Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][N:23]=[C:22]([NH2:25])[C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][N:23]=[C:22]([NH:25][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[C@H:3]3[OH:14])[C:21]=2[CH:26]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: Nc1noc2ccc(Cl)cc12
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Nc2noc3ccc(Cl)cc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-benzo[d]isoxazol-3-ylamine as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25]([CH2:26][C@@H:27]([OH:37])[CH2:28][CH2:29]2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[CH:16][CH3:17]>CC(C)=O>[CH3:14][C:15]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH2:28][CH2:29]2)[C:24](=[O:3])[CH2:23]3)[CH2:20][CH2:19]1)=[CH:16][CH3:17]
Reactant: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.75 h
Yield: 29 %

Procedure:
Jones reagent (2.67M, 2.0 ml. 5.3 mmol) was added to a solution of 20,21 -dimethylpregna-5,20-dien-3β-ol (6, 460.1 mg, 1.400 mmol) in 50 ml of acetone and the reaction was stirred 45 min. After quenching with 2-propanol (1.0 ml) the mixture was poured into 100 ml of water and extracted three times with 50 ml of ethyl acetate. The combined organic extracts were washed with 50 ml of saturated sodium bicarbonate+50 ml of brine, dried over magnesium sulfate, and filtered through Celite. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Flash chromatography (25% ethyl acetate/hexanes on silica gel) and recrystallization of the residue from 95% ethanol gave yellow needles (138.2 mg, 0.4059 mmol, 29%), m.p. 172-178° C.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+].Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]2[S:42][C:43]3[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=3[N:45]=2)=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[S:42]1[C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[N:45]=[C:41]1[C:38]1[CH:39]=[CH:40][C:35]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:36][CH:37]=1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: Brc1ccc(-c2nc3ccccc3s2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Cc1ccccc1N2c1ccc(-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.74 g of acridan (20 mmol), 69 mg of Pd(OAc)2 (0.3 mmol), 44 mg of tri-t-butylphosphine (0.22 mmol), 2.88 g of sodium t-butoxide (30 mmol), and 6.0 g of 2-(4-bromophenyl)benzothiazole (20 mmol) in 60 mL of toluene was stirred at room temperature for 1 h under inert atmosphere, followed by heating at 50° C. for 1 h. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography with 15% ethyl acetate in hexanes. NMR analysis confirmed that 3.1 g of the N-arylated acridan product was isolated.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31](O)=[O:32])[CH2:25][CH2:24]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>O1CCCC1>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[CH2:9][N:8]([C:31](=[O:32])[CH2:30][CH2:29][N:26]1[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]1)[CH2:7][CH2:6]2
Reactant: CN1CCN(CCC(=O)O)CC1
Reactant: O=Cc1cc2c(cc1O)CCNC2
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(CCC(=O)N2CCc3cc(O)c(C=O)cc3C2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 21.7 %

