCl>[C:19]([C:18]([C:17](=[O:22])[CH3:16])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]([F:15])([F:14])[F:13])(=[O:21])[CH3:20]
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)c(OC(F)(F)F)c1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc(C#N)cc1OC(F)(F)F)C(C)=O
Yield: 99.4 %

Procedure:
3.32 g (15.43 mmol) of 4-formyl-3-(trifluoromethoxy)benzonitrile, 1.55 g (15.43 mmol) of 2,4-pentanedione, 1.39 g of acetic acid (23.15 mmol) and 262 mg (3.09 mmol) of piperidine are dissolved in 150 ml of dichloromethane and heated under reflux with an inverse water trap overnight. After complete conversion has been detected by a TLC check, the mixture is diluted with 100 ml of dichloromethane and washed with water and saturated sodium chloride solution. The solvent is removed in a rotary evaporator. 4.56 g (99% of theory) of crude 4-(2-acetyl-3-oxobut-1-en-1-yl)-3-(trifluoromethoxy)benzonitrile are obtained and are reacted directly without further purification.
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][C:19](O)=[O:20].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[Cl:8][C:9]1[C:10]([CH2:18][CH2:19][OH:20])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1c(Cl)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(Cl)c1CCO
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
2.26 g (59.8 mmol) of sodium borohydride was added to 7 ml of tetrahydrofuran, and while cooling on ice, 15 ml of tetrahydrofuran solution containing 6.78 g (31.5 mmol) of the compound (137) obtained above was dropped to the solution through 20 minutes. Then, 15 ml of tetrahydrofuran solution containing 10 ml of borontrifluoride-ether complex was dropped to the solution through 10 minutes, and after stirring for 30 minutes as was, the solution was stirred for 1 hour at room temperature. To 130 ml of water containing 9.6 g of sodium hydrogen carbonate and 170 ml of methylene chloride, the reaction solution was added slowly, and the obtained solution was stirred overnight at room temperature. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, n-hexane was added to crystallize, and the crystals were filtered off and washed with n-hexane to obtain 5.43 g of the subject compound (138) in a 86% yield.
Reaction SMILES: CS(NC1C=CC=CC=1N1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:68])[C@H:39]([NH:48][C:49]([C@@H:51]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][N:52]2C(OC(C)(C)C)=O)=[O:50])[CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[CH2:34][CH2:33]1.N1C=CC=CC=1.[N+:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=1[CH2:84][S:85](Cl)(=[O:87])=[O:86])([O-:77])=[O:76].Cl>C(Cl)CCl.CCOC(C)=O>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C@@H:39]([NH:48][C:49]([C@@H:51]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][NH:52]2)=[O:50])[C:38]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][S:85]([CH2:84][C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][C:78]=3[N+:75]([O-:77])=[O:76])(=[O:86])=[O:87])[CH2:33][CH2:34]2)=[O:68])=[CH:46][CH:45]=1
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(=O)(=O)Cc2ccccc2[N+](=O)[O-])CC1)[C@@H]1Cc2ccccc2CN1
Yield: 6.3 %

Procedure:
Following the procedure for the synthesis of Preparation III, the title compound was prepared from tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperazinyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Preparation IX) (250 mg, 0.40 mmol) in ClCH2CH2Cl (1.5 mL), pyridine (0.040 mL, 0.44 mmol), and 2-nitro-α-toluenesulfonyl chloride (Aldrich) (104 mg, 0.44 mmol). The crude was treated with a soln of HCl satd EtOAc, which resulted in the precipitation of the salt. This material was collected by filtration, dried in vacuo, and recrystallized from MeOH to afford the product as the HCl salt (18 mg). MS (ESI, pos. ion) m/z: 717 (M+H). Calc'd for C36H37ClN6O4S: 716.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].[CH2:15]([Li])CCC.[Br-].[Na+].[F:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Cl)=[CH:25][CH:24]=1>C1COCC1>[CH3:4][C:2]([NH:5][C:6]([C:8]1[C:13]([CH2:14][CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=2)=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=1)=[O:7])([CH3:1])[CH3:3]
Reactant: [Li]CCCC
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: Fc1ccc(CCCl)cc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)NC(C)(C)C)c(CCCc2ccc(F)cc2)c1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
Cool a solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide in dry THF to -40° C. and add 2 equivalents of n-butyl lithium. Add a large excess of sodium bromide and stir for 15 minutes. Add 1 eq. of 4-fluorophenethyl chloride and stir for 2.5 hours while warming to -5° C. Quench the reaction with water and extract the product twice with ethyl acetate, then wash with brine (2X). Dry the organic phase over Na2SO4, filter and remove the solvent to produce the title compound.