Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:22])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC1(c2ccccn2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: [O-][n+]1ccccc1C1(O)CCOCC1

Procedure:
To a stirred solution of 2-(4-hydroxytetrahydropyran-4-yl)pyridine (2.08 g, 11.6 mmol) in dichloromethane (100 mL) was added, with stirring, m-CPBA (77%, 2.86 g, 12.76 mmol) and the mixture stirred at ambient temperature overnight. After this time, potassium carbonate (1.62 g, 11.60 mmol) was added, the reaction stirred for two hours and the mixture filtered. A further aliquot of potassium carbonate (1.62 g, 11.60 mmol) was added to the filtrate and the mixture again stirred for two hours. After filtration and concentration in vacuo, the N-oxide was obtained as a pale brown solid (2.28 g, quant.) and used without further purification; NMR δH (400 MHz, DMSO) 8.33 (1H, dd, J 6.3 Hz, 1.1 Hz), 7.65 (1H, dd, J 8.0 Hz, 2.0 Hz), 7.52 (1H, td, J 7.9 Hz, 1.3 Hz), 7.44 (1H, td, J 7.6 Hz, 2.0 Hz), 7.32 (1H, br s), 3.78 (4H, m), 2.23 (2H, td, J 12.5 Hz, 5.1 Hz), 1.80 (1H, d, J 11.4 Hz); LC-MS Retention time 0.99 min, (M+H)+ 196.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1OC.Cl.C1(=O)C2C(=CC=CC=2)CC1>>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:13]2[CH2:14][C:5]3[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=3)[C:11]2=[O:12])=[CH:17][CH:18]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Agent: Cl
Agent: O=C1CCc2ccccc21
Product: O=C1c2ccccc2CC1Cc1ccncc1

Procedure:
U.S. Pat. No. 6,252,081 teaches the preparation of Donepezil HCl by the reaction of 1-indanone derivative with carbonate ester. The resulting 2-alkoxycarbonyl-1-indanone derivative is halogenated with (4-pyridyl)methyl or a salt thereof and decarboxylated successively to give 2-(4-pyridyl)methyl-1-indanone derivative. On reacting the 2-(4-pyridyl)methyl-1-indanone derivative with benzyl bromide, their quarternary ammonium salts are formed, which on reduction with platinum oxide catalyst gives Donepezil HCl (Examples 1 to 3). Overall yield of Donepezil HCl 82% (98%×85%×100%×99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15]Br)=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[OH-].[NH4+:26]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:26])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CBr
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.1 g, 0.255 mmol) in ethanol (2 ml) containing concentrated aqueous ammonium hydroxide solution (2 ml) was stirred at room temperature for four hours. The solvent was evaporated and the residue treated with ethanolic hydrochloric acid (2 ml) with heating. Crystallization was induced by addition of diethyl ether, giving 0.07 g of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran as a hydrochloride salt, m.p. 231° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=O)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCl.CO>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:32][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]
Reactant: O=Cc1cnc(CO)c(Cl)c1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cnc(CO)c(Cl)c4)CC3)c2c1
Reaction time: 3 h
Yield: 29.7 %

