Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1Br.BrCCBr.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([C:27]=1[CH3:28])[CH:25]=[O:26].O>O1CCCC1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([C:27]=1[CH3:28])[CH:25]([OH:26])[C:4]1[C:5]([CH3:13])=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)c(Br)c(OC)c1OC
Reactant: COc1ccc(Br)c(C)c1C=O
Solvent: C1CCOC1
Solvent: O
Solvent: BrCCBr
Product: COc1cc(C)c(C(O)c2c(OC)ccc(Br)c2C)c(OC)c1OC
Temperature: 30 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
2.36 g of 2,3,4-trimethoxy-6-methylbromobenzene and 0.32 g of agnesium turnings were initially charged in 5 ml of anhydrous tetrahydrofuran, 0.57 ml of 1,2-dibromoethane was added and the reaction mixture was heated at reflux temperature for about 40 min. After cooling to 30° C., 1.40 g of 5-bromo-2-methoxy-6-methylbenzaldehyde were added dropwise, and the solution was stirred for about two hours. Water/2N hydrochloric acid (1/1) was added, the aqueous phase was extracted with ethyl acetate, the organic phases were washed with water and dried and the solvent was distilled off, and the residue was then purified by column chromatography (mobile phase petroleum ether/ethyl acetate 85/5). 1.5 g of the title compound were isolated as a violet viscous oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[CH3:15][NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=[CH:22][C:20]=2[N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCO.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:12]([N:4]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]2[C:2]([C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[C:17]([NH:16][CH3:15])[S:18][C:19]=3[CH:25]=2)=[N:3]1)([CH3:14])[CH3:13]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CNc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CNc1nc2ccc(-c3nn(C(C)C)c4ncnc(N)c34)cc2s1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 34.1 %

Procedure:
A mixture of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (104) (47 mg, 0.16 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (703 (37 mg, 0.13 mmol), Pd(OAc)2 (6 mg, 0.027 mmol), triphenyl phosphine (20 mg, 0.076 mmol) and Na2CO3 (69 mg, 0.65 mmol) was dissolved in a mixture of DMF (4 mL), EtOH (4 mL) and H2O (2 mL). The resulting mixture was degassed and back-filled with argon three times and then stirred at 90° C. for 1.5 h. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (200-300 mesh) eluting with DCM/MeOH (20/1) to give the desired product 1-isopropyl-3-(2-(methylamino)benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (704) (15 mg, 34.1%) as a pale solid. ESI-MS (M+H)+ m/z: 340.05.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C@H:12]([C:14]2[N:15]=[C:16]3[S:30][CH:29]=[C:28]([CH3:31])[N:17]3[C:18](=[O:27])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH3:13])[N:3]=1.N([O-])=[O:33].[Na+]>C(O)(=O)C.O>[F:26][C:22]1[CH:21]=[C:20]([C:19]2[C:18](=[O:27])[N:17]3[C:28]([CH3:31])=[CH:29][S:30][C:16]3=[N:15][C:14]=2[C@@H:12]([NH:11][C:4]2[N:3]=[C:2]([OH:33])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH3:13])[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1csc2nc([C@H](C)Nc3nc(N)nc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1csc2nc([C@H](C)Nc3nc(O)nc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 20 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
A solution of 7-{(1S)-1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (27 mg, 62 μmol) in acetic acid (0.41 mL) and water (84 μL) at 0° C. was treated with a solution of sodium nitrite (13 mg, 0.19 mmol) in water (0.15 mL) dropwise and stirred at 0° C. for 30 minutes and at 20° C. for 16 hours. The reaction mixture was concentrated and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (7 mg, 20%) as a white solid. LCMS for C20H17FN7O2S (M+H)+: m/z=437.8. 1H NMR (300 MHz, DMSO-d6): δ 7.79 (br s, 1H), 7.68-7.61 (m, 1H), 7.50-7.38 (m, 3H), 7.23-7.14 (m, 2H), 7.06 (br s, 1H), 5.02-4.92 (m, 1H), 2.64 (s, 3H), 1.26 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].CS([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])(=O)=O.O>CS(C)=O>[CH2:30]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[CH2:19]
Reactant: C=CCCCCCCCCCCS(C)(=O)=O
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a suspension of sodium theobromine (6.00 g, 30.0 mmol) in dimethylsulfoxide (60 mL) was added 12-methanesulfonyl-1-dodecene and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (120 mL) and extracted with diethyl ether (2×100 mL). The organic portions were combined, dried using magnesium sulfate and evaporated to give a cream solid. Recrystallization from ethyl acetate/hexane 1:1 yields 6.97 g (67% yield) 1-(11-dodecenyl)-3,7-dimethylxanthine (inventive compound no. 2516) as a white solid.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([O:33]CC3C=CC=CC=3)=[C:12]([CH:32]=2)[C:13]([NH:15][C:16]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[O:14])[CH2:4][CH2:3][CH2:2]1.O1CCOCC1>C(OCC)(=O)C.CO.[C].[Pd]>[N:1]1([CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([OH:33])=[C:12]([CH:32]=2)[C:13]([NH:15][C:16]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[O:14])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution mixture of the obtained methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.088 g) in ethyl acetate (1.5 mL), methanol (1.5 mL), and dioxane (1.5 mL), 10% palladium-carbon (0.088 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (0.088 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and then 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 0.033 g of methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[N:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])C.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)CC)C>[F:17][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:4](=[O:5])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=[C:15]3[C:14]=2[N:13]=1
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1Cl
Reactant: NNc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Temperature: 135 °C
Yield: 85 %

