Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:13]#[N:14])=[N:4][N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]=1[CH2:7][CH3:8].[CH3:15][C:16]([CH3:30])([CH3:29])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OC)(C)(C)C.C(O)CC.O>[CH2:7]([C:6]1[N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[N:4]=[C:3]([C:13]#[N:14])[C:2]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:17](=[O:18])[C:16]([CH3:29])([CH3:15])[CH3:30])[CH3:8]
Reactant: CCCCn1nc(C#N)c(Br)c1CC
Reactant: CC(C)(C)C(=O)Nc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCCO
Product: CCCCn1nc(C#N)c(-c2ccccc2NC(=O)C(C)(C)C)c1CC
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 12.8 %

Procedure:
A flask containing a mixture of 4-bromo-1-butyl-5-ethyl-1H-pyrazole-3-carbonitrile (2.56 g, 10 mmol), 2-[(2,2-dimethylpropanoyl)amino]phenylboronic acid (2.87 g, 15 mmol), triphenylphosphine (0.079 g, 0.30 mmol), 2 M aqueous sodium carbonate (15 mL, 30 mmol), water (3 mL) and 1-propanol (20 mL) was placed under vacuum and back-filled with nitrogen three times. Palladium (II) acetate (0.023 g, 0.10 mmol) was added. Again, the flask was placed under vacuum and back-filled with nitrogen. The mixture was heated overnight under a nitrogen atmosphere at 100° C. The reaction was allowed to cool to ambient temperature and methyl tert-butyl ether was added. After the mixture was stirred for about 10 minutes, the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield a brown oil. Hexanes were added to the brown oil, causing the formation of a tan solid that was isolated by filtration. The filtrate was concentrated to an oil that was purified by chromatography on a HORIZON HPFC system (silica gel, eluted with ethyl acetate/hexanes) to provide 0.45 g of N-[2-(5-ethyl-1-butyl-3-cyano-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamide, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:40]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:41].C(=O)([O-])O.[Na+]>O1CCCC1.CCCCCC>[O:42]([C:40]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)=[O:41])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCCCCC
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)Oc1ccccc1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Benzyl 1-[({4-[(2-aminopyridin-4-yl)oxy]-2,5-difluorophenyl}amino)carbonyl]cyclopropanecarboxylate (1.15 g) was dissolved in tetrahydrofuran (12 ml) under a nitrogen atmosphere. Pyridine (0.424 ml) and phenyl chloroformate (0.657 ml) were added at room temperature, and the mixture was stirred for 20 minutes. A saturated aqueous solution of sodium hydrogencarbonate (36 ml) and hexane (36 ml) were added to the mixture, and the mixture was stirred for 55 minutes. The precipitated solid was collected by filtration. The resultant solid was washed with hexane and dried under aeration and dried by hot air (60° C.) for 5 hours. Water (150 ml) was added to the solid, and the mixture was stirred for 2 hours, and the solid was collected by filtration, and the resultant solid was washed with water. The solid was dried by hot air (60° C.) for 3 days to give the title compound (1.117 g, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:13][N:14]1[C:18](=[O:19])[CH:17]([CH:20]([CH3:22])[CH3:21])[NH:16][S:15]1(=[O:24])=[O:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:13][N:14]1[C:18](=[O:19])[CH:17]([CH:20]([CH3:21])[CH3:22])[NH:16][S:15]1(=[O:23])=[O:24])=[O:5]
Reactant: CC(C)C1NS(=O)(=O)N(CCl)C1=O
Reactant: O=C(O)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)C1NS(=O)(=O)N(COC(=O)c2c(Cl)cccc2Cl)C1=O
Yield: 48.9 %

Procedure:
A mixture of 2,6-dichlorobenzoic acid (0.44 g; 2.3 mmol), 2-chloromethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 2.2 mmol) and triethylamine (230 mg; 2.3 mmol) in toluene was allowed to reflux for 2.5 hours, and then cooled. The mixture was concentrated in vacuo and the residue was purified by flash silica gel chromatography (25%-30% ethyl acetate in hexane) to afford 0.41 g (49%) of 2-(2,6-dichlorophenylcarbonyloxymethyl)-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =isopropyl; R3 =H) as a solid, m.p.151°-152° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)no1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)on3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 33.9 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 283a (150 mg, 0.53 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (834 mg, 2.1 mmol), Pd(dppf)Cl2 (21 mg, 0.026 mmol), K3PO4 (224 mg, 0.053 mmol), sodium acetate (87 mg, 1.1 mmol), acetonitrile (10 mL), and water (5 drops). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1 h. Then it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with acetonitrile to afford the 283b (100 mg, 34%) as white solid. MS-ESI: [M+H]+ 557.3
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:22])([CH2:5][CH2:6][C:7](=[N:20]O)[CH2:8]2)[CH2:3]1.CCCCCC.[H][H]>C(O)(C)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:22])([CH2:5][CH2:6][CH:7]([NH2:20])[CH2:8]2)[CH2:3]1
Reactant: COc1cccc(C23CCN(C)CC2(C)CCC(=NO)C3)c1
Reactant: [H][H]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cccc(C23CCN(C)CC2(C)CCC(N)C3)c1
Temperature: 50 °C
Yield: 9.5 %

