Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([C:12]1[C:13]([OH:34])=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:17]2)[CH3:11].ClC(Cl)(Cl)C(=N)O[C@H:39]1[C@@H:44]2[O:45][C:46](=[O:48])[O:47][C@@H:43]2[C@@H:42]([O:49][CH3:50])[C:41]([CH3:52])([CH3:51])[O:40]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:10]([C:12]1[C:13]([O:34][C@H:39]2[C@@H:44]3[O:45][C:46](=[O:48])[O:47][C@@H:43]3[C@@H:42]([O:49][CH3:50])[C:41]([CH3:52])([CH3:51])[O:40]2)=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:17]2)[CH3:11]
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Reactant: CCc1c(O)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1c(O[C@@H]2OC(C)(C)[C@H](OC)[C@H]3OC(=O)O[C@@H]23)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.2 %

Procedure:
Boron trifluoride etherate (19.0 μL, 0.15 mmol) was added to 23h (171 mg, 0.51 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (183 mg, 0.51 mmol) in anhydrous CH2Cl2 (11.0 mL). After stirring at room temperature for 24 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to give 25h as a colorless foam (138 mg, 51%): 1H NMR (CD2Cl2, 400 MHz) δ 8.29 (s, 1H), 7.62 (s, 1H), 7.47-7.38 (m, 5H), 7.36 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 5.25 (s, 2H), 5.10 (dd, J=8.0, 2.0 Hz, 1H), 5.02 (t, J=7.8 Hz, 1H), 3.55 (s, 3H), 3.41 (d, J=7.2 Hz, 1H), 2.87 (q, J=7.4 Hz, 2H), 1.42 (s. 3H), 1.28 (s, 3H), 1.21 (t, J=7.4 Hz, 3H); 13C NMR (CD2Cl2, 100 MHz) δ 158.5, 154.8, 153.2, 153.1, 148.4, 136.0, 128.6 (2C), 128.4, 128.1, 125.6, 122.4, 121.5, 120.7, 114.8, 111.4, 94.8, 82.7, 77.9, 77.2, 76.6, 67.3, 60.3, 27.3, 22.3, 16.4, 13.6; IR (film) νmax 3400, 2980, 2937, 2359, 2339, 1817, 1711, 1607, 1524, 1383, 1366, 1227, 1205, 1175, 1101, 1040, 906, 768, 737, 700 cm−1; [M+Na]+ calcd for C28H29NO10, 562.1689. found, 562.1689.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25](Br)[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH3:41])=[CH:35][CH:34]=1)#[CH:32]>>[CH2:1]([O:3][C:4](=[O:30])[C:5](=[O:6])[N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([C:32]#[C:31][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH3:41])=[CH:35][CH:34]=3)[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1ccc2occ(Br)c2c1
Reactant: C#Cc1ccc(CCC)cc1
Product: CCCc1ccc(C#Cc2coc3ccc(CN(Cc4ccc(C(F)(F)F)cc4)C(=O)C(=O)OCC)cc23)cc1
Yield: 5 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl{[(3-bromo-1-benzofuran-5-yl)methyl][4-(trifluoromethyl)benzyl]amino}(oxo)acetate and 1-ethynyl-4-propylbenzene under microwave conditions (300 W, 120° C., 10 min) gave the title compound as a yellow oil (5%). M−(LC/MS(ESI)): 545.8; M+(LC/MS(ESI)): 548.2 HPLC (Condition A), Rt: 5.85 min (HPLC purity: 92.4%).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12]C)=O.[C:21]1([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:14]([CH2:32][C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Product: O=C1CCC(c2ccccc2-c2ccccc2)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.96 min.; [M+H]+: 410.81 g/mol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:9])=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.O=[C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12]([O:14][CH3:15])=[O:13]>CC1C=CC(S(O)(=O)=O)=CC=1>[F:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1/[N:1]=[C:11](\[CH2:16][C:17]([O:19][CH3:20])=[O:18])/[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC(=O)C(=O)OC
Reactant: Cc1cccc(N)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)C/C(=N\c1cccc(C)c1F)C(=O)OC
Yield: 52.4 %

