Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:10][OH:11].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C1COCC1>[Cl:19][CH2:20][C:21]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:10][OH:11])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: NC(CO)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NC(CO)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In step 2-2, triethylamine (8.15 mL, 58.6 mmol) in a single portion was added to a solution of 2-amino-2-(3-fluorophenyl)ethanol (7.57 g, 48.8 mmol) in THF cooled to 0° C. and chloroacetyl chloride (5.08 mL, 58.6 mmol) was added drop-wise. The mixture was cooled to 0° C. and stirred for 1 hour. The reaction mixture was quenched with water and the organic phase was washed with 0.5 N HCl, saturated NaHCO3, brine, and dried over MgSO4. The organic phase was concentrated and purified with flash chromatography (50% EtOAc/hexanes) to yield 2-chloro-N-(1-(3-fluorophenyl)-2-hydroxyethyl)acetamide (2-2) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])=O)[C:17]([O:19]CC)=[O:18].CC(O)C.C(=O)(O)[O-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:2][C:3]1[C:11]([C:12]2[S:14][C:16]([C:17]([OH:19])=[O:18])=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[N:13]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1nn2ccccc2c1-c1nc(-c2ccccc2[N+](=O)[O-])c(C(=O)O)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
A mixture of 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (1.2 g, 5.2 mmol) obtained in Example 11-B(v), ethyl 2-chloro-3-(2-nitrophenyl)-3-oxopropanoate (1.7 g, 8.4 mmol) obtained above and 2-propanol (20 mL) was stirred at 80° C. for 4 h. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate, EtOAc and THF. Insoluble materials were removed by filtration and the filtrate was extracted with a 1:1 mixture of EtOAc and THF. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. To the residue were added MeOH (10 mL), THF (25 mL) and 8N aqueous sodium hydroxide solution (2.5 mL), and the mixture was stirred at 70° C. for 1 h. The reaction mixture was allowed to, cool to 0° C., 6N hydrochloric acid was added to adjust the solution to about pH 3.0. The resulting precipitate was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (620 mg, 31%) as a yellow solid.
Reaction SMILES: [OH-].[K+].ClC1C=CC=CC=1C[C:7]1[CH:17]=[CH:16][CH:15]=[C:9]2C([NH:12][C:13](=O)[C:8]=12)=O.[ClH:22]>O>[Cl:22][C:7]1[CH:17]=[CH:16][CH:15]=[CH:9][C:8]=1[CH2:13][NH2:12]
Reactant: Cl
Reactant: O=C1NC(=O)c2c(Cc3ccccc3Cl)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NCc1ccccc1Cl
Temperature: 130 °C
Yield: 98 %

Procedure:
A 250 mL, round-bottomed, 3-necked flask was charged with 82.5 g of 20% aqueous potassium hydroxide and 20 g (73.6 mmol) of 2-chlorobenzylphthalimide. The reaction mixture was refluxed (bath temperature 130° C.) for 18.3 h with stirring, and then allowed to cool to room temperature. A mixture containing 50 mL of water and 50 mL of concentrated hydrochloric acid was then added dropwise and the reaction mixture was heated under reflux for a further 22.5 hours. The reaction mixture was then allowed to cool, and the cooled reaction mixture was filtered, and the collected solids were washed with 5×10 mL of water, and dried in a vacuum oven. NMR, IR and GC analysis indicated these to be mainly phthalic acid contaminated with 2-chlorobenzylphthalamic acid (11.2 g, 92%). The filtrate was rendered basic (pH 10) by the addition of potassium hydroxide pellets, and was then extracted with 4×100 mL of methylene chloride. After stripping of the solvent, a 98% yield (10.23 g) of 2-chlorobenzylamine was obtained (purity 99% by GC).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCN(CCCN)CC1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C
Yield: 81.6 %

Procedure:
2 g of 4-fluoronitrobenzene were added to a solution of 20 ml of N-methyl-pyrrolidine, 2.67 g of N-(3-aminopropyl)-N′-methylpiperazine and 2.35 g of K2CO3. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 3.22 g of N-[3-(4-methyl-piperazin-1-yl)propyl]-4-nitro-1-aminobenzene (9) were obtained.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[O:36])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccccn2)CC1
