Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([CH3:32])[N:26]=4)[CH2:21][CH2:20]3)=O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([CH3:32])[N:26]=4)[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCC(C(=O)N3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)nc(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(CN3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)nc(C)n1
Reaction time: 4 h

Procedure:
1-(4-Chlorophenylsulphonyl)-4-[1-(2,6-dimethylpyrimidin-4-yl)-4-piperidylcarbonyl]piperazine (603 mg, 0.96 mol) was refluxed in THF (5 ml), borane-dimethyl sulphide complex was added continuously and reflux continued for 4 hours. Reaction was stirred over a weekend to a residue. THF (5 ml) was added followed by 0.2 μL 6M HCl and stirred for 6 hours. Reaction basified by addition of dilute NaOH and partitioned between DCM and H2O. Organic layer was sepearted and dried in vacuo affording a white solid. Further purification by filtration column chromatography (silica) DCM to 10% MeOH/DCM and concentration of relevant fractions afforded 1-(4-chlorophenylsulphonyl)-4-[1-(2,6-dimethylpyrimidin-4-yl)-4-piperidylmethyl]piperazine a white solid/foam, 0.39 g (80%), mp73-74° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of methyl 3-(4-chlorophenyl)-2-phenylpropionate (Step A, 20 g, 74 mmol) in acetonitrile (100 mL) and water (100 mL) was added lithium hydroxide monohydrate (8.8 g, 0.21 mol). After stirring at room temperature for 3 days, the volatile materials were removed by concentrating on a rotary evaporator and the residue was partitioned between water (300 mL) and hexane/ether (1:1, 200 mL). The water layer was separated, acidified to pH=2-3, and extracted with ethyl acetate (2×200 mL) The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.34-7.10 (m, 9H), 3.82 (dd, 1H), 3.36 (dd, 1H), 2.98 (dd, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C@:17]2([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[O:22][C:21](=[O:23])[CH:20]=[C:19]([OH:24])[CH2:18]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C>[Pd].C1COCC1>[CH:25]1([C@@:17]2([CH2:16][CH2:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)[O:22][C:21](=[O:23])[CH:20]=[C:19]([OH:24])[CH2:18]2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1C=C(O)C[C@@](CCc2cccc(OCc3ccccc3)c2)(C2CCCC2)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1C=C(O)C[C@@](CCc2cccc(O)c2)(C2CCCC2)O1

Procedure:
The title compound was prepared as described in General Method 4 using (S)-6-[2-(3-benzyloxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (0.64 g, 1.63 mmol) from Example EEEEE, 0.1 g of 20% Pd over charcoal and THF (16 mL). Purification by silica gel chromatography, eluting with CH2Cl2 :MeOH (97.5:2.5) gave the title compound. 1H-NMR (DMSO-d6) δ 1.3-1.7 (m, 8 H), 1.85-1.95 (m, 2 H), 2.35 (t, 1 H), 2.4-2.6 (m, 4 H), 4.95 (s, 1 H), 6.55-6.6 (m, 3 H), 7.05 (t, 1 H), 9.25 (s, 1 H), 11.35 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)=[CH:9][N:8]([CH:16]3[C:20]([CH3:22])([OH:21])[CH:19]([OH:23])[CH:18]([CH2:24][OH:25])[O:17]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)[O:28][NH2:29]>C(O)C>[OH:28][NH:29][C:2]1[C:3]2[C:10]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)=[CH:9][N:8]([CH:16]3[C:20]([CH3:22])([OH:21])[CH:19]([OH:23])[CH:18]([CH2:24][OH:25])[O:17]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(O)C(O)C(CO)OC1n1cc(-c2cnco2)c2c(Cl)ncnc21
Reactant: C[Si](C)(C)ON
Solvent: CCO
Product: CC1(O)C(O)C(CO)OC1n1cc(-c2cnco2)c2c(NO)ncnc21

