Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH3:31])[C:18](=[O:32])[N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:22]1[C:21]2[C:20](=[O:30])[N:19]([CH3:31])[C:18](=[O:32])[N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:16]=2[N:15]=[C:14]1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2Cl)n(CC(=O)O)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(nc(N3CCNCC3)n2-c2ccccc2Cl)n(CC(=O)O)c1=O

Procedure:
4-[7-(2-Chlorophenyl)-3-carboxymethyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (26 mg) was dissolved in trifluoroacetic acid, and was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 10.73 mg of the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH:8]1([N:11]2[C:15]3[C:16]([O:34][C@@H:35]([C@H:37]4[CH2:41][NH:40][C:39](=[O:42])[CH2:38]4)[CH3:36])=[N:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[C:22]([O:32][CH3:33])[CH:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:3]([N:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]3[N:17]=[C:16]([O:34][C@@H:35]([C@H:37]4[CH2:41][NH:40][C:39](=[O:42])[CH2:38]4)[CH3:36])[C:15]4[N:11]([CH:8]5[CH2:10][CH2:9]5)[CH:12]=[N:13][C:14]=4[CH:19]=3)=[CH:21][C:22]=2[O:32][CH3:33])[CH2:27][CH2:28]1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an appropriate sized vial the trifluoroacetic acid salt of (R)-4-((R)-1-((3-cyclopropyl-6-(3-methoxy-4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: 3.51 (80 mg, 0.085 mmol) and triethylamine (52 mg, 0.51 mmol) were dissolved in DCM (4 mL). To this mixture acetic anhydride (10.5 mg, 0.1 mmol) was added and the mixture was stirred at room temperature for 30 min. After reaction was complete the solution was concentrated under reduced pressure and the residue was purified via prep HPLC (2-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer) to provide (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: 3.52 as its trifluoroacetic acid salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[C:12]2[O:13][C:14]3[C:19]([Si](C)(C)C)=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[I:31]Cl>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[C:12]2[O:13][C:14]3[C:19]([I:31])=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc2c1oc1c([Si](C)(C)C)cccc12
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=Cc1cccc2c1oc1c(I)cccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 126 %

