Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C(N(C(C)C)C(C)C)C.[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][C:6]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N2CCOCC2)cc1-c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 1.46 g (5.15 mmol) methyl-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine and 1.32 ml (7.73 mmol) N-ethyldiisopropylamine in 15 ml dichloromethane was cooled in an ice bath and 1.8 g (5.67 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was warmed to 35-40° C. for 3h, cooled to room temperature again and was stirred with 25 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 2.9 g (quantitative) of the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:9]=2[CH:10]=1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 29.1 %

Procedure:
To a stirred solution of methyl 6-bromo-1H-indazole-4-carboxylate (10 g, 39.3 mmol) in acetonitrile (100 mL), was added cesium carbonate (19.2 g, 59.05 mmol) followed by bromocyclopentane (11.93 g, 78.3 mmol). The reaction mass was stirred at 90° C. for 3-4 h. On completion of reaction, acetonitrile was removed under reduced pressure and water added. Extraction was carried out using ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography to obtain methyl 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylate (3.7 g, 29.2%). The regiochemistry of the cyclopentyl group was confirmed by a NOE experiment.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:4][C:5]([CH3:22])=[C:6]([CH3:21])[C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH2:30]([O:32][CH2:33][C:34](Cl)=[O:35])[CH3:31]>ClCCl>[CH2:30]([O:32][CH2:33][C:34]([NH:1][C:2]1[C:3]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:4][C:5]([CH3:22])=[C:6]([CH3:21])[C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:35])[CH3:31]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(Oc2ccccc2)nc(C)c(C)c1NCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylaminie (3.3 mL, 23.7 mmol) was added to a chilled (0° C.) mixture of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate (8.60 g, 21.5 mmol) and anhydrous dichloromethane (200 mL). Ethoxyacetyl chloride (2.76 g, 22.5 mmol) was added. After one hour the reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to provide tert-butyl 4-({3-[(ethoxyacetyl)amino]-5,6-dimethyl-2-phenoxypyridin-4-yl}amino)butylcarbamate as a brown oil. The oil was combined with pyridine (130 mL) and heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in dichloromethane and was washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in diethyl ether and then concentrated under reduced pressure to provide 8.21 g of tert-butyl 4-[2-(ethoxymethyl)-6,7-dimethyl4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butylcarbamate.
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[C:4]([C:5]([O:7]C)=[O:6])=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>[OH-].[Na+]>[CH3:1][N:2]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1c(-c2ccccc2)n(C)c(C)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Yield: 86.4 %

Procedure:
6.0 gms of crude methyl 1,6-dimethyl-2-phenyl-4-oxonicotinate is suspended in 66 g of 5% aqueous sodium hydroxide solution. The reaction mixture is heated on a steambath (85°) for two hours. The resulting homogeneous solution is cooled and acidified with dilute HCl. The resulting solid is collected by filtration yielding 4.9 g of 1,6-dimethyl-2-phenyl-4-oxonicotinic acid. mp (acetonitrile/methylene chloride)=246°-249° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][NH2:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][NH:30][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCCCNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12)OCc1ccccc1
Yield: 84.8 %

Procedure:
0.19 g (0.768 mmol) of 2,4-dichloro-3-nitroquinoline and 0.16 g (0.768 mmol) of N-(benzyloxycarbonyl)-1,3-propanediamine was heated at 70° C. in 5 ml of triethylamine for one hour with stirring. After triethylamine was distilled off under reduced pressure, the residue was dissolved in methylene chloride, washed with water, and dried (MgSO4). The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 (v/v)) to obtain 0.27 g (0.651 mmol) of 4-[3-(benzyloxycarbonylamino)propylamino]-2-chloro-3-nitroquinoline shown below as yellow powder. ##STR29## Its spectroscopic data are as follows: 1H-NMR (CDCl3) δ (ppm) :1.79 (2H, m), 3.35 (4H, m), 5.02 (1H, br), 5.18 (2H, s), 7.15 (1H, br), 7.37 (5H, m), 7.57 (1H, t, J=8.0 Hz), 7.73 (1H, t, J=7.8 Hz), 7.90 (1H, d, J=8.4 Hz), 8.21 (1H, d, J=8.0 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([C:14]([CH3:21])([CH3:20])[C:15]([O:17]CC)=[O:16])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([C:14]([CH3:21])([CH3:20])[C:15]([OH:17])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)N(C)NC(=O)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)O
Yield: 36.8 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-4, ethyl 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)-2-methylpropanoate (Compound V-2) (2.932 g, 10 mmol) was reacted with lithium hydroxide monohydrate (839.2 mg, mmol) to obtain the title compound (975.1 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1)[OH:12].[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>N1C=CC=CC=1>[C:23]([O:12][C:7]1([C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:9](=[O:10])[O:8]1)(=[O:25])[CH3:24]
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(OC)nc(C2(OC(C)=O)OC(=O)c3c(Cl)cccc32)n1

