Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1Cl)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][Cl:16])[N:14]=1)=[O:8].[F:21]C1C=C(C=CC=1)CN=C=O>>[Cl:16][CH2:15][C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:21])[CH:3]=2)=[O:8])[S:11][CH:12]=1
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Reactant: O=C=NCc1cccc(F)c1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1

Procedure:
Prepared by same procedure described for Intermediate 2, using 3-fluorobenzyl isocyanate. 1H-NMR (ppm, DMSO-d6): 10.70 (bs, 1H), 7.36 (dd, 1H), 7.07 (m, 4H), 4.63 (s, 2H), 4.34 (d, 2H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccn(CCO)c(C(O)c2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1ccn(CCO)c(C(O)c2ccccc2)c1O

Procedure:
12.37 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one are dissolved in 200 ml of methanol and hydrogenated at room temperature over 1.2 g of palladium on carbon (5%) until 1 mol of H2 per mol of starting material has been taken up. The catalyst is removed by filtration and the filtrate is concentrated to dryness by evaporation using a rotary evaporator. Recrystallisation from methanol yields 3-hydroxy-1-(2-hydroxy-ethyl)-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one in the form of colourless crystals. M.p.: 198°-200° C.
Reaction SMILES: CN[N+]([O-])=O.S(=O)(=O)(O)O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN([N+]([O-])=O)[C:20]1[C:25]([N+]([O-])=O)=[CH:24][C:23]([N+]([O-])=O)=[CH:22][C:21]=1[N+]([O-])=O>>[C:12]1([NH:11][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-])[N+](=O)[O-]
Reactant: Nc1ccccc1
Agent: CN[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: c1ccc(Nc2ccccc2)cc1

Procedure:
Methylnitramine decomposes explosively in contact with concentrated sulfuric acid. It is evolved when aniline reacts with tetryl; a diphenylamine derivative is produced simultaneously. Methylnitramine reacts with picryl chloride to form tetryl.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12]C(=O)OC(C)(C)C)[CH2:10][C:9]2[C:4](=[C:5]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1.Cl.[OH-].[Na+]>C(O)C>[NH2:12][CH:11]1[CH2:10][C:9]2[C:4](=[C:5]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (399 g) was suspended in ethanol (2 L), and concentrated hydrochloric acid (555 mL) was added to the suspension, followed by stirring at 60° C. for 30 minutes. The reaction mixture was neutralized with 25% aqueous sodium hydroxide solution under cooling on ice. The resultant mixture was partitioned between chloroform and water, and the aqueous layer was extracted with chloroform. The organic layers were combined, and the combined organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, whereby the title compound (418 g) in a crude form was yielded, which was employed in the subsequent reaction step without performing further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].C([Li])(CC)C.[C:15](=[O:17])=[O:16]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:17])=[O:16])=[C:3]([CH3:9])[CH:4]=1
Reactant: O=C=O
Reactant: Cc1cc(Cl)ccc1Br
Agent: [Li]C(C)CC
Product: Cc1cc(Cl)ccc1C(=O)O

Procedure:
in stage a) 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound, particularly preferably sec-butyllithium, and CO2 to give 4-chloro-2-methylbenzoic acid,
Reaction SMILES: [CH2:1]([C:3]([C:6]1[C:11]2[N:12]([CH3:25])[C:13]([CH2:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])=[N:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:4][CH3:5])[CH3:2].C(O)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:25])[C:13]([CH2:15][C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])=[N:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC=C(CC)c1cccc2nc(Cc3c(C)cc(C)cc3C)n(C)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(CC)c1cccc2nc(Cc3c(C)cc(C)cc3C)n(C)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 10.8 %

Procedure:
To a solution of 7-[1-ethylprop-1-en-1-yl]-2-(mesitylmethyl)-1-methyl-1H-benzimidazole (110 mg, 0.331 mmol) in tetrahydrofuran (3.5 mL) was added a solution of borane-dimethyl sulfide complex in tetrahydrofuran (1.9 M, 3.5 mL, 6.63 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 15 hr, acetic acid (5.0 mL) was added to the mixture and the mixture was heated at 120° C. for 2 hr. After the reaction mixture was cooled, the mixture was poured into saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL, twice). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10-25% ethyl acetate/n-hexane gradient mixture to give the title compound (12 mg, 0.0359 mmol, 11%) as a colorless solid.
Reaction SMILES: C1([C@@H]([N:9]2[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH:11]=[CH:12]3)C)C=CC=CC=1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C@@H:10]12[CH2:20][C@@H:13]([CH2:12][CH2:11]1)[C@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@@H](C2)N1[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1N[C@H]2CC[C@@H]1C2
Temperature: 45 °C
Yield: 24.8 %

