Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]#[CH:16])[CH:12]=[CH:11][C:10]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu]I>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]#[C:16][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:10]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(F)c(NC(=O)OC(C)(C)C)c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)Nc1cc(C#Cc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 1-(tert-butoxycarbonylamino)-5-ethynyl -2-fluorobenzene (0.11 g), iodobenzene (0.1 g), tetrakis -(triphenylphosphine)palladium(0) (16 mg) and copper (I) iodide (5 mg) in N,N-diisopropylamine (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-(tert -butoxycarbonylamino)-2-fluoro-5-phenylethynylbenzene (0.14 g). This material was dissolved in ethyl acetate (3 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 1-(tert-butoxycarbonylamino)-2-fluoro -5-(2-phenylethyl)benzene (0.11 g). To this material was added hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =8/1 -5/1) to give the title compound (53 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:10]1([C:14]([NH:16][NH2:17])=[O:15])[CH2:13][CH2:12][CH2:11]1>C(O)C>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:17][NH:16][C:14]([CH:10]2[CH2:13][CH2:12][CH2:11]2)=[O:15])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccncc1
Reactant: NNC(=O)C1CCC1
Solvent: CCO
Product: CC(=NNC(=O)C1CCC1)c1ccncc1
Yield: 26.9 %

Procedure:
A mixture of 6.06 gm (0.05 mole) of 4-acetylpyridine, 5.7 gm (0.05 mole) of cyclobutanecarboxylic acid hydrazide, and 100 ml of absolute ethanol is refluxed 5 hours. The reaction mixture is evaporated in vacuo to give a solid. The product is crystallized from ethanol/ethylacetate/diethylether to give 2.92 gm (27%) of the title compound; mp 138.6°.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>>[CH3:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccc(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(N(CCC(=O)O)C(=O)c2ccc3c(c2)nc(CNc2ccc(C(=N)N)cc2)n3C)c1

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH2:5].[NH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C(CN1CCC(O)CC1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (1.0 g, 3.0 mmol) in acetonitrile (10 mL) was added piperidin-4-ol (0.33 g, 1.1 equiv). A gentle stream of nitrogen was placed over the reaction while it stirred overnight. The crude oil which resulted was dissolved in ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.38 g (quant.) as an oil which was used without purification. Mass spec.: 403.42 (MH)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH2:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.[C:32](O)(=[O:36])[C:33]([CH3:35])=[O:34].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:34]=[C:33]([CH3:35])[C:32]([NH:13][C:11](=[O:12])[C@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:2])=[O:36]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)C(=O)NC(=O)[C@@H](N)Cc1ccccc1
Yield: 65.1 %

Procedure:
A suspension of HCl.H-Phe-NH2 (1.0 g, 4.98 mmol) in DCM (49 mL) was neutralized with Et3N (0.69 mL, 4.98 mmol) at 4° C. To this mixture were added HOBt.H2O (0.76 g, 4.98 mmol), pyruvic acid (0.52 mL, 7.47 mmol), and EDC.HCl (1.05 g, 5.47 mmol), and the mixture was stirred at 4° C. for 30 min and at room temperature for 2 h. After removal of the solvent in vacuo, the residue was dissolved in AcOEt, successively washed with 10% citric acid, 5% NaHCO3 and saturated NaCl for three times, dried over Na2SO4, and concentrated in vacuo to obtain 0.76 g (65%) of the title compound as a white solid: mp 138-140° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.34 (d, J=8.6 Hz, 1H), 7.52 (s, 1H), 7.24-7.19 (m, 6H), 4.45-4.37 (m, 1H), 3.11 (dd, J=4.2, 13.8 Hz, 1H), 2.96 (dd, J=9.5, 13.8 Hz, 1H), 2.26 (s, 3H); HRMS (EI): m/z 234.1008 (M+) (calcd for C12H14N2O3: 234.1004).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Cl:14])=[C:9]([N+:15]([O-:17])=[O:16])[C:8]=1[Cl:18])[CH3:2].[CH:21](OCC)(OCC)[O:22][CH2:23][CH3:24].C(OC(=O)C)(=O)C>>[Cl:18][C:8]1[C:9]([N+:15]([O-:17])=[O:16])=[C:10]([Cl:14])[C:11]([F:13])=[CH:12][C:7]=1[C:6]([C:5](=[CH:21][O:22][CH2:23][CH3:24])[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[O:19]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl

Procedure:
244.8 g of ethyl(2,4-dichloro-5-fluoro-3-nitrobenzoyl)acetate are heated with 166 g of triethyl orthoformate and 185 g of acetic anhydride at 150°-160° C. for 3 hours. The mixture is then concentrated in vacuo, and 270 g of ethyl benzoylethoxyacrylate are obtained as an oily residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]2[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[C:6]([F:8])[CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(C(O)c2cc(F)cc(F)c2)ccc1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1cc(Cc2cc(F)cc(F)c2)ccc1F
Yield: 94.3 %

Procedure:
5-[(3,5-Difluoro-phenyl)-hydroxy-methyl]-2-fluoro-benzonitrile (3.5 g, 13.3 mmol) and sodium iodide (20 g, 133 mmol) are stirred in acetonitrile (50 mL) under nitrogen at 60° C. To the reaction mixture is gradually added chlorotrimethylsilane (17 mL, 134 mmol) over a period of 8 hours. The mixture is diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, 10% aqueous sodium thiosulfate and brine. Purification of the crude by chromatography over silica gel (EtOAc/hexane 5:100) afforded 3.1 g of the title compound (88% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:10]=2[CH3:17])[C:4](=[O:18])[CH:3]=1.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O.C(#N)C.O>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:10]=2[CH3:17])[C:4](=[O:18])[CH:3]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1ccc(CO)cc1-n1c(C)cc(O)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Reaction time: 8 h

Procedure:
4-hydroxy-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methyl pyridin-2(1H)-one (from Step 1) (8.0 g, 32.6 mmol) was stirred briskly at room temperature with 2,4-difluorobenzyl bromide (4.2 ml, 32.6 mmol) and K2CO3 (4.5 g, 32.6 mmol) in 50 ml of dimethylformamide. After stirring for 8 hours, H2O (100 ml) was added to reaction mixture. The product was extracted with ethyl acetate. Ethyl acetate layer was separated and dried over Na2SO4. Ethyl acetate was removed in vacuo. A yellow oil was obtained. The oil was passed through a plug of silica gel first eluting with 500 ml of ethyl acetate/hexane (1:1) This eluent was set aside. Next, ethyl acetate (100%) was passed through the plug until desired product was completely flushed from silica (3 liters). Solvent was removed in vacuo. Light yellow oil obtained (7.5 g, 62%). 1H NMR (300 MHz, CD3OD) δ 7.60 (app q, J=6.44 Hz, 1H), 7.42 (d, J=0.81 Hz, 2H), 7.15 (s, 1H) 7.06 (m, 2H), 6.21 (dd, J=1.61, 1.00 Hz, 1H), 6.12 (d, J=2.62 Hz, 1H), 5.16 (s, 2H), 4.65 (s, 2H), 2.07 (s, 3H), 1.93 (s, 3H); LC/MS, tr=2.38 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 372 (M+H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([Cl:21])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(NC(=O)c2ccccc2)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1.5 g of 3-(benzoylamino)benzoic acid suspended in 10 ml of toluene was added 2 ml of thionyl chloride and the resulting mixture was stirred under a reflux condition for 2 hours. The reaction solution was returned to room temperature, and then the solvent was removed under a reduced pressure to obtain 1.53 g of the desired product (Yield: 95%) as a white solid.
Reaction SMILES: [OH-:1].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.O>>[CH:5]12[CH2:4][CH:4]([CH2:7][CH2:6]1)[CH2:5][CH:6]2[C:7]([OH:3])=[O:1]
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC2CCC1C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5.00 g (20.0 mmol) of the Diels-Alder adduct obtained by the step 2 of Example 1 was dissolved in 45 ml of a mixture solvent of tetrahydrofuran-water (5:4), 1.85 g (43.0 mmol) of sodium hydroxide (93%) was added on ice cooling, and the mixture was stirred at room temperature for 24 hours. After tetrahydrofuran was distilled off, the reaction mixture was neutralized with concentrated hydrochloric acid. Then, 280 mg of 5% palladium-carbon powder was added and the mixture was stirred for 30 hours under an atmosphere of hydrogen. The catalyst was filtered off, the filtrate was acidified with concentrated hydrochloric acid and extracted with a mixture solvent of hexane-methylene chloride (98:2) (50 ml×4). The extract was dried over anhydrous magnesium sulfate and filtered, the solvent was distilled off, and 2.66 g of crude 2-norbornanecarboxylic acid was obtained. Crude yield: 95%.
Reaction SMILES: [H][H].[Si:3]([O:10][CH2:11][CH:12]([NH:14]C(=O)OCC1C=CC=CC=1)[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>[Pd].C(O)C>[Si:3]([O:10][CH2:11][CH:12]([NH2:14])[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(N)CO[Si](C)(C)C(C)(C)C
Yield: 80.3 %