Procedure:
1.1 g of 7-chloro-3-(4,6-dimethoxy-2-pyrimidinyl)-3-hydroxy-phthalide is dissolved in 20 ml of pyridine and 0.3 ml of acetic anhydride added with stirring. After stirring for 20 min the mixture is poured into 2N HCl and extracted with two portions of ethyl acetate. The combined ethyl acetate extracts are washed once with 2N HCl, once with H2O and once with brine and dried over magnesium sulfate. Filtration and evaporation produced the title compound as a white solid, m.p. 213°-215°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:16][C:4]2[C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:25])=[O:26])=[CH:20][C:19]=1[C:28]([F:31])([F:29])[F:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)cnc1Oc1ccccc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Oc1ccccc1F)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of 5-chloro-2-(2-fluoro-phenoxy)-pyridin-3-ylamine (75 mg, 0.31 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (103 mg, 0.36 mmol), DMAP (20 mg, 0.16 mmol) in anhydrous pyridine (1 mL) was stirred at room temperature for 2 days. The reaction product was separated by preparative HPLC using acetonitrile-water solvent mixture and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1 H), 7.96 (s, 1 H), 7.89 (d, J=8.0 Hz, 1 H), 7.79 (s, 1 H), 7.62 (d, J=8.0 Hz, 1 H), 7.15-7.13 (m, 3 H), 7.00-6.96 (m, 1 H). MS m/z: 481.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
A slurry of dichlorobis(triphenylphosphine)palladium(II) (119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00 g, 2.79 mmol). The reaction slurry was stirred at 25° C. for 10 min and then treated with a solution of pyridine-4-boronic acid (515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8 mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was heated under reflux for 8 h. The reaction mixture was allowed to cool to 25° C. where it was stirred for 3 d. The reaction mixture was partitioned between water (75 mL) and methylene chloride (75 mL), and the layers were separated. The aqueous layer was further extracted with methylene chloride (75 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester (240 mg, 28%) as a brown oil that was used without further purification and characterization.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.Cl>O.[Pt](=O)=O.O>[OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1
Reactant: OCCCc1ccccn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Product: OCCCC1CCCCN1
Reaction time: 96 h
Yield: 100.1 %