Procedure:
To a solution of ethyl (1R, 3R, 4S)-2-[(S)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (3.84 g, 14.2 mmol) in ethyl acetate (28 ml) was added 20 wt % Pd(OH)2 (4.97 g), and the mixture was stirred under a hydrogen atmosphere at 45° C. 64 hours. After a filtration through Celite, the solvent was concentrated. The residue was purified by silica gel column chromatography (1%–5% methanol/chloroform), to give ethyl (1S, 3R, 4R)-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.595 g, 25%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[N:20]=[C:19]3[C:14]([CH2:15][CH2:16][C:17](=[O:21])[NH:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[C:31]1([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]3[N:20]=[C:19]4[C:14]([CH2:15][CH2:16][C:17](=[O:21])[NH:18]4)=[CH:13][CH:12]=3)[CH2:2][CH2:3]2)[C:32]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCc2ccc(OCCCN3CCNCC3)nc2N1
Reactant: Brc1cccc2ccccc12
Product: O=C1CCc2ccc(OCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1

Procedure:
In a similar manner to the example shown above, 7-(3-piperazin-1-yl-propoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one was coupled to 1-bromo-naphthalene to give the title compound (0.189 g). MS: APCI: M+1: 417.2 (Exact Mass: 416.22).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.[CH3:12][NH2:13]>CCO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:13][CH3:12])[C:5]2=[N:4][CH:3]=1
Reactant: Clc1nccn2c(Br)cnc12
Reactant: CN
Solvent: CCO
Product: CNc1nccn2c(Br)cnc12

Procedure:
(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine was prepared by a process analogous to that described in Example 2 starting from 3-bromo-8-chloro-imidazo[1,2-a]pyrazine and excess methylamine (33% weight in EtOH) at room temperature in EtOH.
Reaction SMILES: Cl[C:2]1[C:3]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([NH2:24])[C:12]([N:17]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH3:18])=[CH:13][C:14]=2[O:15][CH3:16])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:69]([Zn]C#N)#[N:70].CC(N(C)C)=O>CCOC(C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:24][C:11]1[C:12]([N:17]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH3:18])=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[C:2]([C:69]#[N:70])=[CH:7][N:6]=2)[CH:10]=1
Reactant: N#C[Zn]C#N
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C#N)c(-c2cn(C)c3ccccc23)n1
Reaction time: 3.5 h
Yield: 54.8 %

Procedure:
N4-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N1-(2-dimethylaminoethyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine (Intermediate 97, 250 mg, 0.52 mmol), zinc (3.41 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (47.7 mg, 0.05 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 49.7 mg, 0.10 mmol), and dicyanozinc (36.7 mg, 0.31 mmol) were placed in a reaction tube under N2 and then degassed DMA (1.38 mL) was added. The resulting suspension was shined for 3.5 h at 95° C. The mixture was then diluted with EtOAc and washed 5 times with water, and then brine. The solution was then dried (MgSO4) and concentrated in vacuo. The residue was dissolved in CH3OH/CH2Cl2 and the solution was allowed to pass through a stratospheres SPE cartridge PL-Thiol MP SPE (available from Polymer Laboratories)under gravity. The resulting solution was concentrated in vacuo and the residue was triturated with diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether to give the title compound (80 mg) as yellow solid. The aqueous work-up solutions were purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and pure fractions were concentrated in vacuo to give a brown oil (126 mg). Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (94 mg) as a yellow solid. Both batches of product were combined to give (174 mg, 71%) as a yellow solid; m/z: ES+ MH+ 471.33.
Reaction SMILES: C(O[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.C1(N)CCCCC1.C1(C(NC2CCCCC2)=[CH:37][C:38]2CC[CH2:41][CH2:40][N:39]=2)C=CC=CC=1.CS([O-])(=O)=O>C(NCC)C>[C:12]1([C:4]([N:39]([CH2:40][CH3:41])[CH2:38][CH3:37])=[CH:5][C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C(=C(NC1CCCCC1)c1ccccc1)C1=NCCCC1
Reactant: CCOC(=CC1=NCCCC1)c1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCNCC
Solvent: NC1CCCCC1
Product: CCN(CC)C(=CC1=NCCCC1)c1ccccc1