Procedure:
3-Amino-2-fluorotoluene (4.89 g, 39.1 mmol), dimethyl 2-oxobutanedioate (6.26 g, 39.1 mmol), and TosicAcid (0.223 g, 1.172 mmol) were heated at reflux under Dean-Stark conditions for 1 hour. The solvent was removed in vacuo and the residue purified by column chromatography on a silica gel column, eluting with EtOAc/hexane (0-15%) to afford Dimethyl(2E)-2-[(2-fluoro-3-methylphenyl)imino]butanedioate (7-6, 5.48 g, 53% yield) as a clear oil, LCMS shows the compound is 100% pure, LRMS m/z (M+H)+ 268.2 found, 268.1 required.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([O:18][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of sodium (290 mg, 12.5 mmol) in n-butanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 25° C. for 18 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to yield 580 mg (100%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][NH2:7])[CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[N:16][N:17]=1)=O)C>>[CH:1]1([CH2:4][CH2:5][CH2:6][NH:7][C:11]([C:13]2[S:14][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[CH2:22][CH2:23]3)=[N:16][N:17]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: NCCCC1CC1
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: O=C(NCCCC1CC1)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 3-cyclopropylpropylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.50 g, yield 89%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.73 (m, 1H), 7.48-7.63 (m, 2H), 7.28-7.35 (m, 1H), 7.08 (t, J=6.0 Hz, 1H), 3.97-4.08 (m, 1H), 3.79-3.90 (m, 1H), 3.60-3.70 (m, 2H), 3.47-3.53 (m, 2H), 3.37-3.46 (m 2H), 3.28-3.34 (m, 2H), 1.61-1.73 (m, 2H), 1.28 (q, J=7.5 Hz, 2H), 0.55-0.75 (m, 1H), 0.34-0.41 (m, 2H), −0.08-−0.01 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.5, 158.2, 156.0, 134.0, 133.9, 132.4, 129.6, 129.0, 127.6, 127.1, 127.0, 126.9, 125.4, 121.8, 49.5, 49.0, 45.9, 40.7, 39.5, 31.9, 29.4, 10.4, 4.5. MS (ES+) m/z 468.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[CH:15]([CH3:16])[C:14]([O:18][CH3:19])=[O:17])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
4-(4-Chlorophenyl)-2-oxo-4-oxazoline (3.0 g) was dissolved in methanol (30 mL) and methyl acrylate (1.66 mL) and triethylamine (2.14 mL) were added. The obtained mixture was stirred with reflux for 6 h, and the solvent was concentrated under reduced pressure. Isopropanol (9 mL) and isopropyl ether (21 mL) were added, and the mixture was allowed to stand at room temperature overnight and was cooled to not higher than 5° C. and stirred for 1 h. The precipitated crystals were collected by filtration and washed with isopropyl ether to give the title compound (2.81 g; yield 65.0%).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH3:31][S-:32].[Na+]>CN(C=O)C>[CH:27]1([C:25]([N:22]([CH2:21][C:15]2[CH:16]=[C:17]([S:32][CH3:31])[CH:18]=[CH:19][C:14]=2[C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:30])[CH:7]=2)[CH2:23][CH3:24])=[O:26])[CH2:29][CH2:28]1
Reactant: C[S-]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(SC)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To {2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester 0.186 g, 0.45 mmol) in DMF (0.5 mL) was added sodium thiomethoxide (0.035 g, 0.50 mmol), and the reaction was stirred at 85° C. for 2 hours. Analytical LCMS indicated that starting material was still present, so additional sodium thiomethoxide (0.070 g, 1.0 mmol) was added, and the reaction was stirred at 85° C. for another 2 hours. Analytical LCMS showed that no starting material remained, and that the ethyl ester had been hydrolyzed, so an aqueous work-up was performed, and the residue was purified by preparative HPLC to give the title compound. M+H is 414.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[Na].[CH3:20][OH:21]>>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccc(F)cc1
Reactant: CO
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2)c1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
36.44 g (5-chloro-2-nitrophenyl)-(4-fluorophenyl)amine was added to a solution that consists of 6.6 g of sodium in 450 ml of methanol, and it was refluxed for 16 hours. After another 30 hours of stirring at 60° C., it was cooled, and the crystalline product was suctioned off. 34 g of (5-methoxy-2-nitrophenyl)-(4-fluorophenyl)amine was obtained.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH3:32])[C@H:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[N:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:42](OS(C(F)(F)F)(=O)=O)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH3:32])[C@H:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[N:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[O:17][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of (R)-tert-butyl 4-((1R,2R)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-2-methyl-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.0 equiv.) and lutidine (1.8 equiv.) in DCM (0.1M) was added TBSOTf (1.4 equiv.) at −40° C. The reaction mixture was stirred at −40° C. for 2 hours. The solution was diluted with ethyl acetate and washed with sat. NaHCO3, sat. NaCl, dried with magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate and hexanes (1:4) to give (R)-tert-butyl 4-((1R,2R)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(tert-butyldimethylsilyloxy)-2-methyl-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate as the major product (5:2) in 83% yield. LC/MS=577.3 (M+H), Rt=1.33 min (Frac 65%-95% method).
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6](O)=O.[CH3:11][NH2:12]>O>[CH3:11][N:12]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:10]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CN
Solvent: O
Product: CN1CCCCCC1=O

