Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCCN5[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])=NC=4)=CC=3)=CC=2)=CN=1)=O)CCC(F)(F)F.[CH3:58][O:59][C:60](=[O:105])[NH:61][CH:62]([C:71]([N:73]1[CH2:77][CH2:76][CH2:75][CH:74]1[C:78]1[NH:79][C:80]([C:83]2[CH:88]=[CH:87][C:86]([C:89]3[CH:94]=[CH:93][C:92]([C:95]4[NH:96][C:97]([CH:100]5[CH2:104][CH2:103][CH2:102][NH:101]5)=[N:98][CH:99]=4)=[CH:91][CH:90]=3)=[CH:85][CH:84]=2)=[CH:81][N:82]=1)=[O:72])[CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:69])[F:68]>>[CH3:55][O:54][C:52](=[O:53])[NH:51][CH:47]([C:46]([N:101]1[CH2:102][CH2:103][CH2:104][CH:100]1[C:97]1[NH:96][C:95]([C:92]2[CH:93]=[CH:94][C:89]([C:86]3[CH:87]=[CH:88][C:83]([C:80]4[NH:79][C:78]([CH:74]5[CH2:75][CH2:76][CH2:77][N:73]5[C:71](=[O:72])[CH:62]([NH:61][C:60]([O:59][CH3:58])=[O:105])[CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:68])[F:69])=[N:82][CH:81]=4)=[CH:84][CH:85]=3)=[CH:90][CH:91]=2)=[CH:99][N:98]=1)=[O:56])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Product: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Yield: 45 %

Procedure:
This compound was made in 45% yield by the same procedure as (4,4,4-Trifluoro-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester, using [1-(2-{5-[4′-(2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-3-(2,2,2-trifluoroethoxy)-propyl]-carbamic acid methyl ester as the starting material. LCMS-ESI+: calculated for C41H49F3N8O7: 822.87; observed [M+1]+ : 823.45. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82-7.72 (m, 4H), 7.69-7.65 (m, 4H), 7.38-7.32 (m, 2H), 5.22-5.16 (m, 2H), 4.65-4.61 (m, 1H), 4.26-4.21 (m, 1H), 4.04-3.84 (m, 6H), 3.72-3.48 (m, 8H), 2.39-1.98 (m, 10H), 1.88-1.78 (m, 1H), 1.01-0.89 (m, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19].C=O.[C:25](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:9][C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH3:25])[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21]
Reactant: CC(=O)O
Reactant: O=C(Nc1ccc(NCc2ccc(Cl)s2)cc1Cl)C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(Cc1ccc(Cl)s1)c1ccc(NC(=O)C(F)(F)F)c(Cl)c1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide (3.28 g, 8.88 mmol), 37% aqueous formaldehyde (5 mL), and acetic acid (3 mL), sodium cyanoborohydride (NaBH3CN) (1.1 g) in methanol (10 mL) was added dropwise with stirring during 30 minutes. The reaction mixture was allowed to stand at room temperature for 2 hours and poured into water. After the oil solidified, it was filtered, washed with water and dried in vacuo to give 3.26 g of pale yellow-brown solid. Yield 95%. 1H NMR (DMSO-d6): 2.97 (s, 3H, NMe), 4.72 (s, 2H), 6.82 (m, 1H), 6.91 (m, 2H), 6.97 (d, 1H), 7.21 (d, 1H), 10.92 (br. s, 1H, NHCO). LC/MS (m/z) 382.0 (M+); RT=3.66, (UV, ELSD) 85%, 98%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[C:17]([CH:18]=[C:19]4[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]4)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1

Procedure:
5.0 g (16.0 mmol) of 9-(4-tert-butylphenyl)anthracene and 90 mL of carbon tetrachloride were put into a 500-mL three-neck flask and were stirred. A solution in which 2.8 g (18 mmol) of bromine was dissolved in 10 mL of carbon tetrachloride was dropped into the above solution through a dropping funnel. After that, the solution was stirred at the room temperature for 1 hour, and a sodium thiosulfate aqueous solution was added to the reaction solution to complete the reaction. A water layer of the reaction mixture was extracted by chloroform, and the extracted solution and an organic layer were together washed with a saturated sodium hydrogen carbonate solution and saturated saline. The organic layer was dried with magnesium sulfate, and the mixture was filtrated naturally to remove the magnesium sulfate. Then, the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with ethanol, whereby 6.3 g of a yellow powdery solid, which was a target matter, was obtained with the yield of 99%.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)C>[C:1]([C:3](=[CH:12][NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[CH3:16])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Cc1ccccc1N
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccccc1C
Yield: 88.2 %

