Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(C)(C)C(=O)N(I)C1=O.[CH3:12][C:13]([NH:19][C:20]([C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:21])([CH3:18])[CH2:14][S:15]([CH3:17])=[O:16].CN1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[I:1][C:31]1[C:22]([C:20]([NH:19][C:13]([CH3:12])([CH3:18])[CH2:14][S:15]([CH3:17])=[O:16])=[O:21])=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Reactant: COC(=O)c1ccccc1C(=O)NC(C)(C)CS(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cccc(I)c1C(=O)NC(C)(C)CS(C)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 137.3 %

Procedure:
Into the same reactor as in Example 1 were charged 1.5 mg of palladium acetate, 0.83 g of 1,3-diiodo-5,5-dimethylhydantoin, 1.0 g of methyl 2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)benzoate and 5 ml of N-methylpyrrolidone. The mixture thus obtained was heated with stirring at 90° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into water, and the objective product was extracted with ethyl acetate. The organic layer was washed successively with aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, a crude product was obtained. Purification of the crude product by silica gel column chromatography (ethyl acetate/n-hexane=1/3) gave 1.27 g of methyl 3-iodo-2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)-benzoate (yield 89.1%, melting point 150.7–151.8° C.).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([NH:14]C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(N)CC1
Yield: 100.3 %

Procedure:
To a solution of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid tert-butyl ester (3.0 g, 9.009 mmol) in THF (80 mL) is added TEA (0.24 mL, 1.724 mmol) and 10% Pd/C (wet) (420 mg). The mixture stirs under a blanket of hydrogen gas at atmospheric pressure for 12 h. The mixture is then filtered though celite. The celite is washed with MeOH (50 mL). The filtrated is concentrated to afford 1.8 g of 4-amino-cyclohexanecarboxylic acid tert-butyl ester. LC/MS: [M+H]+ 200, Rt=0.39 min (method 6).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][CH2:13][CH2:14][CH2:15]O.O>CCOCC>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[S:11][CH2:15][CH2:14][CH2:13][N:12]=1
Reactant: Cc1cccc(C)c1N=C=S
Reactant: NCCCO
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(C)c1NC1=NCCCS1
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
2,6-Dimethylphenylisothiocyanate (15.0 g, 0.093 mole) was added to 3-amino-1-propanol (6.9 g, 0.093 mole) in 60 ml of ether, and the mixture was heated to reflux for 0.5 hr. After the ether was evaporated, 60 ml of concentrated hydrochloric acid was added and refluxing was continued for 0.5 hr. The cooled reaction mixture was treated with 60 ml of water and filtered. The filtrate was made basic with dilute sodium hydroxide, and the precipitate was collected by filtration and washed with water. Recrystallization from ethanol-water (charcoal) gave 16.3 g (80%) of xylazine, m.p. 136°-138° C. (lit. m.p. 140°-141° C.). This step was run three times with yields ranging from 80 to 93%.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[NH2:8][C:9]([NH:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[C:21]([NH2:23])=[O:22])=[CH:18][CH:17]=[C:16]([C:24]1[CH:29]=C[CH:27]=[C:26](CO)[CH:25]=1)[CH:15]=2)=[O:10]>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[CH:29]=[C:24]([C:16]2[CH:15]=[C:14]3[C:19]([C:20]([C:21]([NH2:23])=[O:22])=[C:12]([NH:11][C:9]([NH2:8])=[O:10])[NH:13]3)=[CH:18][CH:17]=2)[CH:25]=[CH:26][CH:27]=1)(=[O:7])[CH3:6]
Reactant: NC(=O)Nc1[nH]c2cc(-c3cccc(CO)c3)ccc2c1C(N)=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cccc(-c2ccc3c(C(N)=O)c(NC(N)=O)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Pyridine (4 mL) and acetic anhydride (61 μL, 0.65 mmol) were added to 2-aminocarbonylamino-6-(3-hydroxymethylphenyl)indole-3-carboxamide (Compound 12-1, 0.18 g, 0.55 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water (10 mL) was added to the residue. The precipitated solid was separated by filtration. The resultant solid was washed with water (10 mL) and dried under reduced pressure to give the title compound (0.17 g) as a slightly brown solid (yield 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[ClH:10].Br[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Br>ClC1C=CC=CC=1.C(OCC)C>[ClH:10].[ClH:10].[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: BrCCNCCBr
Reactant: Nc1ccc(F)c(F)c1
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(N2CCNCC2)cc1F
Temperature: 25 °C
Yield: 201.2 %