Procedure:
A slurry of oxime 19 (2.35 g, 0.077 mol) in anhydrous isopropanol (100 mL) and anhydrous toluene (200 mL) was heated to reflux until the solution became clear. The heat was turned off, and Na (20 g, 0.87 mol) was added carefully in a such rate that a steady reflux was maintained (make 30-40 pieces and store under hexane) over 1.5 h. The first addition was kept small. (Note hydrogen evolution!). At the end the reaction was slower, so the heating mantle was turned back on to speed things up. The reaction mixture was heated to reflux until all Na was consumed followed by cooling to 50° C. and quenching with careful addition of water (250 mL). The toluene layer was separated and the aqueous layer extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure yielding crude product. The crude product was purified by flash chromatography (50% CMA80 in CHCl3) to afford 2.11 g (94%) of 20 as a colorless oil: LCMS (APCI): m/z 289.4 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.14-7.44 [m, 3H], 6.71-6.74 [m, 1H], 3.80 [s, 3H], 3.05 [m, 1H], 2.77 [m, 1H], 2.64 [d, J=12 Hz, 1H], 2.27-2.30 [m, 2H], 2.26 [s, 3H], 2.02-2.12 [m, 3H], 1.68-1.71 [m, 2H], 1.46-1.49 [m, 2H], 1.24 [m, 3H], 1.20 [s, 3H]; 13C NMR (CDCl3, 300 MHz) δ 159.2, 150.2, 128.5, 121.8, 116.5, 110.0, 65.4, 55.5, 53.0, 47.1, 46.7, 43.8, 43.3, 36.6, 36.2, 32.2, 25.8.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccccc1
Reaction time: 1.25 h

Procedure:
A mixture of 4-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylbut-2-yn-1-one (3-2, 6.60 g, 24.0 mmol, 1 equiv) and 10% Pd/C (4.0 g) in EtOAc (100 mL) was stirred under a hydrogen balloon for 75 minutes. The catalyst was filtered and washed with EtOAc (200 mL). The combined filtrate was concentrated and the residue purified by flash column chromatography (silica, 100% hexanes, grading to 50% EtOAc in hexanes) to provide 4-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylbutan-1-one (3-3) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.97 (m, 2H), 7.55 (m, 1H), 7.46 (m, 2H), 3.71 (t, 2H, J=6.1 Hz), 3.07 (t, 2H, J=7.3 Hz), 1.96 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[Cl:27][CH2:28][C:29]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:30]
Reactant: Fc1cc(-c2ncccn2)ccc1N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Fluoro-4-piperazin-1-yl-phenyl)-pyrimidine (29AB) (675 mg, 2.61 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (5 mL), and triethylamine (1.32 mg, 1.82 mL, 13.05 mmol, 5 equiv) was added, followed by slow addition of a solution of chloroacetyl chloride (591 mg, 417 uL, 5.23 mmol, 2 equiv) in tetrahydrofuran at room temperature. The mixture was then stirred for about 1 hour at room temperature.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[C:11]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH3:26])[CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=2[O:2]1>FC(F)(F)C(O)=O>[CH3:15][O:14][C:12]([CH:11]1[C:16](=[O:27])[C:17]2[C:22](=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH3:26])[CH:18]=2)[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:13]
Reactant: CCCOc1cccc(C(=O)C(=Cc2ccc3c(c2)OCO3)C(=O)OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc2c(c1)C(=O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 868.7 %

