Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].Cl[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][C:13]#[N:14])[CH3:2]
Reactant: N#CCCl
Reactant: CCCCCCCNCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCN(CC)CC#N
Temperature: 125 °C

Procedure:
Combine 7.95 g (0.055 moles) ethyl(heptyl)amine, 3.5 ml (0.055 moles) chloroacetonitrile, 5.8 g (0.055 moles) sodium carbonate and 25 ml toluene in a sealed pressure tube. Heat to 125° C. for 18 hrs. Follow the progress of the reaction by thin layer chromatography on silica gel (CH3CN+MeOH+NH4OH, 85+10+5). At the completion of the reaction, filter the reaction mixture and evaporate the solvents to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25]>CO>[S:8]1[C:4]2[CH:3]=[C:2]([CH:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:11][N:12]([CH3:21])[CH2:13]3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25].[S:8]1[C:4]2[CH:3]=[C:2]([CH:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:11][N:12]([CH3:21])[CH2:13]3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Brc1ccc2ncsc2c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CN1Cc2ccccc2C(c2ccc3ncsc3c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Racemic 4-benzothiazol-6-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 6-bromo-benzothiazole by a method similar to the one described in Example 129 (Steps B to C). The desired tetrahydroisoquinoline (20.5 mg) was dissolved in methanol and treated with a solution of maleic acid in methanol (1 mL) at 0° C. The solution was stirred at room temperature overnight, then concentrated, and the solid was washed with diethyl ether providing (+/−)4-benzothiazol-6-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline, maleate salt (30 mg, 98%, >99% AUC HPLC): 1H NMR (CD3OD, 500 MHz) δ 9.28 (d, J=3.9 Hz, 1H), 8.09-8.08 (m, 1H), 8.00-7.99 (m, 1H), 7.44-7.42 (m, 1H), 7.36-7.25 (m, 3H), 6.93-6.92 (m, 1H), 6.26-6.25 (s, 2H), 4.80-4.78 (m, 1H), 4.64-4.56 (m, 2H), 3.93-3.89 (m, 1H), 3.63-3.61 (m, 1H), 3.08 (s, 3H); ESI-MS m/z=281 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[CH2:13]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH:30]=[O:31])[C:24]=1[F:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CO>[CH2:13]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH:30]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:31])[C:24]=1[F:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Cl)cc23)c1F)OCc1ccccc1
Reaction time: 8 h
Yield: 46.6 %

Procedure:
Into a round bottom flask was added 5-chloro-1H-pyrrolo[2,3-b]pyridine (5, 0.524 g, 3.43 mmol) in 5.00 mL of methanol. Potassium hydroxide (0.800 g, 14.2 mmol) and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (4, 1.02 g, 3.5 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from ethyl acetate to give the desired compound (6, 710 mg, 46%). MS (ESI) [M+H+]+=444.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:23])=[O:22]
Reactant: COC(=O)c1ccnc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccnc(COS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Methyl 2-(hydroxymethyl)isonicotinate (3.17 mmol, 0.530 g) and triethylamine (9.51 mmol, 1.322 mL, 0.963 g) were stirred in dichloromethane (20 mL) at 0° C. Methanesulfonyl chloride (4.76 mmol, 0.368 mL, 0.545 g) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (686 mg). MS (ESI) m/z 246.4 [M+H]+
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:6])[CH:4]=[CH2:5].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1.O>CN(C=O)C.ClCCl>[Si:7]([O:1][CH2:2][CH:3]([CH3:6])[CH:4]=[CH2:5])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: C=CC(C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: C=CC(C)CO[Si](C)(C)C(C)(C)C
Yield: 96.8 %

