Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:16][SH:17])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[C:18]1(=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]1=[O:28]>>[O:28]=[C:19]1[C:20]2[S:17][CH2:16][C:2]3([CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:6][CH2:7]3)[O:1][C:21]=2[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]1=[O:29]
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NC1CCC(O)(CS)CC1
Product: CC(C)(C)OC(=O)NC1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
The crude tert-butyl [4-hydroxy-4-(mercaptomethyl)cyclohexyl]carbamate was reacted with naphthalene-1,2-dione as outlined in procedure G [both step (i) (ii) and (iii)] to afford crude tert-butyl (5′,6′-dioxo-5′,6′-dihydrospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiin]-4-yl)carbamate. The crude product was purified by flash column chromatography (SiO2, 100% dichloromethane) to afford the product as a purple solid. M.p.=224-225° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (dd, J=7.6 Hz, 0.8 Hz, 1H), 7.83 (d, J=6.8 Hz, 1H), 7.75 (td, J=7.6 Hz, 1.2 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.34 (br, 1H), 3.02 (s, 2H), 2.05 (d, J=10.8 Hz, 2H), 1.76-1.53 (m, 6H), 1.39 (s, 9H); LCMS: 416 [M+H].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CN(C=O)C.CC(O)=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(-c2ccncc2)c1
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: c1ccc(NCc2cccc(-c3ccncc3)c2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(pyridin-4-yl)benzaldehyde from Example 1 Step 1 (2 g, 10.9 mmol, 1 equiv) in DMF/AcOH (20/2 mL), aniline (1.02 g, 11.0 mmol, 1 equiv) and NaBH3CN (2.62 g, 41.6 mmol, 4 equiv). The resulting solution was stirred 2 h at 110° C. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 1:1 ethyl acetate/petroleum ether) to give N-(3-(pyridin-4-yl)benzyl)benzenamine as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[C:27]([O:36][CH3:37])=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:25][C:26]4[C:27]([O:36][CH3:37])=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: COc1nc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (161.4 mg, 0.50 mmol) and 3-(chloromethyl)-2-methoxy-6-(trifluoromethyl)pyridine (169 mg, 0.75 mmol) in anhydrous DMF (3.0 mL) at room temperature was added anhydrous K2CO3 (138 mg, 1.0 mmol). The resulting yellow suspension was stirred at 70° C. for 3 h. Analysis by HPLC/MS indicated that starting 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (20 mL×2). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of ethyl acetate (30-100%) in hexanes to afford 210 mg (82%) of the title compound as a yellow solid. HPLC/MS: retention time=3.11 min, [M+H]+=512.2.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[Br-].[Na+].CN1CCCC1=O.C([Br:22])C>O>[CH:1]([CH:3]([Br:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: CCBr
Agent: [Br-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CC(Br)c1ccccc1
Yield: 73 %