Procedure:
Methyl 3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)benzoyl]propenoate (7.4 g, 2.0 mmol) was dissolved in trifluoroacetic acid (50 mL) at 0° C. and the mixture stirred at room temperature for 20 min. The trifluoroacetic acid was removed in vacuo to give the title compound (6.4 g, 87 %) as a white solid after trituration with warm isopropanol m. p. 106°-108° C. Anal. Calc. for C21H20O6 : C, 68.47; H, 5.47. Found: C, 68.12; H, 5.41.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([S:15]C#N)[CH:11]=[CH:12][C:13]=1[OH:14]>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([SH:15])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: N#CSc1ccc(O)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc(S)cc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
Lithium aluminium hydride (as a 1M solution in tetrahydrofuran, 71.0 ml, 71.0 mmol) was added dropwise to an ice cold solution of 3-chloro-4-hydroxyphenyl thiocyanate (4.20 g, 22.6 mmol) in tetrahydrofuran (100 mL) under nitrogen. The reaction mixture was stirred and allowed to warm to room temperature over 5 hours. The mixture was cooled to 5° C. and quenched with a 1:1 mixture of tetrahydrofuran:water until no more gas evolution was seen. 1N hydrochloric acid solution in water (30 mL) was then added, and the mixture extracted with ethyl acetate (2-fold 70 mL). The combined organic layers were dried (sodium sulphate) and concentrated in vacuo affording a colourless crystalline solid, 100% yield, 3.60 g.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:38])=[C:23]([NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:27])[CH:24]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:38])=[C:23]([NH:25][C:26]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[N:34]=[CH:33][CH:32]=[CH:31]4)=[O:27])[CH:24]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1NC(=O)c1ccc2ncccc2c1
Yield: 49.5 %

Procedure:
Triethylamine (0.28 ml) was added to a stirred mixture of 4-chlorobenzoyl chloride (0.29 g), N-(5-amino-2-methylphenyl)quinoline-6-carboxamide (0.28 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with water and with methylene chloride. There was thus obtained the title compound as a solid (0.208 g); NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 7.24 (d, 1H), 7.52-7.62 (m, 4H), 7.87 (s, 1H), 7.98 (d, 2H), 8.12 (d 1H) 8.46 (d, 1H), 8.52 (d, 1H), 8.65 (s, 1H) 9.00 (s, 1H), 10.15 (s, 1H) 10.31 (s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][CH2:31][CH2:32][OH:33]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([NH:30][CH2:31][CH2:32][OH:33])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)NCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-(methyl)-propionic acid (1 g) in tetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole (889 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2-aminoethanol (0.38 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 2-[2-benzyloxycarbonylamino-2-(methyl)propionylamino]ethanol (973 mg).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:21])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:5][CH2:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10].[C:22](=O)([O-])[O-].[Cs+].[Cs+].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:22][O:1][C:2]1[C:3](=[O:21])[N:4]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:5][CH2:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCC(=O)C1=C(OC)C(=O)N(Cc2ccc(OC)cc2)CC1

Procedure:
3-Hydroxy-1-(4-methoxybenzyl)-4-propionyl-5,6-dihydro-1H-pyridin-2-one (17.35 kg, 60 moles) and cesium carbonate (22.126 kg, 67.9 moles) were added to dry dimethylformamide (24 gal, 90.8 L) in a clean, dry 100 gallon tank. The suspension was stirred a half hour to insure dispersion. Dimethyl sulfate (8.552 kg, 67.8 moles) was added neat over a period of 30 minutes keeping the temperature 20-25° C. When the charge was complete the addition funnel was rinsed into the tank with additional DMF (500 ml). The reaction was allowed to stir at 20-25° C. for 16 hours. The reaction was diluted with ethyl acetate (108 gal, 408.8 L) and was washed with water (4×22 gal (83.3 L)). The ethyl acetate solution was washed with a solution made up of 6.94 liters 50% sodium hydroxide in 22 gal (83.3 L) of water followed by washing with a solution made up with 6.94 liters of concentrated HCl in 22 gal (83.3 L) of water. The organic solution was dried by washing with brine (14 gal, 53 L) The ethyl acetate was vacuum stripped to an oil which was suitable for use in the next step. The estimated yield based on NMR analysis of residual solvent was 89%. A small sample was isolated for characterization.
Reaction SMILES: [CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][CH:5]([O:20]C(C=C(C)C)=O)[C:6]1[C:16](=[O:17])[C:15]2[C:10](=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[C:8](=[O:9])[CH:7]=1.CC(C)=CC[C@@H](OC(C)=O)C1C(=O)C2C(O)=CC=C(O)C=2C(=O)C=1>>[CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1
Reactant: CC(C)=CCC(OC(=O)C=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: CC(=O)O[C@H](CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Product: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O

