Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CCOCC.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CCOCC
Product: CC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide, which can be prepared according to the procedure in PCT Publication No. WO 00/41505, and 2-methyl-3-butyn-2-ol were reacted in the presence of CuI and (PhP3)2C]2 by the general procedure of Example 1, Step A, and the mixture stirred at RT for 4 h. The reaction mixture was diluted with 50% Et2O/McOH and filtered through Celite®. The filtrate was concentrated under reduced pressure and further purified by flash chromatography on silica (CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide (97%) as a cream solid; m.p. (CH2Cl2/Hexane) 139-142° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.78 (br s, 1 H), 7.46-7.40 (m, 1 H), 7.28-7.19 (m, 2 H), 7.07 (dd, J=8.4, 1.5 Hz, 1 H), 6.79 (ddd, J=8.7, 8.7, 4.7 Hz, 1 H), 5.43 (br s, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.7 Hz, 2 H), 3.57 (t, J=4.7 Hz, 2 H), 1.45 (s, 6 H). Anal. Calcd for C20H19F3N2O4: C, 58.8; H, 4.7; N, 6.9. Found C, 58.5; H, 4.8; N, 6.7.
Reaction SMILES: [C:1]12([NH:11][C:12]#[N:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:14].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[ClH:14].[C:1]12([NH:11][C:12]([NH:21][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[NH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NC1CCCCC1
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: N=C(NC1CCCCC1)NC12CC3CC(CC(C3)C1)C2
Temperature: 200 °C

Procedure:
Adamantan-1-ylcyanamide (514 mg, 2.92 mmol), and cyclohexylamine hydrochloride (398 mg, 2.93 mmol) were finely ground together, and heated at 200° C. for 10 min. The resultant glassy solid was pulverized, and extracted twice with 50 ml boiling 5% HCl. The insoluble material was filtered, and dried. 346 mg, mp 264°-270° (p.h.b. 240° C.). On cooling the combined aqueous extracts to 25°, a white ppt. formed, and was filtered off, 56 mg. Combined crude yield: 44%. Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.). 1H (CD3OD) 1.208-1.474 (m, 5H), 1.744 (s, 9H), 1.967 (s, 8H), 2.119 (5, 3H), 3.434 (m, 1H), 13C (CD3OD) (broad band decoupled) 25.55, 26.26, 30.96, 33.74, 36.74, 42.73.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C1C(=O)N([Br:19])C(=O)C1>OS(O)(=O)=O>[Br:19][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc2cnccc2c1
Agent: O=S(=O)(O)O
Product: Fc1ccc2cnccc2c1Br

Procedure:
To a stirring mixture of 6-fluoroisoquinoline in H2SO4 (5 mL) at 0° C. was added solid NBS (1.5 EQ) slowly over 5 min. The reaction mixture was reacted at 0° C. for 1 h. To this reaction mixture was added NBS (0.5 EQ). The cold bath was then removed. The reaction mixture was reacted until all the starting material was consumed. To this reaction mixture was neutralized with a cold solution of NaOH (5N) until the pH of this mixture >10. The white solid was filtered off and dissolved in DCM and washed with a solution of NaOH (1N). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified via a column to give 5-bromo-6-fluoroisoquinoline. Retention time (min)=2.810, method [3], MS (ESI) 226.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14](NC(=O)C)=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[OH-].[NH4+:22]>B(F)(F)F.CO>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:22])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Reactant: [NH4+]
Agent: FB(F)F
Agent: [OH-]
Solvent: CO
Product: Nc1ccccc1OCc1nc(Cl)ccc1Cl
Temperature: 0 °C

Procedure:
N-(4-((3,6-Dichloro-2-pyridinyl)methoxy)phenyl)-acetamide (30.27 grams; 0.097 mole) was mixed with a 270 ml. solution of boron trifluoride-methanol (1 gram per 10 ml.) and the resulting reaction mixture refluxed for a period of 4 1/2 hours. The reaction mixture was then diluted and cooled with ice water to a temperature of between about 0° to about 10°C. Concentrated ammonium hydroxide was added until the reaction mixture was basic. The reaction mixture was then extracted with portions of methylene chloride, the extracts combined and the solvent removed by evaporation. The residue thus obtained was extracted with five 500 ml. portions of hexane. The crystalline material which precipitated from the hexane mixture upon cooling was recovered by filtration. As a result of these operations, the desired 4-((3,6-dichloro-2-pyridinyl)-methoxy)benzenamine compound was recovered as a light yellow crystalline solid having a melting point of 74°-75°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][CH3:15])[NH:11][C:10](=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:19].C(=O)(O)[O-].[Na+]>>[Cl:19][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=[C:12]([CH2:14][CH3:15])[N:11]=1
Reactant: CCc1nc(-c2cccc(Cl)c2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1nc(Cl)cc(-c2cccc(Cl)c2)n1
Temperature: 85 °C
Yield: 81 %

