Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12](N)=[O:13]>O>[Br:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[N:11][C:12]([OH:13])=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Br)ccc1C=O
Reactant: NC(N)=O
Solvent: O
Product: Oc1ncc2ccc(Br)cc2n1
Temperature: 180 °C
Yield: 95 %

Procedure:
A mixture of 2-amino-4-bromobenzaldehyde (1 eq) and urea (14 eq) was heated to 180° C. in an oil bath under Argon for 1 h. Water was added to after cooling to ambient temperature. The solid was collected by filtration and air dried to give product in 95% yield. ES/MS m/z 225/227 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:26]([Mg]Br)[CH3:27]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a suspension of 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (166 mg, 0.400 mmol) in tetrahydrofuran (5 mL) was added dropwise ethylmagnesium bromide (3 M solution in diethyl ether, 0.270 mL, 0.810 mmol) at 0° C., and the mixture was stirred at 0° C. for 15 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (170 mg, 0.381 mmol, 95%).
Reaction SMILES: [CH:1]1([N:6]2[C:11](=[O:12])[C:10](N3CCCC3=O)=[CH:9][C:8]([C:19]([OH:21])=O)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=N[C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][C@@H:47]([CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C@H:48]([OH:66])[CH2:49][NH:50][CH:51]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([O:61][CH3:62])[CH:59]=2)[C:54](=[O:63])[C:53]([CH3:65])([CH3:64])[CH2:52]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]1([N:6]2[CH:7]=[C:8]([C:19]([NH:46][C@@H:47]([CH2:67][C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[C@H:48]([OH:66])[CH2:49][NH:50][C@H:51]3[C:60]4[C:55](=[CH:56][CH:57]=[C:58]([O:61][CH3:62])[CH:59]=4)[C:54](=[O:63])[C:53]([CH3:64])([CH3:65])[CH2:52]3)=[O:21])[CH:9]=[C:10]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:36]=3)[C:11]2=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2c(c1)C(NC[C@@H](O)[C@@H](N)Cc1ccccc1)CC(C)(C)C2=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(N2CCCC2=O)c(=O)n(C2CCCC2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@H](NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c3ccccn3)c(=O)n(C3CCCC3)c1)CC(C)(C)C2=O
Reaction time: 0.08 h

Procedure:
1-Cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylic acid (0.076 g, 0.26 mmol) was added to a vial followed by DMF (1 mL). HATU (0.15 g, 0.39 mmol) was added and the mixture was stirred for 5 minutes. 4-((2R,3S)-3-amino-2-hydroxy-4-phenylbutylamino)-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (0.100 g, 0.26 mmol) was added followed by the addition of diisopropylethylamine (0.18 ml, 1.0 mmol). Reaction was allowed to stir at RT. After 2 hours, reaction the crude reaction mixture was purified using the Gilson. The solvent was evaporated to provide the title compound as a white solid. MS m/z: 655.6 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=2)[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Yield: 47.1 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (1.0 g, 3.4 mmol) and 1-methylpiperazine (1.50 ml, 13.6 mmol) in 15 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. 5-(4-methylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (0.50 g, 49%) was obtained by flash column chromatograph (10% ethanol in dichloromethane). 5-(4-methylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine hydrochloride was made by bubbling HCl gas in its ethyl ether solution and crystallized. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 2.75 (s, 3H), 3.03 (dd, J=12.9, 12.0 Hz, 2H), 3.29 (dd, J=11.9, 12.9 Hz, 2H), 3.42 (d, J=12.0 Hz, 2H), 3.90 (d, J=12.9, Hz, 2H), 6.48 (d, J=1.5 Hz, 1H), 6.65 (dd, J=2.6, 9.7 Hz, 1H), 7.2 (m, 1H), 7.23-7.45 (m, 4H), 8.06 (d, J=9.7 Hz, 1H), 9.72 (s, 1H), 11.27 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 40.0, 43.4, 51.5, 96.7, 106.8, 123.5, 124.9, 128.3, 129.6, 138.9, 144.2, 154.5.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:25])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.I[CH2:27][CH3:28].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([O:25][CH2:27][CH3:28])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=3)[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CCI
Reactant: O=c1[nH]c2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nc2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a mixture of 8-chloro-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (437 mg), iodoethane (0.19 ml) and N,N-dimethylformamide (10 ml) was added potassium carbonate (326 mg) at room temperature, and the mixture was stirred at 80° C. for 15 hr, and allowed to be cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (116 mg).
Reaction SMILES: [N+](=C)=[N-].[OH:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:22](O)(=O)C>C(OCC)C.O1CCOCC1>[CH3:22][O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)O
Reactant: O=C1Cc2cccc(Oc3ccccc3O)c2O1
Agent: C=[N+]=[N-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccccc1Oc1cccc2c1OC(=O)C2
Reaction time: 8 h