Procedure:
1-[2-(4-amino-1-piperidinyl)ethyl]-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (Intermediate 29: 100 mg, 0.331 mmol) was dissolved in a mixture of Dichloromethane (DCM) (4 mL) and Methanol (0.444 mL). Aldehyde 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 56.7 mg, 0.331 mmol) was added and the mixture was left at room temp. for 3 hours. Then sodium triacetoxy borohydride (210 mg, 0.992 mmol) was added and after 2 hours 2 more eq. of triacetoxy borohydride were added leaving the reaction under stirring overnight. LCMS overnight showed still imine remaining so 3 eq more of sodium triacetoxy borohydride were added and 2 eq more after 3 hours leaving the reaction overnight. Next morning 2 more eq. of sodium triacetoxy borohydride were added and after 3H reaction was stopped. Volatiles were removed under vacuum and the corresponding crude was diluted with DCM and washed with NaHCO3 several times. Organic layers were dried over Na2SO4, filtered and volatiles removed under vacuum. Corresponding crude was purified by flash master chromatography. Si II, 5 g. DCM/MeOH (0-30%), to obtain a solid which was left in the oven overnight to afford 45 mg of the final compound as a pale yellow solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:74][CH:75]([CH3:77])[CH3:76])[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C@@H:18]([CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:54]([C:55]#[N:56])=[C:53]([S:57][CH2:58][C:59]3[N:60]=[C:61]([C:64]4[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=4)[O:62][CH:63]=3)[N:52]=[C:51]([NH2:71])[C:50]=2[C:72]#[N:73])=[CH:45][CH:44]=1)[CH2:19][O:20][C:21](=[O:40])[CH2:22][CH2:23][NH:24][C:25](=[O:39])[C@H:26]([CH2:35][CH:36]([CH3:38])[CH3:37])[NH:27]C(=O)OC(C)(C)C)=[O:16])=[O:11])=O)(C)(C)C.[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81]>ClCCl>[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[NH2:27][C@@H:26]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:25]([NH:24][CH2:23][CH2:22][C:21]([O:20][CH2:19][C@@H:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:74][CH:75]([CH3:77])[CH3:76])[CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:54]([C:55]#[N:56])=[C:53]([S:57][CH2:58][C:59]3[N:60]=[C:61]([C:64]4[CH:65]=[CH:66][C:67]([Cl:70])=[CH:68][CH:69]=4)[O:62][CH:63]=3)[N:52]=[C:51]([NH2:71])[C:50]=2[C:72]#[N:73])=[CH:45][CH:44]=1)=[O:40])=[O:39]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An amount of 85 mg (0.077 mmol) of the compound from example 33A was introduced in 0.5 ml of dichloromethane, admixed with 0.059 ml (0.771 mmol) of trifluoroacetic acid and stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 47 mg (51% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:3]1[C:2]([CH3:1])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1ccc(F)cc1OCc1ccccc1
Yield: 70 %

Procedure:
A mixture of methyl 3-methyl-5-nitro-2-trifluoromethylsulfonyloxybenzoate (Reference Compound No. 1-4-(3), 13.26 g, 38.6 mmol), 2-benzyloxy-4-fluorophenylboronic acid (14.3 g, 58.1 mmol), potassium phosphate (21.3 g, 100 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.23 g, 2.80 mmol) was suspended in anhydrous 1,4-dioxane (200 mL), and then the mixture was refluxed for 3 days. After cooling down, ethyl acetate (500 mL) was added thereto, and then the whole was washed with water (500 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (10.7 g) as a pale brown solid. (Yield 70%)
Reaction SMILES: [CH2:1]([N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[O:9])[CH:6](Cl)[Cl:7])[CH:2]=[CH2:3].COCCOCCOC.N1CCCC1=O.C(Cl)[Cl:33]>>[CH2:10]([N:4]1[CH2:1][CH:2]([CH2:3][Cl:33])[CH:6]([Cl:7])[C:5]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCCl
Reactant: C=CCN(Cc1ccccc1)C(=O)C(Cl)Cl
Agent: O=C1CCCN1
Solvent: COCCOCCOC
Product: O=C1C(Cl)C(CCl)CN1Cc1ccccc1

Procedure:
Eleven and one-tenth grams of N-allyl-N-benzyl dichloroacetamide was dissolved in 12 ml. of diglyme and 1 g. of anhydrous ferrous chloride added. The mixture was heated at reflux under nitrogen until conversion to the pyrrolidinone was complete as indicated by GLPC. The mixture was diluted with methylene chloride, washed with 5 per cent hydrochloric acid, separated, dried over anhydrous magnesium sulfate, treated with activated carbon and Florisil and stripped under vacuum. Yield was 6 g. of the title compound, nD30 1.5387.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:35]=[C:36]=[O:37])[CH2:32][CH2:33][CH3:34]>C(#N)C>[CH2:31]([NH:35][C:36]([NH:14][S:11]([C:10]1[N:9]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:12])=[O:37])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCN=C=O
Reactant: CCOC(=O)c1cnn(-c2ccc3ccccc3n2)c1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNC(=O)NS(=O)(=O)c1c(C(=O)OCC)cnn1-c1ccc2ccccc2n1
Yield: 90.7 %