Procedure:
A mixture of 6-(3-chlorophenyl)-2-ethylpyrimidin-4(3H)-one (0.240 g, 1.0 mmol) and POCl3 (5 mL) was heated to 85° C. for 6 h. After this time, the reaction was cooled, neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound as an off-white solid (0.210 g, 81%). MW=253.13. 1H NMR (CDCl3, 500 MHz) δ 8.10 (t, J=1.9 Hz, 1H), 7.96-7.92 (m, 1H), 7.55-7:41 (m, 3H), 3.03 (q, J=7.6 Hz, 2H), 1.55 (s, 1H), 1.42 (t, J=7.6 Hz, 3H); APCI MS m/z 254 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[F:8][C:9]([F:19])([F:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(OCC)OCC>>[CH2:1]([O:4][CH:5]=[C:11]([C:10]([C:9]([F:18])([F:19])[F:8])=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
The acetic anhydride (367.6 g, 3.6 moles) is heated to 100-105° C., to which a mixture of crude ethyl trifluoroacetoacetate (˜0.96 mole) and triethyl orthoformate (266.8 g, 1.8 moles) is added drop-wise. The reaction mixture is kept at 100-105° C. for 6 hours. The reaction mixture is cooled to 60-70° C. and then concentrated under vacuum to remove excess acetic anhydride, triethyl orthoformate, and generated ethyl acetate. A pale brown liquid (194.6 g) is obtained. The yield of two steps is 81%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:18][C:7]1[NH:8][C:9]2[C:5]([N:6]=1)=[C:4]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@H:12]1[CH3:17])[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: BrBr
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]c(Br)nc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 39.8 %

Procedure:
To a solution of 2-chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (950 mg, 3.74 mmol) in CH2Cl2(19 mL) was added bromine (0.23 mL, 4.49 mmol). The mixture was stirred at ambient temperature for 19 hours. Saturated sodium thiosulfate was added. The aqueous layer was extracted with dichloromethane two times. Organic layers were combined and dried over Na2SO4 and solvent was removed under reduced pressure. The crude was purified by flash column chromatography (0-70% EtOAc/cyclohexane gradient) to furnish product as a white solid (495 mg, 39%). LC-MS at 254 nm; [M+H] 334.1; Rt 0.89 min; (LCMS method 1).
Reaction SMILES: [C:1]([CH2:3][C:4]1[O:5][C:6](=[O:17])[C:7]2[C:13]([OH:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:8]=2[CH:9]=1)#[N:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C1(C)C=CC=CC=1>CN(C)C=O>[Si:23]([O:14][C:13]1[C:7]2[C:6](=[O:17])[O:5][C:4]([CH2:3][C:1]#[N:2])=[CH:9][C:8]=2[CH:10]=[C:11]([O:15][CH3:16])[CH:12]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(O)c2c(=O)oc(CC#N)cc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(O[Si](C)(C)C(C)(C)C)c2c(=O)oc(CC#N)cc2c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
2.70 g (11.68 mmol) of the 3-cyanomethyl-8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran obtained in Example 3 was suspended in 25 ml of dimethylformamide. 1.59 g (23.4 mmol) of imidazole and 2.82 g (18.7 mmol) of tert-butyldimethylsilyl chloride were successively added thereto under cooling with ice, and the resulting mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was mixed with toluene, washed once with 50 ml of a 10% aqueous solution of sodium chloride, and washed twice with 50 ml portions of a 20% aqueous solution of sodium chloride. The toluene layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo. The resulting residue was recrystallized from 20 ml of ethanol to obtain 3.77 g of the title compound in a 93% yield.
Reaction SMILES: [C:1]1([C:7](O)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[C:13]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:14][C:15]([SH:20])=[C:16]([O:18][CH3:19])[CH:17]=1.O>ClCCCl.[I-].[Zn+2].[I-]>[Cl:11][C:12]1[C:13]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:14][C:15]([S:20][C:7]([CH3:9])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[C:16]([O:18][CH3:19])[CH:17]=1
Reactant: CC(C)(O)c1ccccc1
Reactant: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: O
Product: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1SC(C)(C)c1ccccc1
Yield: 96.4 %

