Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][CH:38]=[N:37]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH3:31])[CH2:33][CH2:34][CH2:35][N:36]5[CH:40]=[CH:39][CH:38]=[N:37]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCCCn1cccn1
Product: CN(CCCn1cccn1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(3-pyrazol-1-yl-propyl)-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and methyl-(3-pyrazol-1-yl-propyl)-amine following General Procedure B.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[OH:9].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)(=O)C>[C:13]([O:16][CH2:2][C:3]1[CH:4]=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[O:9][C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc(O)c(CCl)c1
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(C(C)=O)ccc1OC(C)=O
Temperature: 95 °C

Procedure:
3'-Chloromethyl-4'-hydroxyacetophenone (108 g.) was added to a mixture of anhydrous sodium acetate (54 g.) glacial acetic acid (500 ml.) and acetic anhydride (250 ml.). The mixture was heated at 95° C. for 4 hours, then concentrated by distilling under reduced pressure. The gummy residue was dissolved in water (500 ml.) and the aqueous solution was extracted with chloroform (3×300 ml.). The combined extracts were dried (MgSO4), filtered and evaporated to give a yellow oil. This was distilled under high vacuum to give 3'-acetoxymethyl-4'-acetoxyacetophenone as a colourless viscous liquid (108 g.), b.p. 143°-147° C. (0.3 mm.), which crystallised on cooling to give solid, m.p. 47°-48° C.
Reaction SMILES: Cl.C(O)(=O)C.[F:6][C:7]1[C:16]([CH3:17])=[C:15]([N+:18]([O-:20])=[O:19])[C:14]([F:21])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>O>[F:6][C:7]1[C:16]([CH3:17])=[C:15]([N+:18]([O-:20])=[O:19])[C:14]([F:21])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)c(C(=O)O)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.4 %

Procedure:
Concentrated hydrochloric acid (15 ml) and acetic acid (5 ml) were added to methyl 2,5-difluoro-3-methyl-4-nitrobenzoate (9.1 g), and the mixture was heated under reflux for 3 hours. After the reaction mixture was cooled back to room temperature, water was added to conduct extraction with diethyl ether. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (6.1 g) as a brown oil.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[N:4][C:3]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:16].P(Cl)(Cl)(Cl)=O.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[Cl:16][C:3]1[N:4]=[CH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:7][N:2]=1
Reactant: Cn1cc(-c2ccccn2)cnc1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncc(-c2ccccn2)cn1
Temperature: 120 °C

Procedure:
A mixture of 1-methyl-5-(2-pyridinyl)-2(1H)pyrimidone (8.994 g, 0.048 mole), phosphorus pentachloride (2.156 g, 0.0104 mole), and phosphorus oxychloride (24 mL) was refluxed at 120° C. for 8 h. POCl3 was distilled out under reduced pressure. The residue was cooled to room temperature and ice-water was added. The mixture was extracted with EtOAc, the organic layer was washed with 15% NaCl solution, brine and dried over MgSO4. Solvent was distilled out under reduced pressure to yield a solid. The water layer was adjusted to pH 6-7 by using saturated Na2CO3, then extracted with EtOAc. The organic layer was washed with 15% NaCl, brine, dried over MgSO4. Solvent was distilled out under reduced pressure to give a solid. After trituration with MeOH, additional product was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[O:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:17][C:16]=4[C:12]=3[CH:11]=[C:10]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[B:38]([O:43]C)([O:41]C)OC.Cl>CCCCCC.C(Cl)(Cl)Cl.O1CCCC1>[C:27]1([C:10]2[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([B:38]([OH:41])[OH:43])[CH:7]=[CH:6][CH:5]=3)[C:13]3[O:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:17][C:16]=4[C:12]=3[CH:11]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COB(OC)OC
Reactant: Brc1cccc(-c2cc(-c3ccccc3)cc3c2oc2ccc(-c4ccccc4)cc23)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: OB(O)c1cccc(-c2cc(-c3ccccc3)cc3c2oc2ccc(-c4ccccc4)cc23)c1
Temperature: -80 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
In a 50 mL three-neck flask was put 1.2 g (2.5 mmol) of 4-(3-bromophenyl)-2,8-diphenyldibenzofuran. The air in the flask was replaced with nitrogen. To this mixture was added 15 mL of tetrahydrofuran (THF), and this solution was cooled to −80° C. Then, 1.9 mL (3.0 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After that, this solution was stirred at the same temperature for 1 hour. Then, 0.56 L (5.0 mmol) of trimethyl borate was added to this solution, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. After that, about 10 mL of diluted hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. Then, the aqueous layer of this mixture was extracted with ethyl acetate, and the ethyl acetate solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated to give a solid, and a mixed solvent of chloroform and hexane was added to the solid. The mixture was irradiated with ultrasonic waves, whereby a solid was precipitated. This solid was collected by suction filtration to give 0.62 g of a light-brown powder in 58% □ yield, which was the substance to be produced.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[C:11]([C:15]4[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=4)=[N:12][NH:13][CH:14]=3)=[C:4]2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:29]1([NH:35][C:36]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:11]3[C:10]([C:9]4[CH:8]=[CH:7][N:6]=[C:5]5[NH:1][CH:2]=[CH:3][C:4]=45)=[CH:14][NH:13][N:12]=3)=[CH:16][CH:17]=2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(-c2n[nH]cc2-c2ccnc3[nH]ccc23)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccc(-c2n[nH]cc2-c2ccnc3[nH]ccc23)cc1
Reaction time: 14 h

