Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(Cl)=O.[CH3:19][O:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][C:28]2[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[CH:23][CH:22]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:27][C:28]2[C:29]([NH:34][CH2:11][C:10]3[CH:13]=[CH:14][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: OCc1ccc(N2CCOCC2)cc1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2NCc2ccc(N3CCOCC3)cc2)cc1
Reaction time: 4 h
Yield: 13.8 %

Procedure:
4-(4-Morpholinyl)benzyl alcohol (150 mg, 0.78 mmol) was added to a solution of phosgene in toluene (1.93 M, 1.2 mL). After 4 h, the mixture was treated with a solution of N1-(4-methoxybenzoyl)-1,2-benzenediamine (188 mg, 0.78 mmol) and pyridine (2 mL) in methylene chloride (3 mL). After 16 h, the mixture was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with water (4×), brine (1×), dried with potassium carbonate, and concentrated. The residue was purified by chromatography (SiO2, 5 to 15% EtOAc in CH2Cl2), yielding 45 mg (14%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:18]>C(#N)C.C1COCC1.[Ag-]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:18])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Agent: O=[Ag-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N=[N+]=[N-]
Temperature: 25 °C

Procedure:
24.1 A solution of 1.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 15 ml acetonitrile and 3 ml THF was treated with 3.0 g silver(I) oxide and and 2.7 ml iodomethane. The reaction mixture was stirred over night at r.t., then again treated with 3.0 g silver(I) oxide and 2.7 ml iodomethane. The reaction was agitated over night at r.t., then filtrated. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; cyclohexane/EtOAc 2:1) to give 1.0 g (3S,4S)-3-azido-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS 243.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].[CH3:13][C:14]([CH3:16])=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][CH3:16])[C:7]2=[O:12]
Reactant: O=c1[nH]ccc2c(Cl)cccc12
Reactant: CC(C)=O
Product: CCCn1ccc2c(Cl)cccc2c1=O
Yield: 40 %

Procedure:
According to Scheme 28 Step 3: The title compound was prepared from 5-chloroisoquinolin-1(2H)-one (1 eq, 2.66 mmol, 0.48 g) and 1-bromopropyl (1.1 eq, 2.93 mmol, 0.27 mL) according to the procedure described for Example 1 Step 2. Reaction conditions: microwaved at 150° C. for 60 min. in acetone. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using pure CH2Cl2 to afford 5-chloro-2-propylisoquinolin-1(2H)-one (1.06 mmol, 0.24 g, 40%) as an orange solid.
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC1C=CC=CC=1)[C:3]([OH:5])=[O:4].C(Cl)C1C=CC=CC=1>O1CCOCC1>[C:14]1([CH2:6][C:2](=[O:1])[C:3]([OH:5])=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C(=O)C(Cc1ccccc1)c1ccccc1
Solvent: ClCc1ccccc1
Solvent: C1COCCO1
Product: O=C(O)C(=O)Cc1ccccc1
Yield: 63 %

Procedure:
By the same operation as in Example 61 except that 6 ml of 1,4-dioxane was used as the solvent, 2-oxo-3,4-diphenylbutanoic acid formed in a yield of 63 % by the reaction of 0.49 g (3 mmoles) of phenylpyruvic acid with 0.5 ml of benzyl chloride, as determined by NMR spectral analysis.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:53])([CH3:52])[C:48]([OH:51])([CH3:50])[CH3:49])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]([C:40]2[CH:41]=[CH:42][C:43]([O:46][C:47]([CH3:53])([CH3:52])[C:48]([OH:51])([CH3:50])[CH3:49])=[CH:44][CH:45]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.38 g), sodium hydrogen carbonate (0.55 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({2-ethyl-1-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.36 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.14 g, 35%).
Reaction SMILES: [C:1]([CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:10]([C:12]([CH3:14])=[O:13])=[CH2:11]>C1(C)C=CC=CC=1>[O:13]=[C:12]([CH3:14])[CH2:10][CH2:11][C:3]([C:1]#[N:2])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)C#N
Reactant: C=CC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C#N)CCC(C)=O
Yield: 86.2 %

