Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C(Oc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1
Temperature: 85 °C

Procedure:
4-Benzoyloxybiphenyl (40 g) is mixed with 310 ml of glacial acetic acid and heated to 85° C. Fuming nitric acid (100 ml) is added slowly while maintaining the reaction medium temperature between 85°-90° C. After complete addition, the reaction is cooled to room temperature.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[I-].[O:22]=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]1[CH2:33][CH2:34][N:35]([C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:36](N1C=C[N+](C)=C1)=[O:37]>C(Cl)Cl>[O:32]=[C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:22])[N:24]1[CH2:33][CH2:34][N:35]([C:44]1[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=1)[C:36]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:37]
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: C[n+]1ccn(C(=O)N(CCN2C(=O)c3ccccc3C2=O)c2ccc(F)cc2)c1
Agent: [I-]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCN(C(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a 50 mL round-bottomed flask was added (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (80 mg, 290 μmol), 1-((2-(1,3-dioxoisoindolin-2-yl)ethyl)(4-fluorophenyl)carbamoyl)-3-methyl-1H-imidazol-3-ium iodide (151 mg, 290 μmol, from step 3), CH2Cl2 (2 mL). The reaction mixture was stirred at 40° C. for 48 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give (R)—N-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 588 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[CH:16]=[CH:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(Cl)cc32)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3ccc(Cl)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
Dissolve 4-(6-chloro-2,3-dihydroindol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 9.2 mmol) in tetrahydrofuran (50 mL) and cool to 0° C. under nitrogen. Dissolve DDQ (2.1 g, 1 eq) in tetrahydrofuran (25 mL) and add dropwise to the reaction over 15 minutes. Stir for 30 minutes at 0° C. Dilute with ethyl acetate then wash with saturated sodium bicarbonate followed by brine. Dry over magnesium sulfate, filter and concentrate to give 3.15 g (102%) crude product. MS (ES, m/z): 279.1 (M+1, product—tert butyl).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH2:21][C:22]3[N:27]=[C:26]([C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH:24][CH:23]=3)=[C:11]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O1CCCC1.CO>[CH3:34][S:31]([NH:30][C:28]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:21][C:12]2[C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[NH:10][C:11]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:27]=1)=[O:29])(=[O:32])=[O:33]
Reactant: COc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)n(S(=O)(=O)c3ccccc3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 50 °C
Reaction time: 29 h
Yield: 78.4 %

Procedure:
To a solution of 6-(1-benzenesulfonyl-6-methoxy-2-phenyl-1H-indol-3-ylmethyl)-N-methanesulfonylpyridine-2-carboxamide (632 mg) in tetrahydrofuran/methanol (7.4 mL/3.7 mL) was added cesium carbonate (1.43 g), and this mixture was stirred at 50° C. for 29 hours. Cesium carbonate (1.43 g) was added thereto, and further stirred for additional 45.5 hours. The reaction mixture was left to be cooled. To the reaction mixture was added 1 mol/L hydrochloric acid (20 mL), followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (375 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=3[C:5]=2[CH2:4]1>C(O)C.[Pt]>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: CN(C)C1CCc2oc3ccc([N+](=O)[O-])cc3c2C1
Agent: [Pt]
Solvent: CCO
Product: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Reaction time: 2 h
Yield: 78.8 %

Procedure:
A solution of 0.38 gm (1.46 mMol) of N,N-dimethyl-8-nitro-1,2,3,4-tetrahydro-2-dibenzofuranamine in 150 mL of ethanol was hydrogenated over 200 mg of 5% platinum on carbon at 40 p.s.i. for 2 hours at room temperature. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 2 mm), eluting with 10% methanol (containing about 5% ammonium hydroxide) in chloroform. Fractions containing product were combined and concentrated under reduced pressure to provide 265 mg of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine as a viscous oil. The oil was dissolved in diethyl ether and this solution treated with hydrogen chloride. The precipitated salt was filtered and dried to provide 337 mg (74%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24](OS(C)(=O)=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1

