Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[N+:8]([C:4]1[CH:3]=[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1

Procedure:
To a 1-iodo-3-nitrobenzene (1.0 g, 4.01 mmol) in dry DME (20 mL) was added pyridine-3-boronic acid (641 mg, 5.22 mmol), PdCl2dppf (327 mg, 0.40 mmol), and 2M Na2CO3 (3.0 mL) The resulting mixture was heated to reflux under N2 for 15 h. Solvent was separated from inorganic solid by filtration. The solvent was removed and the residue was extracted with CHCl3. The organic layer was washed with water, brine, and dried over MgSO4. The solvent was removed to give dark brown solid which was purified by chromatography on silica gel. Elution with Hexane:acetone mixture (80:20) gave the final compound as a tan solid. MS m/z: 201.3 (M+H). Calc'd. for C11H8N2O2-200.23.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:9](O)([CH3:12])([CH3:11])[CH3:10].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: CC(C)(C)O
Reactant: C=CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a stirred solution of 5-hexenoic acid q-1 (6.00 g, 52.6 mmol), t-butyl alcohol (72.2 mL, 735.84 mmol) and DMAP (1.28 g, 10.51 mmol) in DCM (150 mL) at −10° C. was added DCC (16.26 g, 78.84 mmol). After stirring at room temperature overnight, solid was filtered off. The filtrate was evaporated under reduced pressure to give a crude oil, which was purified by chromatography (Biotage; 65i). Elution with a gradient of EtOAc/Hexane from 5/95 to 10/90 yielded 4.16 g (46.53%) of t-butyl ester q-2, which displayed a 1H NMR spectrum that matched literature (Johnson, P. Y.; Berchtold, G. A. J. Org. Chem. 1970, 35, 584-592) and was used without further purification).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].[C:14](Cl)(=[O:19])[CH2:15][C:16](Cl)=[O:17]>O1CCOCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:13][C:14](=[O:19])[CH2:15][C:16]([NH:13][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:17])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: C1COCCO1
Product: O=C(CC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reaction time: 8 h
Yield: 58 %

Procedure:
4-Nitroanthranilic acid (5.0 g, 26.6 mmol) was dissolved in dry dioxane (130 ml). To this solution, a solution of malonyl dichloride (1.45 g) in dry dioxane (5 ml) was added dropwise at room temperature. After stirring the mixture overnight, the precipitated crystals were collected by filtration, and washed with water and ether to give a pale yellow crystals of the title compound (2.58 g, 9.8%). m.p., 269°-270.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH:16]([CH2:18][OH:19])[CH:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4O)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O1CCCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:14][CH:15]4[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:19][CH2:18][CH:16]4[CH2:17]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CC(CO)C(c2ccccc2O)C1)C1(c2ccc(Cl)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N1CC2COc3ccccc3C2C1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-[1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-(hydroxymethyl)pyrrolidin-3-yl]phenol (13.0 mg, 0.0000350 mol), triphenylphosphine (20.0 mg, 0.0000762 mol) and diisopropyl azodicarboxylate (15.0 μL, 0.0000762 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) was stirred at rt for 4 h. The mixture was diluted with methanol (0.80 mL) and the desired product from the mixture was isolated and purified by prep-HPLC. LCMS: m/z 354.5 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1.O>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:29]5[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=5)=[O:31])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.65 mmol) in N,N-dimethylacetamide (2.0 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (185 mg, 1.16 mmol). After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2→4-ethyl acetate) and precipitated from hexane/ethyl acetate to give the title compound (70 mg, 25%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39]([OH:41])=[O:40]>>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:38][CH2:37][CH2:36][C@@H:35]4[C:39]([OH:41])=[O:40])=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)[C@H]1CCCN1
Product: O=C1N=C(N2CCC[C@@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and pyrrolidine-2-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[Na+].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: OCCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: c1ccc(COCCOc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Benzyloxy)ethanol (61.0 g, 0.4 mole, and p-toluenesulfonyl chloride (80.0 g, 0.4 mole) were added with stirring to acetonitrile (20 ml) in a litre, four-necked, round-bottom flask, equipped with a mechanical stirrer, reflux condenser, thermometer and a dropping funnel. Aqueous sodium hydroxide (40.0 g, 1.0 mole/80 ml of water) was added slowly from the dropping funnel while the temperature of the reaction mixture was kept below 55° C. After the addition was complete, the reaction mixture was stirred for one hour as it cooled to room temperature. Then, 4-(benzyloxy)phenol (80.0 g, 0.4 mole) was added and the reaction mixture (OV-1 column, 100° C. for 2 minutes, 25° C./min to 300° C.) showed that the reaction was complete.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1>O1CCOCC1>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]1
Reactant: Brc1nccs1
Reactant: OCC(O)CN1CCNCC1
Solvent: C1COCCO1
Product: OCC(O)CN1CCN(c2nccs2)CC1

