Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C1COCC1.CCOCC>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[O:9]
Reactant: Cc1c(Br)cccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1C=O
Reaction time: 2 h
Yield: 70 %

Procedure:
Step 1 A mixture of (3-bromo-2-methylphenyl)methanol (prepared according to the procedures reported in US Pat. Appl. 2006/0173183, 500 mg, 2.49 mmol) in THF (20 mL) was stirred at rt and treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 1.58 g, 3.73 mmol). After 2 h, the mixture was diluted with ether (ca. 100 mL) and washed with 5% aqueous sodium bisulfite, NaHCO3 (aq) and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 55:45 hexane-EtOAc) to provide 3-bromo-2-methylbenzaldehyde as a colorless oil (343 mg, 70%). 1H NMR (400 MHz, chloroform-d) δ 10.26 (1H, s), 7.78 (2H, ddd, J=9.7, 8.0, 1.2 Hz), 7.20-7.27 (1H, m), 2.75 (3H, s).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([C:13]1[C:14](=[O:32])[CH2:15][CH:16]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([N+:28]([O-])=O)[C:21]=2[CH3:31])[CH2:17][C:18]=1[OH:19])(=[O:12])[CH2:10][CH3:11].[OH-].[Na+]>C(O)C>[C:9]([C:13]1[C:14](=[O:32])[CH2:15][CH:16]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([NH2:28])[C:21]=2[CH3:31])[CH2:17][C:18]=1[OH:19])(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Reaction time: 1 h
Yield: 34.4 %

Procedure:
Sodium dithionite (27.74 g, 159 mmol) was added over a period of 30 min to a refluxing solution of 2-propionyl-3-hydroxy-5-(3-nitro-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (9.59 g, 28.9 mmol) and sodium hydroxide (1.10 g, 27.5 mmol) in 50% aqueous ethanol (350 ml). Refluxing was continued for 1 hr. The hot mixture was filtered, neutralized with dilute hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield the crude 2-propionyl-3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a brown oil (3.0 g, 34%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3 ; δ in ppm): 1.17 (3H,t); 2.12 (3H,s); 2.20 (3H,s); 2.25 (3H,s); 2.3-4.2 (7H,m); 6.72 (1H,s).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:3]2[C:2]([Cl:1])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cc2Cl)CC1

Procedure:
5,6-Dichloro-nicotinic acid (5.0 g, 0.026 mol, Aldrich) reacted with piperazine-1-carboxylic acid tert-butyl ester (4.87 g, 0.026 mol, Aldrich) under the conditions of Example 3a to give the title compound as yellow semi-solid, which was used in the next step without further purification. MS (ESI, neg. ion) m/z: 340 (M-1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Br>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:14][CH:16]2[CH2:17][O:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 5.00 g of 4-phenyl-1-butanol, 1.58 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 3.9 ml of epibromohydrin and 110 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using an 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.83 g of the title compound as a colorless oil having an Rf value of 0.77 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: CS(O)(=O)=O.[C:6]([O:30][CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([OH:39])[C:33]([CH3:41])([CH3:40])[CH2:32]1)(=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[N:21]([OH:26])[C:20]([CH3:28])([CH3:27])[CH2:19]1)=[O:16].OO.S([O-])([O-])=O.[Na+].[Na+].[CH2:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>O.CS(O)(=O)=O.C(#N)C>[C:6]([O:30][CH:31]1[CH2:32][C:33]([CH3:41])([CH3:40])[N:34]([O:39][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[C:35]([CH3:38])([CH3:37])[CH2:36]1)(=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH:18]1[CH2:19][C:20]([CH3:27])([CH3:28])[N:21]([O:26][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[C:22]([CH3:24])([CH3:25])[CH2:23]1)=[O:16]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: C1CCCCC1
Agent: CS(=O)(=O)O
Agent: O=S([O-])[O-]
Agent: OO
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 55 °C
Yield: 43 %