Procedure:
Analogously to Example 1, there is obtained, starting with 9.5 g of 2-(2-ethoxy-2-phenyl-ethenyl)-3,4,5,6-tetrahydropyridine-tetrafluoroborate and 30 ml of cyclohexylamine, 2-[(2-phenyl-2-(cyclohexylamino)-ethenyl]-3,4,5,6-tetrahydropyridine, and from this its (1:1)-methanesulphonate, m.p. 172°-173°; and starting with 9.5 g of 2-(2-ethoxy-2-phenyl-ethenyl)-3,4,5,6-tetrahydropyridine-tetrafluoroborate and 30 ml of diethylamine, is obtained 2-[2-phenyl-2-(diethylamino)-ethenyl]-3,4,5,6-tetrahydropyridine, and from this its (1:1)-fumarate, m.p. 169°-170° (from isopropanol).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=3)[CH:11]=2)=[CH:4][N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[Br:33]N1C(=O)CCC1=O>CN(C)C=O>[Br:33][C:4]1[N:3]=[CH:2][O:1][C:5]=1[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[CH:11]=1
Reactant: CC(C)c1nnc2ccc(-c3cnco3)cn12
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3ocnc3Br)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A clean, dry, 1 liter 4 neck round bottom flask equipped with mechanical stirrer, temperature probe, and purged with nitrogen, was charged with 6-[oxazol-5-yl]-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine (45.2 grams 0.198 moles) and dimethylformamide (271 ml). The pot was cooled below −60° C. with a dry ice/acetone bath. Lithium bis(trimethylsilyl)amide, 1 molar solution in tetrahydrofuran (198 ml 0.198 moles), was added, keeping the temperature below −60° C. After the addition was complete, the pot was further cooled to below −70° C. and stirred for 1 hour. While stirring, a solution of N-bromosuccinimide (35.24 g 0.198 moles) and dimethylformamide (105 ml), were stirred in a separate 500 ml round bottom flask under nitrogen. After the one hour stir at −70° C., the solution of N-bromosuccinimide and dimethylformamide was slowly added to the anion keeping the temperature below −70° C. After the addition, the reaction was continued for one hour below −70° C. The batch was then warmed to room temperature and quenched into methylene chloride (452 ml) and 1N sodium hydroxide (452 ml). The organic layer was then separated. The aqueous layer was extracted a second time with methylene chloride (135 ml). The combined organic phase was washed with 1N sodium hydroxide (452 ml) and saturated brine solution (452 ml). The organic phase was then dried over magnesium sulfate (50 grams) and concentrated/displaced with isopropyl ether (226 ml) to a temperature of 42° C. A thick slurry formed upon cooling. The solids were granulated at 20 to 25° C. for two hours, filtered, washed with isopropyl ether (50 ml), and dried to afford 53.0 grams of light yellow solids, 96.4% purity (HPLC), 87% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[N:8]([CH:13]=[CH:14][CH:15]=3)[N:9]([CH3:12])[C:10]=2[CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:35]N1C(=O)CCC1=O.[Al]>C1COCC1>[Br:35][C:13]1[N:8]2[N:9]([CH3:12])[C:10]3[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:6](=[O:16])[C:7]2=[CH:15][CH:14]=1
Reactant: Cn1c2cc(Cl)ccc2c(=O)c2cccn21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Al]
Solvent: C1CCOC1
Product: Cn1c2cc(Cl)ccc2c(=O)c2ccc(Br)n21
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a solution of 7-chloro-5-methylpyrrolo[1,2-b]cinnolin-10(5H)-one (6.0 g) and a catalytic amount of dibenzoyl peroxide in 100 ml of THF was added portionwise N-bromosuccinimide (4.63 g) over 15 min. The flask was covered with aluminum foil and the solution was stirred at room temperature for 24 hrs. The solution was then concentrated and the residue was purified by HPLC (silica, dichloromethane) to give 7.10 g of a light green powder. This powder was recrystallized from ethanol to give 5.7 g of a yellow fibrous material, mp 133°-135°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.C1C(=O)N([Br:25])C(=O)C1>CO.C(Cl)Cl.[Pd]>[Br:25][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(CCN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
To a solution 4-[2-(4-nitro-phenyl)-ethyl]-morpholine (0.70 g, 2.97 mmol) (as prepared in the previous step) in 15 mL of MeOH was added 10% Pd/C (30 mg) and the mixture hydrogenated under 20 psi of H2 for 2 h. The mixture was filtered though Celite and concentrated. The residue was dissolved in DCM (20 mL) and NBS (0.53 g, 2.97 mmol) was added and the reaction stirred for 20 min at RT. The reaction was diluted with DCM (20 mL) and washed with NaHCO3 (2×40 mL) and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 100% EtOAc to give 0.49 g (58%) of a light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C12H17BrN2O, 285.0 (M+H). found 285.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[N:20]2[CH:34]=[N:35][C:36]([C:37]#[N:38])=[C:19]12)=[O:17].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]([N:18]3[CH2:23][CH:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)[N:20]4[CH:34]=[N:35][C:36]([C:37]#[N:38])=[C:19]34)=[O:17])[CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N#Cc1ncn2c1N(C(=O)CN1CCN(Cc3ccccc3)CC1)CC=C2c1cccc(C(F)(F)F)c1
Yield: 84.9 %

