Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[CH3:35][C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](O)=[O:39]>ClCCl.O.C(N(CC)CC)C>[CH3:35][C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:39]
Reactant: Cc1ncccc1C(=O)O
Reactant: CCOC(=O)C1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)c1cccnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
150.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 60.3 g of 1-hydroxybenzotriazole hydrate are added to a suspension of 82.4 g of ethyl piperidine-2-carboxylate in 500 cm3 of dichloromethane. The solution remains milky and 45 g of 2-methylnicotinic acid are added. The solution becomes clear and 161 cm3 of triethylamine are added. The mixture is kept stirred at ambient temperature overnight. The mixture is hydrolysed with 2×1 liter of water. The organic phase is then dried over magnesium sulphate and evaporated at reduced pressure (2.7 kPa). The oil obtained is chromatographed on a column of 8 cm diameter containing 900 g of silica (0.04-0.02). Elution is carried out with ethyl acetate, 70-cm3 fractions being collected. The homogeneous fractions are combined and concentrated at reduced pressure (2.7 kPa). 81.86 g of ethyl N-(2-methylnicotinoyl)piperidine-2-carboxylate are thus obtained in the form of a colourless oil (Rf=0.21; thin layer chromatography on silica gel; ethyl acetate eluent).
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[N:13]=[C:12]([OH:14])[C:11]2[N:10]=[C:9]([CH3:15])[C:8]([CH3:17])([CH3:16])[NH:7][C:6]=2[N:5]=1.NC1N=C(O)C2N=C(CC)C(CCC)(CCC)NC=2N=1>C(O)(=O)C>[NH2:3][C:4]1[N:13]=[C:12]([OH:14])[C:11]2[N:10]=[C:9]([CH2:15][Cl:1])[C:8]([CH3:17])([CH3:16])[NH:7][C:6]=2[N:5]=1
Reactant: CC1=Nc2c(O)nc(N)nc2NC1(C)C
Reactant: ClCl
Agent: CCCC1(CCC)Nc2nc(N)nc(O)c2N=C1CC
Solvent: CC(=O)O
Product: CC1(C)Nc2nc(N)nc(O)c2N=C1CCl

Procedure:
A slight excess of chlorine was added with stirring to 2-amino-4-hydroxy-6-methyl-7,7-dimethyl-7,8-dihydropteridine, (II, X = Me, R1 =R2 =n-Pr) in glacial acetic acid, and the resulting precipitate was filtered off and washed with dry ether, and isolated analogously to the procedure described in Example 3.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](=[NH:6])OC.FC(F)(F)C1N=[N:13][C:14]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:15]=2[N:16]=1>COCCO>[F:8][C:2]([F:1])([F:7])[C:3]1[N:6]=[N:16][C:15]2[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][C:14]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nnc(C(F)(F)F)nc2C1
Reactant: COC(=N)C(F)(F)F
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CCc2nc(C(F)(F)F)nnc2C1

Procedure:
This material was obtained by reaction of tert-butyl 3,4-dioxopiperidine-1-carboxylate from Intermediate 35, Step C, with trifluoroacetamidrazone (2,2,2-trifluoroethanimidohydrazide), prepared from methyl 2,2,2-trifluoroethanimidoate according to the procedure of Brown and Wetzel, J. Org. Chem., 30: 3729-3733 (1965), essentially as described for Intermediate 35, Step D, except that completion of the condensation and ring closure required heating in 2-methoxyethanol at reflux for 2 d. Purification of the evaporation residue by flash chromatography (silica gel, 30% ethyl acetate/hexanes) provided the crude title compound in addition to a minor amount of the other regioisomer, tert-butyl 3-(trifluoromethyl)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylate. Further purification of the product was achieved by preparative HPLC (YMC Pro C18 column, gradient elution, 40-70% acetonitrile/water containing 0.1% trifluoroacetic acid). To prevent decomposition during isolation, excess N,N-diisopropylethylamine was added to the pooled product fractions to neutralize the trifluoroacetic acid prior to concentration in vacuo. The residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give the pure title compound. The regioisomers were assigned on the basis of 1H NMR chemical shift differences reported in several papers for analogous compounds. (See, for example, Konno et al., Heterocycles, 22: 2241-2244 (1984) and Neunhoeffer and Böhnisch, Liebigs Ann. Chem., 153-162 (1976).) 1H NMR (500 MHz, CDCl3) δ 5.08 (s, 2H), 3.90 (m, 2H), 3.21 (m, 2H), 1.54 (s, 9H). LC/MS: 249 (M+1-isobutene).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[CH3:22][N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)[CH3:23]
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(CN(C)C)cc2)ccc1=O
Product: CN(C)Cc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-dimethylaminomethyl-phenyl)-1H-pyridazin-4-one (A-28) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=390.1 (M+H)+
Reaction SMILES: ClC1C=CC(N=C=O)=CC=1.CN.NC(N)=O.C(CC(O)=O)#N.N([O-])=O.[Na+].NC1[N:33]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[C:32](=[O:41])[N:31](C)[C:30](=O)C=1.[H][H].ClC1C=CC(N2C(N)=C(N)C(=O)N(C)C2=O)=CC=1>>[CH3:30][NH:31][C:32]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)=[O:41]
Reactant: [H][H]
Reactant: Cn1c(=O)cc(N)n(-c2ccc(Cl)cc2)c1=O
Agent: CN
Agent: Cn1c(=O)c(N)c(N)n(-c2ccc(Cl)cc2)c1=O
Agent: N#CCC(=O)O
Product: CNC(=O)Nc1ccc(Cl)cc1