Procedure:
A flame-dried, 1 L round-bottomed flask was cooled under Ar and charged with ethyl-6-trimethylsilyl -4-dibenzofuranacrylate (6) (11.37 g, 33.6 mmol), anhydrous K2CO3 (14.22 g, 102.9 mmol), and anhydrous CCl4 (230 mL). The solution was allowed to cool to 0° C. The ICl (5.0 mL, 95.5 mmol) was transferred via a teflon canula to a septum capped graduated cylinder which had been flame-dried under Ar and charged with anhydrous CCl4 (34 mL). The resulting 2.8 M solution was then transferred to the cold reaction flask via the teflon canula. The graduated cylinder and canula were rinsed with an additional 5 mL portion of CCl4. The red wine colored solution was allowed to warm to room temperature and stirred in darkness overnight. The reaction mixture was poured into 500 mL of a 20% Na2S2O3 solution and vigorously stirred. Additional solid Na2S2O3 was added and the mixture was stirred until very pale yellow. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×200 mL). The combined organic layers were washed with 20% Na2S2O3 (3×500 mL), 10% HCl (2×500 mL), 1N NaOH (3×500 mL), and H2O (1×500 mL). The colorless organic layer was then dried over MgSO4 (solution became pale pink) and concentrated in vacuo to give 16.60 g of beige solid. After further drying under high vacuum, the solid was crushed and stirred in a minimal amount of hexanes and ethyl acetate solution (95:5) for 2 hours. This resulted in the removal of the pink color and isolation of a white solid. Drying under high vacuum afforded 12.5 g (95%) of white solid: mp 114-116° C.; 1H NMR (d6-acetone) d 8.15 (dd, Jo=7.7, Jm=1.1, 1H, Ar H8), 8.14 (dd, Jo=7.7, Jm=1.1, 1H, Ar H7), 7.96 (d, J=16.1, 1H, --CHCHCO2Et), 7.95 (d, Jo=7.8, 1H, Ar H9), 7.82 (dt, Jo=7.7, Jp=0.6, 1H, Ar H1), 7.48 (t, Jo=7.6, 1H, Ar H3), 7.25 (t, Jo=7.7, 1H, Ar H2), 7.15 (d, J=16.1, 1H, --CHCHCO2Et), 4.29 (q, J=7.1, 2H, --CO2CH2CH3), 1.34 (t, J=7.1, 3H, --CO2CH2CH3); 13C NMR (d6-acetone) d 167.52, 150.05, 139.50, 137.77, 130.41, 126.59, 126.48, 125.21, 125.03, 124.50, 123.40, 122.41, 121.02, 76.29, 69.67, 61.38, 15.04; MS +FAB (NBA) m/z 393.0001, [M+H]+ calcd for C17H13O3I 392.9988.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5]1.[H-].[Na+].[Cl:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[CH:22][N:21]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([O:1][CH2:2][CH2:3][N:4]2[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:5]2)[CH:23]=[CH:22][N:21]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: O=c1ccc(-c2ccccc2)nn1CCO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2ccccc2)nn1CCOc1ccnc(Cl)c1
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
To a 15 mL round-bottomed flask was added 2-(2-hydroxyethyl)-6-phenylpyridazin-3(2H)-one (0.20 g, 0.92 mmol) and N,N-dimethylformamide (5 mL). To the mixture at 25° C. was added sodium hydride (0.039 g, 1.0 mmol, 60% dispersion in mineral oil). The solution was stirred for 5 min and then 2-chloro-4-fluoropyridine (0.17 g, 1.3 mmol) was added. After stirring for 2 hours the mixture was poured into aq. NaHCO3 (100 mL) and then extracted with 50% EtOAc/hexane (3×75 mL). The combined extracts were washed with H2O (3×75 mL) and brine (75 mL), dried (Na2SO4), and concentrated onto silica. Purification by silica gel chromatography (40 to 90% EtOAc/hexane) afforded the title compound as a white solid (0.24 g, 78% yield). MS (ESI, pos. ion.) m/z: 328 (MH+). Calc'd exact mass for C17H14ClN3O2: 327. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 (t, J=5.0 Hz, 2 H), 4.61 (t, J=5.1 Hz, 2 H), 7.00 (dd, J=5.9, 2.3 Hz, 1 H), 7.08 (d, J=9.8 Hz, 1 H), 7.14 (d, J=2.2 Hz, 1 H), 7.44-7.51 (m, 3 H), 7.85-7.87 (m, 2 H), 8.06 (d, J=9.8 Hz, 1 H), 8.18 (d, J=5.9 Hz, 1 H).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C>C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: BrCCBr
Reactant: c1ccc2c(c1)CCN2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: BrCCN1CCc2ccccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 1,2-dibromoethane (58.0 ml) were added indoline (5.0 g) and triethylamine (28.7 ml), and the mixture was stirred at 90° C. for 2 hr. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with saturated brine (400 ml) and dried over Na2SO4. Ethyl acetate was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (4.09 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](SC)[N:3]=1.OO.Cl.[CH3:23][CH:24]([CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[CH3:25].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(N(CC)CC)C.O1CCOCC1>[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:27]2[CH2:28][CH2:29][CH2:30][CH:26]2[CH:24]([CH3:25])[CH3:23])[N:3]=1
Reactant: CC(C)C1CCCN1
Reactant: CSc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Agent: Cl
Agent: OO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1CCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.25 g, 0.92 mmol) in TFA (8.74 mL) at 0° C. was added aqueous H2O2 (0.375 mL, 3.67 mmol, 30% (w/w)) dropwise over 2 minutes. Upon completion of the addition, the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was cooled back to 0° C. and quenched with dimethyl sulfide (0.54 mL, 7.34 mmol, dropwise addition). The reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled to 0° C. and diluted with Et2O (5 mL) Et2O and hexane (15 mL). The resulting orange precipitate was filtered and transferred to a 25 mL sealable tube under nitrogen. 1,4-Dioxane (5.83 mL), 2-(1-methylethyl)pyrrolidine hydrochloride (0.275 g, 1.84 mmol), and triethylamine (0.51 mL, 3.67 mmol) were added, the tube was sealed, and the reaction mixture was stirred overnight at 95° C. Since LCMS showed a minimal amount of product, additional triethylamine (1 mL) was added, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and decanted. The solution was concentrated, and the resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O w/0.1 mL TFA. The resulting mixture was filtered through a 0.45μ frit and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA) to afford a TFA salt of the title compound (12 mg) as a yellow solid as a mixture of rotamers. LC-MS (ES) m/z=338 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.99 (m, 6H), 1.79-2.04 (m, 4H), 3.58-3.88 (m, 3H), 4.26 (m, 1H), 4-5 (bs), [6.59 (s) and 6.65 (s)] (1H), [7.33 (d, J=8.6 Hz) and 7.37 (d, J=8.6 Hz)] (1H), [7.69 (s) and 7.73 (s)] (1H), 7.91 (d, J=8.6 Hz, 1H), 12.04 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[OH:12].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([S:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:22][CH:21]=2)[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1O
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 98.2 %