Procedure:
A stirred mixture of 1.6 g of 1-benzylpiperazine, 2.9 g of 1-(chloroacetyl)-1,2-dihydro-4-[3-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrimidine-8-carbonitrile and 1.1 g of sodium carbonate in 55 ml of toluene was heated at reflux for 18 hours. The reaction mixture was cooled, then shaken with 20 ml of 1N sodium hydroxide. The layers were separated and the aqueous phase was extracted once with chloroform. The toluene phase above, and the chloroform extract were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a viscous oil. The oil was dissolved in 50 ml of chloroform and passed through hydrous magnesium silicate. The chloroform filtrate was concentrated to an oil. The oil was heated to solution in 25 ml of ethyl acetate and filtered. Then 25 ml of n-hexane was added to the filtrate to crystallize the product. The crystals were collected by filtration, pressed to remove solvent, washed with hexane and dried to give 3.4 g of the product of the example as cream colored crystals, mp 167°-169° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[CH3:30][O:29][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCN1CCCCC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (41 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (268 mg) and piperidine (0.1 ml) were added to the solution, and the mixture was stirred at 80° C. for 2 days. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (24 mg, yield 53%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][NH:27][CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:30])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:31](=O)[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.C(O)(=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27]([CH2:31][CH3:32])[CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:30])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC=O
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCc2c(n(C)c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
To a solution of 4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (120 mg, 0.28 mmol) in dichloromethane/acetic acid (1% acetic acid, 10 mL) were sequentially added acetaldehyde (0.50 mL, 13 mmol) and NaBH(OAc)3 (1.0 g, 4.7 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The mixture was concentrated, and the residue was purified by flash chromatography (silica gel silica gel, (1:1 hexanes/EtOAc)/(10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide), 1:0 to 0:1) to provide 4-(benzyloxy)-1-(2-ethyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (120 mg, 72%) as a white solid. The free base was converted to the HCl salt using 1.25 M HCl in methanol, providing the title compound (120 mg, 95%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 7.57 (d, J=7.5 Hz, 1H), 7.54-7.34 (m, 7H), 6.97 (d, J=8.0 Hz, 1H), 6.10 (dd, J=7.5, 2.0 Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 3.67 (s, 3H), 3.45-3.18 (4H, overlapping with solvent peak), 3.26 (br m, 2H), 2.96 (m, 2H), 1.33 (br m, 3H); ESI MS m/z 414 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=14.6 min.
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[CH3:38][S:39]([O-:42])(=[O:41])=[O:40].CO[Si](CC[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N+:53]=1C)(OC)OC.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[CH3:38][S:39]([O-:42])(=[O:41])=[O:40].[NH+:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:52]=1
Reactant: CO[Si](CCc1cccc[n+]1C)(OC)OC
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CO
Solvent: O
Solvent: CCO
Product: c1cc[nH+]cc1
Temperature: 25 °C

Procedure:
4.93 g of phenyltrimethoxysilane, 72.46 g of tetraethoxysilane, 22.06 g of methyltriethoxysilane, 0.56 g of the 30% methanol solution of trimethoxysilylethylmethylpyridinium methanesulfonate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.13 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-21):