Procedure:
Ten grams of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide is dissolved by heating in 50 ml of ethanol to 60°. Then 5.32 g of 2-methylaniline in 20 ml ethanol is added and the mixture heated at reflux for 4 hours with stirring. Crystals appear on cooling and the mixture is filtered and washed with ether to yield 11.36 g of α-cyano-β-(2-methylanilino)-N-ethoxycarbonylacrylamide, which is dissolved in tetralin and heated at reflux for 3 hours. After cooling, the mixture is filtered, washed with ether, to yield 5-cyano-1-(2-methylphenyl)uracil, m.p. 251.5°-2.52.5°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:16]2[C:15](=O)[O:14][C:13](=[O:18])[C:12]=2[C:11]([O:19][CH2:20][CH3:21])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=1[F:35]>C(O)(=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:20]([O:19][C:11]1[C:12]2[C:13](=[O:18])[N:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=3[F:35])[C:15](=[O:14])[C:16]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=12)[CH3:21]
Reactant: CCOC(=O)Cc1ccc(N)c(F)c1
Reactant: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Temperature: 120 °C
Yield: 68.6 %

Procedure:
4,9-Bis(ethyloxy)naphtho[2,3-c]furan-1,3-dione (0.100 g, 0.35 mmol) in acetic acid (5 ml) was treated with DMAP (0.013 g, 0.11 mmol) then ethyl (4-amino-3-fluorophenyl)acetate (0.138 g, 0.70 mmol) and heated to reflux (120° C.) under argon overnight. The reaction mixture was cooled to room temperature and the solvent evaporated to afford a brown/orange oil which was diluted in DCM and washed with saturated NaHCO3 and then 2N HCl. The organics were dried over MgSO4 and evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0-20%) in hexane over 30 minutes. The evaporated fractions were triturated with hexane to give the title compound as a solid (0.110 g, 0.24 mmol, 69%).
Reaction SMILES: FC(F)(F)C(O[I:6](OC(=O)C(F)(F)F)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:22]([N:26]1[C:32](=[O:33])C2C=CC=CC=2[NH:29][C:28](=[O:38])[CH2:27]1)([CH3:25])([CH3:24])[CH3:23].II>C(Cl)Cl.C(OCC)(=O)C>[C:22]([N:26]1[C:32](=[O:33])[C:11]2[CH:12]=[C:7]([I:6])[CH:8]=[CH:9][C:10]=2[NH:29][C:28](=[O:38])[CH2:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CC(C)(C)N1CC(=O)Nc2ccccc2C1=O
Agent: II
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)N1CC(=O)Nc2ccc(I)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
Bis(trifluoroacetoxy)phenyl iodine (2.05 g, 4.7 mmol) is added to a solution of 4-tert-butyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 4.3 mmol) and iodine (1.1 g, 4.3 mmol) in methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with ethyl acetate, washed sequentially with saturated sodium hydrogen carbonate solution, 1N sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and 20% to 25% ethyl acetate in hexanes solutions gives the title product as a beige solid (0.9 g, mp 230°-232° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(C)C=CC=CC=1>[C:22]([C:16](=[CH:15][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1ccc(OC)c(OC)c1
Temperature: 100 °C

Procedure:
A mixture of 7.66 g of 4-aminoveratrole, 8.49 g of ethyl ethoxymethylenecyanoacetate, and 20 ml of toluene was heated at 100° C. for 90 min. The toluene was evaporated to give a solid, mp 150-155° C.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[O:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15]1.[C:25](=[O:27])=[O:26]>CCCCCC.O>[O:14]1[C:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C=O
Reactant: c1ccc2c(c1)CCCCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCCCC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 17.6 ml n-butyllithium (2.5M, 0.044 mol) in 63 ml hexane is added dropwise (0.044 mol) 5.1 g tetramethylethylenediamine (TMEDA) and 5 g (0.034 mol) of 2,3,4,5-tetrahydro-1-benzoxepin. The reaction mixture is stirred overnight. The reaction mixture is then chilled to 0° C. and carbonated with dry ice for an hour. Water (110 ml) is added and the mixture is filtered and the aqueous phase acidified with 4N HCl. The resultant oil is extracted into methylene chloride and dried (MgSO4). After filtering and concentrating in vacuo, 2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid results as a tan solid.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH3:12][N:13]([CH3:16])[CH:14]=O>>[CH3:12][N:13]([CH:16]=[C:9]1[CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][C:8]1=[O:11])[CH3:14]
Reactant: CN(C)C=O
Reactant: CC(=O)NC1CCC(=O)CC1
Product: CC(=O)NC1CCC(=O)C(=CN(C)C)C1