Procedure:
A mixture of 127 mg (1.0 mmol) of ethyl 2-cyanopropanoate, 0.12 ml (1.5 mmol) of methyl vinyl ketone, and 9.4 mg (0.01 mmol) of Rh(acac)(CO)(L) obtained in Example 8 was stirred in 5 ml of toluene at 0° C. for 13 hours. The reaction mixture was concentrated to yield 170 mg (86%) of ethyl 5-oxo-2-cyano-2-methylhexanoate. The product was found to have an optical purity of 73% e.e. as analyzed by high performance liquid chromatography using a Chiralcel OJ column manufactured by Daicel Chemical Industries, Ltd.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](Cl)=[S:30])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CCOCC>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[S:30])=[CH:24][CH:23]=1
Reactant: COCCN(C)CCCCOc1ccc2c(c1)CCN2
Reactant: S=C(Cl)Oc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: COCCN(C)CCCCOc1ccc2c(c1)CCN2C(=S)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
220 mg (0.8 mmol) [4-(2,3-Dihydro-1H-indol-5-yloxy)-butyl]-(2-methoxy-ethyl)-methyl-amine in 0.5 ml dioxane were treated with 186 mg (0.9 mmol) chloro-thioformic acid (4-chloro-phenyl)ester in 0.5 ml dioxane at 0° C. The solution was stirred at RT for 3 h, was diluted with water and ether and a saturated aqueous solution of NaHCO3 was added. The inorganic layer was extracted with ether, washed with water and dried over Na2SO4. Column chromatography with CH2Cl2/MeOH 19:1 yielded 230 mg (64%) 5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester as yellow viscous oil, MS: 449 (MH+, 1Cl).
Reaction SMILES: CC1C=C2C=CC=CN2N=1.C(OC(=O)C(C)C)(=O)C(C)C.[C:22]([C:27]1[C:28]([CH3:36])=[N:29][N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=12)(=O)[CH:23]([CH3:25])[CH3:24]>S(=O)(=O)(O)O>[CH2:22]([C:27]1[C:28]([CH3:36])=[N:29][N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=12)[CH:23]([CH3:25])[CH3:24]
Reactant: Cc1nn2ccccc2c1C(=O)C(C)C
Agent: CC(C)C(=O)OC(=O)C(C)C
Agent: Cc1cc2ccccn2n1
Agent: O=S(=O)(O)O
Product: Cc1nn2ccccc2c1CC(C)C
Yield: 40 %

Procedure:
2-Methylpyrazolo[1,5-a]pyridine was worked up according to the same process as shown in example 1, with an excess isobutyric anhydride in the presence of 2-3 drops of concentrated sulfuric acid to prepare 3-isobutyryl-2-methylpyrazolo[1,5-a]pyridine (139-140°/5 mmHg). Yield 40%.
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([F:35])[CH:29]=1>C(O)(C)C.CCOCC>[ClH:5].[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[C:13]([O:16][CH3:17])[CH:14]=3)[N:9]=[CH:8][N:7]=2)=[C:30]([F:35])[CH:29]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 50 °C
Yield: 89.9 %

Procedure:
3.5M Hydrogen chloride in ethanol (75 μl, 0.26 mmol) was added to a suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (80 mg, 0.25 mmol), (prepared as described for the starting material in Example 2c), in isopropanol (3 ml), the mixture was heated to 50° C. and 4-chloro-2-fluoroaniline (44 mg, 0.3 mmol) was added. The mixture was heated at reflux for 30 minutes. After cooling, the mixture was diluted with ether (3 ml). The precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (105 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18]C(=O)OC(C)(C)C)[N:14]=[CH:15]2)=[CH:10][N:9]=1.FC(F)(F)C(O)=O>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][N:9]=1
Reactant: Cc1ccncc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2cn1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1-c1cc2cnc(N)cc2cn1
Temperature: 40 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
A suspension of tert-butyl 7-(4-methylpyridin-3-yl)-2,6-naphthyridin-3-ylcarbamate (190 mg, 0.565 mmol) in DCE (3 mL) was treated with trifluoroacetic acid (0.437 mL, 5.65 mmol) and the mixture was stirred at 40° C. for 3 hours. The reaction mixture was concentrated in vacuo and then diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as a bright yellow solid (133 mg, 99%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:15][CH2:16][CH3:17])=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].NC1C=C(C(=CCC)CC(OC)=O)C=CC=1Cl>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCC(=CC(=O)OC)c1ccc(Cl)c(N)c1
Agent: [Pd]
Agent: CCC=C(CC(=O)OC)c1ccc(Cl)c(N)c1
Solvent: CCOC(C)=O
Product: CCCC(CC(=O)OC)c1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
7.70 g (30.3 mmol) of the mixture of methyl 3-(3-amino-4-chlorophenyl)hex-2-enoate and methyl 3-(3-amino-4-chlorophenyl)hex-3-enoate (about 1.5:1, Example 164A) were dissolved in 45 ml of ethyl acetate, 646 mg (0.303 mmol) of palladium on carbon (5%) were added and the mixture was stirred under an atmosphere of hydrogen at atmospheric pressure and RT. After 10 h, the reaction mixture was filtered off through celite, the residue was washed with ethyl acetate and the filtrate was concentrated. The residue was taken up in about 50 ml of ethyl acetate, another about 650 mg of palladium on carbon (5%) were added and the mixture was stirred under an atmosphere of hydrogen at atmospheric pressure and RT. After a further 36 h, the reaction mixture was once more filtered off through celite, the residue was washed with ethyl acetate and the filtrate was concentrated. The residue was taken up in 800 ml of ethyl acetate, once more about 650 mg of palladium on carbon (5%) were added and the mixture was stirred under an atmosphere of hydrogen at atmospheric pressure and RT for 24 h. Again, the reaction mixture was filtered off through celite, the residue was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1 to 10:1). This gave a total of 4.79 g of a mixture of target product and starting material. This mixture was dissolved in 180 ml of ethyl acetate, another 603 mg (0.566 mmol) of palladium on carbon (10%) were added and the mixture was stirred under an atmosphere of hydrogen at atmospheric pressure and RT overnight. The reaction mixture was filtered off through celite, the residue was washed with ethyl acetate, the filtrate was concentrated and the residue was dried under high vacuum. This gave 4.45 g (about 57% of theory) of the target product.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]=[O:13])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].Br[C:16](=[CH:18][CH3:19])[CH3:17].[Cl-].[NH4+]>O1CCCC1.O>[C:1]1([C:7]2[CH:11]=[C:10]([CH:12]([OH:13])[C:16]([CH3:17])=[CH:18][CH3:19])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: CC=C(C)Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC=C(C)C(O)c1cc(-c2ccccc2)no1

