Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]Br>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:12]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:27][CH2:26]2)=[O:18])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc([N+](=O)[O-])cc2)CC1
Yield: 14.6 %

Procedure:
In a manner similar to the procedure described in Example B except that a 100 milliliter three-necked Morton flask was used, 10.0 grams (39.6 mmol) of ethyl 3-[(4-nitrophenyl)amino]-3-oxopropanoate, 13.7 grams (99.1 mmol) of anhydrous potassium carbonate, 40 milliliters of anhydrous dimethylformamide and 3.4 milliliters (40.0 mmol) of 1,2-dibromoethane were reacted for a period of 7 days to give 1.6 grams (5.8 mmol) of ethyl 1-(4-nitrophenylaminocarbonyl)cyclopropanecarboxylate as a pale yellow solid having a melting point of 159.0° C.-161.0° C. The total yield was 15 percent. Recrystallization from methylene chloride-hexane furnished 1.39 grams (5.0 mmol) of 1-(4-nitrophenylaminocarbonyl)cyclopropanecarboxylate as pale yellow needles having a melting point of 159.5° C.-161.0° C. NMR analysis of the product indicated the following:
Reaction SMILES: [CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[O:12][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCC1(C(=O)OCC)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1

Procedure:
12.1 grams of ethyl 1-n-hexyl-2-hydroxy-cyclopentane carboxylate obtained in Example 17 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 6.108 ml of pyridine was slowly added, then 8.876 ml of benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 18.16 g of yellow liquid. MS: 346(M+′), 345(M+−1), 301 (M+—OCH2CH3), 273(M+—CO2CH2CH3), 262, 241 (M+−C6H5CO), 225(M+—C6H5CO2), 195, 185, 151, 140, 105 (base), 77.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:9][CH2:10][C:11](=[O:25])[N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:9][CH2:10][C:11]([N:12]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH2:13][C:14]1[NH:18][CH:17]=[CH:16][N:15]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)N(Cc1ncc[nH]1)C1CCCCC1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCC(=O)N(Cc1ncc[nH]1)C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the white solid (2.60 g, 5.8 mmole) isolated in Step B above, in dichloromethane (45 mL) was added trifluoroacetic acid (45 mL). The resulting solution was stirred at room temperature for 2 hours. The solution was then concentrated. Hydrochloric acid solution (1N, 10 mL) was added and the resulting solution washed with diethyl ether one time. Sodium bicarbonate was added until there was no bubbling observed from the aqueous solution. The solution was extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over magnesium sulfate. The resulting solution was filtered and concentrated to yield 4-amino-4-(S),N-dicyclohexyl-N-(1H-imidazol-2-ylmethyl)-butyramide as a white solid.
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH2:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:4]([SiH:2]([Cl:3])[Cl:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=Cc1ccccc1
Reactant: Cl[SiH2]Cl
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cl[SiH](Cl)CCc1ccccc1
Yield: 99.2 %

Procedure:
73.2 g (725 millimol) of dichlorosilane, and 92.7 g (890 millimol) of styrene were reacted in the presence of 0.1164 g (1.68×10-4 mol) of chlorotris(triphenylphosphine)rhodium (I) as in example 3 at 100° C. for 16 hours and then the reacted liquid was distilled to obtain 147.6 g of monophenethyldichlorosilane (b.p. 95° C./7 mmHg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH:12]([O:15][C:16](=[O:23])[CH:17]=[C:18]([NH2:22])[O:19][CH2:20][CH3:21])([CH3:14])[CH3:13]>C(O)C>[CH:12]([O:15][C:16]([C:17]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:17]([C:16]([O:15][CH:12]([CH3:13])[CH3:14])=[O:23])[C:18]([O:19][CH2:20][CH3:21])=[N:22][C:18]=1[NH2:22])=[O:23])([CH3:14])[CH3:13]
Reactant: CCOC(N)=CC(=O)OC(C)C
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC1=NC(N)=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)C1C(=O)OC(C)C
Yield: 45 %