Procedure:
Commercially available 1-hydroxy-2-methyl-3-butene (1.91 g) was silylated with 5 g t-butyldimethylsilyl chloride and 4.7 g imidazole in 5 mL DMF and 5 mL dichloromethane for 3 hours. The mixture was poured into water and extracted with 9:1 hexane:ether. The extracts were combined and concentrated to afford 4.3 g 1-t-butyldimethylsilyloxy-2-methyl-3-butene which was used without further purification. The silyloxybutene and 3 mg Sudan 7B red dye were dissolved in 50 mL dichloromethane and treated at -78° C. with ozone until the red color was discharged. The solution was then warmed to room temperature for 30 minutes before cooling back to -78° C. A solution of 2.0M ethyl magnesium bromide (30 mL) in THF was added over 10 minutes and the resulting mixture was warmed to room temperature for 45 minutes before cautious addition of aqueous ammonium chloride at low temperature to quench the excess Grignard reagent. Extraction of the mixture with ether and evaporation of the solvent yielded 3.96 g residual oil confirmed by NMR to be the desired product. This was dissolved in 20 mL of methanol with 475 mg of p-toluenesulfonic acid monohydrate and stirred at 20° C. for 2 hours. The methanol was then removed in vacuo and the residual product was flash chromatographed on 400 g of silica gel (1:1 hexane:ethyl acetate) to yield 1.1 g of 1,3-dihydroxy-2-methyl-pentane as a diastereomeric mixture (by NMR). Subsequent conversion to the title phosphonium iodide was accomplished following the procedure set forth in Preparations Y and Z.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]1[S:24][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: O=[N+]([O-])c1cccc(F)c1C(Cl)=Nc1c(F)cncc1F
Reactant: NC(N)=S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(F)c1-c1nc2c(F)cncc2s1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
A suspension of 2-fluoro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzimidoyl chloride (12.05 g, 36.4 mmol), thiourea (12.05 g, 159 mmol) and pyridine (16 mL, 200 mmol) in isopropanol (200 mL) under a nitrogen atmosphere was heated under reflux for 4 hours. Et3N (33.2 mL, 239 mmol) was added over 5 minutes and the reaction mixture was heated under reflux for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc (×5) and the combined organic layers were dried (Na2SO4) and concentrated to dryness. The resultant residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc in cyclohexane to afford the title compound as a yellow solid (4.33 g, 41% yield). LCMS (Method D): RT=3.21 min, m/z: 294 [M+H+].
Reaction SMILES: C(N(CC)C(=O)CC1[N:10]2[C:11]3[CH:27]=[CH:26][C:25](F)=[CH:24][C:12]=3[C:13](C3C=CC=CC=3F)=[N:14][CH:15](C)[C:9]2=NN=1)C.B>>[NH:10]1[C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[CH:13]=[N:14][CH:15]=[CH:9]1
Reactant: CCN(CC)C(=O)Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2C
Agent: B
Product: C1=CNc2ccccc2C=N1

Procedure:
In the manner given in Example 1, N,N-diethyl-4-methyl-8-fluoro-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine-1-acetamide is reduced with borane to give 1-[2-diethylamino)ethyl]-4-methyl-8-fluoro-5,6-dihydro-6-(o-fluorophenyl)-4H-s-triazolo]4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=C(C(O)C)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2N=C(C(=O)C)ON=2)=CC=1.FC1C=CC(C#N)=CC=1.Cl.NO>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:12])[NH:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(O)c1nc(-c2ccc(F)cc2)no1
Agent: CC(=O)c1nc(-c2ccc(F)cc2)no1
Agent: Cl
Agent: N#Cc1ccc(F)cc1
Product: N=C(NO)c1ccc(F)cc1