Procedure:
N-Methyl-N'-(4-chlorophenyl)urea was prepared preliminarily from 4-chlorophenyl isocyanate and methylamine by the same procedure as in Reference Example 1. The urea compound as the starting material was reacted with cyanoacetic acid to form a uracil ring. Using sodium nitrite a nitroso group was introduced into the 5-position of the uracil ring in the obtained 6-amino-1-(4-chlorophenyl)-3-methyluracil and then reduced with hydrogen gas to prepare 1-(4-chlorophenyl)-5,6-diamino-3-methyluracil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].P(Br)(Br)[Br:12].O>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([OH:10])[CH:4]=[CH:5][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(O)c1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Oc1cccc(CBr)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 2-chloro-3-(hydroxymethyl)phenol (400 mg, 2.5 mmol) in anhydrous chloroform (8 mL) was added dropwise a solution of phosphorus tribromide (240 μL, 2.5 mmol) in anhydrous chloroform (2 mL) at 0° C. The mixture was stirred for 2 hours at room temperature. Water was added and extracted 3 times with dichloromethane. The combined organic phase was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 3-(bromomethyl)-2-chlorophenol was obtained (373 mg, 67% yield) and used for next step without further purification; 1H NMR (400 MHz, DMSO-d6): δ 4.70 (s, 2H), 6.94-6.97 (m, 1H), 7.02-7.04 (m, 1H), 7.13 (t, J=7.8 Hz, 1H), 10.32 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 107.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with glycine ethylester hydrochloride (41.0 mg, 0.294 mmol), triethylamine (0.081 mL, 0.58 mmol), acetic acid (0.084 mL, 1.5 mmol) and sodium triacetoxyborohydride (77.0 mg, 0.360 mmol). The reaction mixture was added with water and sodium hydrogen carbonate, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(ethoxycarbonylmethylaminomethyl)indol-2-yl]isoindolinone (39.2 mg).
Reaction SMILES: [NH2:1][C:2]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH2:23]([C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH2:23]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:1][C:2]2([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[CH2:3]2)=[O:38])=[CH:40][CH:41]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCOC(=O)CC1(N)CCN(C(=O)OCc2ccccc2)C1
Reactant: CCCCCCCCCCc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCCCCCCCCc1ccc(C(=O)NC2(CC(=O)OCC)CCN(C(=O)OCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a solution of benzyl 3-amino-3-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (260 mg, 0.85 mmol) and p-decylbenzoic acid (267 mg, 1.03 mmol) in CH2Cl2 (10 mL) was added EDC (195 mg, 1.02 mmol) and triethylamine (0.35 mL, 2.55 mmol). The reaction was stirred overnight at room temperature. Methylene chloride (100 mL) was added and the solution was washed with sat. sodium bicarbonate (2×10 mL), H2O (10 mL) dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (9:1 CH2Cl2/EtOAc) to give the title compound as a yellow solid (127 mg, 26%) 1H NMR (400 MHz, CDCl3) δ 7.64 (d, 2H, J=7.8 Hz), 7.41-7.28 (m, 5H), 7.23 (d, 2H, J=7.5 Hz), 6.40 (s, 1H), 5.21-5.10 (m, 2H), 4.10 (q, 2H, J=7.1 Hz), 4.02 (d, 1H, J=11.9 Hz), 3.64 (d, 1H, J=12.4 Hz), 3.60-3.53 (m, 2H), 3.35-2.86 (m, 2H), 2.64 (t, 2H, J=7.6 Hz), 2.14-2.02 (m, 1H), 1.67-1.56 (m, 4H), 1.36-1.24 (m, 14H), 1.21 (t, 3H, J=7.1 Hz), 0.89 (t, 3H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][C@@H:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:29]=[C:30]4[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][N:31]4[CH:37]=3)=[CH:24][CH:23]=2)[CH2:16][CH2:17][C:18]([OH:20])=O)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([N:40](CC)CC)C.ClC(OCC)=O>C1COCC1>[NH2:40][C:18](=[O:20])[CH2:17][CH2:16][C@@H:15]([NH:14][C:12](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:29]=[C:30]3[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][N:31]3[CH:37]=2)=[CH:26][CH:27]=1
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CCC(=O)O)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CCC(N)=O)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
To a solution of (4R)-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoic acid (900 mg, 1.73 mmol) in anhydrous THF (12.4 mL) at 0° C. under nitrogen was added triethylamine (242 uL, 1.73 mmol) followed by ethyl chloroformate (174 uL, 1.82 mmol). The reaction was stirred for 40 min at 0° C. and then the solids were filtered and washed with 5 mL THF. The filtrate was added to a flask containing NH4OH (5 mL) at room temperature and the reaction mixture was stirred for 1 hour. The product was extracted from the reaction mixture with EtOAc (50 mL). The aqueous layer was extracted with EtOAc (20 mL) and then acidified with 1N HCl solution (30 mL) and re-extracted with EtOAc (10 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a white solid. Purification by recrystallization from hot isopropanol afforded the title compound as a white solid (90%). ESMS [M+H]+=519.4.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=2)[CH2:20][CH3:21])=[CH:15][CH:14]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]([OH:39])=[O:4])=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccccc3CC(=O)OC)cc2)cc1C)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccccc3CC(=O)O)cc2)cc1C)CC
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 74.7 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.160 mL, 0.160 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-biphenyl-2-yl)-acetic acid methyl ester (Example 126-(2); 26.6 mg, 0.053 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the mixture was stirred at 60° C. for 2.5 hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:water=4:1:0.3) to give the target compound as a colorless oil (19.2 mg, 75%).
Reaction SMILES: [C:1]([O-:10])(=[O:9])[CH2:2][C@:3]([CH2:6][CH2:7]O)([CH3:5])[OH:4].O=C[C@@H]([C@H]([C@H](CO)O)O)O>C(OCC)(=O)C>[CH3:5][C:3]1([OH:4])[CH2:2][C:1](=[O:9])[O:10][CH2:7][CH2:6]1
Reactant: C[C@@](O)(CCO)CC(=O)[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Solvent: CCOC(C)=O
Product: CC1(O)CCOC(=O)C1
Reaction time: 8 h