Procedure:
Heating a solution of 6.1 g of 3-nitrobenzaldehyde and 13.9 g of 3-amino-3-ethoxyacrylic acid isopropyl ester in 100 ml of ethanol for 8 hours yields 2-amino-6-ethoxy-4-(3-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester of melting point 130° C (ether/petroleum ether). Yield: 45% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[Sn](Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(O)C>[NH2:11][C:7]1[C:8]([CH3:10])=[CH:9][C:2]([Br:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1cc(Br)c(C#N)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(Br)c(C#N)cc1N
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-4-methyl-5-nitrobenzonitrile (500 mg, 2.07 mmol) in ethanol (20 mL) was added tin chloride (785 mg, 4.14 mmol). The mixture was refluxed for 5 h. After cooling to room temperature, triethylamine (1.01 g, 10 mmol) was added. The mixture was concentrated and purified by silica chromatography (30-50% ethyl acetate in hexanes gradient) to afford 5-Amino-2-bromo-4-methylbenzonitrile a as beige solid; ESMS m/z 211 (M+H+).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]([C:15]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])([CH3:14])[CH3:13]>>[CH:12]([C:15]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:16]=1[C:17]([NH:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:18])([CH3:14])[CH3:13]
Reactant: CC(C)c1cc(C(F)(F)F)ccc1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CC(C)c1cc(C(F)(F)F)ccc1C(=O)NC1CCCC1N1CCCC1

Procedure:
The title compound, orange solid, MS: m/e=369.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-isopropyl-4-trifluoromethyl-benzoic acid (intermediate AH).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>>[C:10]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH:17]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Synthesised according to example 1.59.1 using 4-chlorobenzaldehyde (3.58 g, 25.48 mmol) and 1-(biphenyl-4-yl)ethanone (5.00 g, 25.48 mmol); pale yellow solid; yield: 7.74 g (95%);
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.CN(C)C=O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9-(2-hydroxyethoxymethyl)guanine (4.6 g), dry dimethylformamide (46 ml), acetic anhydride (16 ml) and dry pyridine (24 ml) was stirred at room temperature overnight. The resulting white solid was removed by filtration and dissolved in warm dimethylformamide (100 ml), pyridine (10 ml) and acetic anhydride (8 ml) added and the mixture stirred for 18 hr. The white solid formed was removed by filtration, washed with ethyl acetate and recrystallized from dimethylformamide to give 9-(2-acetyloxyethoxymethyl)guanine (3.3 g), m.p. 240°-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([C:16]([CH3:21])([S:18]([CH3:20])=[O:19])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([C:16]([CH3:17])([S:18]([CH3:20])(=[O:31])=[O:19])[CH3:21])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)C(C)(C)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)S(C)(=O)=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To an ice-cold solution of 2-(2,4-dichlorophenyl)-3-methyl-3-methylsulfinyl-1-(1,2,4-triazol-1-yl)butan-2-ol (Compound 30b, 346 mg) in chloroform (50 ml) was added m-chloroperbenzoic acid (350 mg), and the mixture was stirred at 0 to 10° C. for 1 hour. The reaction mixture was washed with aqueous ammonia and water, dried over magnesium sulfate and evaporated in vacuo. The oily residue was chromatographed on silica gel, eluting with chloroform, to give 2-(2,4-dichlorophenyl)-3-methyl-3-methylsulfonyl-1-(1,2,4-triazol-1-yl)butan-2-ol (120 mg) as crystals. Yield, 31.7 m.p., 209-210° C.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC(F)=C(F)C=1)=[O:10]>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccc(F)c(F)c1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Solid LiOH (0.26 g, 10.86 mmol) was added to a stirred solution of (3,4-difluorophenyl)methyl 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 88; 1.2 g, 2.17 mmol) in tetrahydrofuran (30 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the solvent was removed. The residue was dissolved in water (20 ml) and stirred in ice-water bath. 1N HCl (aq) was added to the mixture to adjust the pH to 4. The solid was filtered, and dried in vacuo to yield the title compound as a white solid. 730 mg.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][S:19][CH2:20][C:21]([O:23]CC)=[O:22])=[N:12][N:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][S:19][CH2:20][C:21]([OH:23])=[O:22])=[N:12][N:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCCCSCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(SCCCSCC(=O)O)s2)ccc(C(C)=O)c1O
Yield: 105.9 %