Procedure:
To a stirred mixture of 6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-7-carbaldehyde hydrobromide (82 mg, 0.46 mmol) and triethylamine (322 μL, 234 mg, 2.3 mmol) in anhydrous tetrahydrofuran (2 mL), 3-(4-methyl-piperazin-1-yl)-propionic acid (80 mg, 0.46 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (98 mg, 0.51 mmol) and 1-hydroxybenzotriazole (69 mg, 0.51 mmol) were added in the above order and the mixture was stirred at room temperature for 7 h. After evaporation, the residue was taken up in chloroform (10 mL) and washed with sat NaHCO3 (2×5 mL) and brine (5 mL). The organic phase was dried over MgSO4 and evaporated. The obtained crude product (94 mg) was purified by column chromatography on silica gel, eluting with CHCl3/MeOH 94/6 mixture. In this manner the title compound (33 mg, 0.10 mmol, 21%) was obtained.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:21][C:22]1[CH:23]=[C:24]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>C(#N)C>[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12][C:34]([NH:33][C:24]2[CH:25]=[CH:26][C:27]([N:28]3[CH2:29][CH:30]([OH:32])[CH2:31]3)=[C:22]([F:21])[CH:23]=2)=[O:35])[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(CN)n(-c2ccc(F)c(F)c2)n1
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(N3CC(O)C3)c(F)c2)n(-c2ccc(F)c(F)c2)n1
Yield: 46.4 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3,4-difluorophenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (85 mg, 0.282 mmol, 1.0 eq) in acetonitrile (6.7 mL) was added TEA (0.16 mL, 1.1 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (86 mg, 0.287 mmol, 1.02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (1:2) as eluent) to get 1-((3-tert-butyl-1-(3,4-difluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)urea (62 mg, 46%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH2:25][C@H:26]([NH:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH2:39][C:40]([F:43])([F:42])[F:41])[CH3:27])=[CH:19][C:20]=2[C:22]([NH2:24])=[O:23])[CH2:15][CH2:14]1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH2:25][C@H:26]([NH:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH2:39][C:40]([F:43])([F:41])[F:42])[CH3:27])=[CH:19][C:20]=2[C:22]([NH2:24])=[O:23])[CH2:15][CH2:14]1
Reactant: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCCOCc1ccccc1)CC2)NCCOc1ccccc1OCC(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCCO)CC2)NCCOc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of (R)-(-)-1-(4-benzyloxybutyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide (200 mg) in ethanol (3.3 ml) were added a 1N hydrochloric acid (0.8 ml) and 10% palladium on carbon (20 mg), and the mixture was stirred at room temperature for 4 hours under an atmosphere of hydrogen. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. To the concentrate were added water (12 ml) and sodium carbonate (106 mg), and the mixture was stirred for overnight at room temperature. The precipitated crystals were collected, washed with water, and dried at 50° C. under reduced pressure to give 160 mg of (R)-(-)-1-(4-hydroxybutyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide melting at 116°-118° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][F:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:17]([NH:16][CH:13]([CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)[CH2:14][F:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C(C(CF)NCc2ccccc2)CCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FCC(NCc1ccccc1)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a solution of 1-benzyl-3-(1-benzylamino-2-fluoroethyl)pyrrolidin-2-one (7.2 g, 22 mmol, Example 16) in tetrahydrofuran (100 mL) at 0° C. was added lithium aluminum hydride (1M in tetrahydrofuran, 22 mL) dropwise. After 1 hour, the mixture was warmed to room temperature and then quenched after 30 minutes with 0.84 mL water, 0.84 mL 15% sodium hydroxide solution and 2.5 mL water. The reaction mixture was then filtered and concentrated. The crude residue was purified by chromatography (97:3 to 90:10 dichloromethane/methanol) to give the title compound (2.5 g) as a mixture of diastereomers. MSCI: m/z=313 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12]1)=[O:10].[C:20]([S:23][CH2:24][CH2:25][C:26](Cl)=[O:27])(=[O:22])[CH3:21]>C(Cl)Cl>[CH3:7][O:8][C:9]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[C:26](=[O:27])[CH2:25][CH2:24][S:23][C:20](=[O:22])[CH3:21])=[O:10]
Reactant: COC(=O)C1Cc2ccccc2N1
Reactant: CC(=O)SCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2N1C(=O)CCSC(C)=O

Procedure:
To the mixture of 7.8 g of powdered potassium carbonate, 5.0 g of indoline-2-carboxylic acid methyl ester and 50 ml of methylene chloride, 4.7 g of 3-acetylthiopropanoyl chloride [Helv. Chim. Acta 40, 2148 (1957)] in 10 ml of methylene chloride are added at room temperature. After 1 hour the mixture is diluted with 100 ml of methylene chloride and washed with 50 ml of water, 50 ml of 1N hydrochloric acid and 50 ml of saturated aqueous sodium bicarbonate. The organic layer is dried and evaporated, to give the 1-(3-acetylthiopropanoyl)-indoline-2-carboxylic acid methyl ester as an oil, showing IR-bands at 1710, 1690 and 1640 cm-1.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([N:13]([CH3:20])C3C=CC=CC=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2].[C:23]1([C:29]2[CH:36]=[CH:35][C:32](CN)=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([NH:13][CH2:20][C:32]3[CH:35]=[CH:36][C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][CH:31]=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2]
Reactant: CSc1nc(N(C)c2ccccc2)n2ncc(C(C)C)c2n1
Reactant: NCc1ccc(-c2ccccc2)cc1
Solvent: CO
Product: CSc1nc(NCc2ccc(-c3ccccc3)cc2)n2ncc(C(C)C)c2n1