Procedure:
According to Reaction Scheme I, 4-acetamido cyclohexanone, prepared by the procedure of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970) is reacted with the dimethylacetal of dimethylformamide to yield 2-dimethylaminomethylene-4-acetamidocyclohexanone (III). Reacting this compound with sodium glycinate followed by a ring closure reaction in the presence of acetic anhydride yields, when R3 is methyl, dl-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (IV). Treatment of this latter compound with base gives dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (V). This latter compound can be preferentially alkylated on the amino group at C-5 using a reductive alkylation procedure; i.e., reaction with an aldehyde (formaldehyde, acetaldehyde, acrolein, or propionaldehyde) in the presence of a strong organometallic reducing agent such as sodium cyanoborohydride. The dialkylated compound, for instance, dl-5-di(n-propyl)amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (VI) can also be alkylated on the pyrrole ring nitrogen under basic conditions using an alkyl halide R2X (methyl iodide, allyl chloride, ethyl bromide, or the like) to yield a dl-2-(C1 -C3 alkyl or allyl)-5 -disubstituted-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole of Formula VII.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29]([O:31]C)=O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:35]>C1COCC1.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:35])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Yield: 43 %

Procedure:
A solution of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (100.0 mg, 0.24 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 24 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 41.0 mg (43%) of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5-6.7 (m, 13H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). MS (ES) m/e 407, 409.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH:15]=O.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH:8]=[CH:15][C:14]2[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:12]([O:11][CH3:10])[CH:13]=2)[O:3]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C=CC2=CC(=O)C(C)(C)O2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.9 %