Procedure:
Hydrogen was introduced into a mixture of 4.0 g of benzyl N-(2-t-butyldimethylsilyloxy-1-methylethyl)-carbamate (prepared as described in Preparation 8), 0.80 g of 10% w/w palladium-on-carbon and 40 ml of ethanol for 1 hour. At the end of this time, the atmosphere was replaced by nitrogen, the palladium-on-carbon was removed by filtration from the reaction mixture, and the filtrate was concentrated by evaporation under reduced pressure, to give 1.88 g of the title compound having an Rf value of 0.27 (on silica gel thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [O:1]1[C:12]2[CH:4]([CH2:5][C:6](=[CH:10][CH:11]=2)[CH2:7][CH:8]=[CH2:9])[O:3][CH2:2]1.[CH2:13]=O.S(=O)(=O)(O)O.CO.[C:22]([OH:25])(=[O:24])[CH3:23]>>[C:22]([O:25][CH2:13][C:10]1[CH:11]=[C:12]2[O:1][CH2:2][O:3][C:4]2=[CH:5][C:6]=1[CH2:7][CH2:8][CH3:9])(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: C=O
Reactant: C=CCC1=CC=C2OCOC2C1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCc1cc2c(cc1COC(C)=O)OCO2

Procedure:
A mixture of dihydrosafrole, 25 g, in acetic acid (25 g) was added, with stirring over 3 hours to a mixture of acetic acid (230 g), paraformaldehyde (45 g) and sulphuric acid (10%, 1.6 g) held at 70° C. After the reaction had been shown to be complete by glc, the excess paraformaldehyde was removed by filtration and the filtrate poured into water (450 ml). Sodium hydroxide solution (20 ml of a 10% solution) was then added. Ether extraction, followed by drying over magnesium sulphate, filtration and evaporation of solvent gave an oil. Methanol (30 ml) was added and after cooling to 0° C. a colourless precipitate of "dimer" (7) was removed by filtration. Evaporation of the filtrate gave 12.7 g of an oil which was purified by distillation to give 7.3 g of colourless oil as 4,5-methylenedioxy-2-propylbenzyl acetate. (b.p. 176°-185° C. at 0.4 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[NH:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]3)[O:7][C:6]2=1.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1>>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[NH:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:35]([C:32]4[CH:33]=[CH:34][C:28]5[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=5[CH:31]=4)=[O:36])[CH2:19][CH2:18]3)[O:7][C:6]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)CN3
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CN3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 7 and in analogy to Example 1 using trans-4-(6-methoxy-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexylamine and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1.[H-].[Na+].Br[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30].O>CN(C=O)C.CCOC(C)=O>[CH2:27]([N:28]([CH2:31][CH3:32])[CH2:29][CH2:30][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:8]2[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=[C:7]2[C:3]2[C:2]([NH2:1])=[N:6][O:5][N:4]=2)=[CH:17][CH:18]=1)[CH3:26]
Reactant: CCN(CC)CCBr
Reactant: Nc1nonc1-c1nc2cnccc2n1-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(-n2c(-c3nonc3N)nc3cnccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16.4 %

Procedure:
To a solution containing 50 mg the product from Example 38 (0.17 mmols) in 3.4 mL of dry DMF was added 14 mg of NaH (0.34 mmols, 60% suspension in oil). After stirring at ambient temperature for 5 min, 44 mg of 2-bromoethyl-diethylamine (0.17 mmols) was added to the reaction. The reaction was warmed to 60° C. for 16 h. After cooling to room temperature, 1 mL of water was carefully added to the reaction mixture. The mixture was diluted with 20 mL of EtOAc and washed with 2N NaOH (3×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in a minimum volume of DMSO and filtered through a 0.45 m acrodisc filter. The resulting solution was purified on the Gilson reverse-phase HPLC. The resulting product was dissolved in a minimum amount of MeOH and treated with excess 1 N HCl in diethylether. The resulting precipitate was collected and washed with diethylether to afford the title product (11 mg, 17%). MS (ES+) m/e 393 [M]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=S)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:23][NH2:24]>C(O)C>[NH:23]([C:12]1[N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[NH2:24]
Reactant: NN
Reactant: CC(C)Oc1cccc(-n2c(=S)[nH]c3ccccc3c2=O)c1
Solvent: CCO
Product: CC(C)Oc1cccc(-n2c(NN)nc3ccccc3c2=O)c1
Yield: 38.7 %

