Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:10]([S:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)/[CH3:28])[CH:26]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 50.6 %

Procedure:
4-(morpholinosulfonyl)benzohydrazide (100 mg, 0.350 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (59.8 mg, 0.350 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-4-(morpholinosulfonyl)benzohydrazide (80 mg, 0.177 mmol, 50.6% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (m, 2H), 7.89 (m, 2H), 7.67 (d, 1H, J=2.4 Hz), 7.35 (dd, 1H, J=2.4 & 8.8 Hz), 6.95 (d, 1H, J=8.4 Hz), 3.64 (m, 4H), 2.92 (m, 4H), 2.49 (s, 3H). Mass [M+H]+: 438.0
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=[CH:8][N:7]=1)=[O:5])C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.Cl>C1COCC1>[CH2:15]([O:14][C:12]([C:11]1[C:6]([C:4]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:5])=[N:7][CH:8]=[N:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1cncnc1C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cncnc1C(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a THF solution(30 ml) of pyrimidine-4,5-dicarboxylic acid diethyl ester(1.46 g,6.52 mmol) which was prepared by the method described in the literature(Chem. Pharm. Bull.,1972,20,1513-1521) was added a THF solution of 4-methoxyphenyl magnesium bromide (1.25M,5.47 ml) dropwise at -78° C. The reaction solution was stirred at -78° C. for 30 min, treated with 1N HCl and extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent under reduced pressure the residue was purified by silica gel column chromatography(E. Merck Kieselgel 60/chloroform) to give 4-(4-methoxyphenylcarbonyl)pyrimidine-5-carboxylic acid ethyl ester(1.57 g) as a pale yellow oil.
Reaction SMILES: C1C=CC(C([S+]([O-])CC(N)=[O:17])C2C=CC=CC=2)=CC=1.[CH:20]([S:33][C:34]([OH:36])=[O:35])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:20]([S@@:33]([C:34]([OH:36])=[O:35])=[O:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)C[S+]([O-])C(c1ccccc1)c1ccccc1
Reactant: O=C(O)SC(c1ccccc1)c1ccccc1
Product: O=C(O)[S@@](=O)C(c1ccccc1)c1ccccc1

Procedure:
In another aspect, a method of preparing an (+)-(S)-enantiomer of modafinil is disclosed. The method includes subjecting benzhydrylsulfanyl carboxylic acid to an oxidation reaction using Beauveria bassiana to obtain (S)-benzhydrylsulfinyl carboxylic acid and subjecting the (S)-benzhydrylsulfinyl carboxylic acid to an amidation reaction using Bacillus subtilis to obtain (+)-(S)-modafinil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.[SH:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:31][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[S:25][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1SCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (193 mg, 0.61 mmol) and 2-mercapto-1-methylimidazole (80 mg, 0.7 mmol) in dry DMF (2 mL) was treated with K2CO3 (97 mg, 0.7 mmol). The mixture was stirred at rt for 2 h, and then it was poured into ice-water. The mixture were extracted with EtOAc and the extract was washed with water and brine, dried over anhydrous MgSO4, and evaporated to yield the crude product, which was crystallized from EtOAc-hexane to give the title compound as colorless rods (142 mg); mp 155-160° C.; 1H NMR (CDCl3) 7.36 (s, 1H), 7.27 (s, 1H), 7.17 (d, J=7.7, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 6.95 (d, J=7.7, 1H), 6.91 (s,13H), 6.14 (s, 2H), 6.07 (s, 2H), 4.53 (s, 2H), 3,51 (s, 3H). Anal. calcd. for C21H16N4O4S: C, 59.99; H 3.84; N 13.33. Found: C, 59.78; H 3.82; N 13.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=[O:12])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C1C=CC=CC=1.II>C(O)(=O)C.C(O)C.CCOCC>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:9]([OH:12])[C:8]=1[CH3:13]
Reactant: COC(=O)CBr
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Agent: II
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)CC1=C(C)C(O)c2cc(OC)ccc21
Reaction time: 3 h