Procedure:
To a solution of 2-phenyl-2-propanol (0.45 g) in 1,2-dichloroethane (5 mL) were added zinc iodide (0.53 g) and a solution of 5-chloro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-mercaptoanisole (1 g) in 1,2-dichloroethane (5 mL) successively, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give 5-chloro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-(1-methyl-1-phenylethylthio)anisole (1.32 g). This material was dissolved in tetrahydrofuran (20 mL). To the solution was added hydrazine monohydrate (0.73 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. To the filtrate were added water and ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (0.74 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3)(=[O:21])[CH3:20]
Reactant: Nc1ccc2c3c1c(=O)c(C(=O)O)cn3CCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c3c1c(=O)c(C(=O)O)cn3CCC2

Procedure:
Using the method of Example 49, 10-amino-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is reacted with acetic anhydride to provide 10-acetamido-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >300° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=O)[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1ccccc1N1CCN(C(=O)OC(C)(C)C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
2.30 ml of a borane-tetrahydrofuran complex (1.2 mol/l) (2.76 mmol) was added to a solution of 303 mg of 4-[2-(3-methoxypropoxy)phenyl]-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10e) (0.77 mmol) in tetrahydrofuran (2.8 ml) under a nitrogen atmosphere and under ice-cooling over five minutes, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled in an ice bath. Then, 2.76 ml of a 1 N sodium hydroxide aqueous solution (2.76 mmol) was slowly added and the mixture was further stirred at room temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=30/1-10/1) to obtain 276 mg of the title compound (yield: 91%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[O:7][C@@H:6]1[CH2:29][O:30][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2]>N1C=CC=CC=1.O1CCCC1.F.N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[O:7][C@@H:6]1[CH2:29][OH:30])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)O[C@@H]1CO
Reaction time: 17 h
Yield: 91.3 %

Procedure:
To a solution of (2R,3S,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3-yl acetate (440 mg, 0.84 mmol) in pyridine/tetrahydrofuran (1:1, 3.4 mL) was added approximately 20 drops of hydrofluoric acid in pyridine (2.0 M). After stirring for 17 h, the reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via flash chromatography (40 to 100% EtOAc/hexanes) afforded 314 mg (91%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]1[CH2:37][CH2:36][N:35]2C(=NC[CH2:33][CH2:34]2)CC1>N1CCCCC1>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22]([N:35]3[CH2:34][CH2:33][CH2:27][CH2:37][CH2:36]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Solvent: C1CCNCC1
Product: COc1cc2c3c(cccc3c1N1CCCCC1)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-5-methoxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.5 g, 1.2 mmol, from Example Z) was reacted in piperidine (3 mL) in the presence of DBU (0.05 mL) following the procedure of Example 18 to give 0.3 g of 2-benzyloxy-5-methoxy-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-5-methoxy-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.3 g, 0.7 mmol) was performed as described in Example 18 to give 0.17 g of the title compound, mp 204-205° C.;
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH2:21][NH2:22])[CH2:13][CH2:12]1)[CH3:3].[CH3:26][CH:27]1[CH2:33][C:32](=O)[O:31][C:29](=[O:30])[CH2:28]1>C1COCC1>[CH3:26][CH:27]1[CH2:28][C:29](=[O:30])[N:22]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH:2]([CH3:1])[CH3:3])[CH2:12][CH2:13]3)[CH:19]=2)[C:32](=[O:31])[CH2:33]1
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN)c2)CC1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1CCOC1
Product: CC1CC(=O)N(Cc2cccc(CN3CCN(c4ccccc4OC(C)C)CC3)c2)C(=O)C1
Temperature: 100 °C