Procedure:
This example illustrates that adipic acid may be successfully hydrogenated in the presence of water and methyl amine to produce N-methyl-caprolactam.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH:6]([CH3:8])[CH3:7].[S-:10][C:11]#[N:12].[K+]>O.Cl>[CH2:5]([C:4]1[N:12]=[C:11]([SH:10])[NH:2][CH:3]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: N#C[S-]
Reactant: CC(C)CC(=O)CN
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)Cc1c[nH]c(S)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
Dissolve 1-amino-4-methyl-2-pentanone hydrochloride (1.4 g, 9.2 mmol) and potassium thiocyanate (1.3 g, 12.9 mmol) in water (3 mL). Stir the solution at 100° C. in a sealed flask for 2 h. Cool the mixture and concentrate in vacuo. Purify the residue by chromatography on silica gel (10 g) eluting with EtOAc to obtain a yellow solid (980 mg, estimated 1:1 product to starting material by NMR). Dissolve the yellow solid (980 mg) in water (2 mL) and concentrated hydrochloric acid (0.5 mL). Add potassium thiocyanate (0.7 g, 7.2 mmol) and heat the mixture at 100° C. for 16 h. Cool the mixture and concentrate in vacuo. Purify the residue by chromatography on silica gel (25 g) eluting with hexane/EtOAc (1:1) to obtain the title compound as a yellow solid (550 mg, 38%). MS (ES+) m/z: 157.2 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)=[N+]=[N-]>[Ni].CO>[N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([CH2:4][NH2:1])[CH:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NCc1ccc2cccnc2c1
Agent: [Ni]
Solvent: CO
Product: NCc1ccc2cccnc2c1
Yield: 98.7 %

Procedure:
7-(Azidomethyl)quinoline (1.1 g, 5.7 mmol) was hydrogenated (1 atm) in the presence of Raney nickel (1.5 g, 26 mmol) in methanol (30 mL) until completion of the reaction. Catalyst was filtered off and the filtrate was concentrated under reduced pressure to a yellow oil which was dissolved in EtOAc (32 mL) and extracted with 1N hydrochloric acid (3×32 mL). The combined acidic aqueous phases were adjust to pH˜10 with 1N sodium hydroxide solution, and extracted with EtOAc (3×35 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford a white solid (0.89 g, 94%).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][CH2:33][CH2:34][CH2:35][CH:36](O)[C:37]([O:39]CC)=[O:38]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][CH:36]([CH2:35][CH2:34][CH2:33][CH3:32])[C:37]([OH:39])=[O:38])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(O)C(=O)OCC
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Product: CCCCC(Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and ethyl DL-2-hydroxycaproate, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 75-76° C.; MS m/e 645 (M−H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.[OH-].[K+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)C(O)c1ccc(-c2ccccc2Cl)cc1

Procedure:
To a solution of 0.144 moles of ethyl 2'-chloro-4-biphenylylglycolate dissolved in 220 ml. of isopropanol is added 38 g. (0.7 mole) of potassium hydroxide. This mixture is then heated at reflux temperature in a nitrogen atmosphere. The solution is concentrated in vacuo to a viscous oil, which is then dissolved in 500 ml. of water and filtered. The filtrate is acidified with 10% HCl and the precipitate is taken up in ether. The ether layer is dried, filtered and the filtrate concentrated to dryness. Recrystallization of residue from benzene-cyclohexane 1:1 gives 2'-chloro-4-biphenylylglycolic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[Cl-:22].[NH4+]>CS(C)=O>[Cl:22][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: [Cl-]
Reactant: COC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)CC1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Temperature: 160 °C
Yield: 27 %