Procedure:
To a solution of 4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.13 mmol) and triethylamine (0.20 mmol) in tetrahydrofuran (1.5 mL) was added phenyl isocyanate (0.13 mmol). After 14 h, the reaction mixture was concentrated in vacuo and the residue was purified by Gilson reverse phase HPLC to provide the title compound. ESMS [M+H]+: 395.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Methoxy-4-methylphenyl)-1,3-benzoxazole (1.0 g, 4.1 mmol), carbon tetrachloride (18 mL), benzoyl peroxide (66 mg, 0.3 mmol) and N-bromosuccinimide (970 mg, 5.4 mmol) was heated to reflux conditions under argon and placed under a UV light. After 1 h, no starting material was observed by TLC. After cooling mixture to rt, filtered, washing with dichoromethane. After concentrating filtrate in vacuo, the resulting colorless solid was purified by flash chromatography, using a gradient elution of 1:4 EtOAc:hexanes to EtOAc. This afforded the desired intermediate, 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole, as a colorless solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[C:13]=1[CH3:14]>CN(C)C=O.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:2][CH3:1])[C:13]=1[CH3:14]
Reactant: Cc1c(Br)cncc1Br
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1C
Temperature: 80 °C

Procedure:
To a freshly prepared sodium methoxide from sodium metal (0.165 g, 0.0072 mol) and methanol (2.5 mL), 3,5-dibromo-4-methyl-pyridine (1.0 g, 0.0040 mol) dissolved in N,N-dimethylformamide (10 mL) was added and heated at 80° C. overnight. Reaction was diluted with ethyl acetate and quenched with ice water, and layers were separated. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.09 (s, 1H), 3.05 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:15])[NH:13][NH2:14])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[Na].[Cl:17][C:18]1[C:19]([OH:27])=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=O.Cl>C(O)C>[Cl:17][C:18]1[C:19]([OH:27])=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=[N:14][NH:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([S:1]([OH:4])(=[O:2])=[O:3])=[CH:10][CH:9]=1)=[S:15]
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: NNC(=S)Nc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=S(=O)(O)c1ccc(NC(=S)NN=Cc2cc(Cl)cc(Cl)c2O)cc1
Yield: 24 %

Procedure:
A mixture of 4-(4-sulfophenyl)-3-thiosemicarbazide, sodium salt (740 mg, 2.75 mmol), 3,5-dichloro-2-hydroxybenzaldehyde (577 mg, 3.02 mmol), concentrated aqueous hydrochloric acid (0.3 mL) and ethanol (10 mL) was heated under reflux for 20 min. then cooled. The solid was filtered, washed (water) and dried to give the title compound (277 mg, 24%) as a solid. MS (ES−) m/e 418, 420 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:6].Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:6][CH:12]=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=S)c1cccc(Br)c1
Reactant: CCOC(=O)CC(=O)CCl
Product: CCOC(=O)Cc1csc(-c2cccc(Br)c2)n1
Yield: 74.8 %