Procedure:
A solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.375 g, 1.93 mmol), (R)-3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (0.513 g, 1.93 mmol), and Cs2CO3 (0.943 g, 2.90 mmol) in anhydrous DMF (5.1 mL) was heated to 100° C. for 6 h. The reaction mixture was partitioned between EtOAc and H2O and separated. The aqueous layer was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (3×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a brown oil. This material crude was purified by chromatography on silica gel [eluting with 12% EtOAc in CHCl3] resulting in the title compound as a viscous oil. 1H NMR (400 MHz, CDCl3): δ=1.32 (s, 12H), 1.47 (s, 9H), 2.36 (q, J=7.0 Hz, 2H), 3.46-3.79 (m, 3H), 3.81-3.92 (m, 1H), 4.90 (quint, J=6.1 Hz, 1H), 7.73 (s, 1H), 7.81 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[C:6]3[C:12]([I:13])=[N:11][NH:10][C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[ClH:27]>O1CCOCC1>[ClH:27].[CH:1]1([C:4]2[C:5]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[C:6]3[C:12]([I:13])=[N:11][NH:10][C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C3CC3)cnc3[nH]nc(I)c23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Ic1n[nH]c2ncc(C3CC3)c(N3CCNCC3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of tert-butyl 4-(5-cyclopropyl-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (200 mg, 0.426 mmol) and 4N HCl in dioxane (4 mL) was stirred at room temperature for 2 hours. The solvent was then removed in vacuo, and the residue was triturated with CH3CN. The solid formed was filtered, washed with Et2O and dried to provide 5-cyclopropyl-3-iodo-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine hydrochloride salt (179 mg, 95% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 9.47 (br s, 2H), 8.32 (s, 1H), 3.67-3.62 (m, 4H), 3.42-3.35 (m, 4H), 2.09-2.03 (m, 1H), 1.07-1.01 (m, 2H), 0.80-0.76 (m, 2H); LCMS (APCI+) m/z 370 (M+H)+, Retention time=1.87 minutes.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:10]2)(=O)=O.[CH2:25]([Sn](CCCC)(CCCC)C#C)[CH2:26]CC.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[F-].N1C=CC=CC=1>C(OCC)C.N1C=CC=CC=1>[C:25]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:10]2)#[CH:26]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCN(CCC)C1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [F-]
Solvent: c1ccncc1
Solvent: CCOCC
Product: C#Cc1ccc2c(c1)CC(N(CCC)CCC)C2
Temperature: 25 °C

Procedure:
To a solution of 5-trifluoromethanesulfonyloxy-2-(di-n-propylamino)indan (Example 2) in 1,4-dixoane is treated with tri-n-butylethynylstannane, lithium chloride, tetrakis(triphenylphosphlne)palladium(0), and a few crystals of 2,6-di-tert-butyl-4-methylphenol under nitrogen (J. Am. Chem. Soc. 1987, 109, 5478). The mixture is refluxed for 6 h, cooled to room temperature, and treated with pyridine and pyridine fluoride and iluted with diethyl ether. The resulting crude product is purified by chromatography to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
1-[2-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone (compound 314) (150 mg), 1-bromo-2-chloroethane (191 mg), and potassium carbonate (307 mg) were suspended in N,N-dimethylformamide (6 ml). The mixture was stirred at room temperature overnight, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (122 mg, 68%).
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.N(C1SC=C(CSCCN)N=1)C(N)=N.[NH:26]([C:30]1[S:31][CH:32]=[C:33]([CH2:35][S:36][CH2:37][CH2:38][NH:39][C:40]2[C:44]([O:45]C)=[N:43][S:42](=[O:48])(=[O:47])[N:41]=2)[N:34]=1)[C:27]([NH2:29])=[NH:28].[OH-].[Na+]>>[NH:26]([C:30]1[S:31][CH:32]=[C:33]([CH2:35][S:36][CH2:37][CH2:38][NH:39][C:40]2[C:44]([OH:45])=[N:43][S:42](=[O:48])(=[O:47])[N:41]=2)[N:34]=1)[C:27]([NH2:29])=[NH:28]
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1
Agent: COC1=NS(=O)(=O)N=C1OC
Agent: N=C(N)Nc1nc(CSCCN)cs1
Agent: [Na+]
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)(=O)N=C2O)cs1