Procedure:
Vinylbenzyl chloride (50.60 g, 0.33 mol, 60:40 mixture of p,m isomers), sodium bromide (6.86 g, 6.67×10−2 mol), N-methylpyrrolidone (300 ml, passed through a short column of basic alumina), ethyl bromide (260 g), and 3-t-butyl-4-hydroxy-5-methyl phenyl sulfide (1.00 g, 2.79×10−3 mol) were combined in a 1 liter round bottomed flask fitted with a reflux condenser and a nitrogen inlet and the mixture was heated at reflux for 72 hours at which point the reaction was found to have proceeded to >95% conversion by gas chromatography. The reaction mixture was poured into 1 liter of water and extracted twice with 300 ml of diethyl ether. The combined ether layers were extracted twice with 1 liter of water, dried over MgSO4, and the solvents were stripped by rotary evaporation to yield yellowish oil. The crude product was purified by vacuum distillation to afford 47.5 g of product (53.1% yield).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1)(C(C)(C)C)(C)C.[Br:20]Br.C([O-])(O)=O.[Na+]>O1CCCC1>[Br:20][CH2:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][CH2:9][OH:8])[CH:12]=1)=[O:19]
Reactant: BrBr
Reactant: CC(=O)c1cccc(CCO[Si](C)(C)C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]ethanone (755 mg) in tetrahydrofuran (4 ml) was added bromine (168 ml) drop wise at 0° C. The mixture was stirred at 25° C. for 1 h. To the reaction mixture was added aq. saturated NaHCO3, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude of 2-bromo-1-[3-(2-hydroxyethyl)phenyl]ethanone as colorless oil. This compound was used for the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>O1CCOCC1>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]([O:18][CH3:19])=[C:2]([N:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)[CH:7]=1)([O:12][CH3:13])[CH3:9]
Reactant: COc1c(Br)cc(C(C)(OC)OC)cc1C(F)(F)F
Reactant: C1COCCN1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1c(N2CCOCC2)cc(C(C)(OC)OC)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1-Bromo-5-(1,1-dimethoxyethyl)-2-methoxy-3-trifluoromethylbenzene (O3.004; 700 mg) was initially charged in dioxane (7 ml) and admixed successively with Pd(II) acetate (46 mg), cesium carbonate (2 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (118 mg) and morpholine (0.27 ml). Thereafter, the reaction mixture was heated to 90° C. for 7 h and then left to stand overnight. Subsequently, it was filtered and the filtrate was concentrated by rotary evaporation. The residue was purified using silica gel (50 g cartridge, n-heptane/EA gradient). 433 mg of the title compound were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:6](N)[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CCOC(C)=O>[CH3:12][C:11]([O:10][C:8]([N:4]1[CH2:5][CH:6]([C:31](=[O:32])[C@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:2]([OH:1])[CH2:3]1)=[O:9])([CH3:14])[CH3:13]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)C1CN(C(=O)OC(C)(C)C)CC1O
Yield: 65.6 %

Procedure:
To a solution of 3-hydroxy-4-amino-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (202 mg, 1.14 mmol) in CH2CI2 (5 mL) was added CBZ-leucine (302.9 mg, 1.14 mmol), HOBT (154 mg, 1.14 mmol) and EDC (262.2 mg, 1.37 mmol). The reaction was allowed to stir until complete by TLC analysis whereupon it was diluted with EtOAc and washed sequentially with pH 4 buffer, sat. K2CO3, water and brine. The organic layer was dried (MgSO4), filtered and concentrated. Column chromatography of the residue (3:1 EtOAc:hexanes) gave 325 mg of the title compound: MS (ES+) 450.3 (MH+), 472.2 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]2[CH:17]=1.Cl.[H][H]>[Pt]=O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH:17]=1
Reactant: [H][H]
Reactant: Clc1ccc(-c2cn3ccccc3n2)c(Cl)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: Clc1ccc(-c2cn3c(n2)CCCC3)c(Cl)c1
Yield: 26.3 %

Procedure:
To 4.5 g (17.1 mmol) of the above 2-(2,4-dichlorophenyl)-imidazo[1,2-a]pyridine in a Paar bottle, 100 ml of ethanol, 1.5 ml of concentrated hydrochloric acid, and 0.4 g of platinum oxide were added. This mixture was placed on a Paar hydrogenator at 45 psi of hydrogen at room temperature for 15 minutes. Thin layer chromatography revealed that the reaction was complete. The mixture was filtered through celite and washed with 300 ml of ethyl acetate. To the filtrate, excess saturated aqueous sodium bicarbonate was slowly added. The ethyl acetate layer was separated, washed with saturated brine, and dried over magnesium sulfate. Evaporating the solvent in vacuo gave a solid residue to which n-butyl chloride was added. The solid was filtered, washed with n-butyl chloride, and dried to give 1.2 g of the title compound (m.p. 134-136° C.). The filtrate was also concentrated in vacuo to give a sludge which on silica gel chromatography (5:1 followed by 3:1 followed in turn by 1:1 hexane/ethyl acetate) afforded another 2.1 g of the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>O1CCCC1.O>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][C:10]([CH3:12])([CH3:11])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrCc1ccccc1Br
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1ccccc1Br
Reaction time: 0.5 h
Yield: 169 %