Yield: 80.1 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.064 g, 0.22 mmol) and diisopropylethylamine (0.089 g, 0.69 mmol) in methylene chloride stirring at 0° C. was added picolinoyl chloride hydrochloride (0.043 g, 0.24 mmol) at room temperature. After 2 h the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 95:5 to 90:10 dichloromethane/methanol) to provide (4-(2-tert-butylphenyl)piperazin-1-yl)(pyridin-2-yl)methanone (0.057 g, 80%) as a brown solid, mp 140-145° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCC#Cc1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(C#CCBr)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A solution of 3-(4-fluorophenyl)prop-2-yn-1-ol (1 g, 6.80 mmol) in DCM (13.6 mL) under N2 was cooled in a ice bath at 0° C. 2.70 g (8.2 mmol, loading 3 mmol/g) of triphenylphosphine polymer supported was then added followed by 2.70 g (8.2 mmol) of carbon tetrabromide. The reaction mixture was stirred 15 min at 0° C. and warmed to room temperature for 90 min. After filtration through celite, the solvent was evaporated under reduce pressure. The crude product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 1.44 g of 1-(3-bromoprop-1-ynyl)-4-fluorobenzene as a yellow oil (Yield: 99%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[CH:3][C:2]=1[C:11]([O:13]C)=O.[Cl-].[Mg+2].[Cl-].[CH3:18][NH:19][CH3:20].Cl>C1COCC1.O>[CH3:18][N:19]([CH3:20])[C:11]([C:2]1[N:1]=[CH:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Reactant: CNC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)N(C)C)nc1
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a 2° C. slurry of dimethyl 2,5-pyridinedicarboxylate (50 g, 0.256 mol) in THF (700 mL) was added magnesium chloride (26.8 g, 0.282 mol). After stirring for 15 min, dimethylamine (2 M in THF, 256 mL, 0.512 mol) was added dropwise over 40 min. The mixture was stirred for 30 min at 2° C. and then at room temperature for 1 h. To the mixture was added water (100 mL) and 1 N HCl (300 mL). The mixture was extracted with ethyl acetate (4×400 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide 53 g (100%) of methyl 6-[(dimethylamino)carbonyl]-3-pyridine carboxylate a pale yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:42]=[CH:41][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:40])[C:22]=2OC(CCCCC(OCC2C=CC=CC=2)=O)=O)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.C(O)C.CC(O)=O.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:40])[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:41][CH:42]=1
Reactant: O=C(CCCCC(=O)Oc1c(-c2ccc(OCc3ccccc3)cc2)oc2ccccc2c1=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(O)cc2)oc2ccccc12
Yield: 88.6 %

Procedure:
A mixture of the 4′-(benzyloxy)-3-(benzyloxycarbonyl butylcarbonyloxy) flavone (400 mg, 0.711 mmol) and Pd(OH)2 (56 mg) in THF (10 mL), ethanol (1.2 mL) and AcOH (100 μL) was treated with hydrogen (50 psi) for 18 h. The reaction mixture was then filtered (Celite) and the pad washed with THF. The filtrate was concentrated and the solid residue was purified by flash chromatography (70% THF/toluene+1% AcOH) and the resultant solid recrystallised from THF/petrol to afford the acid as a colourless solid (150 mg, 55%); mp 177-180° C.; 1H NMR (500 MHz, d6-DMSO) δ 1.56-1.66 (m, 4H, CH2CH2), 2.25 (t, 2H, J=7.0 Hz, CH2CO), 2.64 (t, 2H, J=7.0 Hz, CH2CO), 6.96 (app. d, 2H, J=8.5 Hz, H2′,6′), 7.52 (t, 1H, J6,7=J7,8=7.5 Hz, H7), 7.80 (app. d, 2H, J=7.5 Hz, H3′,5′), 7.78 (m, 1H, H8), 7.85 (t, 1H, J5,6=J6,7=7.5 Hz, H6), 8.06 (d, 1H, J5,6=8.0 Hz, H5); 13C NMR (125 MHz, d6-DMSO) δ 23.8, 23.9, 32.9, 33.3 (4C, CH2), 115.9, 118.5, 119.7, 122.7, 125.0, 125.6, 130.1, 131.9, 134.5, 154.9, 155.8 160.6 (Ar), 170.4 170.9, 174.3 (3C, C═O); IR 3257, 2944, 2869, 1765, 1706, 1595, 854 cm−1; HRMS (ESI+) m/z 383.1123, C21H19O7 [M+H]+ requires 383.1131.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=[O:23])[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[NH:8]1[CH2:13][CH2:12][C:11]2([CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=[O:23])[O:14]2)[CH2:10][CH2:9]1
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C1OC2(CCNCC2)Cc2ccccc21