Procedure:
To a mixture of 6 g of 4-ethoxycarbonyl-1-(2-quinolyl)pyrazole-5-sulfonamide and 3.6 g of anhydrous potassium carbonate dissolved in 40 ml of acetonitrile, was added 1.9 g of n-butylisocyanate at room temperature, followed by heating under reflux for 1.5 hours. After the reaction was completed, acetonitrile was evaporated under reduced pressure, and then the residue was poured into ice water to filter insolubles off, and then the filtrate was precipitated with hydrochloric acid. Crystals precipitated were filtered, washed with water and dried to obtain 7 g of N-(n-butylcarbamoyl)-4-ethoxycarbonyl-1-(2-quinolyl)pyrazole-5-sulfonamide. m.p: 140° to 142° C.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.CN1C(=O)CCC1.Cl[C:14]1[CH:21]=[C:20]([CH3:22])[C:17]([C:18]#[N:19])=[C:16]([O:23][CH3:24])[N:15]=1.C([Mg]Br)CC.Cl>C(OC(=O)C)C>[CH3:24][O:23][C:16]1[N:15]=[C:14]([CH2:2][CH2:1][CH3:5])[CH:21]=[C:20]([CH3:22])[C:17]=1[C:18]#[N:19]
Reactant: COc1nc(Cl)cc(C)c1C#N
Reactant: C1CCOC1
Agent: CCC[Mg]Br
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCc1cc(C)c(C#N)c(OC)n1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A transparent red-colored THF/NMP(50 mL/5 mL) solution of 6-chloro-2-methoxy-4-methyl-nicotinonitrile (2.00 g, 11.0 mmol) and Fe (acac)3 (387 mg, 1.1 mmol) was slowly added with 11 mL of n-propylmagnesium bromide (2M solution in diethyl ether) and then stirred for about 20 minutes. The mixture was then added with 10 mL of 1M HCl solution 10 mL and diluted with 300 mL of ethylacetate. The resulting organic layer was washed with water and a saturated solution of sodium chloride, dried with anhydrous sodium sulfate and then filtered. A silica gel column chromatography (10% EtOAc/Hexane) was performed on the residue obtained by concentrating the above filtrate under reduced pressure and obtained 2.23 g (88%) of 2-methoxy4-methyl-6-propyl-nicotinonitrile in colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][N:15]2[C:27](=[O:44])[CH:28]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C=C)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH:28]([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[C:27](=[O:44])[N:15]1[CH:14]([CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CCOC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)N2
Yield: 96.3 %

