Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+].[F:30][C:31]1[C:36]([Sn](CCCC)(CCCC)CCCC)=[N:35][CH:34]=[CH:33][N:32]=1>CN(C=O)C.Cl[Pd]Cl.[Cu]I>[F:30][C:31]1[C:36]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=2)=[N:35][CH:34]=[CH:33][N:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccnc1F
Reactant: Cc1nc(N)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N)cc(-c2nccnc2F)n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
A microwave tube was charged with 6-chloro-2-methyl-4-pyrimidinamine (SynChem, Inc., Des Plaines, Ill.) (0.223 g, 1.550 mmol), PdCl2 (10.99 mg, 0.062 mmol), tri-t-butylphosphonium tetrafluoroborate (0.036 g, 0.124 mmol), CuI (0.024 g, 0.124 mmol) and CsF (0.471 g, 3.10 mmol). The tube was sealed and evacuated under vaccuum and back-filled with N2 (g) 5 times. Argon was bubbled through the tube and 2-fluoro-3-(tributylstannyl)pyrazine (F. Toudic et al. Tetrahedron, 2003, 29, 6375-6384; 1.80 g, 4.65 mmol) in DMF (4 mL) was added and Ar (g) was bubbled through the solution for 5 minutes. The mixture was heated to 60° C. and stirred for 18 h. Water and EtOAc was added and the mixture was filtered through Celite® (diatomaceous earth). The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 3% MeOH in CH2Cl2. The product was further purified by HPLC (10 to 90% CH3CN and H2O with 0.1% NH4OH, flow rate equal to about 45 mL/min) to afford 6-(3-fluoro-2-pyrazinyl)-2-methyl-4-pyrimidinamine (0.077 g, 0.375 mmol, 24.21% yield) as a white solid. m/z (ESI, +ve) 206.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J=4.50 Hz, 1H); 8.53 (d, J=8.22 Hz, 1H); 7.26 (s, 1H); 5.58 (br. s., 2H); 2.63 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:6]2[NH:5]1)(=O)[CH3:2].B.O1CCCC1.Cl>O1CCCC1>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[C:6]2[NH:5]1)[CH3:2]
Reactant: CC(=O)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCN1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-acetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (59 mg) in tetrahydrofuran was added borane-tetrahydrofuran complex (1.0M solution in tetrahydrofuran, 1 ml) dropwise. The solution was stirred at ambient temperature for 5 hours and to the solution was added dropwise 1N-hydrochloric acid (3 ml). The solution was stirred at 80° C. for 20 minutes and the tetrahydrofuran was evaporated. Then, the aqueous solution was neutralized with an aqueous saturated sodium bicarbonate solution and the separated oil was extracted with dichloromethane. The extract was dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from ethyl acetate to give 2-ethyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (30 ml).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[N+:32]([O-:34])=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)=[CH:19][C:18]=1[N+:32]([O-:34])=[O:33]
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CCOCC2)cc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 65.7 %

Procedure:
2.0 g Trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (8.6 mmol) and 2.89 g 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.3 mmol) were dissolved in a mixture of toluene (20 ml) and ethanol (50 ml) 0.35 g of dichloro (1,1′bis-(diphenylphosphine)ferrocene)palladium(II)dichloromethane (0.43 mmol) was added and heated to 85° C. Then aqueous sodium carbonate (2M) (10 ml) was added and the reaction kept at 85° C. for 45 min. After cooling to ambient temperature the reaction was extracted with ethyl acetate/water, the organic phase was dried over sodium sulfate and concentrated. Column chromatography on silica gel (n-heptane/ethyl acetate 4:1) yielded 1.33 g of 4-(4-methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran (66%) as a yellow solid; M.p.: 117–120° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].FC(F)(F)C(O)=O.C1(OC2NC(N)=C3C(N=2)=NC(OC)=N3)CCC1.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: COc1nc2nc(OC3CCC3)[nH]c(N)c-2n1
Agent: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC3CCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclobutyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.CO.O1CCCC1>O1CCOCC1.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(OCc1ccccc1)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution mixture of the obtained benzyl 2-(benzyloxy)-5-(piperidin-1-yl)benzoate (2.2 g) in dioxane (11 mL), ethyl acetate (17 mL), and methanol (5.5 mL), 10% palladium-carbon (1.1 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Tetrahydrofuran was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 1.1 g of 2-hydroxy-5-(piperidin-1-yl)benzoic acid as a light yellow solid.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Zr+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.C(COC)OC.[CH3:16][Si:17]([CH3:27])([CH3:26])[O:18][CH2:19][CH2:20][C-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[K+]>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[CH:4]1([Zr+2:9][C:21]2([CH2:20][CH2:19][O:18][Si:17]([CH3:16])([CH3:27])[CH3:26])[CH:22]=[CH:23][CH:24]=[CH:25]2)[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: [Zr+3]C1C=CC=C1
Reactant: C[Si](C)(C)OCC[c-]1cccc1
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)OCCC1([Zr+2]C2C=CC=C2)C=CC=C1
Reaction time: 12 h
Yield: 27 %