Procedure:
A mixture of 9-bromo-5-methoxycarbonylmethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (530 mg, 1.50 mmol) and cuprous chloride (1.0 g, 10.1 mmol) in dimethyl sulfoxide (5 mL) was heated at 160° C. for 4.5 h and poured into 1N aqueous ammonium chloride (200 mL). The mixture was extracted with a mixed solvent of THF and ethyl acetate (600 mL). The extract was washed with 1N aqueous ammonium chloride (200 mL×2) and brine (200 mL), dried over magnesium sulfate, and concentrated. The residue was recrystallized from ethanol to give 125 mg of the title compound (27%): mp 218°~220° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.08 (bs, 1H), 7.08 (d, 1H, J=2 Hz), 7.02 (d, 1H, J=2 Hz), 5.04~5.13 (m, 1H), 3.62 (s, 3H), 2.94 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.78 (dm, 1H, J=17.1 Hz), 2.63 (dd, 1H, J=18, 7.2 Hz), 2.57 (dd, 1H, J=18, 3.6 Hz), 2.09 (dm, 1H, J=13.5 Hz), 1.80~1.95 (m, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([CH2:33]O)[CH:32]=1)[C:26]([NH:28][CH3:29])=[O:27]>C(#N)C>[Br:20][CH2:33][C:31]1[CH:30]=[C:25]([CH:24]=[C:23]([Cl:22])[CH:32]=1)[C:26]([NH:28][CH3:29])=[O:27]
Reactant: BrBr
Reactant: CNC(=O)c1cc(Cl)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CNC(=O)c1cc(Cl)cc(CBr)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
(Step 2) Triphenylphosphine (1.45 g) was suspended in acetonitrile (50 ml), bromine (0.29 ml) was added, and the suspension was stirred at 40° C. for 30 min. A solution (10 ml) of 3-chloro-5-(hydroxymethyl)-N-methylbenzamide (1.1 g) obtained in Step 1 in acetonitrile was added to the reaction mixture, and the mixture was stirred at 90° C. for 5 hr. The reaction solution was quenched with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=2:3) to give 3-(bromomethyl)-5-chloro-N-methylbenzamide (0.44 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1.[CH3:28][N:29]=[C:30]=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][C:30](=[O:31])[NH:29][CH3:28])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: CN=C=O
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(O)cc23)CC1
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2[nH]cc(CCCN3CCN(c4ncncc4OC)CC3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.5 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-5-hydroxyindole (0.170 g, 0.46 mmol) in 6 mL of CH2Cl2 was added methyl isocyanate (60 μL, 1.0 mmol) and the mixture was stirred at room temperature for 4 days. The mixture was then evaporated and the resulting pinkish-gray foam was triturated with isopropanol-ether to give a light grey solid. This material was chromatographed (SiO2 /EtOAc-MeOH, 95:5; then 90:10) to give the title compound (0.120 g, 60%) as a light gray solid, m.p. 120°-122° C. IR (KBr) 3400, 3220, 1730 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ8.33 (s, 1H), 8.06 (br s, 1H), 7.88 (s, 1H), 7.34-7.26 (m, 2H), 6.99-6.91 (m, 2H), 5.00 (br m, 1H), 3.85 (s, 3H), 3.79 (t, J=4.7 Hz, 4H), 2.91 (d, J=4.8 Hz, 3H), 2.75 (t, J=7.4 Hz, 2H), 2.54 (t, J=4.8 Hz, 4H), 2.45 (t, J=7.6 Hz, 2H), 2.04-1.83 (m, 2 H) Anal. Calcd. for C22H28N6O3 0.8H2O: C, 60.20; H, 6.80; N, 19.15. Found: C, 60.13; H, 6.40; N, 18.75.
Reaction SMILES: [C:1]([N:6]1[C@H:11]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[CH:13]=2)[CH2:10][O:9][CH2:8][C@@H:7]1/[CH:21]=[CH:22]/[C:23](OC)=O)(=[O:5])CC=C.C(N1[C@H](C2C=C(F)C(F)=C(F)C=2)COC[C@@H]1/C=C\C(OC)=O)(=O)CC=C.C(N(CC)CC)C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[F:18][C:16]1[CH:17]=[C:12]([C@@H:11]2[CH2:10][O:9][CH2:8][C@@H:7]3[CH:21]=[CH:22][CH2:23][C:1](=[O:5])[N:6]23)[CH:13]=[C:14]([F:20])[C:15]=1[F:19]
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OC)COC[C@H]1c1cc(F)c(F)c(F)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: C=CCC(=O)N1[C@@H](/C=C\C(=O)OC)COC[C@H]1c1cc(F)c(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC=C[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Reaction time: 0.17 h
Yield: 114.7 %

Procedure:
Grubbs catalyst 2nd generation (27.7 mg) was added to a solution of methyl (E)-3-[(3S,5R)-4-(3-butenoyl)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]acrylate (109.8 mg) and methyl (Z)-3-[(3S,5R)-4-(3-butenoyl)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]acrylate (132.5 mg) in dichloromethane (12 mL), and the reaction solution was heated under reflux in a nitrogen atmosphere for one hour. The reaction solution was returned to room temperature. Triethylamine (0.5 mL) was added to the reaction solution, which was then stirred for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=4:1->ethyl acetate) to obtain 96.6 mg of the title compound.