Procedure:
3-Bromothiobenzamide (10.8 g) and ethyl 4-chloroacetoacetate (8.3 g) were dissolved in 50 ml of alcohol. The reaction was stirred and heated under reflux for 4 hours. When cooled, the crystalline solid was filtered yielding 12.2 g of product, mp 65°-70° C. When recrystallized from ether-petroleum ether, it melted 68°-70° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C1COCC1.C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCCCCC.O>[CH2:17]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: c1ccsc1
Reactant: CCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Thiophene (67.4 g, 0.801 mol) and THF (200 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. The solution was cooled to −78° C., and a solution (200 ml) of n-butyllithium (2.6 M) in n-hexane was added dropwise to the cooled solution over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred at −78° C. for about one hr. Thereafter, the reaction temperature was raised to room temperature. At that temperature, the mixture was again stirred for one hr, and 1-bromodecane (118.0 g, 0.534 mol) was added dropwise thereto at 0° C. over a period of about one hr. After the completion of the dropwise addition, the reaction temperature was raised to room temperature, and, at that temperature, the mixture was stirred overnight. After the completion of the reaction, water (200 ml) was added, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (n-hexane) to give an objective compound 2-decylthiophene as a yellow liquid (112.8 g, yield 96.60%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.29 (m, 14H), 1.67 (m, 2H), 2.81 (t, 2H, J=7.32 Hz), 6.76 (d, 1H, J=3.91 Hz). 6.90 (dd, 1H, J=3.91 Hz, J=4.88 Hz), 7.09 (d, 1H, J=4.88 Hz.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][CH3:18])[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[NH:29][C:30](=[O:31])[N:17]([C:15]1[CH:16]=[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:5][CH:6]=2)[N:12]=[CH:13][N:14]=1)[CH3:18]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CCN(CC)c1ccc(Nc2cc(NC)ncn2)cc1
Product: CCN(CC)c1ccc(Nc2cc(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncn2)cc1

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(4-diethylamino-phenyl)-N′-methyl-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(OCC)(=O)C>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>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1cnn(C)c1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.100 g; 0.262 mmol) in a mixture of DME-water (3:1) (1 mL) were added potassium carbonate (0.109 g; 0.786 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g; 0.013 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.109 g; 0.524 mmol). The solution was stirred for 30 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-80%) in heptane furnished 0.065 g (58%) of the title compound as a light yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(OCC)(=O)C.O>[CH2:20]([O:19][C:17]([NH:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A suspension of ethyl 1-aminocyclopropanecarboxylate hydrochloride (9.5 g, 57.3 mmol) in 450 mL of ethyl acetate was cooled to 0° C., a solution of NaHCO3 (39.5 g, 470.3 mmol) in 325 mL of water was added slowly. Then benzyl chloroformate (13.3 g, 78.2 mmol) was added drop-wise. The cold bath was removed and the mixture was stirred at room temperature for 16 hours. The organic phase was washed with 1N HCl (100 mL), saturated NaHCO3 solution (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated to give a white solid. The solid was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:3, v/v) to give ethyl 1-(benzyloxycarbonylamino)cyclopropanecarboxylate (13.7 g, 91%) as a white solid. MS: (M+H)+=286.1; 1H NMR (300 MHz, CDCl3): δ 7.37-7.32 (m, 5H), 5.13 (s, 2H), 4.70 (s, 1H), 4.13 (brs, 2H), 1.59-1.53 (m, 2H), 1.23-1.19 (m, 5H).
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7].[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+]>CO>[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:7][C:16]([O:17][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:19]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 6 h
Yield: 188.7 %

