Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.C(OCC)(=O)C>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N

Procedure:
To a Paar bottle (250 mL) was added 10% Palladium on Carbon (50% Wet) followed by a solution of 1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-4-methyl-piperazine (0.90 g, 0.0027 mol) in 2:1 Ethyl acetate:Methanol (100 mL). The mixture was degassed and charged with Hydrogen (50 psi). The reaction was shaken until equilibrium had been reached. A total of 25 psi of Hydrogen was adsorbed. The mixture was degassed and kept under an atmosphere of Nitrogen. The suspension was filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated to yield a light purple solid 2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine. (0.82 g). mp=94-99° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 6.63 (d, 1H, J=8.3 Hz), 6.52 (d, 1H, J=1.5 Hz), 6.44-6.39 (m, 1H), 3.83 (s, 3H), 3.75-3.25 (m, 4H), 2.80-2.25 (m, 14H), 1.96-1.87 (m, 2H), 1.78-1.65 (m, 2H). LC/MS=305.16 (MH)+
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:14]1.I[CH3:31]>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]1[CH2:18][C@@H:17]([O:19][CH3:31])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:14]1
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H](CN2C(=O)c3ccccc3C2=O)C1
Reactant: CI
Solvent: ClCCl
Product: CO[C@@H]1C[C@H](CN2C(=O)c3ccccc3C2=O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.6 %

Procedure:
To cis-phenylmethyl (3RS,5SR)-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-hydroxy-1-piperidinecarboxylate (380 mg, 0.96 mmol) in 5 mL of CH2Cl2 was added iodomethane (1 mL, 16.1 mmol) and Ag2O (1.15 g, 5.0 mmol). The reaction was allowed to stir at room temperature under nitrogen for 48 h. The reaction mixture was filtered through a pad of Celite® which was washed with 25 mL CH2Cl2, and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel using a 10-100% EtOAc/hexanes gradient to provide the desired compound (210 mg; 53%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:22]([CH3:25])=[N:23][N:24]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([CH2:20]O)[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:6]=2[CH:7]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[C:3]2[N:4]([C:22]([CH3:25])=[N:23][N:24]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([CH2:20][N:28]4[CH2:29][CH2:30][CH2:27][CH2:26]4)[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:6]=2[CH:7]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc2c(cc(Br)c3nnc(C)n32)n1Cc1cc(Cl)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNC1
Solvent: ClCCl
Product: Cc1cc2c(cc(Br)c3nnc(C)n32)n1Cc1cc(Cl)cc(CN2CCCC2)c1
Reaction time: 0.5 h

Procedure:
A solution of {3-[(4-bromo-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]-5-chlorophenyl}methanol (0.360 g, 0.858 mmol, from Step 4) in DCM (50. mL) was treated with triethylamine (510 μL, 3.6 mmol) and methanesulfonyl chloride (220 μL, 2.9 mmol, Aldrich). After 30 minutes, the solvent was removed in vacuo, and the residue was dissolved in a mixture of THF (20. mL) and methanol (20. mL). The solution was added to a mixture of pyrrolidine (0.42 mL, 5 mmol, aldrich) and triethylamine (0.61 mL, 4.3 mmol) in THF (10 mL). The reaction was stirred for 1 hour, and then the solvent was removed in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-10% MeOH in DCM, was used to purify product. Yield: (0.30 g, 74%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=4)[C:20]#[N:21])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1.[OH-:25].[K+].[Cl-].[NH4+]>CC(O)(C)C.CS(C)=O>[CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=4)[C:20]([NH2:21])=[O:25])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2[nH]c3ccc(Cc4cccc(C#N)c4)cc3c(=O)c21
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: Cn1ncc2[nH]c3ccc(Cc4cccc(C(N)=O)c4)cc3c(=O)c21
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 51.7 %

Procedure:
A mixture of 3-[(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]benzonitrile (EXAMPLE 28, step 2, 100 mg, 0.32 mmol) and powdered potassium hydroxide (89 mg, 1.59 mmol) in 2-methyl-2-propanol (5 ml) and dimethylsulfoxide (2 ml) was stirred at 65° C. for 4.5 h. After cooling to room temperature, the mixture was poured into saturated aqueous ammonium chloride (50 ml), and the precipitate was collected by filtration. This yellow powder was washed with water, methanol and dichloromethane to give 55 mg (52%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]1[C:14]([C:15]([CH2:17]Br)=[O:16])=[CH:13][CH:12]=[C:11]([F:19])[CH:10]=1>C1COCC1>[F:19][C:11]1[CH:12]=[CH:13][C:14]([C:15](=[O:16])[CH2:17][NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(CNc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1.3 mL 4-fluoroaniline was added to 1 g 2-bromo-4-fluoroacetophenone in 20 mL THF. The reaction was stirred 3 h at RT and 4 h at 40° C. The mixture was filtered and the filtrate diluted with ethyl acetate and extracted with water. The organic layer was dried and evaporated. Diisopropylether was added to the residue. The precipitate was filtered and dried to yield 0.42 g desired product. Rt: 1.53 min (method B), (M+H)+: 248
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][C@@H:13]2[O:16][C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:12]2[CH2:11]1)([O-])=O>CCO.CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][C@@H:13]2[O:16][C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@@H:12]2[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3[N+](=O)[O-])C[C@H]21
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3N)C[C@H]21
Yield: 95 %