Procedure:
A mixture of 2-Methyl-4-nitro-5-chloro phenol (1.5 g, 8.0 mmol), 4-Acetamido thiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74 g, 17.6 mmol) in DMF (10 mL) was heated 2.5 h at 100° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer washed with water and aqueous 10% sodium chloride solution, then, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent removed under vacuum leaving the title compound as a solid (2.5 g, 81%).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].C1(CCNC(C2N=NC(N3CC4C(C4N)C3)=CC=2)=O)CC1.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](Cl)=[O:48]>>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:47](=[O:48])[C:46]3[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=3[C:44]([F:43])([F:54])[F:55])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCC(N)CC2)nn1
Agent: NC1C2CN(c3ccc(C(=O)NCCC4CC4)nn3)CC12
Product: CC(C)CCNC(=O)c1ccc(N2CCC(NC(=O)c3ccccc3C(F)(F)F)CC2)nn1
Yield: 29 %

Procedure:
Following the procedure as described in Example 4, making variations only as required to use 6-(4-aminopiperidin-1-yl)pyridazine-3-carboxylic acid (3-methylbutyl)amide to replace 6-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide to react with 2-trifluoromethylbenzoyl chloride, the title compound was obtained as a white powder in 29% yield. 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=9.5 Hz, 1H), 7.85 (t, J=5.6 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.52-7.61 (m, 3H), 7.01 (d, J=9.6 Hz, 1H), 5.71 (d, J=7.9 Hz, 1H), 4.49 (d, J=13.7 Hz, 2H), 4.30-4.38 (m, 1H), 3.49 (dd, J=6.6 and 13.7 Hz, 2H), 3.22-3.27 (m, 2H), 2.20-2.23 (m, 2H), 1.48-1.76 (m, 5H), 0.94 (d, J=6.6 Hz, 6H). MS (ES+) m/z 463.9 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:10](=[O:11])[N:9]([CH:12]3[C:18](=[O:19])[NH:17][C:15](=[O:16])[CH2:14][CH2:13]3)[CH2:8][C:4]2=[C:5]([NH2:7])[CH:6]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>N1C=CC=CC=1>[O:19]=[C:18]1[CH:12]([N:9]2[CH2:8][C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[NH:7][C:20](=[O:23])[CH2:21][CH3:22])[C:10]2=[O:11])[CH2:13][CH2:14][C:15](=[O:16])[NH:17]1
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A solution of lenalidomide (0.020 g, 0.077 mmol) in pyridine (0.8 mL) was cooled to 0° C. (ice bath). Propionyl chloride (0.009 mL, 0.100 mmol) was added dropwise and the reaction was allowed to warm to room temperature over 16 h. Volatiles were removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0→5% MeOH in DCM as eluant) to afford desired product 27 (0.012 g, 50%) as an off-white powder. 1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 9.79 (s, 1H), 7.80 (dd, J=6.6, 2.3 Hz, 1H), 7.64-7.29 (m, 2H), 5.14 (dd, J=13.2, 4.9 Hz, 2H), 4.35 (q, J=7.5 Hz, 2H), 3.00-2.79 (m, 1H), 2.60 (m, 1H), 2.35 (m, 1H), 2.05-1.92 (m, 1H), 1.08 (t, J=7.5 Hz, 3H). MS (ESI) m/z calcd for C16H18N3O4 [M+H]+ 316.3, found: 316.8.
Reaction SMILES: [H][H].Cl[C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[C:6]([CH3:13])[N:5]=1.C(N(CC)CC)C>[Pd].C(O)C>[CH3:13][C:6]1[N:5]=[CH:4][CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A hydrogen filled balloon was attached to a flask containing 2-chloro-6-methylpyridine-4-carboxylic acid (2 g, 12.0 mmol), palladium 10 wt. % on activated carbon (0.5 g), triethyl amine (4.8 ml) and ethanol (24 ml) and then stirred overnight at room temperature. The is reaction mixture was filtered through celite, washed with methanol and concentrated. The residue was titurated with dichloromethane and then filtered to afford 6-methylpyridine-4-carboxylic acid as a white solid; 1.05 g (66%). 1H NMR (MeOD) δ (ppm): 8.62 (d, 1H), 7.68 (s, 1H), 7.60 (d, 1H), 2.55 (s, 3H).
Reaction SMILES: [C:1]1(=[O:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:11]([N:18]1[C:24](=[O:25])[C@H:23]2CCC[C@H]2[N:21]([C:29](=[O:32])[CH2:30]Br)[C:20]2[CH:33]=[CH:34][CH:35]=[CH:36][C:19]1=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:15]([CH:16]1[CH:30]2[CH:11]([N:18]([C:24](=[O:25])[CH2:23][N:6]3[C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]3=[O:8])[C:19]3[CH:36]=[CH:35][CH:34]=[CH:33][C:20]=3[NH:21][C:29]2=[O:32])[CH2:12][CH2:17]1)[C:14]1[CH:13]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: O=C1CCCC(=O)N1
Reactant: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2N(C(=O)CN2C(=O)CCCC2=O)C2CCC(Cc3ccccc3)C12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.1 %