Procedure:
An excess of a solution of diazomethane in diethyl ether was added to a solution of 7-(2-hydroxyphenoxy)2,3-dihydrobenzofuran-2-one (4.9 g) in a mixture of diethyl ether (50 ml) and dioxane (50 ml), and allowed to stand overnight at room temperature. To the reaction mixture was added acetic acid (1 ml), and the organic solvent was distilled off. The oily residue was purified by column chromatography, and the crude crystals were crystallized from ethyl acetate to give 7-(2-methoxyphenoxy)-2,3-dihydrobenzofuran-2-one (2.3 g). mp 171°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[C:24]([CH3:35])[NH:23][C:22]=1[CH:36]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:36][C:22]4[NH:23][C:24]([CH3:35])=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 102 mg (80%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.27 (br s, 1H, NH), 11.66 (br s, 1H, NH), 9.12 (br s, 1H), 8.29 (s, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.31-7.36 (m, 2H), 3.43 (m, 4H, 2×CH2), 2.30 (s, 3H, CH3), 2.27 (m, 4H, 2×CH2), 2.18 (s, 3H, CH3), 2.12 (s, 3H, CH3). MS 510 [M++1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=3)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(Cl)c3)c3cc(C)sc3n2)cc1

Procedure:
The reaction of 3-chloro-4-methoxy-benzylamine with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-chloro-4-methoxybenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH2:7][CH2:6]1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[N:8]1([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]1
Reactant: O=C(c1nccs1)N1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1nccs1)N1CCNCC1
Yield: 238.7 %

Procedure:
A solution of compound 7a (3.8 g, 0.013 mol) and K2CO3 (3.5 g, 0.026 mol) in MeOH (40 mL) and water (10 mL), was stirred for 4 h. The solid was collected by filtration and the solvent evaporated in vacuo to give compound 7b (6.12 g). MS m/z (M+H+) 198.1.
Reaction SMILES: C[O-].[Na+].[C:4]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][O:6]1)=[O:5].[CH:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=O.C(OCC)(=O)CC>CO>[O:5]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:6])[CH:14]1[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=C1OCc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CO
Product: N#Cc1cccc(C2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.3 %