Procedure:
To a solution of 5.0 g (28.9 mmol) of 3-phenylisoxazole-5-aldehyde in 40 ml of tetrahydrofuran, was added dropwise at -30° C. a solution of 1.5 g of metallic magnesium and 10.1 g (74.8 mmol) of 2-bromo-2-butene in 80 ml of tetrahydrofuran. After they were reacted at the same temperature for 30 minutes, the temperature of the reaction mixture was allowed to rise to room temperature and a saturated aqueous solution of ammonium chloride was added to terminate the reaction. Water was added, followed by extraction with ethyl ether. The organic layer was successively washed with water and saturated saline and then dried over anhydrous sodium sulfate. After ethyl ether was distilled off, the residue was purified by chromatography on a silica gel column (eluent: 9:1 hexane/ethyl acetate) so that 3-phenyl-5-(1-hydroxy-2-methyl-2-butenyl)isoxazole was obtained as oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C(O)=O.[C:26]1(C)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
Resin-bound aryl silane intermediate 4-Scheme 1 (2 g) was suspended in toluene (15 mL) and allowed to swell for 30 minutes. To this was added tetrkistriphenylphosphine (275 mg, 0.25 mmol), phenylboronic acid (500 mg, 4.1 mmol), ethanol (2 mL), sodium carbonate, aq (2 mL, 2M), all of which was heated in an oil bath maintained at 90° for 16 h. The reaction mixture was cooled, filtered washed with methanol, water, methylene chloride and methanol to give a black solid which was taken for the next step. A portion of the above resin (1 g) was treated with trifluoroacetic acid (3 mL) and stored at room temperature for 24 h. Methylene chloride (10 mL) was added and filtered, washed with methylene chloride. Removal of solvents gave a slight brown oil which was triturated with hexane (50 mL). Evaporation of the hexanes yielded biphenyl (78 mg) which was come with an authentic sample.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[F:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([NH2:37])=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[CH:23][CH:22]=1>>[F:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([NH:37][C:9]4[C:8]5[C:13](=[CH:14][CH:15]=[CH:16][C:7]=5[O:6][C@H:4]([CH3:5])[C:3]([N:2]([CH3:19])[CH3:1])=[O:18])[N:12]=[CH:11][N:10]=4)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[CH:23][CH:22]=1
Reactant: Nc1ccc2c(cnn2Cc2ccc(F)nc2)c1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccc(F)nc4)c3)c12)C(=O)N(C)C
Yield: 60.2 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol) and 1-[(6-fluoropyridin-3-yl)methyl]-1H-indazol-5-amine (204 mg, 0.84 mmol) were reacted to give the title compound as a white solid (225 mg, 60%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 3.07 (s, 3H), 3.15 (s, 3H), 5.44 (q, 1H), 5.59 (s, 2H), 6.84 (m, 2H), 7.37 (d, 1H), 7.8-7.45 (m, 3H), 7.87 (dd, 1H), 8.07 (s, 1H), 8.21 (s, 1H), 8.44 (s, 1H), 8.62 (s, 1H); Mass spectrum 486.
Reaction SMILES: C([N:8]([CH:19]([CH3:39])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=1)C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[C:35]([C:23]1[CH:22]=[C:21]([CH2:20][CH:19]([NH2:8])[CH3:39])[CH:26]=[CH:25][C:24]=1[OH:27])([CH3:38])([CH3:36])[CH3:37]
Reactant: [H][H]
Reactant: CC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)N(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(N)Cc1ccc(O)c(C(C)(C)C)c1
Yield: 96.5 %