Procedure:
The compound from Step 2 is suspended in dry ethanol and O-trimethylsilyl hydroxylamine (10 eq.) is added. The mixture is refluxed for 2 h, evaporated and the crude mixture purified by RP HPLC on a Phenominex column (250×20 mm) using a gradient of acetonitrile in water from 0 to 30% over 30 minutes at 10 mL/minute to yield the title compound.
Reaction SMILES: Br[CH:2]1[CH:7]([CH3:8])[CH2:6][O:5][CH:4]([C:9]2[O:13][N:12]=[C:11]([C:14]([O-:16])=O)[C:10]=2[CH3:17])[CH2:3]1.[K+].CC1C(C([O-])=O)=NOC=1C1CC=C(C)CO1.[K+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C:61]1[C:62](=[O:74])[N:63]([CH:68]2[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]2)[N:64]([CH3:67])[C:65]=1[CH3:66].C(N(CC)CC)C>CN1C(=O)CCC1>[CH:68]1([N:63]2[C:62](=[O:74])[C:61]([NH:60][C:14]([C:11]3[C:10]([CH3:17])=[C:9]([CH:4]4[CH2:3][CH:2]=[C:7]([CH3:8])[CH2:6][O:5]4)[O:13][N:12]=3)=[O:16])=[C:65]([CH3:66])[N:64]2[CH3:67])[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73]1
Reactant: Cc1c(C(=O)[O-])noc1C1CC(Br)C(C)CO1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CC1=CCC(c2onc(C(=O)[O-])c2C)OC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC1=CCC(c2onc(C(=O)Nc3c(C)n(C)n(C4CCCCC4)c3=O)c2C)OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of potassium 5-(4-bromo-5-methyltetrahydro-2H-pyran-2-yl)-4-methylisoxazole-3-carboxylate and potassium 4-methyl-5-(5-methyl-3,6-dihydro-2H-pyran-2-yl)isoxazole-3-carboxylate (crude mixture) (217 mg, 0.634 mmol) in dry NMP (4 mL) was added HATU (Fluorochem) (265 mg, 0.697 mmol), 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (133 mg, 0.634 mmol) and triethylamine (0.194 mL, 1.395 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between EtOAc (25 mL) and 1M NaOH (25 mL). The organics were washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in DMSO and purified using UV-directed automated reverse phase chromatography over a 9.5 minute gradient of 30-70% MeCN in water (0.1% formic acid). The product fractions were added to EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (50 mL). The organic layers were dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the title compounds.
Reaction SMILES: C[O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[OH-].[Na+]>CO>[C:17]([O:16][C:14]([NH:13][C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:21])=[O:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1/C=C/C(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(E)-3-(2-tert-Butyloxycarbonylamino-5-chlorophenyl)-acrylic acid methyl ester (1.8 g, 5.77 mmol) was dissolved in MeOH (115 ml), 2N NaOH (4.3 ml, 8.6 mmol) added and stirred at 60°C. for 2 hours. The reaction mixture was evaporated to dryness, acidified to pH 3.5 by adding water (200 ml) and 2N HCl (4.35 ml) and extracted twice with TBME. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield the title acid as a solid, which was recrystallised from TBME/hexanes to render the title compound as colorless crystals (1.0 g, 59%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C1(C)C=CC=CC=1.O>[CH2:9]([O:16][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(OCc2ccccc2)nc1

Procedure:
A mixture of 2,5-dibromopyridine, benzyl alcohol (1.3 eq), potassium hydroxide pellets (2.4 eq) and dibenzo-18-crown-6 (0.05 eq) in toluene (4 ml/mmol) was refluxed with azeotropic removal of water for 3 hours. After evaporation of the toluene, the resulting mixture was partitioned between chloroform and water. The crude product from the organic phase was recrystallized from ether-hexane to afford the 2-Benzyloxy-5-bromopyridine compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([OH:10])=[C:5]([CH3:11])[CH:4]=1)#[N:2].[OH-].[K+].[I-].[K+].Cl[CH:17]([CH3:26])[CH2:18][C:19]1[O:23][N:22]=[C:21]([CH2:24][CH3:25])[CH:20]=1>C(#N)C>[CH3:11][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[C:7]([CH3:9])[C:6]=1[O:10][CH2:26][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH2:24][CH3:25])[CH:20]=1
Reactant: CCc1cc(CC(C)Cl)on1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCc1cc(CCCOc2c(C)cc(C#N)cc2C)on1
Yield: 66 %

Procedure:
To a mixture of 7.84 g 4-cyano-2,6-dimethylphenol, 3.57 g potassium hydroxide and 10.6 g potassium iodide in 200 ml acetonitrile was added 12 g 5-(2-chloropropyl)-3-ethylisoxazole, and the mixture was heated at reflux for about 16 hrs. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with aqueous sodium hydroxide (10%) until the excess starting phenol was removed, and the solution concentrated to give 10 g of 5-[3-(2,6-dimethyl-4-cyanophenoxy)propyl]-3-ethylisoxazole as a yellow oil. A sample of the latter was obtained in crystalline form, m.p. 50°-51° C. by crystallization from methanol at -50° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([Cl:29])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[O:12][CH:13]([CH3:17])[C:14](O)=[O:15]>C1(C)C=CC=CC=1>[Cl:29][C:21]1[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=[C:6]([Cl:5])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[O:12][CH:13]([CH3:17])[C:14]([Cl:3])=[O:15]
Reactant: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)C(=O)Cl
Temperature: 100 °C