Procedure:
A solution of 0.268 g (0.964 mmol) of ferrous sulfate heptahydrate and 0.350 g (3.64 mmol) of methanesulfonic acid in 3.7 g of water is added to a mixture of 10.3 g (20.2 mmol) of bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 110 ml of acetonitrile, and 60 ml of cyclohexane. The mixture is heated to 55° C. A solution of 11.0 g (162 mmol) of 50% aqueous hydrogen peroxide is added dropwise to the reaction mixture over 4.75 hours while the reaction temperature is brought to and maintained at reflux. A solution of 0.098 g of ferrous sulfate heptahydrate and 0.128 g of methanesulfonic acid in 0.3 g of water is added to the reaction mixture 2.25 hours after the peroxide addition is started. A solution of 0.053 g of ferrous sulfate heptahydrate and 0.070 g of methanesulfonic acid in 0.4 g of water is added to the reaction mixture 4 hours after the peroxide addition is started. After all the peroxide is added, the reaction mixture is heated at reflux for 45 minutes. The reaction mixture is allowed to cool slowly to room temperature while stirring is continued. Peroxide is decomposed by the addition of 4.5 g of sodium sulfite. The aqueous layer is discarded, and after concentration of the organic solution, the crude product is purified by flash chromatography on silica gel with 20:1 heptane-ethyl acetate to afford 5.9 g (43% yield) of the title compound, a colorless oil. The structure of the reaction product is verified by NMR analysis.
Reaction SMILES: [BH4-].[Na+].[ClH:3].[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[N:15]=[C:16]([C:33](=[O:35])[CH3:34])[CH:17]=[C:18]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:19]=12.O>CO>[ClH:3].[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[N:15]=[C:16]([CH:33]([OH:35])[CH3:34])[CH:17]=[C:18]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:19]=12
Reactant: CC(=O)c1cc2c(C)c(C)n(Cc3cccc(F)c3)c2c(N2CCc3ccccc3C2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(C(C)O)cc12
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
Sodium borohydride (5.3 mg, 0.14 mmol) was added at 0° C. to a solution of 1-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-ethanone hydrochloride (20 mg, 0.05 mmol) prepared in Example 855 in anhydrous methanol (2 ml). The reaction mixture was stirred for 10 minutes at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v). The resulting residue was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 7.1 mg of the titled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1.C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC1(C)C(=O)N(CC2CCCO2)c2cc([N+](=O)[O-])c(N)cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated using 2-bromomethyl-tetrahydro-furan (1.7 ml; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 30° C. for 3 days. After aqueous work-up the crude material is de-acetylated in MeOH (150 ml) using DBU (2,3 ml) at reflux. After aqueous work-up and purification by RP chromatography 5-amino-3,3-dimethyl-6-nitro-1-(tetrahydro-furan-2-ylmethyl)-1,3-dihydro-indol-2-one (1.88 g) is obtained.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3]([C:21]#[C:22][C:23]2[C:24](=[O:43])[NH:25][C:26](=[O:42])[N:27]([CH:41]=2)[C@@H:28]2[O:40][C@H:31]([CH2:32][O:33]C(=O)C(C)(C)C)[CH2:30][CH2:29]2)[CH:2]=1.CO>C(O)(=O)C>[CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3]([C:21]#[C:22][C:23]2[C:24](=[O:43])[NH:25][C:26](=[O:42])[N:27]([CH:41]=2)[C@@H:28]2[O:40][C@H:31]([CH2:32][OH:33])[CH2:30][CH2:29]2)[CH:2]=1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CC[C@H](n2cc(C#Cc3ccc4c5cccc6cccc(c7cccc3c74)c65)c(=O)[nH]c2=O)O1
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2CC[C@@H](CO)O2)cc1C#Cc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a suspension of 5-(perylen-3-ylethynyl)-5′-O-pivaloyl-2′,3′-dideoxyuridine (350 mg, 0.613 mmol) in 80 mL of MeOH solid KOH (310 mg, 5.517 mmol) was added, and the mixture was stirred overnight. The mixture was then neutralized with acetic acid, evaporated under reduced pressure, co-evaporated with MeOH twice to give a crude product, which was chromatographically purified on a silica gel column using a 0 to 3% EtOH/CHCl3 gradient to give a chromatographically homogeneous (Rf 0.46, 37.5% acetone/CHCl3) product as orange solid (130 mg, 43%). 1H-NMR (DMSO-d6): 11.74 (s, 1H, NH), 8.76 (s, 1H, H-6), 8.45 (d, 1H, J 7.7), 8.41-8.38 (m, 2H), 8.36 (d, 1H, J 7.7), 8.30 (d, 1H, J 7.7), 7.71-7.54 (m, 6H) (perylenyl), 5.99-5.98 (m, 1H, H-1′), 5.35 (br. s, 1H, OH), 4.15-4.10 (m, 1H, H-4′), 3.70 (app. d, 1H, H-5′), 3.63 (app. d, 1H, H-5′), 2.38-2.31 (m, 1H, H-2′), 2.17-2.13 (m, 1H, H-2′), 2.01-1.94 (m, 1H, H-3′), 1.91-1.86 (m, 1H, H-3′).
Reaction SMILES: C(O)=[O:2].OO.[C:6]12(C)[C:12](C)(C)[CH:9]([CH:10]=[CH:11]1)[CH2:8][CH:7]2[S:15]([O-:18])(=[O:17])=[O:16].[Na+].S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>>[OH:2][CH:10]1[CH:11]2[CH:6]3[CH:7]([CH2:8][CH:9]1[CH2:12]3)[S:15](=[O:18])(=[O:17])[O:16]2
Reactant: CC1(C)C2C=CC1(C)C(S(=O)(=O)[O-])C2
Reactant: O=CO
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: OO
Product: O=S1(=O)OC2C(O)C3CC2C1C3
Temperature: 10 °C
Reaction time: 17 h

