Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C>C(O)(C)(C)C>[C:5]1([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: O=C(O)Cc1ccccc1
Yield: 113.5 %

Procedure:
A mixture of 8.3 g of 2-tosyltropone, 4.5 g of p-aminophenylacetic acid and 9 ml of triethylamine in 200 ml of tert-butylalcohol was refluxed for 24 hours. The mixture was concentrated and acidified with 2 N hydrochloric acid, followed by extraction with dichloromethane. The dichloromethane solution was extracted with a saturated sodium bicarbonate aqueous solution. The aqueous layer was acidified and extracted with dichloromethane. The dichloromethane solution was washed with water and dried over anhydrous magnesium sulfate and evaporated to give a yellow crystalline solid, which was recrystallized from ethanol to yield 4.6 g of p-(2-troponylamino) phenylacetic acid; m.p. 175°-176° C.; Analysis--Calculated for C15H13NO3 : C 70.58%, H 5.13%, N 5.49%; Found: C70.34%, H 5.30%, N 5.55%.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].BrC1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[C:18]#[N:19].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:12]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=2[C:18]#[N:19])[CH2:13][CH2:14]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: COc1ccc(Br)c(C#N)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c1
Temperature: 90 °C
Yield: 92.3 %

Procedure:
A mixture of Boc-homopiperazine (483 mg, 2.59 mmol), 2-bromo-5-methoxybenzonitrile (500 mg, 2.36 mmol), Pd2(dba)3 (108 mg, 0.12 mmol), xantphos (205 mg, 0.35 mmol), sodium t-butoxide (666 mg, 7.08 mmol) in degassed anhydrous dioxane (10 mL) was heated at 90° C. for 2 h. The mixture was allowed to cool and filtered through celite. The filtrate was concentrated and purified by chromatography (EtOAc/hexanes) to yield the title compound (691 mg, 92%). m/z (M+1) 318.39.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:9]([O-:12])(=[O:11])[CH3:10].[K+]>C(O)(=O)C>[CH2:6]([CH:7]1[O:12][C:9](=[O:11])[CH2:10][CH2:8]1)[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CC(=O)[O-]
Reactant: C=CCCCCCC
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCCCC1CCC(=O)O1
Yield: 74 %

Procedure:
Octene-1 in an amount of 3.37 g. and 4.8 g. of freshly prepared MnO2.4H2O were mixed with and heated under nitrogen in 300 ml. glacial acetic acid containing 90 g. potassium acetate. After a reaction time of less than two hours, gamma-n-hexyl-butyrolactone was obtained in 74% yield.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([C:49]([F:52])([F:51])[F:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([C:49]([F:52])([F:50])[F:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C(F)(F)F)c2)CCN3)cc1
Reaction time: 7 h
Yield: 81.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (155 mg) in ethanol (10 ml) was added sodium borohydride (79 mg) and the mixture was stirred for 7 hours. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and recrystallized from diisopropyl ether-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (110 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[CH:6]=[CH:5]2.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[CH2:6][CH2:5]2
Reactant: CC1(C)OC[C@H](C2C=Cc3cc(F)ccc3O2)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)OC[C@H](C2CCc3cc(F)ccc3O2)O1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
A 75:25 diastereoisomeric mixture of 6-fluoro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (50 mg, 0.18 mmol, 90.4% A) was dissolved in ethanol and stirred under nitrogen athmosphere at 25° C. Ammonium formiate (60.5 mg, 0.96 mmol) and 10% palladium on carbon (50 mg) were added to the stirred solution and the reaction mixture refluxed for 15 h. The reaction mixture was checked to show complete conversion of the starting material. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to furnish 6-fluoro-3,4-dihydro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (40 mg, 0.115 mmol, 72.6% A, 64% yield) as a 75:25 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]=[C:14]([OH:20])[CH:13]=[C:12]3[Br:21])=[CH:4][CH:3]=1.[CH3:29]N(C)C=O.C([O-])([O-])=O.[Cs+].[Cs+].CI>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]([CH3:29])[C:14](=[O:20])[CH:13]=[C:12]3[Br:21])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4,8-dibromoquinolin-2-ol (360 mg, 0.67 mmol, 1.00 equip), N,N-dimethylformamide (15 mL), Cs2CO3 (654 mg, 2.01 mmol, 3.00 equip), and CH3I (190 mg, 1.34 mmol, 2.00 equip). The resulting solution was stirred overnight at 80° C. The resulting solution was diluted with water (80 mL). The solids were collected by filtration to yield 6-[bis(4-chlorophenyl)methyl]-4,8-dibromo-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 552 [M+H]+
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=[C:6]([NH:22][CH3:23])[N:5]=1)[CH3:2].C1COCC1.CCN(C(C)C)C(C)C.[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=[C:6]([N:22]([C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([F:38])=[CH:40][CH:41]=2)[CH3:23])[N:5]=1)[CH3:2]
Reactant: CCSc1nc(NC)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCSc1nc(N(C)C(=O)c2ccc(F)cc2)cc(C)c1C(=O)NCc1cccc(F)c1
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a solution of 150 mg (0.45 mmol) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(methyl-amino)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 123) in DCM (3 ml) and THF (3 ml) was added 160 μl (0.95 mmol) DIPEA. At 0° C. 56 μl (0.47 mmol) 4-fluoro-benzoylchloride was added dropwise and stirring was continued at 0° C. for 2 h and RT for 16 h. Then the mixture was partiotionated between EtOAc and a 1M aq. NaHCO3 sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 171 mg (0.38 mmol, 83%) 2-Ethylsulfanyl-6-[(4-fluoro-benzoyl)-methyl-amino]-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (example 120). [M+H]+ 456.1
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([C:7]([C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27].O>CN(C=O)C>[CH3:24][N:25]([CH3:30])[S:26]([N:11]1[CH:12]=[N:13][C:9]([C:7](=[O:8])[C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)=[N:10]1)(=[O:28])=[O:27]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cnc(C(=O)c2ccc(C(F)(F)F)cc2)n1
Yield: 69.2 %