Procedure:
A mixture of 3-(3-isopropoxy-phenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-one (Example 1) (3.12 g, 10 mmol) and anhydrous hydrazine (3.2 g, 100 mmol) in 100 mL of ethanol was refluxed for 18 hours The reaction mixture was then cooled and white solid was separated which was filtered to obtain 1.2 g (38%) of title compound as white solid. The filtrate was concentrated and an additional 1.6 g (50.4%) of title compound was isolated by crystallization from ethyl acetate, mp 158°-160° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:18][C:19](=O)[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:23]([O:33][CH2:34][CH2:35][OH:36])=[C:22]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH:21]=1)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:19](=[O:18])[C:20]2[CH:21]=[C:22]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[C:23]([O:33][CH2:34][CH2:35][OH:36])=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NCCCc1ccccc1)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a flamed dried round bottom flask with 3-phenyl-1-propylamine (0.404 mL, 2.84 mmol) and THF (5 mL) cooled to −78° C. was added n-BuLi (1.14 mL, 2.5 M in hexane, 2.84 mmol) dropwise over a 5 min. period. The resulting solution was stirred at this temperature for 0.5 h, warmed to 0° C. for 10 min., and then cooled back to −40° C. This lithiated amine solution was added dropwise to a solution (at −40° C.) of 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.350 g, 0.811 mmol) in THF (15 mL) over 5 min. The final mixture was stirred at −40° C. for 15 min. and then warmed to room temperature for 15 min. At this point, the reaction mixture was quenched with H2O (20 mL) and diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (20 to 40% EtOAc/hexane gradient) to afford the product (0.347 g, 82%) as a solid; 1H NMR (CDCl3) δ 1.44-1.68 (bs, 1H), 2.01 (t, J=7.0 Hz, 2H), 2.74 (t, J=7.7 Hz, 2H), 3.27-3.46 (m, 4H), 3.53 (dd, J=7.7, 14.7 Hz, 2H), 5.94-6.08 (bs, 1H), 7.02-7.13 (m, 1H), 7.13-7.33 (m, 4H), 7.33-7.46 (m, 4H), 7.46-7.54 (m, 2H), 7.61 (s, 4H); mass spectrum [(+) APCI], m/z 520/522 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[NH:42][C:43]([C:45]1[N:46]([CH3:54])[C:47]2[C:52]([CH:53]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([NH:42][C:43]([C:45]4[N:46]([CH3:54])[C:47]5[C:52]([CH:53]=4)=[CH:51][CH:50]=[CH:49][CH:48]=5)=[O:44])=[C:27]([O:26][CH3:25])[CH:32]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 21.5 h

Procedure:
A suspension of trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) in ethylene glycol dimethyl ether (8 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.097 g, 0.238 mmol), tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol), and a solution of sodium carbonate (0.057 g, 0.538 mmol) in water (4 mL). The reaction mixture was stirred for 21.5 h at 80° C. The precipitate was filtered, and the organic layer was evaporated under reduced pressure. Dichloromethane (15 mL) was added and the layers were partitioned. 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 a 10% methanol in dichloromethane to 50% methanol in dichloromethane step gradient on Sq 16× ISCO CombiFlash. The column afforded 0.083 g (68%) of trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (d6-DMSO) δ 9.4316 (s, 1H), 8.2427 (s, 1H), 8.1207-8.1003 (d, 1H, J=8.16 Hz), 7.7173-7.6974 (d, 1H, J=7.96 Hz), 7.5979-7.5769 (d, 1H, J=8.4 Hz), 7.3507-7.2758 (m, 4H), 7.1695-7.1321 (t, 1H), 4.6893-4.6324 (m, 1H), 4.0400 (s, 3H), 3.9571 (s, 3H), 2.5 (m, 3H), 2.4055-2.3279 (m, 5H), 2.1606 (s, 3H), 2.1094-1.9367 (m, 6H), 1.5214-1.4624 (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 2.12 min (100%), M+ 594.3.