Procedure:
A suspension of N-benzyl-2-(4-benzyloxy-3-tert-butylphenyl)-1-methyl-N-(benzyloxycarbonyl)-ethylamine (2.35 g, 4.50 mmol) and 20% palladium hydroxide/carbon catalyst (0.50 g) in methanol (30 ml) was stirred in a hydrogen atmosphere overnight. The mixture was filtered to remove the catalyst and the filtrate was evaporated to remove the solvent under reduced pressure, giving 2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethylamine (T21) (0.90 g, 96%).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[C:13](=[O:16])([O-])[O-].[K+].[K+].[OH2:19]>CS(C)=O.ClC1C=CC(C(O)=O)=CC=1>[CH:6]1[C:7]([N+:10]([O-:11])=[O:19])=[CH:8][CH:9]=[C:13]([O:16][C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[CH:5]=1
Reactant: O
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
1,4-Dinitrobenzene (3.52 g, 20.5 mmol), potassium carbonate (1.38 g, 10 mmol), and 4-chlorobenzoic acid (30 mg, 0.19 mmol) were heated in dimethylsulfoxide (8 mL) at about 100° C. for approximately 5.8 hours. The reaction was allowed to cool and was poured into water (20 mL). The reaction vessel was rinsed with an additional 10 mL of water and the rinses were combined. The combined aqueous suspensions were allowed to stand overnight. The solid was collected, washed with water, and dried to give 2.51 g (80% pure) of 4,4'-dinitrodiphenyl ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.[Br-].[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([Zn]C)=[CH:29][CH:28]=1)=[O:20].O1CCC[CH2:36]1>[Zn]>[CH2:12]([C:4]1[CH:3]=[C:2]([CH2:36][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1cc(Cl)c2ccccc2n1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccccc1-c1ccc([Zn]C)cc1
Agent: [Br-]
Agent: [Zn]
Product: CCCCc1cc(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2n1

Procedure:
Using the procedure of Step G of Example 1, 500 mg of 2-butyl -4-chloro quinoline of Step D were introduced into a previously prepared solution of 475 mg of electrolytic zinc, 275 mg of tetrakistriphenyl-phosphine palladium and 2.075 g of [[2'-(methoxycarbonyl) (1,1'-biphenyl)-4-yl]-methyl zinc bromide prepared as in Example 1 in 13 ml of tetrahydrofuran. After chromatographing on silica (eluant: chloroform-hexane-ethyl acetate 100-100-10), 621 mg of the expected product were obtained.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH:10]([CH3:12])[CH3:11].O>CN(C)C=O>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH:10]([CH3:12])[CH3:11])[CH:8]=1
Reactant: CC(C)Br
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(I)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, 96 mg of 60% sodium hydride was suspended in 6 ml of N,N-dimethylformamide, and 388 mg of 4-iodo-1H-pyrazol was added at 0° C., and the mixture was stirred at 0° C. for 30 minutes. Subsequently, 0.21 ml of 2-bromopropane was added and the reaction mixture was stirred at 100° C. for 2 hours. The reaction solution was added with water. The solution was subjected to extraction with ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 328 mg of the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][N:11]([CH3:13])[CH3:12])=[O:4].N#N.[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[N:10]([C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:23]=1[Cl:22])[N:11]([CH3:13])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NN(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: N#N
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)N(C)C
Reaction time: 1.5 h
Yield: 5.3 %

Procedure:
To a solution of 3-(N′,N′-Dimethyl-hydrazino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.72 mmol) in 1,2-dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichloro-benzoyl chloride (0.228 g, 1.08 mmol). The reaction mixture was stirred for 1.5 h at reflux. Then, the solvents were removed and the residue was purified by preparative tlc (8:2 Hexane/EtOAc) to obtain 0.017 g (5%) of 3-[N-(2,4-Dichloro-benzoyl)-N′,N′-dimethyl-hydrazino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): δ 7.62(m, 2H), 7.40 (m, 3H), 7.23 (d, 1H), 3.87 (s, 3H), 2.52 (s, 6H).