Procedure:
A mixture of 3,4-difluoroaniline (3.6 g) and bis(2-bromoethyl)amine hydrochloride (5.0 g) in 50 mL of chlorobenzene is warmed to reflux under argon for 48 hours. The mixture is cooled to room temperature, diluted with 100 mL of diethyl ether, and extracted with three 150 mL portions of 1N HCl. The aqueous extracts are backwashed with three 50 mL portions of ether, which are discarded. The combined aqueous fractions are basified to pH 11 with 12N NaOH. The resulting mixture is extracted with three 50 mL portions of methylene chloride, and the combined organic extracts are dried over sodium sulfate. The solvent is removed under reduced pressure, and the resulting residue is taken up in 50 mL of diethyl ether and filtered through Celite. The resulting solution is treated with a 1 M ethereal HCl solution (56 mL), and the resulting precipitate is collected and dried under vacuum to give 5.1 g of the title compound, mp 100-104° C. (decomposes). ##STR7## Preparation of 2-[4-(3,4-difluoro-phenyl)-piperazin-1-ylmethyl]-quinoline
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCc1ccc2c(c1)OCCO2
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc2c(c1)OCCO2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.36 g--see Preparation 1), 6-(2-bromoethyl)-1,4-benzodioxan (0.32 g), anhydrous potassium carbonate (0.75 g) and acetonitrile (20 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give a foam which was further purified by column chromatography on alumina eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.11 g.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH3:18][NH2:19]>C(O)C.CCOCC>[N+:1]([CH:4]=[C:5]([NH:19][CH3:18])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Reactant: CN
Solvent: CCO
Solvent: CCOCC
Product: CNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene with methylamine according to the process of Example 8(ii) yielded the title compound, m.p. 103°-104°, (from ethanol ether).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])([CH3:11])([CH3:10])[CH3:9].C1(C)C=CC(S([Cl:28])(=O)=O)=CC=1>O1CCCC1>[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([Cl:28])[C:13]1=[O:18])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)C1CCCCC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C1CCCC(Cl)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
N-butyl lithium is added dropwise to a solution, cooled to 0° C., of diisopropylamine (5.5 mmol) in dry tetrahydrofuran. After the addition is complete the mixture is cooled to −78° C., and a solution of 2-tert-butylcyclohexanone (5 mmol) in dry tetrahydrofuran (50 ml) is introduced, followed by the addition of p-toluenesulphonyl chloride (5 mmol), also dissolved in dry tetrahydrofuran (50 ml). The reaction mixture is heated to room temperature and after stirring for 30 mins over silica gel filtered with ether as eluant. After concentration by evaporation in a vacuum 2-tert-butyl-6-chlorcyclohexanone (760 mg) is obtained in a yield of 81% (Tet. Lett. 1999, 40(12), 2231-2234).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][C:33]=1[Cl:47]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH:15]([CH2:31][C:32]1[C:33]([Cl:47])=[CH:34][C:35]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:36][C:37]=1[Cl:38])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -75 °C
Yield: 86 %

Procedure:
Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (345 g, 1.33 mol) and THF (1.8 L) in a 12 L 3-neck round bottom flask, with internal temperature probe/nitrogen inlet and addition funnel, under a nitrogen atmosphere and cool to −75° C. Transfer 1 M LiHMDS (1.6 L) to the addition funnel and add at a rate such that the internal temperature does not reach above −60° C. After the addition is complete, allow the reaction to stir at −25° C. for 30 min then cool to about −60° C. At this point add solid 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene portionwise over 5 min. After the addition is complete, transfer the reaction vessel to a −10° C. acetone bath and maintain the internal reaction temperature below 10° C. for 1 hr. Cool the mixture to 0° C. then quench with 2 L aqueous 1N hydrochloric acid. Transfer the mixture to a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether. Separate the layers and extract the aqueous layer with ether. Dry the combined organic phase over anhydrous magnesium sulfate, filter and concentrate to 800 g of a thick oil. Purify by silica gel chromatography using hexanes:ethyl acetate to obtain 597 g, (86%) of a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:9]=[CH:8]2.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C(#N)C>[F:20][C:19]([F:22])([F:21])[C:15]1[CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]3[C:12](=[C:3]([CH2:2][NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: NC1CCCC1
Reactant: FC(F)(F)c1cccc(-c2ccc3cccc(CCl)c3n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1cccc(-c2ccc3cccc(CNC4CCCC4)c3n2)c1
Yield: 91.8 %