Procedure:
GC-MS analysis for in vivo mevalonate production. As for screening the single mutation library, a single colony harboring pBADMevT (wild type tHMGR or its mutant variants) was inoculated into LB medium containing Cm50 and grown overnight at 37° C. An aliquot (50 μl) of this seed culture was inoculated into fresh LB medium (5 ml) containing Cm50 and 13.3 mM (+)-L-arabinose, and grown for 24 hours at 37° C. An aliquot of culture (560 μl) was mixed with 140 μl of 0.5 M HC1 to dehydrate the mevalonate to form mevalonolactone, and 700 μl of ethyl acetate was then added to the sample. The mixture was vortexed for 5 minutes, and the ethyl acetate was analyzed by GC-MS using a GC oven temperature program of 90° C. for 1 min, then ramping 30° C./min to 250° C. for CyclosilB capillary column analysis. Mevalonolactone was identified from its mass spectra and retention time by comparison to an authentic standard.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][C:10]#[N:11])[N:3]=1.C[O-].[Na+].[C:15](O)(=[O:17])C>CO>[NH2:1][C:2]1[N:7]=[C:6]([O:17][CH3:15])[CH:5]=[C:4]([CH2:9][C:10]#[N:11])[N:3]=1
Reactant: CC(=O)O
Reactant: N#CCc1cc(Cl)nc(N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CC#N)nc(N)n1