Procedure:
Lithium diisopropylamide (2M in hexane, 1.5 mL, 3.0 mmol) was added to a solution of ethyl isobutyrate (233 mg, 2.01 mmol) in tetrahydrofuran (1 mL) at −78° C. and the reaction mixture was stirred at this temperature for 30 min. Then, a solution of 2-bromobenzyl bromide (250 mg, 1.00 mmol) in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for another 1 hr and then at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate, and concentrated to give 482 mg of ethyl 3-(2-bromophenyl)-2,2-dimethylpropanoate as a yellow oil. The crude intermediate was used directly in the next step.
Reaction SMILES: CCCCC.C([Li])(C)(C)C.O1CCCC1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[N:26]=[C:25]([C:36]3[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=3)[N:24]=2)=[CH:19][CH:18]=1.Br[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:51]=2)=[CH:46][N:45]=1>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>[C:56]([C:53]1[CH:54]=[CH:55][C:50]([C:47]2[CH:48]=[CH:49][C:44]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[N:24]=[C:25]([C:36]5[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=5)[N:26]=[C:27]([C:29]5[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=5)[N:28]=4)=[CH:21][CH:22]=3)=[N:45][CH:46]=2)=[CH:51][CH:52]=1)([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)c1ccc(-c2ccc(Br)nc2)cc1
Reactant: Cc1cccc(-c2nc(-c3ccc(Br)cc3)nc(-c3cccc(C)c3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(-c3ccc(-c4ccc(-c5ccc(C(C)(C)C)cc5)cn4)cc3)nc(-c3cccc(C)c3)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Under a stream of argon, 5.3 ml of a pentane solution containing 7.8 mmol of tert-butyl lithium was slowly added to 25 ml of tetrahydrofuran cooled to −78° C., and 15 ml of tetrahydrofuran in which 1.13 g of 2-bromo-5-(4-tert-butylphenyl)pyridine had been dissolved was further added dropwise to this solution. After stirring at −78° C. for 30 minutes, 2.47 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 50 ml portion of tetrahydrofuran prepared by dissolving 1.25 g of 2-(4-bromophenyl)-4,6-di-m-tolyl-1,3,5-triazine synthesized by the method of Reference Example 2 and 0.17 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 3 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:dichloromethane=3:2 to 4:3) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2-{4-[5-(4-tert-butylphenyl)pyridin-2-yl]phenyl}-4,6-di-m-tolyl-1,3,5-triazine (1.55 g, yield 94%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[Cl:19])[CH:7]=2)[CH:13]=1
Reactant: Nc1ccccc1Cl
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccccc2Cl)nc(N)n1
Yield: 31 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 2-chloroaniline provided the title compound (31% yield). 1H NMR (DMSO-d6) δ 1.19-1.22 (t, 3H, CH3), 4.0-4.1 (q, 2H, CH2), 6.0-6.30 (s, 2H, NH2), 6.65 (s, 1H, Ar), 7.05-7.29 (m, 4H, Ar), 7.316 (d, 1H, Ar) 7.354 (d, 1H, Ar) 7.90 (d, 1H, Ar) 8.8 (br s, 1H, NH).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([Si](C)(C)C)([F:19])[F:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:17]([F:19])([F:18])[F:16])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dry tetrahydrofuran (20 ml) was added to a stirred mixture of 1-benzyl-3-methylpiperidin-4-one (4 g, 19.7 mmole) and (Trifluoromethyl) trimethylsilane (3.35 g, 23.64 mmole) at 0° C. and stirred for 5 min. Tetrabutyl ammonium fluoride (0.05 g) was added to it at 0° C. and stirred for another 30 min at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 3 hr, acidified with 2N HCl to pH 2 and extracted with ether (3×50 ml). Ether extract was dried (Na2SO4) and concentrated in vacuum to give 1-benzyl-3-methyl-4-hydroxy-4-trifluoromethylpiperidine. Yield 5.1 g (95%), C14H18F3NO, m/z 274 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C)C(=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:16][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:6]=1[CH3:7]
Reactant: COCCBr
Reactant: Cc1c(I)cnn1CC1(O)CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCCOC1(Cn2ncc(I)c2C)CCCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 151B (356 mg) in N,N-dimethylacetamide (6 mL) was added NaH (128 mg, 60% in mineral oil). The mixture was stirred for 30 minutes. Then, 1-bromo-2-methoxyethane (740 mg) was added to the mixture, which was stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. After filtration and concentration, the residue containing the crude title compound was used in the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]3[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=3)=[O:43])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:48]([C:47]5[CH:50]=[CH:51][C:44]([C:42](=[O:43])[NH:41][C:38]6[CH:39]=[CH:40][C:35]([N:32]7[CH2:31][CH2:30][O:29][CH2:34][CH2:33]7)=[CH:36][CH:37]=6)=[CH:45][CH:46]=5)=[N:1][C:4]=4[CH:5]=3)=[O:28])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)cc2)CC1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: CN1CCN(c2ccc(C(=O)Nc3ccc4[nH]c(-c5ccc(C(=O)Nc6ccc(N7CCOCC7)cc6)cc5)nc4c3)cc2)CC1