Procedure:
A solution of 8-(chloromethyl)-2-(3-(trifluoromethyl)phenyl)quinoline (70 mg, 0.22 mmol), cyclopentylamine (0.1 ml, 1.09 mmol) and DIPEA (0.18 ml, 1.09 mmol) in acetonitrile (2 ml) was stirred at 100° C. under microwave for 10 min. The mixture was concentrated. Purified by Prep-TLC to give a white solid (74.8 mg, 91% yield). MS (ESI) calcd for C22H21F3N2 (m/z): 370.17. found: 371 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].[CH2:13](OC(C1NC2C(C=1)=CC=CC=2)=O)[CH3:14]>>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([CH:11]=[O:12])=[CH:6]1)[CH3:14]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Product: CCn1cc(C=O)c2cc(F)ccc21
Yield: 57 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 5-fluoro-1H-indole-3-carboxaldehyde (0.41 g, 2.5 mmole) for the ethylindole-2-carboxylate, the title compound (0.20 g, 57%) was prepared as a viscous oil: MS (ES) m/e 191 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH3:22])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC)c(O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,4-Dihydroxybenzoic acid ethyl ester (3.00 g, 16.0 mmol) was suspended in DMF (10 ml), potassium carbonate (2.21 g, 16.0 mmol) was added, the mixture was stirred for 5 min at room temperature, and then iodoethane (2.49 g, 16.0 mmol) was added. The mixture was stirred overnight, the addition of potassium carbonate and of iodoethane was repeated, and the mixture was stirred overnight again. The mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the combined organic extracts were washed with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:19]1[C:24]([I:25])=[CH:23][N:22]=[CH:21][N:20]=1>C(O)(C)C>[I:25][C:24]1[C:19]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[N:20][CH:21]=[N:22][CH:23]=1
Reactant: Clc1ncncc1I
Reactant: Cc1ccc(C(=O)O)cc1-c1cccc(N)c1
Solvent: CC(C)O
Product: Cc1ccc(C(=O)O)cc1-c1cccc(Nc2ncncc2I)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3′-Amino-6-methylbiphenyl-3-carboxylic acid (3.00 g, 0.0132 mol) was mixed with 4-chloro-5-iodopyrimidine (3.30 g, 0.0137 mol) and isopropyl alcohol (60 mL). The resulting mixture was heated to 80° C., at which temperature solution occurred. A short time later, the product began to precipitate. After 2 h, HPLC showed 95% conversion of to product. HPLC Method: Zorbax SB C18, 5 μm, 15 cm, 35 C, flow 1.2 mL/min, 25% CH3CN—H20 (0.05% TFA), to 100% CH3CN in 8.0 min; stop time 11 min; detector 254 &220 nm; retention time starting material, 2.8 min (UVmax 205 & 230 nm); pyrimidine, 4.8 min (UVmax 240 & 270 nm); product, 4.9 min (UV max 204, 228, & 290 nm). The reaction was cooled to 20° C. The product was isolated by filtration, rinsed with iPrOH, then vacuum dried. Yield 5.35 g of a light tan powder. The product is believed to be the HCl salt or partial salt. 1H NMR (300 MHz, DMSO) δ 9.62 (br s, 1H, NH); 8.83 (s, 1H); 8.69 (s, 1H); 7.83 (dd, 1H); 7.76 (d, 1H); 7.42-7.58 (m, 4H); 7.25 (dt, 1H); 2.33 (s, 3H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[O:8][C:9]([C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10].[Cl:18]N1C(=O)CCC1=O>CN(C=O)C>[ClH:18].[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[O:8][C:9]([C:11]2[C:16]([C:17]=1[Cl:1])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NCCCOc1cc2ccccc2c(=O)o1
Agent: Cl
Solvent: CN(C)C=O
Product: NCCCOc1oc(=O)c2ccccc2c1Cl
Yield: 6.2 %