Procedure:
To a mixture of 2,2,5-trimethyl-3(2H)-furanone (2.5 g, 19.8 mM) and 3,4,5-trimethoxybenzaldehyde (4.7 g, 23.8 mM) in ethanol was added 1N aqueous sodium hydroxide (4 mL, 4mM). After the reaction mixture was stirred for 48 hours at room temperature, the solution was concentrated to 50 mL and diluted with water (300 mL). The aqueous layer was extracted with diethyl ether (4×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a dark yellow crystalline solid. The crude product was purified by chromatography (silica gel, petroleum ether-ethyl acetate) to give light yellow crystals (5.0 g, 83% yield), m.p. 149°-150° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10](=[CH2:17])[C:11]([O:13][CH2:14][CH2:15][NH2:16])=[O:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>C(#N)C>[CH3:17][C:10](=[CH2:9])[C:11]([O:13][CH2:14][CH2:15][NH:16][S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])=[O:12]
Reactant: C=C(C)C(=O)OCCN
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCNS(=O)(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
In a 1-liter three-neck flask equipped with a thermometer, a reflex condenser and a calcium chloride tube were placed 350 g of acetonitrile, 70.7 g (0.699 mol) of triethylamine, 33.1 g (0.200 mol) of 2-aminoethyl 2-methylacrylate hydrochloride and 0.2 g of phenothiazine, followed by cooling to −30o C with stirring. After the inside temperature of the flask reached −30° C., 40.3 g (0.239 mol) of trifluoromethanesulfonyl chloride was introduced as a gas into the slurry over 1 hour. Upon completion of the gas introduction, the reaction solution was stirred for 1 hour and then warmed to room temperature. The solvent (acetonitrile) and the unreacted reaction substrate (trifluoromethanesulfonyl chloride) were evaporated from the reaction solution under a reduced pressure. To the solution was added 1 liter of diisopropyl ether. The resulting slurry was subjected to filtration to filter out a precipitate of triethylamine hydrochloride. The filtrate was washed three times with 200 g of 10% aqueous sodium chloride solution, and then, dried with 40 g of magnesium sulfate. The magnesium sulfate was removed by filtration. After that, 0.2 g of phenothiazine was added to the organic phase. The solvent was evaporated to obtain 22.5 g of a crude reaction product. The crude reaction product was subjected to distillation under a reduced pressure, thereby yielding 9.9 g of target 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate as an organic fraction at 105-115° C. /13Pa. The purity of the 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate was determined by gas chromatography to be 98.0%. The yield of the 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate was 19%.
Reaction SMILES: [Mg].II.[C:4]1([CH2:10][CH2:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C1COCC1>[OH:16][C:12]([CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH2:13][CH2:14][CH3:15])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCl
Reactant: CCCC(=O)CCc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
Magnesium (1.98 g, 81.4 mmole) was suspended in THF (15 mL), and iodine (10 mg) was added thereto. To the suspension was added 1 mL from a mixture (total amount: 20 mL) of 1-phenyl-3-hexanone (8.93 g, 50.7 mmole) and ethyl chloroacetate (9.94 g, 81.1 mmole) at 25° C. in a thin stream. The mixture was stirred for 10 min and allowed to warm the internal temperature to 30° C. The remaining (19 mL) of the above-mentioned mixture (total amount: 20 mL) of 1-phenyl-3-hexanone and ethyl chloroacetate was added at 30° C.-40° C. over 2 hr in a thin stream. The mixture was stirred at 30° C. for 1 hr, and 10% hydrochloric acid (30 mL) was added for partitioning, which have a THF solution containing ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate (10.2 g, 76%; quantified by absolute calibration curve method (external standard method) using HPLC).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12](OS(C(F)(F)F)(=O)=O)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[CH3:22][N:23](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[C:22]([C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:23]
Reactant: CN(C)C=O
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOc1cc(C#N)cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-ethoxy-5-trifluoromethanesulfonyloxybenzoate (308 mg, 0.94 mmol), zinc cyanide (165 mg, 1.41 mmol), tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.05 mmol) and DMF (2.0 mL) was stirred in a nitrogen atmosphere at 80° C. for 12 hours. After left cooled, the reaction mixture was diluted with ethyl acetate (30 mL), washed with aqueous 14% ammonia and aqueous saturated sodium chloride solution, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:2].P(Cl)(Cl)(Cl)=O.[Cl:23][C:24]([Cl:29])(Cl)[C:25](Cl)=[O:26]>C(OCC)C.[Cu].[Zn]>[CH2:11]([O:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH:1]1[CH2:2][C:25](=[O:26])[C:24]1([Cl:29])[Cl:23])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=Cc1cc(F)ccc1OCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1CC(c2cc(F)ccc2OCc2ccccc2)C1(Cl)Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Zinc-copper couple (1.71 g, 13.1 mmol) was added to a solution of benzyl 2-ethenyl-4-fluorophenyl ether (C17) (1.0 g, 4.38 mmol) in diethyl ether (15 mL). To this mixture was added drop-wise a mixture of phosphorus oxychloride (446 μL, 4.82 mmol) and trichloroacetyl chloride (978 μL, 8.76 mmol) in diethyl ether (5 mL). The mixture was stirred at 40° C. for 2 hours, cooled to room temperature and stirred for an additional 18 hours. The solution was filtered through Celite, and the filtrate was washed with water (2×100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a colorless oil. Yield: 1.4 g, 4.13 mmol, 94%. 1H NMR (400 MHz, CDCl3) δ 3.57 (dd, half of ABX pattern, J=18.0, 10.5 Hz, 1H), 3.65 (dd, half of ABX pattern, J=18.0, 9.4 Hz, 1H), 4.49 (dd, J=10.1, 9.8 Hz, 1H), 5.14 (AB quartet, JAB=12.0 Hz, ΔνAB=12.2 Hz, 2H), 6.91-6.95 (m, 2H), 7.01 (ddd, J=9.0, 7.8, 2.9 Hz, 1H), 7.32-7.44 (m, 3H), 7.45-7.49 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]([SnH:24]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].C(Cl)(Cl)(Cl)Cl>O1CCCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])/[C:16](=[CH:15]/[C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=1)/[C:17]([NH2:19])=[O:18])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(N)=O)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/c1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(N)=O
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid amide (1.13 g, 4.12 mmol) prepared in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (23 ml) in nitrogen atmosphere, and tetrakistriphenylphosphine palladium(0) (95.2 mg, 0.082 mmol) was added under cooling with ice, and then a tetrahydrofuran solution (17 ml) of tri-n-butyltin hydride (5.2 ml, 19.3 mmol) was dropwise added. After stirring for 30 minutes, carbon tetrachloride was added to terminate the reaction, and potassium fluoride was added, followed by stirring for 30 minutes. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give (E)-2-(tributylstannyl)-3-(4-tert-butyldimethylsilyloxyphenyl)acrylamide (1.51 g, 65%) as a pale yellow oily substance.