Procedure:
In a vial were added 4a, phenyl hydrazine and triethylamine. The vial was sealed and heated to 135° C. for 12 hours. The product was collected by filtration and was washed with methanol in 85% yield. 1H-NMR (DMSO-d6) δ (ppm): 7.18 (1H, dd, J=7.41, 7.14 Hz), 7.50 (3H, m), 8.26 (3H, m), 8.81 (1H, s). m/z 281.3 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][O:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:7][CH:6]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:13]1([CH2:12][CH2:11][O:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:19][CH:18]=2)[CH:17]=[CH:16][N:15]=[N:14]1
Reactant: C=CCOc1ccc(COCCn2ccnn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: Oc1ccc(COCCn2ccnn2)cc1
Temperature: 40 °C
Reaction time: 4.5 h
Yield: 58.6 %

Procedure:
A solution of 500 mg (1.93 mmol) 1-[2-(4-allyloxy-benzyloxy)-ethyl]-1H-[1,2,3]-triazole in 10 ml dichloromethane was added to a solution of 904 mg (5.79 mmol) 1,3-dimethylbarbituric acid and 58 mg (0.05 mmol) Pd(PPh3)4 in 20 ml dichloromethane and stirred for 4.5 h at 40° C. The mixture was extracted with 3×20 ml sat. NaHCO3-solution and 8 ml water and the combined aqueous phases were reextracted with 2×10 ml dichloromethane. The organic extracts were combined and dried over MgSO4. Solvents were distilled off and the residue purified by chromatography on silica gel (ethyl acetate) to yield 248 mg (59%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=1)=[O:6].[H-].[Na+].O.[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[I:14][C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCBr)Nc1cccc(I)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCN1c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
To a solution of 4-bromo-N-(3-iodo-phenyl)-butyramide (1.60 g, 4.36 mmol) in dry DMF (20 mL) at 0° C. was added portionwise sodium hydride (60% in oil, 0.20 g, 5.01 mmol). After 15 min at 0° C., the reaction mixture was then stirred at room temperature overnight. As the reaction was incomplete as judged by TLC, sodium hydride (60% in oil, 45 nmg, 1.09 mmol) was added. After two hours, water (40 mL) and an aqueous solution of saturated ammonium chloride (40 mL) were added to the reaction mixture. The aqueous phase was extractred with EtOAc and then the organic extracts were washed with brine, dried (Na2SO4), filtered, concentrated under vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of EtOAc (0-30%) in cyclohexane to yield the title compound as a yellow solid (0.94 g, 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[N:18]=[CH:17]3)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[N:18]=[CH:17]3)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(NC(=O)Nc2ccc3c(cnn3CCN3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
A mixture of 1-(4-nitro-phenyl)-3-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-yl]-urea (3.1 g, 7.8 mmol), iron powder (3.5 g, 63 mmol), and ammonium chloride (0.21 g, 3.9 mmol) in a 4:1 ethanol/H2O solution (50 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes followed by filteration through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (2.6 g, 92%). 1H NMR (300 MHz, DMSO-d6) ppm 1.89 (m, 4H), 3.06 (m, 4H), 3.64(m, 2H), 4.75 (d, J=6.44, 2H), 6.52 (m, 2H), 7.09 (m, 2H), 7.39 (m, 1H), 7.66 (m, 1H), 7.92 (m, 1H), 8.06 (s, 1H), 8.31 (m, 1H), 8.70 (s, 1H); MS (DCI/NH3) m/z 365 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)#[CH:12].N>>[N:6]1[CH:5]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[O:1][N:2]=2)[CH:9]=[N:8][CH:7]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1ccc(C)cc1
Agent: N
Product: Cc1ccc(-c2cc(-c3cncnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-4-methylbenzene (Apollo, 58 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 2.40 (s, 3H), 7.42 (d, J=8.1 Hz, 2H), 7.70 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 9.32 (s, 2H), 9.34 (s, 1H) ppm; MS (DCI/NH3) m/z 238 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:24][CH2:25][CH3:26])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:23])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([OH:19])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])[CH3:2].[Br:27][CH2:28][CH2:29]Br.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.CCCCCC>CC(C)=O.O>[CH2:1]([O:3][CH:4]([S:24][CH2:25][CH3:26])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:23])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:29][CH2:28][Br:27])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(O)cc1[N+](=O)[O-]
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCBr)cc1[N+](=O)[O-]