Procedure:
A solution of 13.4 g. of 6-methoxy-2-methylindanone and 19.3 g. of methyl bromoacetate in 45 ml. benzene is added over a period of 5 minutes to 21 g. of zinc amalgam (prepared according to Org. Syn. Coll., vol. 3) in 110 ml. benzene and 40 ml. dry ether. A few crystals of iodine are added to start the reaction, and the reaction mixture is maintained at reflux temperature (ca. 65°) with external heating. At three hour intervals, two batches of 10 g. zinc amalgam and 10 g. bromoester are added, and the mixture is then refluxed for eight hours. After addition of 30 ml. ethanol and 150 ml. of acetic acid, the mixture is poured into 700 ml. of 1:1 aqueous acetic acid. The organic layer is separated, and the aqueous layer is extracted twice with ether. The combined organic layers are washed thoroughly with water, ammonium hydroxide and water. Drying over sodium sulfate, evaporation of solvent in vacuo followed by pumping at 80° (bath temp.) (1-2 mm.) gives crude methyl(1-hydroxy-2-methyl-6-methoxy-indenyl)acetate.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:7][CH:6]2[CH2:20][CH:4]1[C:5]2([CH3:22])[CH3:21].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[O:19]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[CH:8]1[CH2:7][CH:6]2[CH2:20][CH:4]([C:5]2([CH3:21])[CH3:22])[CH:3]1[CH:2]=[O:1]
Reactant: CC1(C)C2CC(N3C(=O)c4ccccc4C3=O)C(CO)C1C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)C2CC(N3C(=O)c4ccccc4C3=O)C(C=O)C1C2
Yield: 61 %

Procedure:
rac-2-[2-(Hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-1H-isoindole-1,3(2H)-dione (750 mg, 2.51 mmol), silica gel (0.75 g) and pyridinium chlorochromate (1.08 g, 5.01 mmol) were stirred in dichloromethane (20 mL) at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was evaporated. The resulting residue was purified by column chromatography (hexane/ethyl acetate=5/1→3/1) to give the desired product (61% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>CCCCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.6 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (3.0 g, 15 mmol) and DIEA (2.4 g, 18.5 mmol) in n-BuOH (30 ml) was slowly added 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16.2 mmol) at 25° C. The resulting solution was stirred at 25° C. for 5 minutes and concentrated to dryness to give the title compound (3.1 g). NMR (CDCl3) 0.80 (m, 2H), 1.05 (m, 2H), 6.60 (s, 1H), 9.20 (s, 1H), 9.70 (br s, 1H), 10.40 (br s, 1H).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8].[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:10][CH3:11]>>[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28][N:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8])[CH2:10][CH3:11]
Reactant: O=C1COCC(=O)N1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)COCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
4-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)morpholine-3,5-dione was prepared as for Example 10 from morpholine-3,5-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH:33]=O)[CH:23]=1)[CH2:20][CH3:21]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][NH:18][CH2:33][C:24]3[CH:23]=[C:22]([CH2:19][CH2:20][CH3:21])[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=3)[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: CCCc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1-c1ccccc1
Yield: 78.6 %

Procedure:
Compound 51 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([CH2:11][OH:12])[O:6][CH:7]2[OH:10])[O:3]1.C(N(CC)CC)C.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([CH2:11][O:12][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:6][CH:7]2[OH:10])[O:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)OC(O)[C@@H]2O1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2,3-O-Isopropylidene-D-ribofuranose (20 g, 105.2 mmol) was dissolved in dichloromethane (200 mL) at 0° C. Triethylamine (10.9 g, 107.5 mmol) and a catalytic. amount of pyridine were added to the reaction mixture, followed by the addition of trityl chloride (27.8 g, 0.1 mol). The mixture was stirred at 0° C. for 3 h and further 12 h at room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate (80 mL) and the phases were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvents were removed in vacuo. The crude product was used without further purification in the next step.
Reaction SMILES: [I:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:3]1[C:2]([I:1])=[CH:7][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][N:4]=1
Reactant: CS(=O)(=O)c1c[nH]c(=O)c(I)c1
Reactant: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1cnc(Cl)c(I)c1