Procedure:
Weigh 5.0 mg of shikonin, β,β-dimethylacrylshikonin, acetylshikonin obtained in Preparation example 1 or Preparation example 2, respectively. Dissolve the compounds in 1 ml DMSO. After diluting by 50 times with RPMI-1640 culture medium, pack them separately and further dilute into the following concentration: 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 (μg/ml).
Reaction SMILES: [N:1]1([C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].Cl.[NH2:24][OH:25]>CO.O>[N:1]1([C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8](=[N:24][OH:25])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCC(c2ccccc2)(N2CCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C1CCC(c2ccccc2)(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(azetidin-1-yl)-4-phenylcyclohexanone (8.4 g) in methanol (84 ml), water (84 ml) and sodium hydrogen carbonate (10.08 g) was stirred for 5 min at room temperature, then hydroxylamine hydrochloride (6.95 g) was added in portions and the mixture was stirred for 8 hours at RT. A further 0.4 equiv. of sodium hydrogen carbonate and hydroxylamine hydrochloride were then added, and stirring was carried out for 16 h at room temperature. Then the reaction mixture was concentrated under reduced pressure, the organic phase was separated off and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield the desired crude product. Yield: 6 g (67% crude)
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:23]([OH:25])=[O:24])[CH:11]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[N+:14]([O-])=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[NH2:14][C:13]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[C:8]2[C:7]=1[O:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9]2
Reactant: [H][H]
Reactant: CC(C)(C)c1nc2c(C(=O)O)cc(-c3ccccc3)c([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1nc2c(C(=O)O)cc(-c3ccccc3)c(N)c2o1

Procedure:
2-tert-Butyl-7-nitro-6-phenyl-1,3-benzoxazole-4-carboxylic acid (I-223) (6.27 mmol) was dissolved in methanol (30 ml), then at room temperature, 10% palladium-carbon (430 mg) was added. The suspension was stirred at room temperature under atmospheric pressure of hydrogen for 16 hour. The catalyst was removed by filtration with washing with methanol, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:methanol=98:2) to obtain the entitled compound (1.274 g, 66% from I-222) as a pale brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].[CH3:11][N:12]=[C:13]=[O:14]>C1C=CC=CC=1>[CH3:10][C:6]1[C:3]([CH2:4][OH:5])=[C:2]([NH:1][C:13]([NH:12][CH3:11])=[O:14])[CH:9]=[CH:8][CH:7]=1
Reactant: CN=C=O
Reactant: Cc1cccc(N)c1CO
Solvent: c1ccccc1
Product: CNC(=O)Nc1cccc(C)c1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
A mixture of 2-amino-6-methylbenzyl alcohol (0.274 g) and methyl isocyanate (0.11 g) in benzene (5.2 ml) was stirred at room temperature for 15 minutes. The resulting precipitates were collected by filtration and dried to give 6-methyl-2-(3-methyl ureido)benzyl alcohol (0.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>CN(C)C=O.CS(C)=O>[N+:19]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[C:13]=1[NH:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([O-:21])=[O:20]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)ccc1Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 336 h
Yield: 42.7 %

Procedure:
3.0 g (19.3 mmol) of 2-amino-5-fluorobenzoic acid and 5.88 g (29.0 mmol) of 1-chloro-2,6-dinitrobenzene were dissolved in a mixture of 30 ml of dimethylformamide with 30 ml of dimethyl sulfoxide. After adding 6.74 ml of triethylamine, the reaction mixture was stirred in a nitrogen atmosphere at room temperature for 14 days and concentrated followed by the addition of 1N hydrochloric acid thereto. Then it was extracted with ethyl acetate, washed with 1N hydrochloric acid and dried over magnesium sulfate. After concentrating, chloroform was added thereto. The crystals thus precipitated were collected. Thus 2.65 g of the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11](O)=[O:12])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH3:23][N:24]([CH3:26])[NH2:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:10][C:11]([NH:25][N:24]([CH3:26])[CH3:23])=[O:12])=[CH:5][C:4]=1[C:19]([F:20])([F:22])[F:21])#[N:2]
Reactant: CN(C)N
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Product: CN(C)NC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and 1,1-dimethylhydrazine: 1H NMR (400 MHz, CD3OD) δ 7.77 (d, J=9.6 Hz, 1H), 7.14 (bs, 2H), 7.08 (s, 1H), 4.36 (q, J=9.0 Hz, 2H), 4.26 (s, 2H), 2.69 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[O:1][CH:2]=[CH:3][C:4]2=3)=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Reactant: OC1CNCc2occc21
Product: FC(F)(F)c1cc(Br)ccc1OC1CNCc2occc21

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 4) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 5-bromo-2-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.