Procedure:
To a suspension of 3.52 g (10 mmol) of an adduct of cyclopentadienyl zirconium trichloride with dimethoxyethane in toluene, a suspension of 2.2 g (10 mmol) of potassium (2-trimethylsiloxy-ethyl)-cyclopentadienide in toluene is added. The addition is carried out at −78° C. An orange-brown suspension is immediately formed; it is maintained under stirring for 12 hours; then it is left settling and it is filtered. The obtained orange solution is concentrated up to 5 ml and hexane is added, so that a brown solid is obtained. (1.1 g, 2.7 mmol. Yield: 27%). 1H-NMR: 6.00 (t, 2H), 5.87 (s, 5H), 5.67 (t, 2H), 3.66 (t, 2H), 2.92 (t, 2H), 0.11 (s, 9H). Mass spectrum. M+-65: (343): 33%.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]N(C=O)C>>[CH3:18][N:9]1[C:8](=[O:13])[C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:12][CH2:11][CH2:10]1
Reactant: O=C1NCCOc2cc([N+](=O)[O-])ccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN1CCOc2cc([N+](=O)[O-])ccc2C1=O
Reaction time: 15 h
Yield: 77 %

Procedure:
A solution of 8-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.25 g, 0.0012 mol) in DMF (8 mL) at 5° C. under nitrogen, was treated with sodium hydride (0.058 g, 0.0015 mol). After stirring 15 hrs. at room temperature, the reaction was evaporated. The residue was treated with ethyl acetate and 1N HCl (pH 5), separated, washed, dried (MgSO4) to give 4-methyl-8-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.2 g, 77%) as a tan solid. MP: 130-2° C.; 1H-NMR (DMSO-d6) δ 7.90-8 (d, 1H), 7.88 (d, 1H), 7.80 (d, 1H), 4.46-8 (m, 2H), 3.56-9 (m, 2H), 3.11 (s, 3H); LC/MS (ESI+): 223 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[N:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[N:15][C:14]=12.[CH3:30]I>CN(C)C(=O)C.O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[N:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([N:23]3[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[CH2:27][CH2:28]3)=[N:15][C:14]=12
Reactant: OC1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reaction time: 18 h
Yield: 65.7 %

Procedure:
Sodium hydride (60% dispersion in oil) (0.044 g, 1.10 mmol) was added to a solution of 3-(2-fluorophenyl)-5-(4-hydroxypiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (Example 9) (10 g, 0.27 mmol) in N,N-dimethylacetamide (4 ml). The mixture was stirred for 30 min before addition of methyl iodide (0.17 ml, 2.8 mmol) and then stirred for a further 18 h. The mixture was diluted with water (20 ml) and extracted with CH2Cl2 (2×50 ml). The combined organic extracts were washed with brine (20 ml), dried over MgSO4 and evaporated to give a colourless oil. Purification by preparative thin layer chromatography eluting with CH2Cl2:MeOH:NH3(c) (95:5:0.5) gave 3-(2-fluorophenyl)-5-(4-methoxypiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.067 g, 65%) as a yellow solid. δH (360 MHz; CDCl3) 1.84-1.90 (2H, m), 2.11-2.16 (2H, m), 3.36-3.41 (2H, m), 3.42 (3H, s), 3.51-3.54 (1H, m), 3.88-3.95 (2H, m), 7.19-7.29 (2H, m), 7.32-7.37 (1H, m), 7.60 (1H, ddd, J=8, 8 and 1), 7.88 (1H, ddd, J=8, 8 and 1), 8.01 (1H, d, J=8), 8.15 (1H, ddd, J=7, 7 and 2), 8.67 (1H, dd, J=8 and 1); m/z (ES+) 378 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)([O-:3])=[O:2].[NH2:9]N1C=NN=C1.[Cl-].[NH4+]>CS(C)=O>[N+:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH2:9])([O-:3])=[O:2]
Reactant: Nn1cnnc1
Reactant: O=[N+]([O-])c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Nc1ccsc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
12.8 g of 85% 2-nitro-thiophene and 33.6 g of 4-amino-4H-1,2,4-triazole (1-1, 3-4) were dissolved at ambient temperature in 100 ml of anhydrous dimethyl-sulfoxide and the solution was cooled down to 5° C. A solution of 22.4 g of potassium terbutylate in 100 ml of anhydrous dimethyl-sulfoxide was added over about 15 minutes and the suspension was stirred for a further 15 minutes at ambient temperature, then poured into 0.6 liter of a saturated solution of ammonium chloride. Extraction was carried out 3 times with 500 ml of ethyl acetate and the extracts were washed 3 times with 400 ml of water, dried, filtered and evaporated to dryness. The product was dissolved in 800 ml of methylene chloride, followed by filtration and evaporation to dryness. The product was crystallized from 20 ml of isopropyl ether and the crystals were separated out, washed with isopropyl ether and then dried at 80° C. under reduced pressure to obtain 5.1 g of the expected product melting at 159° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH3:12].[CH2:13]([O:20][C:21]1[N:22]=[N:23][C:24]([CH:35]=[CH2:36])=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:13]([O:20][C:21]1[N:22]=[N:23][C:24](/[CH:35]=[CH:36]/[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[CH3:12])=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Cc1cc(C(F)(F)F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)ccc1/C=C/c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 54.7 %