Procedure:
A solution of 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl amine (2.32 g, 6.84 mmol; prepared as described in Example 7), 3-methylglutaric anhydride (0.88 g, 6.84 mmol), and THF (20 mL) was stirred at room temperature for 3 h and then concentrated to an oily residue. This material was dissolved in acetic anhydride (25 mL), heated at 100° C. for 4 h, cooled, and added slowly to saturated aqueous NaHCO3. Extraction with CH2Cl2, separation of the organic layer, drying, filtration and evaporation afforded an oil. This material was chromatographed on flash grade silica using 97:3/CH2Cl2 :MeOH to give 4-methyl-1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]piperidine-2,6-dione as an oil. This was dissolved in ether and added to ethereal HCI causing a solid to form. Filtration afforded 4-methyl-1-[[3-[[ 1-[2-(1 -methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]piperidine-2,6-dione dihydrochloride (1.43 g, 40%), m.p. 196°-200° C. H-1 NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:34][C:35]([C:37]2[C:42](=[O:43])[N:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[CH:40]=[CH:39][N:38]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:16]=[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:10]=12.[CH:51](=O)[CH3:52].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]2[C:11]3=[N:12][CH:13]=[CH:14][C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:34][C:35]([C:37]5[C:42](=[O:43])[N:41]([C:44]6[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=6)[CH:40]=[CH:39][N:38]=5)=[O:36])=[CH:3][C:2]=4[F:1])=[C:10]3[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:51][CH3:52])[CH2:21][CH2:20]3)=[N:16]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(Cn2nc(CC3CCNCC3)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN1CCC(Cc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-(4-(1-(4-methoxybenzyl)-3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide (17 mg, 0.025 mmol; prepared as in Example 152, Step B) was added to a small round bottom flask and dissolved in dry THF (1.5 mL). Acetaldehyde (5.56 mg, 0.126 mmol) and a drop of acetic acid (d 1.049) were added. The reaction mixture was stirred for 10 minutes under N2(g) at room temperature. NaBH(OAc)3 (53.5 mg, 0.252 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was partitioned between water and DCM and extracted with a second portion of DCM (10 mL). The combined organics were dried over sodium sulfate and evaporated to afford desired product, used as crude in next step. Yield 18.6 mg, 90% purity by HPLC, 94%. LRMS (APCI pos) m/e 706.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:32][OH:33]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([NH:32][OH:33])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 76.8 %

Procedure:
3-(3-Ethoxy-4methoxyphenyl)-N-hydroxy-3-(3-nitrophthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propanoic acid (3.64 g, 8.86 mmol), N,N′-carbonyldiimidazole (1.50 g, 9.25 mmol) and hydroxylamine hydrochloride (672 mg, 9.67 mmol) in tetrahydrofuran (20 mL) to afford 3-(3-ethoxy-4methoxyphenyl)-N-hydroxy-3-(3-nitrophthalimido)propionamide as a yellow solid (2.92 g, 77% yield): mp, 162.5–163.5° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H, CH3), 3.02 (dd, J=7.5, 14.8 Hz, 1H, CHH), 3.17 (dd, J=8.3, 14.8 Hz, 1H, CHH), 3.72 (s, 3H, CH3), 4.00 (q, J=6.9 Hz, 2H, CH2), 5.68 (t, J=7.7 Hz, 1H, NCH), 6.87–6.96 (m, 2H, Ar), 7.01 (br s, 1H, Ar), 8.05 (t, J=7.7 Hz, 1H, Ar), 8.15 (d, J=7.0 Hz, 1H, Ar), 8.27 (d, J=7.8 Hz, 1H, Ar), 8.82 (s, 1H, OH), 10.62 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.66, 33.92, 50.59, 55.46, 63.74, 111.69, 112.59, 119.89, 122.48, 126.91, 128.43, 130.42, 133.13, 136.35, 144.33, 147.67, 148.67, 162.99, 165.70, 165.87. Anal. Calcd for C20H19N3O8+0.4 mole ethyl acetate: C, 55.83; H, 4.86; N, 8.96. Found: C, 55.86; H, 4.94; N, 8.73.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].F[C:13]1C=C[C:16]2C(C3CCNCC3)=N[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O:4][CH2:13][CH2:14][CH:15]([OH:19])[CH3:16])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Temperature: 25 °C

Procedure:
Racemic 3-hydroxybutyl tosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of the racemic tosylate (9.2 g, 37.7 mmol) in acetonitrile (190 ml) was added 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (8.3 g, 37.7 mmol) followed by milled potassium carbonate (7.8 g, 56.6 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 4.5 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc. The combined filtrates were concentrated to give the crude product. Purification via preparative HPLC (silica gel, 10% MeOH/EtOAc) afforded 6.3 g (57%), m.p.=100°-102° C.