Procedure:
2-(3-Hydroxypropyl)pyridine (5 g, 36.4 mmoles) was dissolved in 1N HCl (36.4 mL, 36.4 mmoles) and water (63.6 mL) and platinum (IV) oxide monohydrate (1 g, 4.08 mmoles) was added under an argon atmosphere. The mixture was hydrogenated at 55 psi in a Parr bomb at 25° C. for 96 h. The catalyst was filtered off through Celite® and washed with water. The combined filtrates were treated with BioRad AG1-X8 (OH) resin until basic. The resin was filtered off and washed with water. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 10% increasing to 20% (10% conc. NH4OH in methanol)dichloromethane as the eluant to give the title compound (5.22 g, 100%): CIMS: m/z 144.40 (MH+); δC (d6-DMSO) CH2: 24.0, 25.3, 28.8, 31.5, 32.8, 45.9, 60.8; CH: 56.1.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:22])[CH3:21]>C1COCC1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH3:8])[CH2:21][O:22]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(Cl)cc2Cl)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for one h. THF is added at same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(2,4-dichlorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31]C1C2C(=O)NC([C@H]3[C@H](C)CNC3)=NC=2N(C2CCOCC2)N=1>>[CH3:31][C:23]1[C:18]2[C:17](=[O:30])[NH:16][C:15]([C@H:3]3[C@H:2]([CH3:1])[CH2:6][N:5]([CH2:7][C:8]4[CH:13]=[N:12][C:11]([CH3:14])=[N:10][CH:9]=4)[CH2:4]3)=[N:20][C:19]=2[N:21]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:22]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: Cc1nn(C2CCOCC2)c2nc([C@@H]3CNC[C@H]3C)[nH]c(=O)c12
Product: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(c(C)nn4C4CCOCC4)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 3-methyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.63 (s, 2H), 4.74-4.68 (m, 1H), 4.11-4.08 (m, 2H), 3.74-3.63 (m, 2H), 3.60-3.52 (m, 2H), 3.28 (t, J=8.3 Hz, 1H), 3.03 (d, J=9.5 Hz, 1H), 2.85-2.83 (m, 1H), 2.71 (s, 3H), 2.65-2.61 (m, 1H), 2.53 (s, 3H), 2.48-2.29 (m, 2H), 1.98 (t, J=8.7 Hz, 1H), 1.87-1.80 (m, 3H), 1.19 (d, J=7.1 Hz, 3H). MS: (M+H m/z 424.2).
Reaction SMILES: Br[CH2:2][Mg].Cl[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:8]=[CH:7][N:6]=1.Cl>[Ni](Cl)Cl.C1COCC1>[CH3:2][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: COc1cc(-c2ccnc(Cl)c2)cc(OC)c1OC
Reactant: [Mg]CBr
Agent: Cl[Ni]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(-c2ccnc(C)c2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Nickel chloride (3.0 mg) was added to THF (1 mL) under an argon atmosphere, and the mixture was kept at 0° C. To the mixture, a THF solution (0.38 mL) of 0.93 M bromomethylmagnesium was slowly added, and a THF solution (2 mL) of 2-chloro-4-(3,4,5-Trimethoxyphenyl)pyridine (50 mg) was then slowly added. The mixture was stirred at 0° C. for 10 minutes and then at 70° C. for 1.5 hours. A small amount was diluted hydrochloric acid was added to the reaction mixture at 0° C. to conduct extraction with ethyl acetate. The resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=15:1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.F[B-](F)(F)F.[CH3:21][O+](C)C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([O:12][CH3:21])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: C[O+](C)C
Reactant: O=C1Nc2ccc(Cl)cc2C2CCCC12
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=Nc2ccc(Cl)cc2C2CCCC12

Procedure:
A solution of 8-chloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (200 mg, 0.9 mmol) in dichloromethane (20 ml) is stirred with trimethyloxonium tetrafluoroborate (134 mg, 0.9 mmol) for 24 hours at room temperature. After triethylamine (0.13 ml, 0.9 mmol) is added, the batch is concentrated by evaporation and purified by column chromatography (SiO2, 40% moist) with ethyl acetate-hexane: 180 mg (85%) of product.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:3].[CH3:12][S:13]([N:16]([CH2:31][CH2:32][Cl:33])[N:17]([S:27]([CH3:30])(=[O:29])=[O:28])C(OC1C=CC=CC=1)=O)(=[O:15])=[O:14]>>[CH3:12][S:13]([N:16]([CH2:31][CH2:32][Cl:33])[N:17]([S:27]([CH3:30])(=[O:29])=[O:28])[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:3])(=[O:14])=[O:15]
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Product: Cc1ccc(OC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)cc1