Procedure:
1-Bromo-2-methyl-4-(trifluoromethyl)benzene (1.144 g, 4.79 mmol), 3,4-bis(benzyloxy)-6-ethenylpyridazine (Intermediate 78; 1.27 g, 3.99 mmol), palladium(II) acetate (0.045 g, 0.199 mmol), triethylamine (10.56 ml, 76 mmol), tri-o-tolylphosphine (0.243 g, 0.798 mmol) and acetonitrile (8 ml) were combined. The reaction mixture was subjected to microwave irradiation at 120° C. for 30 minutes before being quenched with water and extracted into ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford an orange gum. This was purified by column chromatography (silica, eluting with 0-30% ethyl acetate in petrol) to afford 3,4-bis(benzyloxy)-6-[(E)-2-[2-methyl-4-(trifluoromethyl)phenyl]ethenyl]pyridazine as a white solid (1.04 g, 55%).
Reaction SMILES: CO[C:3]1[CH:8]=[C:7](C)[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[Cl:26]C1C=CC=C(C)C=1S(Cl)(=O)=O>>[Cl:26][C:7]1[CH:8]=[CH:3][CH:4]=[C:5]([CH3:25])[C:6]=1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:11]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCC[C@H]1COCC(=O)O

Procedure:
Synthesis of this acid unit was carried out in analogy to (S)-2-((1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (AC28) employing 2-chloro-6-methylbenzene-1-sulfonyl chloride in step (ii).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]([F:48])=[CH:35][C:34]=1[N:49]1[CH2:61][CH2:60][N:52]2[C:53]3[CH2:54][CH2:55][CH2:56][CH2:57][C:58]=3[CH:59]=[C:51]2[C:50]1=[O:62])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:48][C:36]1[CH:37]=[C:38]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH:24]5[CH2:27][O:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[C:33]([CH2:32][OH:31])=[C:34]([N:49]2[CH2:61][CH2:60][N:52]3[C:53]4[CH2:54][CH2:55][CH2:56][CH2:57][C:58]=4[CH:59]=[C:51]3[C:50]2=[O:62])[CH:35]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nccn2c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1c2cc3c(n2CCN1c1cc(F)cc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4nccn4c2)c1CO)CCCC3
Temperature: 140 °C
Yield: 11.6 %

Procedure:
To a solution of 102c (180 mg, 0.468 mol) in dioxane/H2O (12 mL/1 mL) was added 2-(5-fluoro-2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 101l (225 mg, 0.468 mmol), Pd2(dba)3 (43 mg, 0.0468 mmol), tricyclohexylphosphine (131 mg, 0.468 mmol), and Cs2CO3 (305 mg, 0.935 mmol). This mixture was heated in microwave at 140° C. for 1 h. Then, the solid was filtered and the filtrate was concentrated to give a yellow solid, which was further purified by reverse-phase prep-HPLC to afford 102 as a white solid (36 mg, 11%). LCMS: [M+H]+ 663. 1H NMR (500 MHz, DMSO) δ 8.53 (d, J=2.5, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.92-7.91 (d, J=2.5, 1H), 7.57 (s, 1H), 7.42-7.36 (m, 2H), 7.36-7.33 (m, 1H), 7.27-7.25 (d, J=9, 1H), 6.53 (s, 1H), 4.88-4.86 (t, J=9, 1H), 4.57-4.54 (m, 2H), 4.47-4.45 (m, 2H), 4.31-4.30 (d, J=4.5, 2H), 4.18-4.13 (m, 3H), 3.92-3.90 (m, 1H), 3.45-3.42 (m, 1H), 3.09-3.10 (m, 4H), 2.64-2.54 (m, 2H), 2.47-2.45 (m, 2H), 2.39-2.38 (m, 4H), 1.79-1.78 (m, 2H), 1.69-1.67 (m, 2H)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[N:20]1[O:21][N:22]=[C:23]2[CH:28]=[C:27]([CH2:29][CH:30]=O)[CH:26]=[CH:25][C:24]=12>>[N:20]1[O:21][N:22]=[C:23]2[CH:28]=[C:27]([CH2:29][CH2:30][N:6]3[CH2:5][CH2:4][N:3]([CH:8]4[CH2:17][CH2:16][C:15]5[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=5[CH2:9]4)[C:2](=[O:1])[CH2:7]3)[CH:26]=[CH:25][C:24]=12
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: O=CCc1ccc2nonc2c1
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4nonc4c3)CC1=O)C2