Procedure:
In another embodiment, intermediate compounds 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanol and 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanone may be prepared as described in Scheme 10D. In this route, 4-fluoro-benzonitrile is reacted with hydroxylamine hydrochloride to provide 4-fluoro-N-hydroxybenzimidamide. In one embodiment, the reaction is performed at refluxing temperatures. In another embodiment, the reaction is performed in the presence of a lower alkyl alcohol such as ethanol, and a base such as sodium hydroxide or potassium hydroxide. The resultant compound is then reacted with 2-hydroxy-propionic acid to provide 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanol. In one embodiment, the reaction is performed in the presence of DMSO, DCC, and HOBt. 1-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanol is then oxidized to 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanone. In one embodiment, the oxidation is performed using manganese dioxide in dioxane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[CH2:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1)=[N+]=[N-].O>C1COCC1.C(OCC)(=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([CH:23]([NH2:20])[CH2:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(CC(N=[N+]=[N-])c2cccc(Cl)c2)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CC(N)c2cccc(Cl)c2)on1
Temperature: 50 °C

Procedure:
Triphenylphosphine (137 g, 0.522 mol, 1.19 eq) was added to a solution of 5-(2-azido-2-(3-chlorophenyl)ethyl)-3-methylisoxazole (Preparation 48, 115 g, 0.437 mol, 1 eq) in THF (1 L) under nitrogen atmosphere. The reaction mixture was stirred for 1 hr after which water (45 mL) was added and it was heated at 50° C. overnight. The reaction mixture was concentrated, the crude oil so obtained was dissolved in 1 L ethyl acetate and cooled to 0° C. It was extracted with 6M HCl (3×500 mL). The aqueous phase was saturated by sodium chloride and basified with 6M sodium hydroxide to pH-10 (2 L) and was extracted with ethyl acetate (2 L). Organics were washed by brine, dried and concentrated to yield a liquid, which solidifies upon refrigeration. The title compound was obtained as white solid (30 g, 0.127 mol, 29%).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)=[O:4]>CO>[OH:4][CH2:3][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Sodium borohydride (111 mg) was added to the compound (400 mg) prepared in Example 4 in methanol solution (10 mL) and stirred for 1 hour at room temperature. The reaction mixture was concentrated and extracted with 1 mol/L hydrochloric acid and ethyl acetate. The organic layer was washed with saturated sodium and dried by anhydrous sodium sulfate, and then concentrated to obtain the titled compound (400 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:15](O)=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][C:7]=1[C:15]([C:14]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]([F:11])[CH:13]=1)=[O:16]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1cccc(Br)c1
Agent: Cl
Product: COc1ccc(C(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c(Br)c1

Procedure:
Synthesized from 3-bromoanisole (1.1 ml) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (3.3 g) according to an analogous synthetic method to Preparation Example 66, the title compound (1.6 g) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[CH2:26].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH:26]=[CH:25][C:24]3[CH:23]=[C:22]([CH3:21])[CH:29]=[CH:28][CH:27]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2]
Reactant: C=Cc1cccc(C)c1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCN1c2ncc(C=Cc3cccc(C)c3)cc2C(=O)N(C)c2cccnc21
Temperature: 90 °C
Yield: 87.7 %

Procedure:
A mixture of 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.15 g, 0.4 mmol), 3-methylstyrene (0.05 mL, 0.4 mmol), palladium acetate (29 mg, 0.13 mmol), sodium bicarbonate (83 mg, 1.0 mmol), tetrabutylammonium chloride (0.11 g, 0.47 mmol), and 1 crystal of BHT in 2 mL of N,N-dimethylformamide was heated at 90° C. under argon for 4.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and concentrated. Purification by flash chromatography, eluting with ethyl acetate/hexanes, afforded 0.13 g of the title compound, m.p. 207°-208° C. (ethyl acetate/hexanes).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11][CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11][CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([Cl:25])=[O:16])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1CSc1cccc2cccnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1CSc1cccc2cccnc12
Temperature: 25 °C