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a suspension of 10% palladium on carbon (5 mg) in ethanol (5 mL) was added of 1'-benzylspiro[3H-2-benzopyran-3,4' -piperidine]-1(4H)-one (20 mg, 0.058 mmol). (Hashigaki et al Chem. Pharm. Bull. 32 pg 3561-3568 (1984)). Hydrogenation was performed at 1 atmosphere pressure at room temperature. The reaction was stirred for 2 hours under hydrogen atmosphere, until TLC analysis indicated that the reaction was complete. The catalyst was removed by vacuum filtration through celite 545 and the filtrate was concentrated to give the desired product (12.4 mg, 98.5%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH3:7])(=[O:6])=[O:5].[C:8]([C:12]1[C:21]([N:22]([CH3:24])[CH3:23])=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][C:13]=1[N:25]([CH3:27])[CH3:26])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O>[C:8]([C:12]1[C:13]([N:25]([CH3:27])[CH3:26])=[CH:14][C:15]([C:16](=[O:17])[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])=[CH:20][C:21]=1[N:22]([CH3:24])[CH3:23])([CH3:11])([CH3:9])[CH3:10]
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1cc(N(C)C)c(C(C)(C)C)c(N(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(C(=O)CS(C)(=O)=O)cc(N(C)C)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2.4 g. of sodium hydride (50% suspension in oil) and 7.05 g. of dimethylsulfone in 17.5 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 2 hours at 50° C. 6.9 G. of methyl 4-tert. butyl-3,5-bis(dimethylamino)benzoate were then added, and the mixture was stirred at room temperature for 1.5 hours. The solution was diluted with 150 ml. of ice water, the precipitated solid material filtered off, washed with water and recrystallized from methanol, there being obtained 4'-tert. butyl-3',5'-bis(dimethylamino)-2-methylsulfonylacetophenone having a melting point of 177°-179° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15](C=C[CH:21]=2)[C:16](O)=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1CCCCC1>>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][NH:24][CH2:21]2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Product: COC1=C(OC)C(=O)C(CC2CCCNC2)=C(C)C1=O
Yield: 37 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (85 mg, 0.27 mmol) obtained in Example 41 and piperidine (0.036 ml, 0.41 mmol) were used, and a method similar to that described in Example 42 was employed to obtain the title compound (40 mg, 0.10 mmol, yield 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 69.7 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added benzenesulfonyl chloride (0.0099 g, 0.0072 mL, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 35 minutes. The reaction was cooled to 25° C., diluted with ethyl acetate (40 mL), washed with 1 N hydrochloric acid, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99:1 dichloromethane:methanol to give the title compound (18.6 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.68 (m, 1 H) 4.46 (m, 2 H) 7.47 (m, 3 H) 7.61 (m, 4 H) 7.80 (d, J=6.99 Hz, 2 H) 8.54 (dd, J=7.91, 1.65 Hz, 1 H) 8.87 (dd, J=4.23, 1.29 Hz, 1 H) 10.85 (s, 1 H) 14.08 (br s, 1 H). MS (ESI−) m/z 566 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)[NH:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[CH2:26][CH:27]([OH:30])[CH2:28][OH:29]>CN(C)C=O>[CH2:3]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([C:22]([O:24][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:23])=[CH:18][CH:19]=2)[NH:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC1Cc2ccc(C(=O)OCC(O)CO)cc2N1
Yield: 60.3 %

Procedure:
Sodium hydride (0.32 g of a 50% oil dispersion) was added to a stirred solution of (RS)-2-(n-decyl)indoline-6-carboxylic acid (2 g; prepared as described hereinbefore in Example 57) in dry dimethylformamide (50 ml). When the addition was complete, the mixture was warmed on the steam bath for 1 hour with stirring, and 3-chloro-1,2-propanediol (0.8 g) was added. The mixture was warmed on the steam bath for 20 hours with stirring. The solvent was then evaporated to dryness and the residue was dissolved in dichloromethane. The solution in dichloromethane was washed with water, dried over magnesium sulphate and filtered, and the solvent evaporated to dryness to give an oil which slowly solidified. This solid was washed with petroleum ether (b.p. 60°-80° C.), filtered off and dried in air to give (RS)(RS)-2,3-dihydroxyprop-1-yl 2-(n-decyl)indoline-6-carboxylate (1.5 g), in the form of an off-white powder m.p. 102°-110° C.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.C(N(CC)CC)C.C(OCC)(=O)C>C(O)C>[Cl:20][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:19])[C:14]3[C:15]([OH:17])=[N:30][N:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[C:3](=[O:4])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: NNc1ccc(F)cc1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(F)cc3)nc(O)c12