Procedure:
Into a three-necked flask having an inner volume of 3 L equipped with a stirrer, a thermometer and a dropping funnel, the whole amount of “Aqueous Solution A” obtained above was poured, and cooled down to 10° C. 99% Formic acid (93.27 g, 2.01 mol) was weighed into a dropping funnel, and added dropwise to the reaction system so that the inner temperature of the reaction system was maintained in a range of 11 to 15° C. After that, the inner temperature was raised up to 50 to 53° C. by heating, and then 30% hydrogen peroxide aqueous solution (162.50 g, 1.43 mol) weighed and contained in another dropping funnel was added dropwise to the reaction system over 3 hours. It should be noted that, after completion of the dropping, the inner temperature of the reaction system was also maintained at around 50° C. After 17 hours from completion of the dropping, the reaction liquid was analyzed by HPLC to confirm that conversion ratio of sodium 5-bornene-2-sulfonate was 98.7%. After cooling down the reaction liquid to 15° C., sodium sulfite was added slowly to the reaction system so that the inner temperature of the reaction system maintained in a range of 15 to 19° C. until a starch paper did not detect hydrogen peroxide. Subsequently, sodium hydrogen carbonate was added slowly to adjust pH of the reaction liquid at 7.3 so that the inner temperature of the reaction system was maintained in a range of 15 to 17° C. The reaction liquid was extracted with ethyl acetate (900 g) twice, and the obtained organic layers were combined, washed with water (200 g), and then concentrated under the reduced pressure until the amount of the liquid became 138.3 g. Isopropyl ether (103.7 g) was added to the resultant concentrated liquid in a heated state at 50° C., then the reaction liquid was cooled down to 5° C. at a rate of about 10° C./hour, to precipitate crystal of the product. After filtering the precipitated crystal, the filtered out crystal was washed with isopropyl ether (50 g) at 5° C., and dried at 40° C. for 2 hours under the reduced pressure, to obtain 2-hydroxy-4-oxa-5-thiatricyclo[4.2.1.03,7]nonane 5,5-dioxide (53.9 g, purity: 99.1%, 0.281 mol). It should be noted that, yield of the product from 5-norbornene-2-sulfonyl chloride was 38.1%.
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][N:14]2[C:17](=O)[C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1>C1COCC1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][N:14]2[CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:10][CH:9]=1
Reactant: O=C(N1CCc2ccc(Br)cc21)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Product: FC(F)(F)CN1CCc2ccc(Br)cc21
Temperature: 0 °C
Yield: 78.2 %

Procedure:
A solution of BH3.THF (1M in THF) (6.12 mL, 6.12 mmol) was added to a solution of 1-(6-bromoindolin-1-yl)-2,2,2-trifluoroethanone (D74) (900 mg, 3.06 mmol) in dry THF (2.0 mL) stirred at 0° C. The mixture was then heated at reflux for overnight (ca. 16 hours). The reaction mixture was quenched with aqueous ammonium chloride, and was partitioned between water (25 mL) and ethyl acetate (100 mL). The aqueous phase was separated and extracted with additional ethyl acetate (100 mL). The organic extracts were combined, washed with brine (25 mL), dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. The residues were purified on silica eluting with cyclohexane and ethyl acetate (0-100%). The appropriate fractions were combined and evaporated to dryness producing title compound (670 mg). LCMS (A): m/z (M+H)+ 280/282, C10H9BrF3N requires 279/281 (acidic).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>FC(F)(F)C(O)=O>[N+:14]([C:3]1[CH:2]=[CH:1][C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)oc1ccccc12
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Temperature: 0 °C
Yield: 80.4 %