Procedure:
In a sealed tube, a solution of 8-isopropyl-4-(N-methyl-N-phenylamino)-2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazine (114 mg, 0.36 mmol) and of 4-phenylbenzylamine (100 mg, 0.55 mmol) is heated at 140° C. for 24 h. After cooling, the solvent is evaporated off. The crude compound collected is purified by flash chromatography (EP/Et2O 9:1) so as to give IIa.1 (95 mg, 67%). Mp=134-135° C. (MeOH). 1H NMR (300 MHz, CDCl3): δ 7.75 (s, 1H, Harom), 7.59-7.56 (m, 4H, Harom), 7.45-7.34 (m, 5H, Harom), 6.93 (bs, 1H, NH), 4.85 (d, 2H, J=5.7 Hz, CH2), 3.18 (hept, 1H, J=7.2 Hz, CH), 2.58, (s, 3H, CH3), 1.33 (d, 6H, J=7.2 Hz, 2 CH3). MS (EST): m/z 390 (MH′).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:41]=[CH:40][C:33]4[O:34][C:35]([CH3:39])(C)[O:36][CH2:37][C:32]=4[CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=[O:44]>O>[C:35]([O:34][C:33]1[CH:40]=[CH:41][C:30]([C@@H:28]([OH:29])[CH2:27][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:7])=[O:8])[CH:10]=2)=[CH:31][C:32]=1[CH2:37][OH:44])(=[O:36])[CH3:39]
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(=O)(=O)C4CCCC4)c3)ccc2O1
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)cc1CO

Procedure:
A stirred solution of (1R)-2-[(6-{4-[3-(Cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (110 mg) in glacial AcOH (5 ml) and water (0.3 ml) was heated at 85° C. for 40 min. The solution was evaporated to dryness and the residue was purified by Biotage™ column chromatography on silica using DCM-EtOH-ammonia (50:8:1) as eluent. The residue was dissolved in MeOH, treated with glacial AcOH and the solvent was removed to give the title compound (76 mg). LCMS RT=2.6 min ES+ve 548
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([OH:16])[CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>O.[OH-].[OH-].[Pd+2]>[C:17]1([C:11]2([OH:16])[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1(c2ccccc2)CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: OC1(c2ccccc2)CC2CCC(C1)N2
Yield: 76.1 %

Procedure:
8-Benzyl-3-phenyl-8-aza-bicyclo[3.2.1]octan-3-ol (0.24 g, 0.84 mmol) was dissolved in IMS (4.5 mL) and water (0.5 mL). Ammonium formate (0.5 g) and Pearlman's catalyst (0.12 g) were added. The mixture was heated to reflux for 0.5 hour, filtered and the solution concentrated to give an oil which was purified by chromatography on an SCX cartridge eluting with ammonia (2 M) in methanol. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.13 g) as an oil.
Reaction SMILES: [F:1][C:2]1[C:10](I)=[C:9]2[C:5]([CH2:6][N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[C:8]2=[O:12])=[CH:4][CH:3]=1.[CH3:25][N:26](C=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[C:8](=[O:12])[C:9]=2[C:10]=1[C:25]#[N:26]
Reactant: CN(C)C=O
Reactant: O=C1c2c(ccc(F)c2I)CN1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: N#Cc1c(F)ccc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
A mixture of 6-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-one (0.100 g, 0.22 mmol), PdCl2(dppf)2 (0.008 g, 0.011 mmol), zinc cyanide (0.051 g, 0.44 mmol), and zinc (0.007 g, 0.011 mmol) in DMF (5 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate afforded 5-fluoro-3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.015 g, 19%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.31 (s, 2H), 4.81 (s, 2H), 7.19 (d, 2H), 7.37 (m, 3H), 7.64 (m, 1H). GC-MS: m/z 350 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.[I:22]I>C1(C)C=CC=CC=1.C1COCC1.CCCCCC.C1CCCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][C:7]=1[I:22]
Reactant: II
Reactant: CCCc1ccc(-c2cccc(F)c2)cc1
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CCCc1ccc(-c2ccc(I)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 3-fluoro-4′-propylbiphenyl (T-1) (23.1 g) and THF (250 ml) were added, and cooling was carried out to −74° C. Thereto, a sec-butyllithium (1.06 M), cyclohexane, n-hexane solution (122 ml) was added dropwise in a temperature range of −74° C. to −70° C., and stirring was carried out for another 2 hours. Subsequently, a THF (200 ml) solution of iodine (35.6 g) was added dropwise in a temperature range of −75° C. to −70° C., and stirring was carried out for 6 hours while returning to room temperature. The resultant reaction mixture was poured into ice water (500 ml), and mixing was carried out. Toluene (400 ml) was added to separate layers into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with an aqueous solution of sodium thiosulfate and water, and drying over anhydrous magnesium sulfate was carried out. The resultant solution was concentrated under reduced pressure, and a residue was purified by means of column chromatography (silica gel; heptane), and further purified by recrystallization from Solmix A-11, and thus 3-fluoro-4-iodo-4′-propylbiphenyl (T-2) (25.4 g) was obtained. The yield based on compound (T-1) was 69%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][C:13]=1[CH2:23][OH:24].C(N(CC)CC)C>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][C:13]=1[CH:23]=[O:24]
Reactant: Cc1c(CO)cnn1-c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(C=O)cnn1-c1ccccn1
Temperature: -78 °C
Yield: 100 %