Procedure:
15 g (0.126 mol) of thionyl chloride were added dropwise to a stirred solution of 19.7 g (0.05 mol) of the R enantiomer of 2-[3-(2,6-dichloro-4-trifluoromethylphenoxy)-phenoxy]-propionic acid in 100 ml of toluene at 20° C. The mixture was heated to 100° C. for 2 hours. Thereafter, the reaction mixture was evaporated down by stripping off the volatile constituents under reduced pressure. In this manner, the R enantiomer of 2-[3-(2,6-dichloro-4-trifluoromethyl-phenoxy)-phenoxy]-propionic acid-chloride was obtained in the form of an oily product, which was used for the further reaction. ##STR37##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:5]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: Brc1ccccc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(-c2ccccc2)c1
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a solution of 3-cyanophenylboronic acid (1.0 g, 6.81 mmol) and bromobenzene (1.07 g, 6.81 mmol) in N,N-dimethylformamide (100 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.393 g, 0.341 mmol) and cesium carbonate (2.77 g, 8.51 mmol) under nitrogen atmosphere, and the mixture was stirred for 4 hours under reflux. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and biphenyl-3-carbonitrile (821 mg, 67%) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]1[C:27](O)=[O:28])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:27]([C@H:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:28])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
1-Benzylpiperazine (2.7 ml) and (2R)-1-BOC-piperazine-2-carboxylic acid (3.571 g) were suspended in DMF (150 ml) and stirred at 0° C. Triethylamine (4.33 ml) was added followed by PyBOP reagent (8.08 g). The mixture was allowed to warm to room temperature overnight, concentrated to approximately a third of the volume in vacuo and partitioned between brine (75 ml) and ethyl acetate (2×200 ml). Combined organic extracts were treated with saturated aqueous sodium bicarbonate (75 ml) and brine (75 ml), dried (sodium sulphate), concentrated in vacuo using high vacuum to remove DMF traces and purified by chromatography eluting with 0-15% methanol/dichloromethane. This gave tert-butyl (2R)-2-[(4-benzylpiperazin-1-yl)carbonyl]piperazine-1-carboxylate as a white glass (5.01 g).
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH2:35][C:36]#[N:37])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)C1C=CC=CC=1.[OH-].[Na+].C(CC(COCCCCCCCCCCCCCCCC)CO)#N>CO.O1CCCC1>[C:36]([CH2:35][CH:11]([CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][OH:9])#[N:37]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)COC(=O)c1ccccc1
Agent: CCCCCCCCCCCCCCCCOCC(CO)CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)CC#N
Yield: 81.3 %

Procedure:
A mixture of 1.49 g (2.96 mM) of 2-cyanomethyl-3-n-octadecylcarbamoyloxypropyl benzoate n5', 1.66 ml (3.32 mM) of 2N aqueous sodium hydroxide in 15 ml of methanol and 15 ml of tetrahydrofuran is allowed to react by the same procedure as described in (137) and 966 mg (76.8% yield) of the titled compound Vn2 is obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH:10]1[CH:13]([CH:14]=[CH2:15])[N:12]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:11]1=[O:23].[CH2:24]=[O:25]>O1CCCC1>[CH3:9][C:10]1([CH2:24][OH:25])[CH:13]([CH:14]=[CH2:15])[N:12]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[C:11]1=[O:23]
Reactant: C=O
Reactant: C=CC1C(C)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC1N([Si](C)(C)C(C)(C)C)C(=O)C1(C)CO
Reaction time: 0.17 h