Procedure:
2-amino-4-chloro-6-pyrimidylacetonitrile (31.6 g, 204.6 mmol) was dissolved in methanol (500 ml) and then sodium methoxide in methanol (46.8 ml, 204.6 mmol) was added at 25° C. The resultant dark solution was heated at reflux for 1 hour and after this time TLC indicated complete reaction. The reaction was cooled and acidified to pH 6 with acetic acid and the mixture was filtered. The filtrated was concentrated and the residue was taken up in ethyl acetate and washed with water and brine and dried with magnesium sulfate. The brown solid was chromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent to furnish two fractions. Fraction A furnished 6.9 g of pure subject as a yellow solid, m.p. 117°-118° C. Fraction B furnished 4.23 g of impure subject as a pink solid, m.p. 95°-98° C. NMR (fraction A) (90 mHz) D6-acetone δ 6.2-5.9 (bs, 2 H), 6.1 (s, 1 H), 3.9 (s, 3 H), 3.7 (s, 2 H). EXAMPLE 4
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].C(NC(C)C)(C)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21]Br)=[CH:16][CH:15]=1>O1CCCC1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH2:21][CH:2]([CH3:3])[CH:1]=[O:4])=[O:23])=[CH:16][CH:15]=1
Reactant: CCC=O
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(C)C=O)cc1
Reaction time: 3 h
Yield: 54.7 %

Procedure:
4.36 g (75 mmol) of propionaldehyde were added dropwise under a stream of nitrogen to a solution of 6.46 g (50 mmol) of diisopropylamine, 39 g of molecular sieves 4 Å and 10 mg of 2,6-di-t-butyl-4-methylphenol in 50 ml of tetrahydrofuran, and the mixture was left to stand for 3 hours. At the end of this time, 5.73 g (25 mmol) of 4′-methoxy-2-bromoacetophenone were added to the mixture, and the mixture was left to stand at room temperature overnight. The reaction mixture was then filtered, and 55 ml of 1N aqueous hydrochloric acid were added to the filtrate to separate it into liquid phases. The aqueous layer was separated and extracted twice with ethyl acetate. The organic extracts were combined and washed with water and with a saturated aqueous solution of sodium chloride, in that order. The resulting solution was then dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 2:1 by volume mixture of hexane and ethyl acetate, to give 2.82 g (yield 26%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[CH3:1][N:2]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:18][CH:17]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(CCCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Reactant: O=C1CSC(=O)N1
Product: CN(CCCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2o1

Procedure:
The title compound (m.p. 202°-204° C.) was prepared from 4-[3-(N-methyl-N-(2-benzoxazolyl)amino)propoxy]benzaldehyde (5.3 g) and 2,4-thiazolidinedione (2.2 g) by a similar procedure to that described in Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:23][CH3:24])(=[O:9])=[O:10])=[CH:15][CH:16]=2)=[O:21])=[CH:34][CH:35]=1)[CH3:26]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1

Procedure:
The title compound was prepared as for example 8, steps 1 to 4. Step 1 was performed using 5-chloro-2-methoxybenzensulfonyl chloride and yielded 1-(5-chloro-2-methoxybenzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester, which was hydrolyzed to 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid in step 2 and coupled to (4-amino-phenyl)-acetic acid ethyl ester and yielded (4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-phenyl)-acetic acid ethyl ester, which was hydrolyzed to (4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-phenyl)-acetic acid in step 4, MS (ISP): m/e=499.1 (M−H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=O)([OH:3])=[O:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[C:22]1(=[O:28])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:25](=[O:27])[CH:24]=[CH:23]1
Reactant: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A mixture of N-(17-carboxyheptadecyl)maleamic acid (400 mg, 1.01 mmoles), 2.83 ml of acetic anhydride, and anhydrous sodium acetate (41.0 mg, 0.50 mmoles) was heated at 100° C. with stirring for 1 hour. The reaction mixture was allowed to cool, then poured onto ice and stirred for 1 hour. The resulting mixture was extracted with chloroform. The separated organic layer was washed with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and isolated and purified by silica gel column chromatography [eluent: mixture of benzene and chloroform (volume ratio: 1:1)], to give 18-maleimidooctadecanoic acid (172 mg, 45%) having the following properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[Cl:24])[C@H:12]([CH3:16])[CH2:13][CH2:14]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:49]I>C(OCC)C.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[Cl:24])[C@H:12]([CH3:16])[CH2:13][CH2:14][I:49])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: II
Reactant: C[C@H](CCO)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: C[C@H](CCI)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 96 %

Procedure:
To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[1(R)-methyl-(3-hydroxy)-propyl]benzene-sulfonamide (1.40 g, 3.40 mmol), triphenylphosphine (0.900 g, 3.40 mmol) and imidazole (0.230 g, 3.40 mmol) in diethyl ether/CH3CN (2:1, 7.0 mL) was added iodine (0.860 g, 3.40 mmol) at 0° C. under nitrogen and stirred for 12 h. The solvent was removed, the residue was taken into CH2Cl2, washed with water, dried over Na2SO4 and filtered. The organic solution was concentrated to afford the title compound as a light yellow oil in 96% yield.