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 2,1,3-benzoxadiazol-5-ylacetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 402 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH2:31])[NH:27][C:26](=[O:32])[CH2:25]2>>[NH2:31][C:30]1[CH:29]=[C:28]2[C:24]([C:25](=[CH:16][C:13]3[NH:12][C:9]4[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=4[C:14]=3[CH3:15])[C:26](=[O:32])[NH:27]2)=[CH:23][C:22]=1[F:21]
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Yield: 61.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-amino-1,3-dihydro-indol-2-one (prepared according to J. Heterocylic Chem., 31, 1513, 1994) as starting materials to give 2-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (42 mg, 61.8%) as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([NH2:20])=O)[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:26][CH3:27].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]#[N:20])[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc2cc(-c3ccsc3)n(Cc3cccc(C(N)=O)n3)c2cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2cc(-c3ccsc3)n(Cc3cccc(C#N)n3)c2cc1F
Reaction time: 0.83 h
Yield: 42.6 %

Procedure:
To a solution of 6-[6-fluoro-5-methoxy-2-(thiophen-3-yl)indol-1-ylmethyl]pyridine-2-carboxamide (165 mg) in N,N-dimethylformamide (2.1 mL) was added phosphoryl chloride (0.058 mL) under ice-cooling. This mixture was stirred for 50 minutes. The reaction mixture was quenched with a saturated aqueous sodium hydrogen carbonate solution (10 mL). Ethyl acetate and water were then added to the mixture to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (67 mg). 1H-NMR (CDCl3) δ ppm: 3.94 (3H, s), 5.47 (2H, s), 6.62 (1H, s), 6.80 (1H, d, J=8.3 Hz), 6.87 (1H, d, J=11.3 Hz), 7.10-7.30 (3H, m), 7.35-7.45 (1H, m), 7.59 (1H, d, J=7.7 Hz), 7.65-7.75 (1H, m).
Reaction SMILES: [N:1]1([C:10]2([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N+:18](=[CH2:20])=[N-:19].CNC(N)=O.[OH-].[K+]>O1CCCC1.CCOCC.CCCCCC.C(OCC)(=O)C>[N+:18](=[CH:20][C:15]([C:10]1([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16])=[N-:19]
Reactant: O=C(Cl)C1(n2ccc3cccnc32)CCCC1
Reactant: C=[N+]=[N-]
Agent: CNC(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: [N-]=[N+]=CC(=O)C1(n2ccc3cccnc32)CCCC1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarbonyl chloride (395) (1.2 g, 8.83 mmol) in tetrahydrofuran (80 mL) was dropwise added a solution of diazomethane [which was freshly synthesized following the standard procedure, starting from methylurea via formation of NMU and followed by KOH treatment] in ether (80 mL) at −5° C., while stirring very slowly. The reaction mixture was left standing for 1 h at 0° C. (TLC, 30% ethyl acetate in hexane, Rf=0.6). Volatiles were removed to get the crude product which was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 2-diazo-1-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-ethanone (396) (1.1 g, 90%) as a yellow sticky solid.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.0585 g, 52%). MP: 219° C. (dec.). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.27-8.22 (m, 1H), 8.13-8.10 (m, 1H), 8.02 (d, 1H, J=1.3 Hz), 7.53 (s, 1H), 7.43 (s, 1H), 6.63 (s, 1H), 6.56-6.53 (m, 1H), 6.52-6.47 (m, 1H), 6.07-5.75 (m, 1H), 3.92 (s, 3H), 3.91-3.87 (m, 4H), 3.86 (s, 3H), 3.18-3.12 (m, 4H), 2.97-2.75 (m, 10H). MS: 575 (MH)+.