Procedure:
To a solution of glutarimide (136 mg, 1.2 mmol) in N,N-dimethylformamide (2 mL) was added, at 0° C., sodium hydride (60% liquid paraffin dispersion, 44 mg, 1.1 mmol), and the mixture was stirred for 5 minutes. To this mixture was added (3aR*,10aS*)-9-benzyl-4-(bromoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]-cyclopenta[e][1,4]diazepin-10(1H)-one (413 mg, 1 mmol), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (4 mL), which was subjected to extraction twice with chloroform. Organic layers were combined, washed with water and dried over magnesium sulfate, which was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was crystallized from ethyl acetate-diethyl ether to give 305 mg (yield 68%) of the titled compound, m.p. 220°-221° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH:13]([CH3:25])[C:11]3=2)[NH:6][CH:5]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>CN(C=O)C>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][NH:14][CH:13]([CH3:25])[C:11]3=2)[N:6]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1c2c(ccc3[nH]cc(Cl)c23)OCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1NCCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.010 g, 0.42 mmol) was added to tert-butyl 10-chloro-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 43, 18 mg, 0.050 mmol) and benzenesulfonyl chloride (0.030 mL, 0.23 mmol) in DMF (2 mL). The mixture was was stirred at room temperature for 30 minutes. TFA (0.50 mL) was added to the reaction mixture and the solvent was evaporated. The residue was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (16.8 mg) in the form of the trifluoroacetate salt. MS m/z 377 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:24])=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C@H:41](O)[C@H:40]([F:45])[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C@@H:41]([N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=3[C:27]([F:28])([F:30])[F:29])[N:8]=[C:9]4[CH3:24])[S:21][C:20]2=[O:22])[C@H:40]([F:45])[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)NC3=O)cc12
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(=O)N([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4F)C3=O)cc12

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-3-methyl-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-(trans)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)-benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 36) and (cis)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (prepared as described in U.S. Pat. Pub. No. 2007/0249589) following General Procedure J.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[C:18]1(/[C:24](/[C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29]I)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1(/[C:24](/[C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29][CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[C:12]([O:14][CH3:15])=[O:13])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CS(=O)(=O)c1ccc(C)cc1
Reactant: ICCCC/C=C(/c1ccccc1)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CCCC/C=C(/c1ccccc1)c1cccnc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Methyl p-methylphenylsulfonylacetate (0.43 g, 2 mmole) was dissolved in dimethylformamide, and after the solution was cooled to 0° C. under argon, sodium hydride (0.1 g) was added, followed by stirring for 10 minutes. A solution of (Z)-6-phenyl-6-(3-pyridyl)-1-iodo-5-hexene (0.8 g) in dimethylformamide (4 ml) was added to the reaction solution, and the reaction was carried out at room temperature for 3 hours. After the completion of the reaction, water (30 ml) was added, and the product was extracted with ethyl acetate. Working up in the usual procedure, the resulting product was chromatographed on silica gel, and development was effected with isopropyl ether:ethyl acetate (1:1) to yield methyl (Z)-8-phenyl-8-(3-pyridyl)-2-(p-methylphenylsulfonyl)-7-octenoate (1-c) (0.6 g, 61%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][C:15]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:38][C:39]1[NH:43][N:42]=[C:41]([NH2:44])[CH:40]=1>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:44][C:41]3[CH:40]=[C:39]([CH3:38])[NH:43][N:42]=3)=[N:14][C:15]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(OCc3ccccc3)cc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(OCc4ccccc4)ccc23)n[nH]1
Temperature: 40 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To (7-(benzyloxy)-4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone (380 mg, 0.97 mmol) in DMF (10 mL) at rt were added DIEA (500 uL, 2.90 mmol), 5-methyl-1H-pyrazol-3-amine (280 mg, 2.90 mmol), and KI (161 mg, 0.97 mmol). After stirring at 40° C. for 18 h, the solution was cooled and diluted with water. After standing at 0° C. for 1 h, the precipitate was collected by filtration and dried under reduced pressure to afford (7-(benzyloxy)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone as a yellow solid (365 mg, 83%) 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 5.30 (s, 2H) 6.48 (s, 1H) 7.33-7.44 (m, 8H) 7.50-7.52 (m, 2H) 8.07 (m, 2H) 8.65 (m, 1H) 10.53 (s, 1H) 12.18 (s, 1H). LC-MS (ESI) m/z 454 (M+H)+
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>>[N+:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Reactant: C[Si](C)(C)CCOCn1ccc2c(N)cccc21
Product: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc4c(c3[N+](=O)[O-])CCCC4)cccc21

Procedure:
1-Nitro-5,6,7,8-tetrahydronaphthalen-2-yl triflate and 4-amino-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole were used in a process similar to Example 1(1) to give the titled compound.