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a stirred suspension of dimethyl7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.59 g, 8.79 mM) and 4-fluorophenyl hydrazine hydrochloride (10.0 g, 61.5 mM) in ethanol (48 mL) was added triethylamine (9.8 mL, 70.3 mM). The resulting brown solution was refluxed for 48 hours, cooled to room temperature and dilutedwith ethyl acetate (150 mL) to give a white crystalline precipitate which was removed by filtration and discarded. The filtrate was washed with hydrochloric acid (3×500 mL, 1N) which caused precipitation in the ethyl acetate layer. The precipitate was collected and washed successivelywith ethyl acetate/ether and ether to give the 4-fluorophenyl hydrazine salt of the title compound (2.14 g). This material was refluxed in glacialacetic acid (20 mL) for 2 hours. After cooling the acetic acid solution to room temperature, a precipitate formed and the solids were collected to give the title compound (1.48 g, 47%) as a yellow powder, mp 390°-392° C.; MS(CI): 358 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB(/[CH:9]=[CH:10]/[CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)O1.[NH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[C:23]=1[C:24]#[N:25]>>[NH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26](/[CH:9]=[CH:10]/[CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:23]=1[C:24]#[N:25]
Reactant: N#Cc1c(N)cccc1Br
Reactant: CC1(C)OB(/C=C/CCOC2CCCCO2)OC1(C)C
Product: N#Cc1c(N)cccc1/C=C/CCOC1CCCCO1
Yield: 47 %

Procedure:
Prepared as in Example 270a from (E)-4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-2-yloxy)but-1-enyl)-1,3,2-dioxaborolane (Example 273b) and 2-amino-6-bromobenzonitrile in 47% yield as a yellow gum. 1H NMR (400 MHz, CDCl3) δ 1.570 (m, 4H), 1.727 (m, 2H), 1.837 (m, 2H), 2.565 (q, J=6 Hz, 2H), 3.541 (m, 2H), 3.879 (m, 2H), 4.387 (br. s, 2H), 4.635 (m, 1H), 6.423 (d of t, J=7 Hz, 16 Hz, 1H), 6.586 (d, J=8 Hz, 1H), 6.710 (d, J=16 Hz, 1H), 6.905 (d, J=8 Hz, 1H), 7.237 (t, J=8 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([O:10][C@@H:11]2[C@H:16]([CH3:17])[O:15][C@@H:14]([CH2:18]/[CH:19]=[CH:20]/[CH:21]=[CH2:22])[CH2:13][C@@H:12]2[NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:32]1(=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[CH:34]=[CH:33]1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@@H:11]2[C@H:16]([CH3:17])[O:15][C@@H:14]([CH2:18][CH:19]3[CH:33]4[CH:34]([C:35](=[O:42])[C:36]5[C:41]([C:32]4=[O:43])=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:22][CH:21]=[CH:20]3)[CH2:13][C@@H:12]2[NH:23][C:24](=[O:29])[C:25]([F:28])([F:26])[F:27])=[O:9])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: C=C/C=C/C[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H](C)O1
Solvent: Cc1ccccc1
Product: C[C@@H]1O[C@@H](CC2C=CCC3C(=O)c4ccccc4C(=O)C23)C[C@H](NC(=O)C(F)(F)F)[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 65.4 %

Procedure:
Ninety mg (0.203 mmoles) of (E)-1-(2,3,6-trideoxy-4-O-p-nitrobenzoyl-3-trifluoroacetamido-α-L-lyxo-hexopyranosyl)-2,4-pentadiene and 22.0 mg (0.140 mmoles) of 1,4 naphthoquinone were mixed in 10 ml toluene and the mixture was heated under N2 at 80°-88° C. for 4 hr. The reaction was chilled to 0° C. and filtered to give 55 mg (65%) 1,4,4a,9a-tetrahydro-1-[(2,3,6-trideoxy-4-O-p-nitrobenzoyl-3-trifluoroacetamido-α-L-lyxo-hexo-pyranosyl)methyl]-anthracene-9,10-dione in impure form.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC(c4cccc5c4OCC5)CC3)c3ccc(Cl)cc32)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncc(Cl)cc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncc(Cl)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
0.3 g of 5-(4-chlorophenyl)-4-(5-chloro-3-fluoro-2-pyridyl)-6-methyl—2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed. The mixture was stirred for 1.5 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, the, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.3 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.22 g of 3-chloro-5-(4-chlorophenyl)-4-(5-chloro-3-fluoro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (14) of the present invention.).