Procedure:
To 80 mL trifluoroacetic acid in a 250 mL round bottom flask was added dibenzofuran (7.06 g, 42 mmol) and stirred vigorously to dissolve the content at room temperature. The solution was then cooled on ice and 1.2 equivalent 70% HNO3 (4.54 g, 50.40 mmol) in 20 mL trifluoroacetic acid was poured into the stirred solution slowly. After stirring for 30 minutes contents from the flask was poured into 150 mL ice-water and stirred for another 15 minutes. Off white color precipitate was then filtered out and finally washed with 2M NaOH and water. Moist material was then recrystallized from 1.5 L boiling ethanol in the form of light yellow color crystal. 7.2 g of product was isolated.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14]C)=[O:12])[C:6]([O:8][CH2:9]C)=[O:7])=[O:2].C(C=C)=O.CO>C(O)C>[CH:1]([CH:3]1[CH2:5][C:4]1([C:6]([O:8][CH3:9])=[O:7])[C:11]([O:13][CH3:14])=[O:12])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1C=O
Agent: C=CC=O
Solvent: CO
Solvent: CCO
Product: COC(=O)C1(C(=O)OC)CC1C=O

Procedure:
By following the procedure of D. T. Warner, cited above, used for preparing diethyl 2-formylcyclopropane-1,1-dicarboxylate from acrolein but using equivalent amounts of dimethylbromoalonate and methanol instead of diethylbromomalonate and ethanol, respectively, the title compound, nmr (CDCl3) δ 1.98 (m, 2H), 2.80 (m, 1H), 3.79 (s, 6H), 8.82 (d, J = 4 cps, 1H), is obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.Cl.CN.[CH2:16]([N:18](CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl>CN(C=O)C>[CH3:16][NH:18][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1cc2ccccc2o1
Reaction time: 8 h

Procedure:
To a solution of 2-benzofurancarboxylic acid (1.62 g, 10 mmole), methylamine hydrochloride (0.79 g, 11 mmole), triethylamine (3.1 mL, 22 mmole), and HOBt.H2O (1.5 g, 11 mmole) in DMF (30 mL) was added EDC (2.1 g, 11 mmole). The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) the title compound (1.75 g, 100%) as white solid: MS (ES) m/e 176 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH3:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:13]([C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]=1)[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2)no1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nc(-c2ccc(Cl)cc2)no1
Temperature: 100 °C
Yield: 30.2 %

Procedure:
To a solution of 3-(4-Chloro-phenyl)-5-ethyl-[1,2,4]oxadiazole (0.29 g, 1.38 mmol) in CCl4 (10 mL) was added NBS (0.24 g, 1.38 mmol) and AIBN (0.02 g, 0.0001 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 1% ethyl acetate/hexane as eluent to give the desired product (0.12 g, 30%).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCC(=O)CC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and piperidin-4-one as starting raw materials, to produce an intended compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(Cl)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(Cl)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 2-chloro-4-methoxyphenylboronic acid (187 mg, 1.0 mmol) to afford after chromatographic purification the title compound (133 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ 7.23 (d, 1H, J=8.8 Hz), 7.01 (s, 2H), 6.97 (s, 1H), 6.84 (dd, 1H, J=8.5, 2.6 Hz), 3.84-4.24 (m, 2H), 3.84 (s, 3H), 3.68-3.74 (m, 1H), 3.24-3.54 (m, 4H), 2.86-3.26 (m, 3H), 1.84-1.8 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 441 [M+H+].
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(OCC)(=O)C>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: ClCc1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a stirred solution of N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (500 mg, 1.61 mmol) in DMF (2.5 mL) was added potassium carbonate (446 mg, 3.22 mmol). The resulting mixture was stirred at room temperature for 15 minutes. 2-Chloromethyl-pyridine hydrochloride (291 mg, 1.78 mmol) was added and the resulting mixture stirred and heated to 50° C. for 18 h. The mixture was cooled to room temperature and saturated aqueous potassium carbonate solution (15 mL) and ethyl acetate (5 mL) were added. The resulting mixture was stirred for 20 minutes. The solid was collected by filtration, washed with saturated aqueous potassium carbonate solution, ethyl acetate and isohexane and dried giving the title compound as a solid (425 mg, 60%); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.29 (s, 3H), 2.86 (m, 1H), 5.33 (s, 2H), 7.16 (m, 2H), 7.34 (m, 2H), 7.55 (m, 1H), 7.62 (m, 1H), 7.81 (s, 1H), 7.86 (m, 1H), 7.98 (m, 2H), 8.36 (s, 1H), 8.60 (m, 1H), 10.00 (s, 1H); Mass Spectrum: M+H+ 401.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: Nc1cccc(-c2ccc(F)cc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccc(F)cc2)c1

Procedure:
Using the same method as in Example 1-(ii), 4′-fluorobiphenyl-3-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4′-fluorobiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 82%).