Procedure:
0.31 g of 3-(4-trifluoromethylbenzoyl) -1,2,4-triazole was dissolved in 3 ml of DMF, 0.21 g of potassium carbonate was added thereto, and then 0.22 g of dimethylsulfamoyl chloride was added at room temperature with stirring. After stirring the reaction mixture for 1.5 hours at room temperature, water was added to precipitate crystals, and the crystals were collected by filtration and washed with diethyl ether. Drying of the mixture under reducing pressure afforded 0.31 g of the titled compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:22]([O:24][C:25](=[O:49])[C@H:26]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](OS(C(F)(F)F)(=O)=O)[CH:36]=1)[NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH3:23]>C(COC)OC.C(OCC)(=O)C.O.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>[CH2:22]([O:24][C:25](=[O:49])[C@H:26]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:36]=1)[NH:27][C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])[CH3:23]
Reactant: CCOC(=O)[C@H](Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)NC(=O)C(F)(F)F
Reactant: OB(O)c1ccc2ccccc2c1
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: O
Solvent: COCCOC
Product: CCOC(=O)[C@H](Cc1cccc(-c2ccc3ccccc3c2)c1)NC(=O)C(F)(F)F
Temperature: 85 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
2-Naphthaleneboronic acid (142 mg, 0.824 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.069 mmol) and potassium phosphate (120 mg, 0.563 mmol) were added in turn to a solution of N-trifluoroacetyl-3-trifluoromethane-sulfonyloxy-L-phenylalanine ethyl ester (300 mg, 0.686 mmol) in degassed dimetoxyethane (2 ml). The mixture was stirred under argon atmosphere at 85° C. for 3 hrs. After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate and water and then extracted with ethyl acetate. The extract was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=9) to give N-trifluoroacetyl-3-(2-naphthyl)-L-phenylalanine ethyl ester (173 mg, 61%) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([C:2]2[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=23)=[CH:27][CH:28]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1Br
Product: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1-c1ccc(Cl)nc1