Procedure:
A solution of (2S)-N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)pyrrolidine-2-carbox-aldehyde diethylthioacetal of formula I (800 mg, 2 mmol), 1,2-dibromoethane (940 mg, 2.5 mmol) and K2CO3 (828 mg, 3 mmol) in dry acetone (40 ml) was refluxed for 48 h. After the completion of reaction as indicated by TLC, EtOAc-hexane (7:3), the reaction mixture was poured on to the water and then extracted with ethylacetate. Evaporation of the organic layer gave the crude product, which was further purified by column chromatography on silica gel eluting with EtOAc-hexane (1:1) gave the pure (2S)-N-[4-(2-bromoethoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula II.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=1.C[Sn](C)C.C[Sn](C)C.Cl[C:21]1[N:26]=[C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:24]2=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:36]=[CH:37][N:23]2[N:22]=1.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:38]1([C:35]2[CH:36]=[CH:37][N:23]3[C:24]=2[C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:26][C:21]([C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=2)=[N:22]3)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(=O)Nc1cncc(Cl)n1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)n1
Temperature: 100 °C
Yield: 15.4 %

Procedure:
A solution of N-(6-chloropyrazin-2-yl)acetamide (77.0 mg, 0.447 mmol) and hexamethylditin (0.124 mL, 0.596 mmol) in 1,4-dioxane (15 mL) was purged with argon gas for 30 min. Pd(Ph3P)4 (34.0 mg, 0.0300 mmol) was added and the reaction mixture was heated at 100° C. for 1 h. Then the reaction mixture was allowed to cool to RT and then 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.100 g, 0.298 mmol) was added followed by LiCl (13.0 mg, 0.298 mmol). The reaction mixture was heated at 100° C. for 12 h. The cooled reaction mixture was filtered through the CELITE® and washed with ethyl acetate (10 mL). The filtrate was evaporated under reduced pressure to give a residue which was purified by preparative TLC plate (40% ethylacetate/petroleum ether) then further purified by preparative HPLC (Condition B-100 as described in general methods) to give N-(6-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrazin-2-yl)acetamide (20.0 mg, 15.4%). LCMS Condition B-34: retention time 2.27 min, [M+1]=437.0. HPLC Condition B-5: retention time 6.86 min, purity 97.45%. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 3H), 4.93 (d, J=4.5 Hz, 2H), 6.85-6.88 (m, 1H), 7.29 (ddd, J=7.5 Hz, J=5.0 Hz, J=1.0 Hz, 1H), 7.38 (t, J=4.5 Hz, 1H), 7.46-7.50 (m, 2H), 7.52-7.57 (m, 2H), 7.58-7.63 (m, 2H), 7.79 (td, J=7.7 Hz, J=1.8 Hz, 1H), 7.89 (d, J=2.5 Hz, 1H), 8.39 (td, J=2.5 Hz, J=1.0 Hz, 1H), 9.17 (s, 1H), 9.43 (s, 1H), 11.15 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(CN2CCc3ccccc32)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
Indoline (12.70 g, 106.5 mmol) was dissolved in MeOH (120 ml), stirred at room temperature and treated with potassium carbonate (14.70 g, 106.5 mmol). Benzyl bromide (18.20 g, 106.5 mmol) was then added and the mixture heated to reflux for 4 hr. The solution was cooled and filtered to remove the carbonate. The filtered solution was washed with water (2×100 ml) and extracted into DCM (2×100 ml), dried (MgSO4) and reduced under vacuum to give the title compound (18.65 g, 83%) as a brown semisolid. δH (d6 DMSO) 7.27 (5H, br m), 6.98 (1H, t), 6.95 (1H, t), 6.50 (2H, d), 4.18 (2H, s), 3.17 (2H, t, J 7.3 Hz), 2.84 (2H, t, J 7.2 Hz); m/z (ES+, 70V) 210 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Br:11]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[Br:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: Clc1ccc2[nH]ncc2c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2[nH]nc(Br)c2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A flask was charged with 5-chloro-1H-indazole (4.9 g, 32.11 mmol) and DMF (30 mL). It was then cooled to 0° C., and a solution of bromine (2.4 mL, 46.86 mmol) in DMF (30 mL) was added over several minutes. After addition was complete, the flask was warmed to rt and stirred for 4 hours. Additional bromine (0.89 mL, 16 mmol) was added, and the reaction stirred at room temperature for 20 minutes. The reaction was poured into 600 mL of ice-cold 1% (w/v) Na2S2O3 solution, and the precipitated product was filtered off. The product was redissolved in EtOAc (500 mL), washed with saturated aqueous NaHCO3 then brine, dried over Na2SO4, and concentrated to afford the product. 1H NMR (400 MHz, DMSO-d6) δ 13.60 (br s, 1H), 7.68-7.54 (m, 2H), 7.44 (dd, J=9.0, 1.8 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[CH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(CCO)c2ccccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1ccc(CC=O)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-(2-hydroxyethyl)naphthalene-1-carbonitrile (25 mg, 0.13 mmol) in DCM (4 mL) was treated with Dess-Martin periodinane (75 mg, 0.18 mmol) and was stirred at room temperature for 3 hours. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate (3×). The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give the title aldehyde as an oil which was used directly in subsequent reductive amination reaction.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:24][C:25](=[O:27])[CH3:26])=[CH:15][C:16]=3[O:20][C:21](=[O:23])[CH3:22])[O:11][C:10]=2[CH3:28])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:49]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:24][C:25](=[O:27])[CH3:26])=[CH:15][C:16]=3[O:20][C:21](=[O:23])[CH3:22])[O:11][C:10]=2[CH2:28][Br:49])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(-c2c(C)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(-c2c(CBr)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Yield: 72.1 %

Procedure:
A solution of 4',5,7-triacetoxy-2-methylisoflavone (5 g), benzoyl peroxide (0.3 g) and N-bromosuccinimide (3.9 g) in 300 ml carbon tetrachloride was heated under reflux for 12 hours, the solvent was distilled off under reduced pressure, water was added to the solid residue, the mixture was stirred well, and the crude product collected by filtration was recrystallized from a methanol/chloroform mixed solvent, affording 4.3 g of 4',5,7-triacetoxy-2-bromomethylisoflavone.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[OH:14][CH:13]([C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1)[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: Cn1cncc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.42 h

Procedure:
A solution of 5-bromo-1-methyl-1H-imidazole (25.0 g, 155 mmol; dried over 3 Å molecular sieves, then filtered) in DCM (310 mL) was stirred in an ice bath while iPrMgCl (72 mL, 2.01 M solution in THF, 145 mmol) was added rapidly dropwise under argon via pressure-equalizing addition funnel. Residual iPrMgCl was rinsed down with 50 mL THF, and the ice bath was removed and the reaction stirred for 25 minutes. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (27.6 g, 130 mmol) in THF (65 mL) was added dropwise over ˜5 minutes via pressure-equalizing addition funnel at room temperature. After stirring 1 hour at room temperature, the yellow mixture was quenched with 5 M aqueous NH4Cl (250 mL) in one portion. The organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear light amber oil.