Procedure:
Grams 6.4 of 1-(2,3-dihydroxypropyl)piperazine and 3.3 g of 2-bromo-1,3-thiazole in 50 ml dioxane were refluxed for 24 hours. The reaction mixture was evaporated to dryness and the so obtained residue was purified on column eluting with chloroform:methanol (9:1). Grams 1.5 of 3-[4-(1,3-thiazol-2-yl)piperazin-1-yl] propane-1,2-diol which, by recrystallization from acetone, melted at 138°-139° C., were obtained.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[C:15]([N:25]1[CH2:28][C:27]([C:30]2[CH:46]=[CH:45][C:33]([NH:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])=[CH:32][C:31]=2[F:47])(O)[CH2:26]1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl>[C:15]([N:25]1[CH2:26][CH:27]([C:30]2[CH:46]=[CH:45][C:33]([NH:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])=[CH:32][C:31]=2[F:47])[CH2:28]1)([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: O=C(Nc1ccc(C2(O)CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C2CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1
Reaction time: 48 h

Procedure:
Triethylsilane (30 mL) and trifluoroacetic acid (12 mL) were added to a solution of N-carbobenzyloxy-3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)-3-hydroxyazetidine (Example 81, Step 3, 4.3 g, 9.55 mmol) in methylene chloride (40 mL) and stirred for 2 days. Removal of the solvents at 45°/0.75 mm gave an amber oil. Chromatography over silica gel (150 g, 40-60 μm) eluting with 1-3% methanol-chloroform yielded the title compound as a solid, m.p. 95°.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11]>[Pd].O1CCCC1.O>[ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cc1[nH]cnc1/C=C/C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]cnc1CCC(=O)O
Reaction time: 19 h
Yield: 81.4 %

Procedure:
60 mg of 10% palladium-on-charcoal are introduced into a solution of 387 mg (2.1 mmol) of (E)-3-(5-methyl-1H-imidazol-4-yl)acrylic acid hydrochloride in 8 ml of 1/1 tetrahydrofuran/water, purged beforehand with nitrogen. The reaction medium is placed under a hydrogen atmosphere and then stirred for 19 hours. After filtering through Celite and rinsing thoroughly with dichloromethane, the recovered filtrate is concentrated under vacuum. The crude residue is taken up in toluene and concentrated again in order to remove the residual water, and is then taken up in a mixture of heptane and diisopropyl ether (80/20) with stirring for about 2 hours. The desired product precipitates and is filtered off under vacuum. 326 mg (83%) of 3-(5-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride are obtained in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[C:12]#[N:13])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH2:26]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[C:12]([NH2:13])=[O:26])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O
Reactant: N#CC(=C1Nc2ccc([N+](=O)[O-])cc2S1)c1nccc(C(F)(F)F)n1
Agent: O=S(=O)(O)O
Product: NC(=O)C(=C1Nc2ccc([N+](=O)[O-])cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
2-(6-Nitrobenzothiazol-2(3H)-ylidene)-2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (296 mg, 0.81 mmol) was dissolved in concentrated sulfuric acid (3.0 mL). The reddish mixture was stirred at 50° C. for 8 hr, then poured into cold water (25 mL). The yellow precipitate was collected by filtration, washed with hexanes (30 mL), and dried under vacuum to give 2-[6-nitrobenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (280 mg, 89% yield) as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Br[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CCC(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OC(CC)CC

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-ethoxy-4-hydroxy-benzaldehyde with 3-bromo-pentane in DMF using K2CO3 as base. MS (ISP): 237.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([C:19]([OH:21])=[O:20])[N:4]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:5]P(O)=O)[CH3:2].[P:22]([Cl:25])(Cl)[Cl:23]>C1C=CC=CC=1>[CH2:1]([CH:3]([C:19]([OH:21])=[O:20])[N:4]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:5][P:22]([Cl:25])[Cl:23])[CH3:2]
Reactant: ClP(Cl)Cl
Reactant: CCC(C(=O)O)N(C[PH](=O)O)C(=O)OCc1ccccc1
Solvent: c1ccccc1
Product: CCC(C(=O)O)N(CP(Cl)Cl)C(=O)OCc1ccccc1