Procedure:
To a mixed solvent of methanol (50 ml) and water (100 ml) were added L-phenylalanine methyl ester hydrochloride (21.6 g), sodium carbonate (11.64 g), and a solution of di-tert-butoxydicarbonate (21.8 g) in methanol (100 ml). The resulting mixture was heated to 40° C., followed by stirring for 6 hours. The reaction mixture was concentrated to remove the methanol. The concentrate was extracted by adding ethyl acetate and water. The resulting ethyl acetate layer was washed with 0.1 N hydrochloric acid, water, an aqueous sodium hydrogencarbonate solution and a saturated solution of sodium chloride. The ethyl acetate layer after washed was dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off. The solvent was distilled off under reduced pressure to give the target N-tert-butoxycarbonyl-L-phenylalanine methyl ester (26.4 g) in a yield of 95%.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][N:6]1[CH2:10][CH:11]1[CH2:15][CH2:14][O:13][CH2:12]1)([O-:3])=[O:2].[CH:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH:20]=O.Cl>C(#N)C>[N+:1]([C:4]1[CH:16]2[O:22][CH:20]([CH2:19][CH2:18][CH2:17]2)[N:9]2[CH2:8][CH2:7][N:6]([CH2:10][CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)[C:5]=12)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C1NCCN1CC1CCOC1
Reactant: O=CCCCC=O
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])C1=C2N(CC3CCOC3)CCN2C2CCCC1O2
Temperature: 25 °C
Yield: 36 %

Procedure:
To a 50 ml round bottom flask was added 1.065 g (0.005 mol) 2-(nitromethylene)-1-((tetrahydrofuran-3-yl)methyl)imidazolidine, 30 ml acetonitrile, 3 ml 25% glutaraldehyde aqueous solution and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as yellow powder with 36% yield.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:21][O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 70 h
Yield: 99.8 %

Procedure:
Estrone (1, 100.0 g, 370 mmol) was dissolved in MeOH (1.5 L), followed by the addition of K2CO3 (300.0 g, 2.17 mol). MeI (310 mL, 4.98 mol) was added and the mixture stirred at room temperature for 70 h. The reaction mixture was concentrated in vacuo to remove some of the MeOH and was then poured into ice water forming a precipitate. The solid was collected and dried by partitioning into CH2Cl2. The organic layer was dried over MgSO4, and the solvent was removed in vacuo to yield compound 2 (105.0 g) as white crystals in quantitative yield. 1H NMR (250 MHz, CDCl3); δ 0.91 (s, 3, C-18 H), 3.78 (s, 3, MeO), 6.65 (s, 1, C-4 H), 6.72 (d, 1, J=8.57 Hz, C-2 H), 7.21 (d, 1, J=8.57 Hz, C-1 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C:10]([CH3:29])([CH3:28])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH2:39])[CH:34]=[CH:35][CH:36]=1>>[CH3:29][C:10]1([CH3:28])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:39][CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NCCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C)(C)C1
Product: CC1(C)CNCCN1Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 141 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H3O+ of 438. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.75 (s, 1H) 8.36 (d, 2H) 7.96 (d, 1H) 7.65 (m, 2H) 7.27 (m, 1H) 7.18 (m, 2H)) 6.92 (m, 1H) 4.54 (s, 2H) 3.96 (t, 2H) 3.72 (s, 2H) 3.59 (t, 2H) 3.35 (t, 2H) 3.08 (t, 2H) 1.74 (s, 6H).
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:35]2[NH:40][C:39](=[O:41])[C:38]([C:42]3[CH:43]=[N:44][NH:45][CH:46]=3)=[CH:37][CH:36]=2)=[CH:17]\[C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[N:19]2CC2C=CC(OC)=CC=2OC)=[CH:12][CH:11]=1>FC(F)(F)C(O)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:35]2[NH:40][C:39](=[O:41])[C:38]([C:42]3[CH:46]=[N:45][NH:44][CH:43]=3)=[CH:37][CH:36]=2)=[CH:17]\[C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[NH:19]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(Cl)cc2)c2ccc(-c3cn[nH]c3)c(=O)[nH]2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C1CC[C@H](/C=C(\c2ccc(Cl)cc2)c2ccc(-c3cn[nH]c3)c(=O)[nH]2)N1
Temperature: 70 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
Anisole (0.5 mL) was added to a solution of 6-{(E)-1-(4-chlorophenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-(1H-pyrazol-4-yl)pyridin-2(1H)-one (100 mg) in trifluoroacetic acid (1 mL), and the mixture was stirred at 70° C. for five hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) and recrystallized from ethyl acetate-hexane to give the title compound as a pale yellow powder (51.2 mg).