Procedure:
A solution of 1.0 eq. of 2-(quinolin-8-ylsulfanylmethyl)benzoic acid in CH2Cl2 was cooled to 0° C. To this was added 1.1 eq. of oxalyl chloride followed by one drop of DMF. The mixture was warmed to room temperature and stirred for a time sufficient for reaction completion. The mixture was concentrated to give 42 which was used directly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH:23]=[CH:22]1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH:23]2[C:24](=[O:25])[O:26][C:21](=[O:27])[CH:22]2[C:18]2[C:17]3[CH:16]=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH2:9]1
Reactant: O=C1C=CC(=O)O1
Reactant: COc1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1
Solvent: Cc1ccccc1C
Product: COc1ccc2[nH]c3c(c2c1)C1C(=O)OC(=O)C1C(c1ccccc1Cl)C3

Procedure:
A solution of trans-diene (27) (0.30 g, 1.06 mmol) prepared as described in example 37 and maleic anhydride (0.16 g, 1.59 mmol) in xylene (30 mL) were heated at reflux for 18 hours, before being concentrated in vacuo and chromatographed on silica eluting with ethyl acetatelhexane (1:2). Crystallisation from ethyl acetate/hexane then gave anhydride (286) (0.29 g, 72%) as a pale brown powder, mp 189–191° C. 1H NMR δ (CD3)2SO] 11.16 (br s, 1H), 7.69 (dd, J=7.7, 1.4 Hz, 1H), 7.51 (dd, J=7.7, 1.4 Hz, 1H), 7.43 (ddd, J=7.7, 7.7, 1.4 Hz, 1H), 7.36 (ddd, J=7.7, 7.7, 1.4 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.77 (dd, J=8.6, 2.4 Hz, 1H), 4.70 (d, J=7.7 Hz, 1H), 4.47 (dd, J=7.7, 3.5 Hz, 1H), 3.78 (s, 3H), 3.71–3.66 (m, 1H), 3.36 (dd, J=15.9, 13.0 Hz, 1H), 2.99 (dd, J=15.9, 4.1 Hz, 1H). Found: C, 65.85; H, 3.95; N, 3.70. C21H16ClNO4 requires: C, 66.06; H, 4.22; N, 3.67.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[CH:8]1([CH:11]([OH:36])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][S:19]([NH:22][C:23]([NH:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)=[O:24])(=[O:21])=[O:20])[CH2:10][CH2:9]1.C(OCC)(=O)C>N1C=CC=CC=1.O>[C:1]([OH:4])(=[O:3])[CH3:2].[CH:8]1([CH:11]([OH:36])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][S:19]([NH:22][C:23]([NH:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)=[O:24])(=[O:21])=[O:20])[CH2:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Agent: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nc2ccccc2C(O)C2CC2)n1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetic anhydride (0.18 mL, 0.19 g, 1.9 mmol) is added to a mixture of 1-[(α-cyclopropyl-α-hydroxy-o-tolyl)sulfamoyl]-3-(4,6-dimethoxy-2-pyrimidinyl)urea (0.40 g, 0.9 mmol) in pyridine. The reaction mixture is stirred at room temperature for 18 hours, treated with additional acetic anhydride (0.27 mL, 2.9 mmol), stirred for 5 hours, diluted with water and extracted with ether. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and 50% to 75% ethyl acetate in hexanes solutions gives the title product as a white powder (0.10 g, 23%, mp 156°-158° C.) which is identified by 1HNMR and MS spectral analyses.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:8]=[CH:9][C:3]=2[O:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>ClCCl.CO>[CH3:31][CH:30]([CH2:29][NH:33][C:14](/[CH:13]=[CH:12]/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1)=[O:16])[CH3:32]
Reactant: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2
Reactant: CC(C)CN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)/C=C/C=C/c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
A mixture of piperinic acid (350 mg, 0.0016 mole, 1 eq) and triethylamine (0.4 ml, 0.0032 mole, 2 eq) in dichloromethane (50 ml) was stirred for 15 min at 0° C. To this mixture methanesulfonyl chloride (0.18 ml, 0.0024 mole, 1.5 eq) was added and stirred for further 30 min at 0° C. Isobutylamine (0.23 ml, 0.0024 mole, 1.5 eq) was added to the mixture and stirred for 1 h at 0° C. and 2 h at room temperature. Dichloromethane (50 ml) was added to the mixture which was then washed with 5% HCl (3×100 ml), saturated aqueous NaHCO3 (3×100 ml) and water (3×100 ml). The organic fraction was dried over anhydrous sodium sulphate, filtered and rotary evaporated to yield a yellowish solid residue. Recrystallisation from methanol yielded colourless needles of piperlonguminine (120 mg, 32% yield)2. The reaction is presumed to proceed through a mesylate ester intermediate. Piperlonguminine (RV-A06)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(NC1C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1)(=O)C.C(N(CC)CC)C>C(#N)C>[N+:27](=[C:8]([C:7](=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]([O:11][CH3:12])=[O:10])=[N-:28]
Reactant: COCCCCC(=O)CC(=O)OC
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCCCC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 121.8 %