Procedure:
When 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with one equivalent of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine and the resultant 3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with sodium hydroxide according to the procedure described in Example 17, Step B, the title compound is produced.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:13][C:14]1[CH:43]=[CH:42][C:17]([C:18](/[N:20]=[C:21]2\NC3C=CC(CO)=CC=3[N:25]\2[C@@H:26]2[CH2:31][CH2:30][C@H:29]([C:32](OC)=[O:33])[CH2:28][CH2:27]2)=[O:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:43]=[CH:42][C:17]([C:18]([NH:20][C:21]2[N:1]([C@@H:2]3[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]3)[C:31]3[CH:30]=[C:29]([CH2:32][OH:33])[CH:28]=[CH:27][C:26]=3[N:25]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(CO)cc32)CC1

Procedure:
The title compound was prepared in 6 steps from cis-ethyl 4-aminocyclohexanecarboxylate using a method analogous to the preparation of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate. MS m/z=440.2 [M+H]. Calc'd for C24H26FN3O4: 439.2.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CS(C)=O.O>[CH3:13][O:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=[C:2]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: COc1cc(F)cc(O)c1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCOCC2)cc(O)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 26.2 %

Procedure:
To a stirred solution of 5-fluoro-3-methoxy-2-nitro-phenol (2.0 g, 10.6 mmol) in dimethylsulfoxide (25 ml) is added morpholine (9.2 ml, 106 mmol) at room temperature. The resulting mixture is heated at 100° C. for 2 h. After completion of reaction (monitored by TLC), the mixture is diluted with water (40 ml) and the aqueous layer is extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (30 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (45% ethyl acetate/hexane) to yield 3-methoxy-5-morpholin-4-yl-2-nitro-phenol (0.71 g, 2.78 mmol, 26%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]2[CH:16]=[CH:15][NH:14][C:9]=2[N:10]=[C:11](Cl)[N:12]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]2[CH:16]=[CH:15][NH:14][C:9]=2[N:10]=[C:11]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=2)[N:12]=1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: NCCCCNc1nc(Cl)nc2[nH]ccc12
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NCCCCN)c3cc[nH]c3n2)cc1
Temperature: 116 °C
Yield: 5.2 %

Procedure:
A mixture of N-(4-aminobutyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (63 mg, 0.26 mmol), N-(4-aminophenyl)-N-methylacetamide (81 mg, 0.49 mmol) and trimethylsilyl chloride (0.067 mL, 0.52 mmol) in nBuOH (3 mL) was heated at 116° C. for 4 h. It was then purified by HPLC to give the titled compound (5 mg). MS 368.2 (M+H); UV 203.8, 268.7, 301.9 nm.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[NH:18][C:19]4[C:20]([N:25]=3)=[N:21][CH:22]=[CH:23][CH:24]=4)=[O:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O.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]>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[NH:18][C:19]3[C:20]([N:25]=2)=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:16])=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ncccc2[nH]1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(Oc2ncccc2-c2cccnc2)cc1)c1nc2ncccc2[nH]1
Reaction time: 8 h