Procedure:
To a solution of 1-{[1-(2-tert-butoxycarbonylamino-non-8-enoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester (1.63 g, 2.56 mmoL) in 640 mL of methylene chloride was added 215 mg (0.26 mmoL) of tricyclohexylphosphine[1,3-bis(2,4,6-tri[benzylidene]ruthenium(IV)dichloride. The mixture was heated at reflux for 15 min. The residue was concentrated in vacuo, and then purified by flash chromatography eluting with 30% ethyl acetate/hexane. To further decolorize the sample, the crude product was chromatographed a second time eluting with 50% ether in hexane to give 1.5 g (96%) of 14-tert-butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester as a white solid. 1H NMR (500 MHz, CD3Cl) δ 0.06 (s, 3 H), 0.07 (s, 3H), 0.86 (s, 9H), 1.18-1.24 (m, 6H), 1.34-1.64 (m, 14H), 1.86-1.96 (m, 3H), 2.02-2.09 (m, 1H), 2.11-2.17 (m, 1H), 2.19-2.28 (m, 1H), 2.57-2.63 (m, 1 H), 3.50-3.54 (m, 1H), 3.71 (dd, J=10.22, 6.26 Hz, 1H), 4.06-4.17 (m, 2H), 4.52-4.58 (m, 2H), 4.75 (d, J=8.55 Hz, 1H), 5.21 (t, J=9.92 Hz, 1H), 5.35 (d, J=7.63 Hz, 1H), 5.45-5.50 (m, 1H), 6.94 (s, 1H); MS m/z 608 (M++1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[N:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]2[N:31]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[CH:24]=2)=[CH:11]1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.Cl>CC#N>[CH3:22][O:21][C:15]1[N:14]=[C:13]2[C:12]([C:23]3[N:31]([S:32]([C:35]4[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=4)(=[O:33])=[O:34])[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[CH:24]=3)=[CH:11][N:10]([CH2:9][CH2:8][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)[C:18]2=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCN(C)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
Add K2CO3 (1.1 equiv., 13.2 mg, 0.095 mmol) to bisazaindole iodide 18 (52 mg, 0.0862 mmol) in CH3CN (6.0 mL) at 60° C., then add 1-methylpiperazine (1.10 equiv., 9.515 mg, 10.55 μL, 0.095 mmol). After stirring for 2 h at 60° C., add extra K2CO3 (13.2 mg) and 1-methylpiperazine (21 μL) and continue stirring at 60° C. for 30 h. The reaction mixture is then concentrated to give a residue, which is treated with 2N HCl and washed with CH2Cl2. The aqueous phase is then treated with 2N NaOH until pH>10 and extracted with CH2Cl2, dried (MgSO4) and concentrated under vacuum, to give 21 (10 mg, 20.2%) as an ivory-colored solid: 1H NMR (CDCl3) δ 8.35 (dd, 1H, J=4.4, 1.1 Hz), 7.72 (dd, 1H, J=4.4, 1.1 Hz), 7.67 (d, 2H, J=8.4 Hz), 7.60 (s, 1H), 7.15 (m, 2H), 7.03 (d, 2H, J=8.4 Hz), 6.98 (s, 1H), 5.28 (s, 3H), 4.26 (t, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 2.86 (t, 2H), 2.55 (m broad, 8H), 2.30 (s, 3H). TLC (MeOH at 10%/CH2Cl2, 0.25% of NH3) Rf=0.35, m/z obs.=575 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10]O2)=[CH:4][CH:3]=1.NC(N)=[S:13].O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][S:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2CO2)cc1
Reactant: NC(N)=S
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(C2CS2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-(4-fluoro-phenyl)-oxirane (1.38 g, 10.0 mmol), thiourea (760 mg, 10.0 mmol) and silica gel (200 mg) in CH2Cl2 (10 mL) was stirred at room temperature for 12 hours. Water (20 mL) was added to the suspension and the mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide the title product.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[C:7]([O:6][C:4]([C:3]1[C:2]([NH:1][C:48](=[O:49])[C:47]2[CH:51]=[C:43]([CH2:42][C:36]3[C:37](=[O:41])[C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[C:34](=[O:57])[C:35]=3[CH3:56])[CH:44]=[CH:45][C:46]=2[O:52][C:53](=[O:55])[CH3:54])=[N:14][CH:13]=[CH:12][CH:11]=1)=[O:5])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)c1cccnc1N
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ncccc3C(=O)OC(C)(C)C)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 53.3 %

Procedure:
tert-Butyl 2-aminonicotinate (0.311 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=15:1) to obtain the titled compound (0.157 g, 0.285 mmol, 53%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1CCCCC1=O.O>C(OCC)(=O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: CN1CCCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Yield: 86.9 %

Procedure:
21.5 g 2,5-difluoro-nitrobenzene, 52.3 g 1-benzyl-4-amino-piperidine and 100 ml N-methyl-piperidone were stirred at 100° C. for 3 h. After cooling the mixture was treated distributed between water and ethyl acetate and the aqeous layer was extracted 2× with ethyl acteate. The combined organic layers were extracted 5× with water, and the solvent was removed by evaporation. The target compound was crystallized from methanol to yield 38.7 g orange crystals (mp. 86–87° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:22]([C:21]([F:20])([F:35])[F:36])[CH:23]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)CNc1cnccc1-c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC(F)(F)F)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (138 mg, 63%). MS (ESI): m/z=527.057 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[I:36]>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[CH:28][C:27]=3[I:36])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (400 mg, 1.28 mmol) was treated with NaH (60% in oil, 128 mg, 3.2 mmol) and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (Example 70, 466 mg, 1.28 mmol) as described in Example 66 to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.06 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 7.82 (s, 2H), 7.61 (s, 1H), 7.33 (dd, J=8.2, 1.4 Hz, 1H), 5.79 (d, J=7.8 hz, 1H), 4.91 (d, J=16 Hz, 1H), 4.40 (d, J=16 Hz, 1H), 4.16-4.06 (m, 1H), 0.83 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.[CH:18](=[O:20])[CH3:19]>>[CH3:19][CH:18]([C:5]1[N:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)[OH:20]
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Reactant: CC=O
Product: CC(C)Cn1c(C(C)O)nc2cnc3ccccc3c21

Procedure:
Using the general method of Example 45, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (20 g; 89 mmol) was reacted with acetaldehyde to provide the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.