Procedure:
To a solution (100 ml) of methyl 7-methoxy-3-oxoheptanoate (5.00 g) and 4-(acetylamino)benzenesulfonyl azide (7.02 g) in acetonitrile was added triethylamine (11.1 ml) and the mixture was stirred at room temperature for 2 days. Insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was suspended in diethyl ether and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object product (6.93 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[N:14]=[C:13]([CH:15]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][CH:10]=1)#[N:8].[OH-].[Na+].[H][H]>CCOCC.O>[NH2:8][CH2:7][C:9]1[N:14]=[C:13]([CH:15]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: N#Cc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Reaction time: 4 h

Procedure:
To a solution of 0.81 g of 95 percent lithium aluminum hydride in 25 ml of ether was slowly added a solution of 5.90 g of 6-cyano-2-(diphenoxymethyl)pyridine in 60 ml of ether so as to maintain a gentle reflux. The mixture was allowed to stir for about 4 hours. An additional 0.2-0.3 g of lithium aluminum hydride was added. Since no additional reaction occured, 5 ml of water, 5 ml of 15 percent sodium hydroxide and 20 ml of water were added consecutively. The reaction mixture was filtered and the organic portion separated. The aqueous portion was washed with ether and the combined organic portions were dried over magnesium sulfate. The solvent was stripped off and the residue was dissolved in methylene chloride and then diluted with ~900 ml of hexane. The solution was passed through a silica gel column and the silica gel was rinsed with methylene chloride and then with methanol. The methanol was stripped off leaving the above named product in a yield of 3.0 grams. The structure of the product was confirmed by its NMR and IR Spectrum. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 72.44, 5.92 and 8.82 percent, respectively as compared with the theoretical contents of 74.51, 5.88 and 9.15 percent, respectively as calculated for the above named compound (Compound 30).
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]2[O:13][C@@H:14]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][C@H:20]([C:24]4[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=4)[CH2:19]3)[CH2:15][O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OCC)C>CCOC(C)=O.[Pd]>[OH:30][C:26]1[CH:25]=[C:24]([C@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([CH2:17][C@@H:14]3[O:13][C:12]4[CH:31]=[CH:32][C:9]([OH:8])=[CH:10][C:11]=4[O:16][CH2:15]3)[CH2:19]2)[CH:29]=[CH:28][CH:27]=1
Reactant: Oc1cccc([C@H]2CCCN(C[C@H]3COc4cc(OCc5ccccc5)ccc4O3)C2)c1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4cc(O)ccc4O3)C2)c1
Reaction time: 3 h

Procedure:
To a solution of 10% Pd/C (33 mg) in EtOAc (10 ml) was added 3-[(R*)-1-((S)-6-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol (66 mg, 0.125 mmol). The mixture was stirred under hydrogen for 3 h at normal pressure. The mixture was then filtered and evaporated to give an oil. After trituration with diethyl ether the title compound was obtained as a white solid (40 mg).