Procedure:
A suspension of 9.0 g of 3-iodo-5-(methylsulfonyl)-2(1H)-pyridinone in 30 ml of phosphorus oxychloride was refluxed under nitrogen for 4 hours and gave a homogeneous mixture. This solidified on cooling and unreacted phosphorus oxychloride was removed under reduced pressure. The resulting white solid residue was dissolved in methylene chloride and extracted first with water and twice with aqueous 1N sodium hydroxide solution. The mixture was shaken until the aqueous phase remained basic. The methylene chloride solution was then dried over magnesium sulfate and concentrated to leave a white solid residue. This was recrystallized from ethyl acetate/hexane to give 2-chloro-3-iodo-5-(methylsulfonyl)pyridine as colorless needles melting at about 178.5°-180.5° C.
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[CH:7]2[CH2:8][CH:4]([CH:5]=[CH:6]2)[C:3]1([C:11]#[N:12])[C:9]#[N:10].[H][H]>C(OCC)(=O)C.[Pt]>[Cl:1][C:2]1([Cl:13])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]1([C:11]#[N:12])[C:9]#[N:10]
Reactant: [H][H]
Reactant: N#CC1(C#N)C2C=CC(C2)C1(Cl)Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Product: N#CC1(C#N)C2CCC(C2)C1(Cl)Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
30 g (0.14 mol) of the (IV) prepared in Example 1 are dissolved in 170 ml of ethyl acetate, the solution is introduced into an autoclave, and 2 g of 1% strength platinum on carbon are added. The mixture is warmed to 40° C., and hydrogen is forced in until a pressure of 10 bar is reached. After approx. 2 hours, the reaction is complete. The catalyst is filtered off and the solvent is evaporated. 30 g (99%) of 3,3-dichlorobicyclo[2,2,1]heptane-2,2-dicarbonitrile, m.p. 148° C., are obtained.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([N+:18]([O-:20])=[O:19])=[C:13]([CH3:21])[N:12]=1.CCN(C(C)C)C(C)C>CCCCO.CCCCCC>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[C:14]([N+:18]([O-:20])=[O:19])=[C:13]([CH3:21])[N:12]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCCCCC
Product: Cc1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
A solution of 5-cyclopropyl-1H-pyrazol-3-amine (1.8 g, 14.0 mmol) in n-BuOH (25 ml) was slowly added to the n-BuOH (60 ml) solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (3.0 g, 14.0 mmol) and DIEA (2.4 g, 19.0 mmol). After 5 minutes, the reaction was diluted with hexane (100 ml). The resulting precipitate was collected by filtration to yield the title compound (4.1 g, 96%). MS: Calcd.: 294; Found: [M+H]+ 295.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[OH:12].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:12][CH2:22][O:23][CH3:24])=[CH:4][C:5]=1[CH:9]([CH3:10])[CH3:11]
Reactant: COCCl
Reactant: CC(C)c1cc(O)c(Br)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C(C)C)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of 2,4-dibromo-5-isopropylphenol (512 g, 1.74 mol) in chloroform (1.74 L), N,N-diisopropylethylamine (364 mL, 2.09 mol) was added, and cooled on ice. Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 60 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled on ice, and a 1M aqueous solution of sodium hydroxide (1.5 L) was added dropwise to separate the organic layer. The organic layer was washed with a 1M aqueous solution of sodium hydroxide (1.5 L) and water (1.5 L), and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. The resulting residue was purified by distillation under reduced pressure (0.93 to 1.5 hpa, 122° C. to 137° C.) to give 1,5-dibromo-2-isopropyl-4-(methoxymethoxy)benzene (548 g, 96%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([NH2:20])=O)[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15].N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]#[N:20])[N:6]2[CH2:13][C:14]([F:16])([F:17])[F:15]
Reactant: N#Cc1ccc2c(cc(C(N)=O)n2CC(F)(F)F)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc2c(cc(C#N)n2CC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.4 %

Procedure:
To a suspension of 4-chloro-5-cyano-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (0.05 g, 0.17 mmol) in CH2Cl2 (6 mL) was added pyridine (0.104 g, 1.32 mmol), followed by dropwise addition of TFAA (0.14 g, 0.66 mmol). The mixture was stirred at rt for 4 h and then concentrated in vacuo. The residue was partitioned between EtOAc and 0.5N HCl. The organic phase was washed with 0.5N HCl and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.033 g, 72% yield): MS (ES) m/z 284 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[C:13](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC.N1C2C(=CC=CC=2)C=C1>O.CN(C)C=O>[CH3:13][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1c[nH]c2ccccc12
Agent: [K+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Solvent: O
Product: Cn1cc(CC#N)c2ccccc21
Temperature: 124 °C
Reaction time: 10 h
Yield: 158.1 %

Procedure:
A 500 mL, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with indole-3-acetonitrile (10.0 g, 0.064 mol), potassium carbonate (5.0 g, 36 mmol), N,N-dimethylformamide (60 mL) and dimethyl carbonate (11.0 mL, 0.13 mol). The resulting mixture was heated to 124±1° C. The progress of the reaction was monitored by HPLC. After 10 h at this temperature, the presence of the starting indole could not be detected. The reaction mixture was then cooled to zero to −5° C. Water (140 mL) was added which resulted in the formation of a precipitate. The mixture was stirred at −5° C. for 1 hour, then the solid was collected by filtration, washed with water (150 mL), and dried under high vacuum at 45° C. for 24 h to give 1-methylindole-3-acetonitrile (I and II, 9.69 g, 89%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH:17]([CH2:19][CH2:20][CH2:21][CH2:22]CC)C)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25].C(O[N:34]=[C:35](C(CCCCCC)C)[C:36]1C=CC=CC=1)C1C=CC=CC=1>>[ClH:25].[CH2:1]([O:8]/[N:9]=[C:10](\[CH:17]1[CH2:19][CH:20]2[CH2:21][CH2:22][N:34]1[CH2:35][CH2:36]2)/[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)C(=NOCc1ccccc1)c1ccccc1
Agent: Cl
Product: c1ccc(CO/N=C(/c2ccccc2)C2CC3CCN2CC3)cc1