Procedure:
Ethyl-N-(benzyloxycarbonyl)-N-(hydroxyphosphinylmethyl)glycine was dissolved in benzene and added dropwise to a stirred solution of phosphorus trichloride to yield ethyl-N-(benzyloxycarbonyl)-N-[bis(chloro)phosphinomethyl]glycine. After stirring for 5-10 minutes, the solution was filtered and concentrated in vacuo to yield the phosphine dichloride (21.8 g, 0.0619 mole) which was dissolved in tetrahydrofuran. To the tetrahydrofuran solution was added isopropanol (3.71 g, 0.0619 mole) and triethylamine (6.255 g., 0.0619 mole) dissolved in 50 ml. of tetrahydrofuran. After stirring for one hour, thiophenol (6.86 g., 0.0619 mole) and triethylamine (6.255 g., 0.0619 mole) dissolved in 50 ml. of tetrahydrofuran was added. The reaction mixture was then stirred for two hours and sulfur (1.98 g., 0.0619 mole) was added and stirring continued overnight. The reaction mixture was then filtered, concentrated to dryness and dissolved in diethyl ether. The diethyl ether solution was then washed with 5% hydrochloric acid, 5% aqueous sodium bicarbonate and dried over magnesium sulfate. The ethereal solution was then filtered and concentrated in vacuo to yield a residue. The residue was dissolved in methanol and centrifuged to remove unreacted sulfur; the supernatant liquid was decanted and concentrated to dryness. This residue was chromatographed on silica gel employing diethyl ether as a solvent to yield ethyl-N-(benzyloxycarbonyl)-N-[(phenylthio, isopropoxy)phosphinothioylmethyl]glycine (23 g.) as an oil having a refractive index of ND25 =1.5755 and having the following analysis.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=O)[NH:9][C:5]=2[CH:4]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[NH:9][C:5]2[CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:12]=[CH:11][C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]1
Product: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Temperature: 25 °C

Procedure:
A solution of the dihydrobenzoimidazol-2-one from step (b) above (2.02 g, 10 mmol) in POCl3 (30 mL) was heated at 95° C. for 16 h. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the resulting oily residue subjected to azeotropic distillation with toluene (3×50 mL) at 50° C. The crude product was dissolved in EtOAc (50 mL), washed with brine (10 mL) then dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was recrystallized from EtOAc/hexane to give the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](O)=[O:41])=[CH:31]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:1]([C@@H:8]1[CH2:13][N:12]([C:40](=[O:41])[CH2:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1c[nH]c2ccccc12)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 5 h
Yield: 82.3 %

Procedure:
To a stirred mixture of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) and 2-(1H-indol-3-yl)acetic acid (0.13 g) in dichloromethane (8 ml) containing triethylamine (0.25 ml) was added 2-chloro-1-methylpyridinium iodide (0.22 g) at room temperature under nitrogen atmosphere. After being stirred for 5 hours, the reaction mixture was diluted with dichloromethane and washed with 0.1N hydrochloric acid, aqueous saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel using chloroform-methanol (50:1) as eluent to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-(1H-indol-3-yl)acetyl]piperazine (0.34 g) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCCSc1ccccc1
Reactant: O=C1CCc2cc(O)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 4 from 6-hydroxy-3,4-dihydro-carbostyril and 4-(phenylmercapto)-butyl bromide (b.p. 96°-103° C. at 0.02 mm Hg; prepared from thiophenol and 1.4-dibromo butane).
Reaction SMILES: [CH2:1]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][N:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].C(N(CC)CC)C>C(O)(C)C>[CH2:1]([N:8]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]([OH:20])[CH2:21][N:23]([CH2:24][CH2:25][N:26]2[N:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH3:22])=[CH:17][CH:18]=1)[S:9]([CH3:12])(=[O:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCn1ncc2ccccc2c1=O
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1ccc(C2CO2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(N(Cc2ccccc2)S(C)(=O)=O)cc1

Procedure:
2-{4-(N-Benzylmethanesulphonamido)phenyl]oxirane (1.5 g), N-methyl-2-(phthalazin-1-on-2-yl)ethylamine (1.4 g) and triethylamine (1.4 g) in isopropanol (50 ml) were stirred at reflux temperature for 5 hours. The solvent was evaporated, the residue dissolved in methylene chloride and washed three times with sodium carbonate solution and three times with brine. The organic layer was dried and evaporated to give an oil which was purified by column chromatography on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methylene chloride containing methanol (0% up to 2%). Combination and evaporation of the appropriate fractions gave a foam which was chromatographed a second time on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methyl isobutyl ketone (MIBK) containing acetone (0% up to 20%). The appropriate fractions were combined and evaporated then re-evaporated from diethyl ether to give the title compound as a foam, yield 450 mg.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: C1COCCN1
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 49.3 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (355 mg, 0.998 mmol) and morpholine (1.3 ml, 15 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (200 mg, 49%), MS (ISP) m/e=407.3 [(M+H)+].
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:18]=[CH:17][C:10]([C:11](N(C)OC)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:19]([Mg]Br)=[CH2:20].Cl>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([CH:19]=[CH2:20])=[O:12])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=C[Mg]Br
Reactant: CCCCCOc1ccc(C(=O)N(C)OC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)c1ccc(OCCCCC)cc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a solution of N-(4-n-pentyloxybenzoyl)-N,O-dimethylhydroxylamine (4.52 g) in tetrahydrofuran (25 ml) was added 1.6 molar tetrahydrofuran solution of vinylmagnesium bromide (25.5 ml) at −50° C. dropwise and the mixture was stirred for 3 hours at −20° C. To the mixture was added 1N HCl (50 ml) dropwise and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate)=(8/2) to give 1-(4-n-pentyloxyphenyl)acrolein (2.40 g).