Procedure:
The product from Example 140A and 2-chloropyridine-5-boronic acid were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48-10.92 (bs, 1H), 9.13 (dd, J=7.0, 1.7 Hz, 1H), 8.72 (d, J=1.9 Hz, 1H), 8.65 (dd, J=4.2, 1.7 Hz, 1H), 8.05 (dd, J=8.5, 2.2 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.32-7.36 (m, 2H), 7.13-7.19 (m, 3H), 3.69 (s, 2H); MS (APCI) m/z 382 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]4C(=O)C5=CC=CC=C5C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O.NN.[ClH:35]>CO.O>[ClH:35].[ClH:35].[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidinyl]butyl]phthalimide (6.9 g, 16.4 mmol) and hydrazine monohydrate (1.64 g, 32.8 mmol) in methanol (70 ml) was heated at reflux for 3 hours. At the end of the reaction, methanol was removed to leave a crude solid. This was dissolved in water and acidified with HCl to pH 2 The insolubles were filtered. The aqueous solution was basified with 50% NaOH, and then extracted with dichloromethane. The dichloromethane solution was washed with water and brine, and then dried over MgSO4. The solvent was removed to a colorless oil: 4.48 g. This oil was treated with equivalents of HCl in ethanol. The solid was collected. Recrystallization from ethanol (65 ml) and methanol (20 ml) gave 2.0 g of l-(4aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride as white crystals, m.p.=234-237° C.
Reaction SMILES: N[C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.OC1C=CC=CC=1C=CC1C2C(N=C3C=1C=CC=C3)=CC=CC=2.CN(C1C=CC2C=C3C(=NC=2C=1)C=C(N(C)C)C=C3)C.CC1C=C2C(=CC=1N)N=C1C(C=C(C)C(N)=C1)=C2.Cl>>[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2nc3ccccc3cc12
Agent: CN(C)c1ccc2cc3ccc(N(C)C)cc3nc2c1
Agent: Cc1cc2cc3cc(C)c(N)cc3nc2cc1N
Agent: Cl
Product: c1ccc2nc3ccccc3cc2c1

Procedure:
1-aminoacridine, 9-(2'-hydroxystyryl)acridine, acridine orange, acridine yellow, and the like.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH:6]([NH2:13])[C:7](=O)[C:8]([F:11])([F:10])[F:9])[CH3:3].C(OC([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][C:23]1=[O:29])=O)(C)(C)C.C([O-])(=O)C.[Na+]>O.O1CCOCC1>[CH2:2]([O:4][C:5]([C:6]1[NH:13][C:25]2[CH2:26][CH2:27][NH:22][C:23](=[O:29])[C:24]=2[C:7]=1[C:8]([F:11])([F:10])[F:9])=[O:14])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1=O
Reactant: CCOC(=O)C(N)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1[nH]c2c(c1C(F)(F)F)C(=O)NCC2
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A stirred mixture of 2-amino-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester hydrochloride (7.54 g, 32 mmol), 2,4-dioxo-piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 29.1 mmol) and sodium acetate (2.39 g, 29.1 mmol) in water (35 ml) and dioxane (35 ml) was heated to reflux for 2 hours. The mixture was cooled down to room temperature, and extracted with 15 to 1 solvent mixture of ethyl acetate and methanol (160 ml×3), the combined organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by the silica gel column chromatography with dichloromethane:tetrahydrofuran:methanol (40:5:1) as eluents to give 3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (2.8 g, 35%) as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=1.[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:7][C:6]=2[C:21]2[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCOc2ccc(NC(=O)c3cccc(F)c3)cc2-c2ccnn2C)CC1
Temperature: 120 °C
Yield: 64.2 %