Procedure:
A mixture of 27% sodium methoxide solution in methanol (400 g, 2 mol) and methanol (150 ml) was added dropwise between ambient temperature and 30° C. over 15 minutes to a stirred mixture of phthalide (67 g, 0.5 mol), 3-formylbenzonitrile (65.5 g, 0.5 mol) and ethyl propionate (250 ml), the mixture was stirred at ambient temperature for 40 minutes and at reflux temperature for 1 hour, then it was allowed to cool to ambient temperature. The resulting red solid was collected by filtration, washed with ethyl acetate (2×50 ml) and dissolved in water (1800 ml). The solution was acidified by the addition of acetic acid (60 ml) and the resulting red solid was collected by filtration, washed with water (2×200 ml) and dried in vacuo to give 3-(1,3-dioxoindan-2-yl)benzonitrile (83.2 g) as a dark red solid, m.pt. 179-182° C., m/z (M+H)+• 248, which was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][C:3]1=O.[C:17]1(C)C=CC=CC=1.[NH2:24][NH2:25]>CO>[CH3:1][C@@H:2]1[C:7]2[C:6](=[CH:17][NH:24][N:25]=2)[C@@H:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1=O
Reactant: NN
Reactant: Cc1ccccc1
Solvent: CO
Product: C[C@H]1CC[C@H](c2ccc(C#N)cc2)c2c[nH]nc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
(+/−)-(trans)-4-(4-Methyl-3-oxo-cyclohexyl)benzonitrile (0.55 g, 2.58 mmol) is added to toluene (10.0 mL) and tert-butoxybis(dimtheylamino)methane (0.67 mL, 3.22 mmols) and stirred at 120° C. for 16 hours. The mixture is cooled to room temperature and concentrated in vacuo. The residue is added to MeOH (10.0 mL) and hydrazine (0.07 mL, 2.32 mmol) and stirred at 80° C. for 1.0 hour. The mixture is cooled to room temperature and concentrated in vacuo. The residue is purified by silica gel chromatography (35%-55% EtOAc/hexanes) to give (+/−)-(trans)-4-[7-methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]benzonitrile (0.18 g, 29%).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:3].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([F:11])[CH:8]=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-methylcarbonyl 3-fluoroaniline (5 g, 32.0 mmol) is dissolved in 25 ml of conc. sulfuric acid and is cooled to 0°. A mixture of 90% nitric acid (2.5 ml) in conc. sulfuric acid (25 ml) is added dropwise over a period of about 1 hour, with the temperature maintained at 0°. The reaction is allowed to warm to RT and is stirred at RT for 3 hours. The reaction is then carefully poured into ice. The resulting solid is washed several times with 10% ethyl acetate/hexane, and the combined organic extracts are stripped to give N-methylcarbonyl 2-nitro-5-fluoroaniline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH:37]([C:39]1[N:40]=[CH:41][NH:42][CH:43]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH2:37][C:39]4[N:40]=[CH:41][NH:42][CH:43]=4)[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: O=Cc1c[nH]cn1
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(Cc4c[nH]cn4)C3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.200 g, 0.415 mmol) in dichloroethane (5 mL) was treated with 4-formylimidazole (0.08 g, 0.83 mmol) and sodium triacetoxy borohydride (0.176 g, 0.83 mmol). The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (20 min), 15% methanol in dichloromethane (10 min), 20% methanol in dichloromethane (10 min) and 50% methanol in dichloromethane (8 min) as the eluent. The column afforded 0.074 g (25%) of pure N2-(4-{4-amino-1-[1-(1H-4-imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.446 (s, 1H), 8.252 (s, 1H), 8.126-8.1082 (d, 1H, J=8.16 Hz), 7.7198-7.7 (d, 1H, J=7.92 Hz), 7.6-7.569 (m, 2H), 7.35-7.298 (m, 4H), 7.171-7.134 (m, 1H), 6.946 (s, 1H), 5.422-5.385 (m, 1H), 4.043 (s, 3H), 3.961 (s, 3H), 3.691 (s, 2H), 3.175-3.162 (m, 2H), 2.9-2.883 (m, 3H), 2.385-2.332 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.13 min (100%), MH+ 563.3.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:13]=1[CH:14]=[CH:15][CH:16]([S:26]([CH:29]([CH:39]=[CH:40][C:41]1[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH2:38])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH2:25])[CH:18]=1>O1CCCC1>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:12]([O:11][CH3:10])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=1[O:47][CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccccc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccccc3)c2)c(OC)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of benzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) was added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzyl-sulfone (10 mmol) in tetrahydrofuran. The solution was stirred overnight and the completion of the reaction was monitored by TLC. The solvent was removed and the residue was taken up in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to give (E)-2,4,6-trimethoxystyryl-3-benzamido-4-methoxybenzylsulfone in 76% yield. m.p. 163-166° C. NMR (DMSO-d6) δ 3.82 (s, 3H), 3.83 (s, 6H), 3.86 (s, 3H), 4.2 (s, 2H), 6.14 (s, 2H), 7.10-7.18 (d, 1H vinylic), 7.00-7.86 (m, aromatic), 8.90 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[N:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]2=[O:11].[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:18][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[N:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]2=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CN1C(=O)c2cccc(O)c2C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CN1C(=O)c2cccc(OC)c2C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of methyl 2-(4-hydroxy-1,3-dioxoisoindolin-2-yl)acetate (160 mg, 0.680 mmol) in DMF (5 ml), K2CO3 (94 mg, 0.680 mmol) and iodomethane (88 μl, 1.361 mmol) were added, and the mixture was stirred under microwave irradiation at 100° C. for 1 hour. The insoluble inorganic salts were filtered off, the solvent was removed and the resulting crude product (130 mg, 0.522 mmol, 77% yield) was used in the following step without further purification. MS/ESI+ 250.1 [MH]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1([Mg]Cl)[CH2:12][CH2:11][CH2:10][CH2:9]1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[CH:8]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cl[Mg]C1CCCC1
Reactant: Brc1cccnc1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cncc(C2CCCC2)c1
Temperature: -5 °C
Yield: 29.5 %

Procedure:
3-Bromopyridine (3.9 ml, 40 mmol) and [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) (160 mg, 0.3 mmol) were dissolved in dry tetrahydrofuran (25 ml) and cooled to −5° C. Cyclopentylmagnesium chloride (2.0M in diethyl ether, 20 ml, 40 mmol) was added dropwise over 5–10 minutes and the reaction was allowed to warm slowly to room temperature. Further cyclopentylmagnesium chloride (2.0M in diethyl ether, 5 ml, 10 mmol) was added. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 20–35% ethyl acetate/i-hexane, to give the title compound (1.74 g, 30%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:6]=[N:7][C:2]([N:48]6[CH2:53][CH2:52][O:51][CH2:50][CH2:49]6)=[CH:3][CH:4]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Reactant: C1COCCN1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N4CCOCC4)nc3)cn2)cc1
Yield: 74.3 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.307 mmol) obtained in Step A in Example 1-D-48 and morpholine (40.2 mg, 0.462 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Step B in Example 1-D-48, amination was carried out, to obtain a crude product of bis-(4-methoxy-benzyl)-{5-[2-morpholin-4-yl-7-(6-morpholin-4-yl-pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-amine as a yellow solid (160 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-110) as a yellow powder (56 mg, 53%).