Procedure:
Following Method 2 of Example 49, (3aR,7aS)-tert-butyl 5-(3-nitropyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate in EtOH and EtOAc (1:1, 0.15 M) was reduced yielding (3aR,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate in >95% yield. LCMS (m/z): 335.0 (MH+), LC Rt=1.68 min.
Reaction SMILES: CO[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.[C:16](#[N:18])[CH3:17].[H-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:14][C:4]([CH3:13])([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[C:3](=[O:15])[CH2:17][C:16]#[N:18]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)COC1CCCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(COC1CCCCO1)C(=O)CC#N
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester (7.67 g, 35.46 mmol) and acetonitrile (2.6 mL, 49.65 mmol) in toluene (20 mL) is added dropwise to the refluxing suspension of 60% sodium hydride in mineral oil (1.99 g, 49.65 mmol) in toluene (40 mL). After the addition, the reaction mixture is stirred at reflux for 3 hours. After this time, the reaction mixture is cooled to room temperature and the aqueous layer is neutralized to PH˜6-7 by adding 1N hydrochloric acid aqueous solution. The layers are combined and the aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the title compound. It is used without purification.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.Br[C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[F:24].C(N(CC)C(C)C)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(=O)([O-])[O-].[Ag+2]>[F:24][C:15]1[CH:14]=[CH:19][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:17][C:16]=1[CH:3]1[CH:4]=[CH:5][N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2]1
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Agent: [Ag+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C=CC(c2cc(C(F)(F)F)ccc2F)C1

Procedure:
A deoxygenated solution of tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (3.38 g, 20.0 mmol, 10.0 equiv), 2-bromo-1-fluoro-4-(trifluoromethyl)benzene (486 mg, 2.00 mmol, 1 equiv), N,N-diisopropylethylamine (1.39 mL, 8.00 mmol, 4.00 equiv), tri-o-tolylphosphine (67 mg, 0.22 mmol, 0.11 equiv), palladium(II) acetate (22 mg, 0.10 mmol, 0.050 equiv), and silver carbonate (386 mg, 1.40 mmol, 0.700 equiv) in DMF (8.0 mL) was heated under nitrogen at 100° C. for 20 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography (20% CH2Cl2 in hexanes, grading to 50% CH2Cl2 in hexanes) to give tert-butyl 3-[2-fluoro-5-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrole-1-carboxylate (3-1) as a colorless gum. 1H NMR (500 MHz, CDCl3) major rotamer: δ 7.51 (m, 2H), 7.15 (t, 1H, J=9.1 Hz), 6.74 (br s, 1H), 5.03 (br s, 1H), 4.48 (m, 1H), 4.17 (m, 1H), 3.61 (m, 1H), 1.50 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Li+].CC([N-]C(C)C)C.B(OC)(OC)[O:18]C>C1COCC1.CCCCCCC.C1COCC1>[OH:18][C:7]1[C:2]([F:1])=[N:3][C:4]([F:8])=[CH:5][CH:6]=1
Reactant: Fc1cccc(F)n1
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Oc1ccc(F)nc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 2, 6-difluoropyridine (6.7 mL, 73.8 mmole) in THF (100 mL, cooled to -78° C.) was added a 2M solution of LDA in heptane/THF/ethylbenene (38 mL, 76 mmol). The mixture was stirred at -78° C. for 1 hour, and trimethyl borate (6.8 mL, 89.7 mmol) was added. The mixture was stirred for 1 hour and allowed to warm to 20° C., then the reaction was quenched with HOAc (10 mL). The solution was made basic with 20% aq NaOH (20 mL), H2O2 (50%, 200 mL) was added, and the mixture stirred for 16 hours. The mixture was neutralized by addition of HCl (2M, aq) and extracted with EtOAc. The combined EtOAc extracts were dried (MgSO4). The solvent was evaporated under vacuum, and the crude product was chromatographed (silica gel; hexane/EtOAc 9:1 to 6:4) to yield 2.7g (28%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ: 6.75 (dd, J=3.0, 5.5 Hz, 1H), 7.48 (m, 1H). MS (DCI/NH3) m/e 149 (M+NH4)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21]>>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C#N)cc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (30 mg, 35%), MS (ISP) m/z=341.6 [(M+H)+], mp 314° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a suspension of O-tert-butyl N-(piperidin-4-yl)carbamate (4.0 g) in dichloromethane (40 ml) were added pyridine (1.94 ml), dichloromethane (40 ml), acetic anhydride (20.8 ml) and then N,N-dimethylaminopyridine (0.1 g) at ambient temperature. After stirring for 3 hours, the mixture was washed with 0.1N hydrochloric acid, water, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. After rinse with diisopropyl ether, O-tert-butyl N-(1-acetylpiperidin-4-yl)carbamate (4.01 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14]CC2C=CC=CC=2)=[O:13])=[O:8])=[CH:3]1>O1CCCC1.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:3]1
Reactant: Cn1ccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1ccc(C(=O)NCCC(=O)O)c1
Reaction time: 72 h
Yield: 84 %