Procedure:
In 2 ml of 90% methanol was suspended 0.14 g of ethyl [[3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]propyl]thio]acetate obtained in Example 25. Further 1 ml of a 1N aqueous sodium hydroxide solution was added to the suspension followed by stirring at room temperature for 45 minutes An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and then dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was applied to silica gel column chromatography. Elution with a solvent mixture of hexane-ethyl acetate (1:2) gave 0.14 g of oily [[3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]propyl]thio]acetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].Cl>CN1C(=O)CCC1>[CH2:50]([O:14][C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=C(NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a mixture of 2-benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid (400 g), potassium carbonate (192.5 g) in NMP (1460 ml) maintained at 20° C., was added dropwise 1-Bromo octadecane (425 g). The reaction mixture was allowed to slowly come to room temperature and further stirred for 24 hours. The reaction mixture was then poured onto ice water and the pH was adjusted to 7 with dilute HCl. The solid was filtered, dried and purified by column chromatography using hexane:ethyl acetate (95:5) as an eluant to yield pure 2-benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid stearyl ester (430 g) as a white powder with a melting point of 56-59° C. The product was further characterized by IH NMR (CDCl3) δ 0.90 (t, 3H, CH3), 1.30 (m, 30H, 15×CH2), 1.60 (m, 2H, CH2), 3.05-3.25 (m, 2H, CH2), 4.20 (m, 2H, CH2), 4.65 (m, 1H, CH), 5.15 (m, 2H, CH2), 5.40 (d, 1H, NH), 7.30 (m, 54H, Ar), 7.45 (d, 2H, Ar), 8.15 (d, 2H, Ar)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:18]([NH:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1cc(N)cn1Cc1ccc(F)cc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)c1cc(NCc2ccccc2)cn1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round bottomed flask with a stirring bar, addition funnel and an argon inlet was added 1-[4-amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-2-1 (1.00 g, 4.31 mmol), MeOH (20 mL), benzaldehyde (0.875 mL, 8.61 mmol) and sodium cyanoborohydride (0.541 g, 8.61 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.246 mL, 4.31 mmol) in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5 h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18 h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3, aqueous sodium potassium tartrate and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30% EtOAc in hexanes as eluant to give 1-[4-Benzylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVIII-1-1 as a crystalline solid. 1H NMR (CDCl3) δ 2.34 (3H, s), 3.35 (1H, br s), 4.16 (2H, s), 5.41 (2H, s), 6.36 (1H, d, j=2.2 Hz), 6.49 (1H, d, j=2.2 Hz), 6.93 (2H, m), 7.06 (2H, m), 7.30 to 7.37 (5H, complex multiplet).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:32]=[CH:31][C:25]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:32]=[CH:31][C:25]([CH:26]=[CH:27][C:28]([N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N+:2]([O-:1])=[N:3]3)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: On1nnc2ccccc21
Reactant: CCCCCc1ccc(-c2ccc(C=CC(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(C=CC(=O)n3n[n+]([O-])c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.9 %