Procedure:
0.13 g of 3-(3-aminopropoxy)isocoumarin hydrochloride (0.5 mmole) was chlorinated with 0.007 g of N-chlorosuccinimide (0.5 mmole) in 5 ml of DMF at r.t. overnight. The reaction mixture was purified by silica gel column chromatography (methylene chloride:methanol=5:1) and crystallized from MeOH-ether to give 0.009 g of 3-(3-aminopropoxy)-4-chloro-isocoumarin hydrochloride (yield, 60%). The NMR spectrum of this compound is similar to 3-(3-aminopropoxy)isocoumarin without the peak at δ6.2 ppm; m.p. 160°-163° C.; mass spectrum, m/e=254 (M+ -Cl). Anal. Calc. for C12H13N1O3Cl2.1/4H2O: C, 48.88; H, 4.61; N, 4.75; Cl, 24.06. Found: C, 48.85; H, 4.54; N, 4.74; Cl, 24.02.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([C:22]([NH:35][CH:36]2[C:56](=[O:57])[N:38]3[CH:39]([C:44](=[N:46][CH2:47][C:48]4[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=4)[NH2:45])[C:40]([CH3:43])([CH3:42])[S:41][C@H:37]23)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:58](O)(=[O:63])[CH2:59][C:60](O)=[O:61]>CN(C)C=O.C(Cl)Cl>[C:29]1([C:22]([NH:35][CH:36]2[C:56](=[O:57])[N:38]3[CH:39]([C:44]4[N:46]([CH2:47][C:48]5[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=5)[C:58](=[O:63])[CH2:59][C:60](=[O:61])[N:45]=4)[C:40]([CH3:43])([CH3:42])[S:41][C@H:37]23)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(CN=C(N)C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Reactant: O=C(O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CC(=O)N=C2C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 21.44 g. (104 mmoles) of N,N'-dicyclohexylcarbodiimide in 122 ml. of methylene chloride and 15 ml. dimethylformamide at -5° C., a solution of 29.9 g. (52 mmoles) of 6-(triphenylmethylamino)-2,2-dimethyl-3-[N'-(4-methoxybenzyl)amidino]penam and 5.41 g. (52 mmoles) of malonic acid in 122 ml. methylene chloride and 15 ml. dimethylformamide is added dropwise over 2 hours. The mixture is then stirred for 24 hours at 25° C. The N,N'-dicyclohexylurea precipitate (18.6 g., 79.8% of theory) is filtered off, and the filtrate washed with six 150 ml. portions of water. It is dried over anhydrous sodium sulfate and then rotoevaporated to yield the title compound in crude form as an orange foam (32.6 g.). The crude product is divided into two equal portions for silica gel chromatography (ethyl acetate elution) affording a total of 10.61 g. (31.6%) of the purified title compound. 1H-NMR (CDCl3) ppm (δ) 1.01 (3H, s, 2-CH3); 1.44 (3H, s, 2CH3); 3.80 (3H, s, --OCH3); 4.31-4.73 (3H, m; 3-, 5- and 6H); 5.25 (2H, s, --CH2 --); 4H, AB, Ha within a 7.18-7.68 multiplet, Hb centered at 6.91, J = 8 Hz, CH3O--C6-4H--); 7.18-7.68 (15H, m, C6-5H--).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][CH2:36][C:37]([NH:39][CH2:40][CH2:41][C:42](O)=[O:43])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:42](=[O:43])[CH2:41][CH2:40][NH:39][C:37](=[O:38])[CH2:36][CH2:35][NH:34][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:33])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCCC(=O)O
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Product: CC(C)(C)OC(=O)NCCC(=O)NCCC(=O)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Yield: 13 %

Procedure:
The title compound was prepared from (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol and 3-(3-tert-butoxycarbonylamino-propionylamino)-propionic acid in 13% yield as a colorless solid.
Reaction SMILES: Cl.Cl[C:3]1[NH:4][C:5](=[O:14])[C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:13][C:12]1[C:6]2[C:5](=[O:14])[NH:4][C:3]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:8][C:7]=2[N:9]=[CH:10][CH:11]=1
Reactant: Cc1ccnc2nc(Cl)[nH]c(=O)c12
Reactant: OCCCCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccnc2nc(OCCCCCc3ccccc3)[nH]c(=O)c12
Temperature: 120 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
2-Chloro-5-methyl-3H-pyrido[2,3-d]pyrimidin-4-one hydrochloride (36 mg, 155 μmol) was dissolved in DMSO (0.8 ml). Molecular sieves 4Å, 5-phenyl-1-pentanol (80 μl, 465 μmmol) and potassium tert-butylate (35 mg, 310 μmol) were added and the suspension was stirred at 120° C. for 48 h under an argon atmosphere. The molecular sieves were filtered off, the filtrate was poured onto ice water/isopropyl acetate 1/1, the layers were separated and the aqueous layer was extracted two times with isopropyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, isopropyl acetate/heptane) to give 5-methyl-2-(5-phenyl-pentyloxy)-3H-pyrido[2,3-d]pyrimidin-4-one (16 mg, 50 μmol; 32%) as yellow crystals. MS: m/e=324.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.O.C([O-])(O)=O.[Na+].[CH3:23][CH2:24]O>CCOCC>[CH2:23]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([OH:11])[CH:4]=1)[CH3:24]
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(Cl)c(O)c1

Procedure:
A solution of 4-chloro-3-hydroxy-benzoic acid (29.3 mmol) in EtOH (110 mL) is treated with conc. sulfuric acid (23.6 mL) and heated to reflux for 16 h. Water (600 mL), NaHCO3 (100 g) and ether (300 mL) are added successively, the layers are separated and the aqueous layer is extracted twice with ether. The combined organic layers are washed twice with brine, dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (CDCl3): δ=7.73 (s, 1H); 7.58 (d, J=8.3 Hz, 1H); 7.40 (d, J=8.3 Hz, 1H); 5.87 (s, 1H); 4.39 (q, J=7.0 Hz, 2H); 1.41 (t, J=7.0 Hz, 3H).