Procedure:
5%-palladium/carbon (716 mg) was added to a solution of Compound 3 (7.16 g, 25 mmole) in tetrahydrofuran (hereinafter called “THF”) (300 ml), followed by stirring for 72 hours under a hydrogen gas stream. The reaction mixture was filtered, and the solid was washed with methanol. The filtrate and the washing were combined, followed by concentration under reduced pressure. The residue was recrystallized from acetonitrile, whereby the title compound (4.14 g) was obtained (yield: 84%).
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC=CC=1)([O-])=O.[NH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].Cl>O.C(#N)C>[C:18]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CC#N
Product: C=C(C)C(=O)NCCC(=O)O
Temperature: 0 °C
Yield: 45.2 %

Procedure:
In a mixture composed of 80 g (2.0 mols) of sodium hydroxide, 400 ml of water and 4 ml of nitrobenzene was dissolved 178 g (2.0 mols) of β-alanine with stirring and the resulting solution was cooled to 0° C. To the aqueous solution, there were simultaneously added dropwise 230 g (2.2 mols) of methacrylic chloride and an aqueous solution containing 96 g (2.4 mols) of sodium hydroxide dissolved in 200 ml of water. After the completion of the reaction, 800 ml of acetonitrile was added to the reaction solution and the mixture was then acidified by adding 160 ml of concentrated hydrochloric acid. 1 Liter of acetonitrile was further added to extract and the acetonitrile layer was separated. The acetonitrile solution was concentrated and the crystals thus deposited were collected and recrystallized from ethyl acetate to obtain 142 g of N-methacryloyl-β-alanine.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Cl:9][C:10]1[C:24]([Cl:25])=[CH:23][C:13]2[NH:14][C:15]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[N:16][C:12]=2[CH:11]=1>C1COCC1>[Cl:25][C:24]1[C:10]([Cl:9])=[CH:11][C:12]2[NH:16][C:15]([C:17]([OH:22])([C:18]([F:21])([F:19])[F:20])[CH2:2][C:1]#[N:3])=[N:14][C:13]=2[CH:23]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of dry acetonitrile (0.4 mL) in THF (10 mL) at −78° C. was added n-BuLi (2.9 mL of 2.5 M in hexanes). The resulting mixture was stirred for 45 min. at −78° C. To the solution was then added a solution of 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (930 mg) in THF (5 mL). The resulting mixture was stirred at −78° C. for 1 hr. The reaction was quenched with NH4Cl (aq) and the resulting mixture extracted with EtOAc. The combined extracts were washed with brine and dried over Na2SO4. The resulting crude material was purified by column chromatography (SiO2; 0-15% ethyl acetate/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Br[CH2:46][CH2:47][CH2:48][C:49](Cl)=[O:50].[H-].[Na+]>C1COCC1.C(Cl)Cl.CCOC(C)=O.O>[CH3:35][C:20]1[C:21]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:34])=[CH:22][CH:23]=[CH:24][C:19]=1[C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([CH2:2][N:1]4[CH2:46][CH2:47][CH2:48][C:49]4=[O:50])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Reactant: O=C(Cl)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN5CCCC5=O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 4.3 %