Procedure:
Compound 249 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(4-methylpiperazinyl)benzamide and 4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C36H37N7O3: 616.30; found: 616.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:45][O:46][CH2:47][CH2:48]Br.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[N:13]([CH2:48][CH2:47][O:46][CH3:45])[C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(=O)n(Cc2ccc(OC)cc2OC)c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
500 mg (0.977 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.271 mmol) of cesium carbonate and 149 mg (1.075 mmol) of 2-bromoethyl methyl ether were added and the mixture was stirred at RT for 18 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum. 453 mg (74% of theory) of the title compound were obtained.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH-].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11]>CO>[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:4]2[C:5](=[O:6])[CH2:7][NH:1][C:2]2=[O:3])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C1CNC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CNC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 57.9 %

Procedure:
A solution of hydantoin (5.0 g, Aldrich) in 2N aqu. NaOH (25 ml) was stirred at room temperature for 1 hour, then a solution of p-nitrobenzyl bromide (10.8 g, Aldrich) in methanol (50 ml) was added and the mixture refluxed for 16 hours. The mixture was cooled and the pale yellow precipitate filtered off, dried in vacuo, and recrystalised from ethanol to give the desired product as pale yellow crystals (6.8 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(Cl)Cl.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17].[CH3:18][CH:19]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:20]>CCOCC>[CH3:18][C:19]1([CH3:20])[C:13]2[C:14](=[CH:15][C:16]3[CH2:8][C:9](=[O:17])[CH2:10][C:11]=3[CH:12]=2)[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21]1
Reactant: CC(C)CCC(C)C
Reactant: O=C1Cc2ccccc2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)CC(=O)C3
Temperature: -20 °C

Procedure:
A 1 L 3-neck flask was charged with AlCl3 (80.8 g, 0.606 mol), fitted with a mechanical stirrer, and a 250 mL addition funnel, charged with anhydrous methylene chloride (370 mL). The slurry was cooled to −20° C. and stirred. The addition funnel was then charged (in two portions over the course of the reaction) with a solution of 2-indanone (40.0 g, 0.303 mol) {Note: Aldrich brand 2-indanone was rinsed with ether to remove brown impurities}, 2,5-dichloro, 2,5-dimethylhexane (55.4 g, 0.303 mol) and anhydrous methylene chloride (180 mL). The solution was dripped onto the cold, stirring AlCl3 slurry over the course of 50 min. After stirring for 2.5 h after the addition was complete, a solution of 2,5-dichloro, 2,5-dimethylhexane (13 g, 0.071 mol) and anhydrous methylene chloride (42 mL). After stirring an additional hour, the reaction mixture was poured onto ice (1 L) and treated with ether (500 mL). The organic layer was separated and the aqueous layer extracted with ether (2×200 mL). The combined organic layers were washed with 2.5 M NaCl (aq) (3×75 mL) then water (25 mL) then dried over MgSO4. The dried organic solution was filtered into a 3 L flask and the solvent was slowly removed with a nitrogen blowing over the surface of the solution. The solid that remained was washed with cold pentane and the solids isolated by filtration. The product, a fine crystalline material, was separated manually from a small amount of chunky oily solids that contained product and an impurity. Yield 21 g.