Procedure:
To a solution of freshly prepared lithium diisopropylamide (7.82 mmoles) in 36 ml anhydrous tetrahydrofuran under a nitrogen atmosphere at -75° C. is added a solution of 3-methyl-[1-(t-butyldimethylsilyl)-4-vinyl-2-azetidinone], 24, (1.60 g, 7.11 mmoles) in 10 ml anhydrous THF. The resulting yellow solution of the lithium enolate is, after 16 minutes, treated with excess formaldehyde (see Example 15, below). In 10 minutes, the reaction is quenched by adding 30 ml of a saturated aqueous ammonium chloride solution. This mixture is extracted with 50 ml and 25 ml portions of ethyl acetate. The combined ethyl acetate solutions are washed with 50 ml of brine and dried over anhydrous magnesium sulfate. The drying agent is removed by filtrate is evaporated in vacuo to give the crude product as a yellow oil. Purification by chromatography on silica gel eluting with 10% ethyl acetate/chloroform gives 3-methyl-[1-(t-butyldimethylsilyl)-3-(hydroxymethyl)-4-vinyl-2-azetidinone], 25. ##STR40##
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:17]=[CH:16][O:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[O:15]1[CH:16]=[CH:17][C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[O:2])=[CH:14]1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Brc1ccoc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccccc1-c1ccoc1
Temperature: 150 °C
Yield: 31.9 %

Procedure:
A microwave vial (20 ml) was charged with 2-formylphenylboronic acid (298 mg, 2.0 mmol), 3-bromo-furan (350 mg, 2.4 mmol) and 8 ml of acetonitrile. To this mixture was added 4 ml of aqueous sodium carbonate (1M), followed by 100 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was evaporated to provide crude material which was purified by ISCO to give 110 mg of 2-furan-3-yl-benzaldehyde (30% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8](O)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(=O)OCC.[NH2:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][C:49]=1[NH:50][CH2:51][CH2:52][N:53]([CH3:55])[CH3:54])[C:42]([N:44]([CH3:46])[CH3:45])=[O:43]>C(Cl)(Cl)Cl>[CH3:54][N:53]([CH3:55])[CH2:52][CH2:51][N:50]1[C:49]2[CH:48]=[CH:47][C:41]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[CH:40][C:39]=2[N:38]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN(C)CCNc1ccc(C(=O)N(C)C)cc1N
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCc1nc2cc(C(=O)N(C)C)ccc2n1CCN(C)C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
Triethylamine (1.52 ml) was added to a suspension containing n-docosanoic acid (3.339 g) in chloroform (34 ml), and then ethyl chlorocarbonate (1.04 ml) was added thereto while being cooled with ice. The reaction mixture was stirred for 1.5 hours, and then a solution containing 3-amino-4-{[2-(dimethylarnino)ethyl]amino}-N,N-dimethylbenzamide (2.454 g) in chloroform (12 ml) was added thereto. After being stirred for 3 hours while being cooled with ice, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (8.2 ml) was added to a suspension containing the residue (6.094 g) in ethanol (61 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (5.119 g) was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=50:1-30:1), thereby yielding the entitled compound (3.320 g) as white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)Cl.[C:31]([O:40][CH2:41][CH3:42])(=[O:39])[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH2:34]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=1[C:31]([O:40][CH2:41][CH3:42])=[O:39])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)c1ccccc1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1NC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Under an ice-cooled condition, 332 mg (1 mmol) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl) pyridine-3-carboxylic acid was suspended in dried dichloromemethane. The mixture was stirred with addition of 229 mg (1.1 mmol) of phosphorus pentachloride little by little for one hour. At -30° C., 1650 mg (10 mmol) of ethyl anthranilate was added to the reaction mixture. The reaction mixture was further stirred at room temperature for one hour. After washing with water, the raction mixture was dried over anhydrous sodium sulfate. The thus obtained mixture was chromatographed on a silica gel column for purification, whereby 486 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].[Cl:42][C:43]1[CH:52]=[CH:51][C:46]([CH:47]=[CH:48][CH2:49]Cl)=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:52]=[CH:51][C:46]([CH:47]=[CH:48][CH2:49][N:35]2[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=3)=[N:36]2)=[CH:45][CH:44]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: ClCC=Cc1ccc(Cl)cc1
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 51.1 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamyl chloride were reacted to yield the title compound as a pale yellow crystalline powder (yield: 51.1%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]#[N:12].[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[N:13][OH:14])[C:11]#[N:12]
Reactant: O=N[O-]
Reactant: N#CCc1nc2ccccc2[nH]1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(=NO)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To an ice-cooled stirred solution of 10 g of 2-benzimidazolylacetonitrile (63.6 mmol, 1 eq) in 50 ml of glacial acetic acid is added dropwise a solution of 4.83 g of sodium nitrite (70 mmol, 1.1 eq) dissolved in a minimum amount of water (10 mL). When the addition is completed, the reaction mixture is allowed to stir at room temperature for 1 h. The precipitate formed in the course of the reaction is filtered and washed with 2×20 ml of cold water and 2×30 ml of diethylether to provide 11.8 g of the product as light yellow solid.