Procedure:
A solution of 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 80 mg, 0.087 mmol) in THF (3 mL) was treated with DIEA (0.030 mL, 0.174 mmol) and a solution of 4-bromobutanoyl chloride (10 μL, 0.087 mmol) in DCM (1 mL) and the mixture was stirred at rt for 35 min. The reaction mixture was diluted with EtOAc, washed with NaHCO3 (aq) and brine, and dried and concentrated. The residue was dissolved in THF (6 mL) and treated with sodium hydride (60% oil dispersion, 24.32 mg, 0.608 mmol). The resulting mixture was stirred at 50° C. for 2 h, then was diluted with water and extracted with EtOAc. The organic phase was dried and concentrated, and the residue was purified by preparative HPLC to provide 4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-7-((2-oxopyrrolidin-1-yl)methyl)-9H-carbazole-1-carboxamide as a white solid (2 mg, 3%). 1H NMR (400 MHz, DMSO-d6) δ 11.44 (1H, s), 8.11 (1H, br. s.), 7.95 (1H, d, J=7.9 Hz), 7.73 (1H, d, J=7.5 Hz), 7.62 (2H, d, J=3.7 Hz), 7.46-7.57 (3H, m), 7.42 (2H, t, J=7.7 Hz), 7.23-7.29 (1H, m), 6.90-6.99 (2H, m), 6.74 (1H, dd, J=8.1, 1.5 Hz), 4.79-5.00 (2H, m), 4.25-4.51 (2H, m), 3.11-3.22 (2H, m), 2.19-2.29 (2H, m), 1.80-1.93 (2H, m), 1.77 (3H, s). Mass spectrum m/z 529.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[H-].[Na+].[CH2:11]1[O:33][C:32]2[CH:31]=[CH:30][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:26](Cl)(=[O:28])=[O:27])=[CH:14][C:13]=2[O:12]1>C1COCC1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:26]([C:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[S:21][C:17]=2[CH2:16][C:15]2[CH:30]=[CH:31][C:32]3[O:33][CH2:11][O:12][C:13]=3[CH:14]=2)(=[O:28])=[O:27])[O:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12
Reactant: Cc1noc(N)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ccccc23)c1C

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-methylenedioxybenzyl)benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 3,4-dimethyl-5-aminoisoxazole (1.0 mmoles, 0.11 g), NaH (2.5 mmoles, 60 mg) and 2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonylchloride (1.1 mmoles, 0.40 9) in THF (6 ml) yielded, after flash chromatography using 50% ethyl acetate/hexanes followed by recrystallization from chloroform and hexanes, 0.35 g (79%) of a tan solid, m.p. 135-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CC(O)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH:17][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Fc1ccc(CNCc2cc(Cl)cc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dichlorobenzaldehyde (3.9 g, 22.3 mmol) in 2-propanol (20 mL) and CH2Cl2 (20 mL) was added 4-fluorobenzylamine (2.93 mL, 25.6 mmol). The resulting mixture was stirred at rt for 1 h. The mixture was cooled to ice bath temperature and was treated with sodium triacetoxyborohydride (7.56 g, 35.7 mmol) under N2 atmosphere. The resulting mixture was stirred at rt for 22 h. To the reaction mixture was added saturated aq NaHCO3 solution and it was stirred for 0.2 h, and concentrated in vacuo. The residue was mixed with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash silica gel column chromatography on silica gel to obtain (ISCO. Condition: 40 g column. Eluents: 0-6% of B, gradient, solvent A: CH2Cl2, solvent B: ethyl acetate (5% 2 M ammonia in MeOH). 35 min run. The desired product peak came from 5 min to 15 min) the desired product as a colorless oil (5.6 g, 80%). 1H NMR (CDCl3): δ 7.34-7.27 (m, 5H), 7.08-7.03 (m, 2H), 3.78 (s, 2H), 3.77 (s, 2H), 1.85 (bs, 1H); MS (ESI): [M+H]+=284.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.CCOCC>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][O:20][C:16]1[CH:15]=[C:14]([CH2:13][OH:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OCc1cccc(O)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OCc1cccc(OCCCBr)c1
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
1,3-dibromopropane (23 mL, 0.22 mol) is gradually added to a suspension of K2CO3 (3.2 g, 23 mmol) and 3-(hydroxymethyl)phenol (5 g, 40.3 mmol) in dimethylformamide (DMF) (30 mL) stirred beforehand for 5 min at 65° C. The reaction medium is maintained under stirring for 45 min at the same temperature. After cooling to room temperature (RT), Et2O (150 mL) is added and the organic phase is extracted 4 times with a saturated NaCl aqueous solution. The organic phase is dried on Na2SO4. After evaporation of the solvent under reduced pressure, a viscous colorless oil is obtained (6.7 g, 68%) which gradually crystallizes.