Procedure:
To a suspension of 1-hydroxybenzotriazole (0.20 g) and 4-(4-pentylphenyl)cinnamic acid (0.40 g) in dichloromethane (12.0 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.33 g) (WSCD.HCl), and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was diluted with dichloromethane, and washed with brine, and dried over magnesium sulfate. After magnesium sulfate was filtered off, evaporation of the filtrate and trituration with acetonitrile gave 1-[4-(4-Pentylphenyl)cinnamoyl]benzotriazole 3-oxide (0.24 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:20])[C:10]2([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21]I.[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([O:20][CH3:21])[C:10]2([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(Br)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1ccc(Cl)c(Br)c1)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
16.0 g (44.2 mmol) of (+/−)-tert-butyl 1-[(3-bromo-4-chlorophenyl)(hydroxy)methyl]cyclopropanecarboxylate were dissolved in 80 ml of DMF, and 4.1 ml (66.6 mmol) of methyl iodide were added at RT. The reaction mixture was cooled to +10° C., and 1.95 g (60% in mineral oil, 48.7 mmol) of sodium hydride were added in several portions. Ten minutes after the addition had ended, the mixture was warmed to RT and stirred at RT for a further 1.5 h. The reaction mixture was then added to water and extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 15.3 g of the target compound (92.2% of theory).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]([CH3:8])[O:5][C:6]=1[CH3:7].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)Cl>[CH3:7][CH:6]1[C:2](=[O:1])[C:3]([O:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH3:8])[O:5]1
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(OC(=O)C(C)(C)C)C(=O)C(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Hydroxy-2,5-dimethyl-3(2H)-furanone (1.0 g, TOKYO KASEI KOGYO CO., LTD.) and 4-dimethylaminopyridine (0.05 g) were dissolved in a mixture solution of pyridine (10 ml) and methylene chloride (10 ml) under an argon stream in a 50 ml two-necked flask. To the resulting solution, pivaloyl chloride (1.06 ml) was added dropwise under cooling with ice and the mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture solution was mixed with a 0.5N ice-cooled aqueous solution of HCl (10 ml) and subjected to extraction with diethyl ether (30 ml). The ether-extraction was repeated 3 times. The ether layer was washed 3 times with a 0.5N aqueous solution of HCl, twice with a saturated aqueous solution of sodium bicarbonate and once with a saturated saline solution and dried over sodium sulfate. The ether layer was then concentrated under a reduced pressure and applied to a silica gel column for separation and purification. Thus, 2,5-dimethyl-4-pivaloyloxy-3(2H)-furanone (1.40 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.O.[Br:16]Br>C(O)(=O)C>[Br:16][C:12]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:14])[N:9]2[CH3:13])=[N:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2c(n1)CCC(=O)N2C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1nc2c(cc1Br)N(C)C(=O)CC2
Temperature: 60 °C
Yield: 82.1 %

Procedure:
To a solution of 0.6 g (3.1 mmol) 6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one in 8 ml of acetic acid was added 8 ml of water. To this mixture was added 0.32 ml (6.2 mmol) of bromine. The reaction mixture was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and poured into 50 ml of water. The suspension was extracted with ethyl acetate. The ethyl acetate extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using chloroform as the elutant. Appropriate fractions were combined and evaporated to yield 0.69 g of 7-bromo-6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one. TLC Rf=0.8 (10:1 ethyl acetate/chloroform). 1H NMR (CDCl3) δ 7.42 (s, 1H), 4.0 (s, 3H), 3.3 (s, 3H), 3.0 (m, 2H), 2.7 (m, 2H). Mass Spectrum: m/e=271.2, 273.2 (p+1,3).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>CC#N>[CH3:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: Cc1ccccc1CBr
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1CN1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 2.00 g of 4-piperidone monohydrate hydrochloride and 5.40 g of potassium carbonate in 30 ml of CH3CN was added dropwise 1.57 ml of 2-methyl benzyl bromide at 0° C. After stirred at 0° C. or 3.5 h, the mixture was stirred at room temperature for an hour. At 0° C., the mixture was quenched with water and extracted with CHCl3. The organic layer was washed with water, aqueous NaOH, and brine, and dried over anhydrous Na2SO4. The organic solvent was evaporated to give the crude product of 2.52 g of N-(2-methylbenzyl)-4-piperidone as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1cccc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)OCC)n1cnc2c([N+](=O)[O-])cccc21
Reaction time: 0.5 h

Procedure:
4-Nitrobenzimidazole (41.7 mmoles, 6.8 g) was dissolved in 200 ml DMF. Sodium hydride (47.5 mmoles, 1.9 g of 60% in mineral oil) was added portionwise. The reaction was stirred for 30 minutes. Ethyl 2-bromooctanoate was added. The reaction stirred at room temperature for 3 hours and concentrated. Ethyl acetate and water were added; and the layers separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The intermediate was purified by HPLC over silica gel eluted with a gradient of 0-50% ethyl acetate in hexane. The reaction yielded 10.3 g of ethyl 2-(4-nitro-1H-benzimidazol-1-yl)octanoate. (MS)