Procedure:
To a round bottomed flask was added (4-(3-bromopyridin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone (0.250 g, 0.633 mmol), pyridin-3-ylboronic acid (0.233 g, 1.898 mmol), PdCl2(dppf) (0.035 g, 0.063 mmol), and sodium carbonate (0.335 g, 3.16 mmol) in DMSO (1.581 mL) and Water (0.527 mL) at 80° C. to stir overnight. The reaction was worked up via seperatory funnel. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 mM, 0.1% TFA in ACN/H2O, gradient 25% to 100% over 15 min to provide (4-(3,3′-bipyridin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone. MS (ESI, pos. ion) m/z: 394.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@H:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.C(#N)C.C(N(CC)C(C)C)(C)C.[Cl:39][C:40]1[C:41]([CH3:50])=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1.C(O)(C(F)(F)F)=O>O1CCOCC1.CO>[Cl:39][C:40]1[C:41]([CH3:50])=[C:42]([S:46]([NH:18][C@H:15]2[CH2:16][CH2:17][N:13]([C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)=[O:12])[CH2:14]2)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(Cl)cccc1S(=O)(=O)N[C@H]1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl ((3S)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)carbamate (7.30 mg, 0.0000200 mol) was treated with hydrogen chloride in 1,4-dioxane (4.0 M, 0.50 mL) at rt for 30 minutes. The solvent was evaporated under reduced pressure and acetonitrile (1.0 mL, 0.019 mol) was added. The mixture was then treated with N,N-diisopropylethylamine (20.0 μL, 0.000115 mol), followed by the addition of 3-chloro-2-methylbenzenesulfonyl chloride (4.50 mg, 0.0000200 mol) at rt. The reaction mixture was stirred at rt for 1 h and then acidified (pH 2.0) with TFA. The solution was diluted with methanol (0.80 mL) and was submitted for purification by prep-HPLC to give the desired product. LCMS: m/z 454.1 (M+H)+
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1[OH:17])(C)(C)C.[H-].[Na+].[CH3:21]I>>[CH3:21][O:17][C@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:8]1[NH2:7]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [H-]
Agent: [Na+]
Product: CO[C@H]1Cc2ccccc2[C@H]1N

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 57, Step 2 starting from tert-butyl[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate, sodium hydride and methyl iodide.
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[N:9]1([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>N1C=CC=CC=1>[CH3:3][C:2]1[C:1](=[O:8])[N:19]([C:18]2[CH:17]=[CH:16][C:15]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:21][CH:20]=2)[C:5](=[O:6])[CH:4]=1
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: CC1=CC(=O)OC1=O
Solvent: c1ccncc1
Product: CC1=CC(=O)N(c2ccc(N3CCCCC3)cc2)C1=O
Temperature: 90 °C

Procedure:
A solution of citraconic anhydride (0. 1 M) in pyridine (20 ml)was treated with 4-(1-piperidyl)aniline (0. 1 M). The reaction mixture was heated to 90° C. for six hours. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[C:7]([F:17])([C:13]([F:16])([F:15])[F:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[C:7]([F:17])([C:13]([F:14])([F:15])[F:16])[C:6]=2[CH:5]=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: FC(F)(F)C1(F)c2cccc(Cl)c2OC1(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)c2c(c1)C(F)(C(F)(F)F)C(F)(F)O2
Temperature: 80 °C

Procedure:
A stirred mixture of 3.3 g (0.012 mole) 7-chloro-2,2,3-trifluoro-3-trifluoromethyl-2,3-dihydrobenzofuran, 10 ml of concentrated sulfuric acid and 15 ml of concentrated nitric acid was heated at 80° C. for approximately 18 hours. The mixture was cooled and poured into ice water. The aqueous mixture was extracted with three 100 ml portions of diethyl ether and the extracts were combined. After drying over anhydrous magnesium sulfate the extract was filtered. The filtrate was evaporated under reduced pressure leaving an oil which crystallized upon standing. Recrystallization from n-heptane yielded 1.65 g of 7-chloro-2,2,3-trifluoro-3-trifluoromethyl-2,3-dihydro-5-nitrobenzofuran (mp 46°-47° C.). The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.S(Cl)(Cl)=O.C([N:34]([CH:37]([CH3:39])[CH3:38])CC)(C)C.C1(N)CC1>C(OCC)(=O)C.O1CCOCC1>[CH:37]1([NH:34][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[N:16][N:15]=[CH:14]4)[CH:4]=2)[CH2:39][CH2:38]1
Reactant: O=C(O)c1ccc(F)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: O=C(NC1CC1)c1ccc(F)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To 4-fluoro-3-(1-morpholinophthalazin-6-yl)benzoic acid (200 mg, 566 μmol) was added thionyl chloride (2.83 mL) before it was heated to 65° C. for 1 h. The reaction mixture was concentrated in vacuo and azeotropically dried with toluene. Dioxane (2.83 mL,), diisopropylethylamine (493 μl, 2830 μmol), and cyclopropylamine (323 μl, 5660 μmol) were added and the mixture was stirred at RT overnight. The reaction mixture was diluted with 50 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 20 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to give the title compound. MS (ES+): 393 (M+H)+.