Procedure:
Dissolve dimethyl sulfoxide (0.751 mL, 10.6 mmol) in DCM (20 mL) and cool to −78° C. Add oxalyl chloride (0.577 mL, 6.62 mmol) dropwise in DCM (8 mL) and stir for 15 min. Add (5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-methanol (0.501 g, 2.65 mmol) in DCM (20 mL) dropwise and stir for 1 hr. at −78° C. Add triethylamine (1.85 mL, 13.2 mmol) and warm the mixture to room temperature for 1 hr. Dilute the mixture with saturated sodium bicarbonate and extract three times with DCM. Dry (sodium sulfate) the solution, filter and concentrate to give 5-methyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde as a white solid (0.496 g, 100%). MS (m/z): 188 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 103 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.37–7.23 (m, 14H), 6.93 (d, 1H, J=7.6 Hz), 6.20 (br s, 1H), 3.37 (dd, 2H, J=6.4, 12.4 Hz), 2.89 (d, 2H, 7.2 Hz), 2.45 (m, 1H), 2.30 (m, 2H), 2.18 (s, 3H), 2.01 (s, 3H), 1.94 (t, 2H, J=11.6 Hz), 1.76–1.53 (m, 6H); ESMS m/e: 484.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)=[CH:29][CH:28]=1.ClC(Cl)C.C(O)(=O)C.[Na].C([O-])(O)=O.[Na+]>C1CCCCC1.CCOC(C)=O.C(Cl)Cl>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][N:22]3[CH2:21][CH2:20][CH:19]([C:3]4[CH:4]=[C:5]([NH:8][C:9]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[O:10])[CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:24][CH2:23]3)=[CH:36][CH:35]=2)=[CH:31][CH:32]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1C1CCNCC1
Reactant: COc1ccc(Sc2ccc(C=O)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COc1ccc(Sc2ccc(CN3CCC(c4cc(NC(=O)OCc5ccccc5)ccc4C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
A mixture of N-(4-methyl-3-(4-piperidyl)phenyl)(phenylmethoxy)carboxamide (324 mg, 1.00 mmol) and 4-(4-methoxyphenylthio)benzaldehyde (244 mg, 1.00 mmol), dichloroethane (5.00 mL), acetic acid (60.0 mg, 1.00 mmol) and sodium triacetoxborohydride (424 mg, 2.00 mmol) was stirred under nitrogen at room temperature for 18 h. Saturated NaHCO3 solution and CH2Cl2 was added. The mixture was separated, and the organic layer was washed with water (10 mL), dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (eluent: cyclohexane:EtOAc (85:15 then 7:3)) gave N-[3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenyl](phenylmethoxy) carboxamide (486 mg, 88.0% yield) as a white foam. ESMS m/e: 553.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[NH2:21].[S]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[NH:20][C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([CH3:13])[C:15]=4[N:21]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=Cc1n[nH]c2ncc(Br)cc12
Agent: [S]
Solvent: CN(C)C=O
Product: Cc1cccc2[nH]c(-c3n[nH]c4ncc(Br)cc34)nc12
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde Compound 5a (50 mg, 0.22 mmol) and 3-methyl-benzene-1,2-diamine Compound 5b (27 mg, 0.22 mmol) and sulfur (9 mg, 0.28 mmol) in DMF (1 mL) was heated to 100° C. overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% to 50% of ethyl acetate in hexanes) to yield 5-bromo-3-(4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine Compound 5c (50 mg, 69% yield) as a grey powder. 1H NMR (400 MHz, MeOD) δ 9.03 (s, 1H), 8.68 (s, 1H), 7.18 (t, 1H, J=8.4 Hz), 7.09 (m, 2H), 2.69 (s, 3H); MS (ESI) m/z: 329 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:14]1([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:6]([CH2:5][CH:4]([OH:13])[CH2:3][CH2:2][N:17]1[CH2:16][CH2:15][N:14]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:25]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccccc1
Product: CC(=O)Nc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
Following the procedure of Example 25, the title compound is prepared from 4-chloro-1-phenoxy-2-butanol and N-[4-(1-piperazinyl)phenyl]acetamide.