Procedure:
A mixture of N-[4-(2-Bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide (105 mg, 0.251 mmol), 1-acetylpiperazine (34 mg, 0.264 mmol) and potassium carbonate (42 mg, 0.301 mmol) in DMF (3 mL) was heated in microwave at 120° C. for 20 min. The mixture was purified by HPLC to give title compound (75 mg, 64%) as a white solid as TFA salt. 1H NMR (CD3CN, 400 MHz) δ 2.09 (s, 3H), 3.32-3.38 (m, 6H), 3.48 (t, J=5.05 Hz, 4H), 3.79 (s, 3H), 4.43 (t, J=4.55 Hz, 2H), 6.39 (d, J=2.02 Hz, 1H), 7.18 (d, J=9.09 Hz, 1H), 7.40 (dt, J=2.78, 8.59 Hz, 1H), 7.57-7.63 (m, 2H), 7.70-7.74 (m, 2H), 7.80-7.82 (m, 1H), 7.85 (dd, J=2.78, 9.09 Hz, 1H), 8.93 (s, 1H). Exact mass calculated for C25H28FN5O3 465.2. found 466.4 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[N:17]([CH3:42])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH2:40][CH3:41])[N:19]=3)([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([C:11]4([O:14][CH3:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:17]3[CH3:42])=[C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)[CH3:41]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCNCC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (915 mg, 1.59 mmol) in DCM (15 mL) was added TFA (3 mL) and the resulting mixture allowed to stir at r.t. for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 2-(2-Ethylbenzoimidazol-1-yl)-8-(4-methoxypiperidin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purine (775 mg, quant.). LCMS (method H): RT 1.95 min, [M+H]+ 477.3
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26]([OH:27])[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1.[CH2:34]([C:37]#[N:38])[CH2:35]O.C(N(CC)CC)C>C(Cl)Cl>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26]([O:27][CH2:35][CH2:34][C:37]#[N:38])[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1
Reactant: N#CCCO
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: N#CCCOC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
Under ice cooling and stirring, 0.27 ml of thionyl chloride was added 1.5 g of 2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 36 suspended in 30 ml of methylene chloride and the mixture was stirred at the same temperature for 40 minutes. After completion of the reaction, the reaction mixture was condensed under reduced pressure, the residue was dissolved in 12 ml of methylene chloride, 0.81 ml of ethylenecyanhydrin and 0.94 ml of triethylamine were added to the solution under ice cooling and stirring and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate. Solid obtained by removing the solvent was washed with a diethyl ether-hexane mixed solution to obtain 1.31 g of the title compound.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:28]4[C:24](=[N:25][NH:26][N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[N:52]=[C:51]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:50]=1.[H-].[Na+].C(=O)=O>ClC1C=CC=CC=1.CN(C)C=O>[C:8]1([N:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:28]4[C:24](=[N:25][N:26]([C:49]5[C:58]6[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=6)[N:52]=[C:51]([C:59]6[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=6)[CH:50]=5)[N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: c1ccc(-c2cc(-n3nc4c(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)ccc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)c4n3)c3ccccc3n2)cc1
Temperature: 50 °C

Procedure:
A mixture of Intermediate D (605 mg, 1.0 mmol), 4-chloro-2-phenylquinoline (481 mg, 2.0 mmol), 60% NaH (80 mg, 2.0 mmol), and dimethylformamide (15 mL) was stirred under argon and heated at 50° C. for 3 hours. After cooling, the mixture was diluted with chlorobenzene (50 mL) and treated with a piece of dry ice to reduce the pH. The volatiles were removed under reduced pressure, and the residue was chromatographed using silica gel and hexane/dichloromethane (2:1) as an eluent to give 4,7-bis(4-(N,N-diphenylamino)phenyl)-2-(2-phenylquinolin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 17) as orange-pink crystals, 640 mg (79%). 1H NMR (400 MHz, CDCl3): δ 8.70 (m, 3H, 2-phenylquinazolin-4-yl), 8.22 (d, J=8.4 Hz, 1H, 2-phenylquinazolin-4-yl), 8.12 (d, J=8.8 Hz, 4H, p-phenylene), 7.97 (ddd, J=8.4, 6.9 and 1.4 Hz, 1H, 2-phenylquinazolin-4-yl), 7.76 (s, 2H, benzotriazole), 7.68 (ddd, J=8.5, 7.0 and 1.1 Hz, 1H, 2-phenylquinazolin-4-yl), 7.53 (m, 3H, 2-phenylquinazolin-4-yl), 7.25-7.30 (m, 8H, Ph), 7.21 (d, J=8.4 Hz, 4H, p-phenylene), 7.16-7.19 (m, 8H, Ph), 7.05 (tt, J=7.3 and 1.1 Hz, 4H, Ph), 2.86 (s, 3H, quinaldine). UV-vis spectrum (dichloromethane): λmax=452 nm. Fluorimetry (dichloromethane): λmax=654 nm.