Procedure:
There are obtained 0.5 g of a fraction corresponding to (E)-1-azabicyclo[2.2.2.]oct-2-yl(phenyl)methanone O-benzyloxime and 2.25 g of another fraction corresponding to (Z)-1-azabicyclo[2.2.2.]oct-2-yl(phenyl)methanone O-benzyloxime hydrochloride
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.O.Cl>CO>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]=1
Reactant: O=C1CCNCC1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
To a solution of sodium (60 g , 2.6 mol) in 1000 ml of methanol was added 5-fluoroindole (49 g, 0.36 mol) and 4-piperidone.H2O.HCl (170 g, 1.11 mol). The mixture was heated under reflux for 18 h, then concentrated , water was added and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated. The resulting solid was dissolved in methanol (about 200 ml) and then diluted with water (about 1000-1500 ml). The precipitate was collected , washed with water and petroleum ether and then dried in a vacuum oven at 60° C. Yield 74 g (95%) of a yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:47]CC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[CH2:17][S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:13])=[C:7]([C:27]2[CH:32]=[C:31]([C:33](=[O:46])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[CH:30]=[CH:29][N:28]=2)[CH:6]=1)CC.CNC>CS(C)=O>[CH3:47][N:4]([CH3:1])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[CH2:17][S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:13])=[C:7]([C:27]2[CH:32]=[C:31]([C:33](=[O:46])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[CH:30]=[CH:29][N:28]=2)[CH:6]=1
Reactant: CCCN(CCC)c1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CNC
Solvent: CS(C)=O
Product: CN(C)c1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-(Dipropylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid Example 19, using dimethylamine in place of dipropylamine. (ES, m/z): 637 [M+H]+(300 MHz, DMSO, ppm): 12.10 (s, 1H), 9.53 (t, J=6.0 Hz, 1H), 8.97 (d, J=5.1 Hz, 1H), 8.33 (s, 1H), 8.26 (d, J=8.7 Hz, 1H), 7.85-7.87 (m, 2H), 7.72-7.77 (m, 2H), 7.45-7.69 (m, 5H), 7.35 (s, 1H), 7.09 (d, J=7.8 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 3.87 (s, 2H), 3.04 (s, 6H), 2.53-2.64 (m, 4H).
Reaction SMILES: COC1C=CC(C[N:10]2[CH2:14][C:13]3([CH2:19][CH2:18][CH2:17][C:16]([CH2:29][N:30]4[C:34]5[CH:35]=[C:36]([C:39]#[N:40])[CH:37]=[CH:38][C:33]=5[N:32]=[CH:31]4)([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:15]3)[O:12][C:11]2=[O:41])=CC=1.C(OCC)(=O)C.[OH-].[Na+]>C(#N)C>[O:41]=[C:11]1[NH:10][CH2:14][C:13]2([CH2:19][CH2:18][CH2:17][C:16]([CH2:29][N:30]3[C:34]4[CH:35]=[C:36]([C:39]#[N:40])[CH:37]=[CH:38][C:33]=4[N:32]=[CH:31]3)([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15]2)[O:12]1
Reactant: COc1ccc(CN2CC3(CCCC(COCc4ccccc4)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2ncn(CC3(COCc4ccccc4)CCCC4(CNC(=O)O4)C3)c2c1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a colorless solution of 1-[(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazole-6-carbonitrile (1.55 g, 2.81 mmol) in acetonitrile (28.1 mL) was added ceric ammonium nitrate (3.09 g, 5.63 mmol) and the mixture was stirred at room temperature. The reaction was then heated to 60° C. and stirred for 22 h. The reaction was then cooled to RT and the orange suspension was filtered using Buchner vacuum filtration. The solid was rinsed with MeCN (3×20 mL) and the filtrate concentrated to yield a glassy orange oil. Ethyl acetate (75 mL) and 2 N NaOH (50 mL) were then added. The mixture was filtered using Buchner vacuum filtration. The filtrate layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The concentrated organic layer was loaded onto florisil and purified using silica gel chromatography CISCO): 1-4% methanol/dichloromethane (25 min), 40 g silica. The product eluted at 11 minutes to yield 1-[(2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazole-6-carbonitrile as a orange foam (653 mg, 51% yield). MS (m/z) 431.0 (M+H+).