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-tolyloxy)carbonyl]hydrazine (compound 10e) was prepared by reacting compound 2 with 4-tolyl chloroformate using a procedure similar to that employed for compound 10d. The product was recrystallized from ethanol, and the yield was about 31.2% by weight. The Mp was approximately 85-86° C. 1H NMR (CDCl3): δ 7.3 and 7.1 (4H, 2d, aromatic H), 3.7-4.2 (4H, m, CH2CH2Cl), 3.5 and 3.2 (6H, 2s, 2 CH3SO2), 2.4 (3H, s, ArCH3).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[N:31]1([CH2:36][CH2:37][O:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[CH3:27][N:22]1[C:23]2[C:19](=[C:18]([NH:17][C:15]3[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=[C:11]([NH:43][C:42]4[CH:44]=[CH:45][C:39]([O:38][CH2:37][CH2:36][N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:40][CH:41]=4)[N:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1ccc2c(Nc3nc(Nc4ccc(OCCN5CCCC5)cc4)ncc3C(N)=O)cccc21
Temperature: 100 °C
Yield: 45.2 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (62 mg, 0.15 mmol) in NMP (1 ml) was added 4-(2-(pyrrolidin-1-yl)ethoxy)aniline (31 mg, 0.15 mmol) and p-toluenesulfonic acid hydrate (28 mg, 0.15 mmol). It was heated at 100° C. for 4 h, and was purified by preparative HPLC to give 4-(1-methyl-1H-indol-4-ylamino)-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidine-5-carboxamide (32 mg). MS found for C26H29N7O2 as (M+H)+ 472.4. UV: λ=216.9, 257.0.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:22][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[CH:17]=[C:16]([Cl:20])[C:15]([CH3:21])=[N:14]3)=O)(C)(C)C>CC(O)=O.C(Cl)Cl>[Cl:20][C:16]1[C:15]([CH3:21])=[N:14][C:13]2[N:18]([N:19]=[C:11]3[CH2:10][NH:9][CH2:22][C:12]3=2)[CH:17]=1
Reactant: Cc1nc2c3c(nn2cc1Cl)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2c3c(nn2cc1Cl)CNC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
A 32% solution of HCl (1.79 mL) was added to a solution of 6-chloro-5-methyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (1.70 g; 5.51 mmol; 1 eq.) in AcOH (5.8 mL) and the reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with DCM, washed with 1M NaOH (2×), dried over sodium sulfate and concentrated in vacuo to afford the title compound (900 mg, 78%) as a yellow solid. 1H NMR (DMSO-d6) δ 9.37 (s, 1H), 4.09-3.98 (m, 4H), 3.70-3.53 (m, 1M), 2.55 (s, 3H). HPLC (max plot) 99.8%, Rt 1.20 min. UPLC/MS: (MS+) 209.1 ([M+H]+).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[NH2:22][C:23]1[C:32]2[C:27](=[C:28](Br)[CH:29]=[CH:30][CH:31]=2)[N:26]=[N:25][C:24]=1[C:34]([NH2:36])=[O:35]>>[NH2:22][C:23]1[C:32]2[C:27](=[C:28]([C:11]3[CH:10]=[CH:9][C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=[N:6][C:7]=4[CH:12]=3)[CH:29]=[CH:30][CH:31]=2)[N:26]=[N:25][C:24]=1[C:34]([NH2:36])=[O:35]
Reactant: CC(C)n1cnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Product: CC(C)n1cnc2cc(-c3cccc4c(N)c(C(N)=O)nnc34)ccc21

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 4-amino-8-bromocinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 1.70 (d, J=8 Hz, 6 H), 7.61 (dd, J=8, 4 Hz, 1 H), 7.76 (dd, J=8, 4 Hz, 1 H), 7.78-7.84 (m, 1 H), 7.85-7.92 (m, 1 H), 7.93 (m, 1 H), 8.30 (dd, J=8, 4 Hz, 1 H), 8.37 (s, 1 H); ESI-MS m/z [M+H]+ 347.3.
Reaction SMILES: [I-:1].[Na+].[CH3:3][C:4](=O)[CH2:5][CH3:6]>>[CH:3](/[C:4]1[CH:3]=[C:4]([CH2:5][CH2:6][I:1])[CH:3]=[CH:6][CH:5]=1)=[CH:4]\[CH2:5][CH2:6][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCC(C)=O
Reactant: [I-]
Agent: [Na+]
Product: CCCCCC/C=C/c1cccc(CCI)c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Sodium iodide (3.99 g) was added to a solution of the above-mentioned compound (5.51 g) in 2-butanone (60 ml) and the mixture was stirred at 45° C. for 3 hours. The reaction mixture was concentrated, poured into ice water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=100:1) to give 4.75 g of the subject compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][N:31]1[CH2:30][CH2:29][N:28]([C:23]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=2)[CH2:33][CH2:32]1)[CH2:13][CH3:14]
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc21
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Product: CCC1(CCCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)C(=O)Nc2c(Cl)cc(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 5,7-dichloro-3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3,4-dichlorophenyl)-piperazine.