Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C)C=O>[C:1]([Cl:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)Cl
Reaction time: 16 h
Yield: 39.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5.0 grams (0.027 mole) of undecanoic acid in 75 mL of methylene chloride was stirred and 2.8 ml (0.032 mole) of oxalyl chloride and 5 drops of N,N-dimethylformamide were added. Upon completion of addition, the reaction mixture was stirred for about 16 hours, then it was concentrated under reduced pressure, yielding 2.2 grams of undecanoyl chloride.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:29]([N+:30]([O-:32])=[O:31])=[C:28]2[C:33]3[C:24](=[CH:25][CH:26]=[CH:27]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=3[CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:15]2[C:29]([N+:30]([O-:32])=[O:31])=[C:28]3[C:33]4[C:24](=[CH:25][CH:26]=[CH:27]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=4[CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1c(Br)cc2c3c(cccc13)-c1ccccc1-2
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: O=[N+]([O-])c1c(-c2cccc3ccccc23)cc2c3c(cccc13)-c1ccccc1-2
Temperature: 25 °C
Yield: 61.8 %

Procedure:
Under an argon atmosphere, 8.53 g of 1-naphthalene boronic acid, 14.7 g of 2-bromo-3-nitrofluoranthene, 1.04 g of tetrakistriphenylphosphine palladium(0), 70 mL of 1,2-dimethoxyethane, 70 mL of toluene, and 70 mL of a 2 M aqueous solution of sodium carbonate were charged in a flask, and the resultant mixture was refluxed for 8 h under heating and stirring. After cooling to room temperature, the reaction solution was extracted with toluene and then the aqueous layer was removed. The organic layer was washed with a saturated saline, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 10.4 g of 2-(1-naphthyl)-3-nitrofluoranthene.
Reaction SMILES: [N:1]1([C:6]2[C:15]3[C:10](=[CH:11][C:12]([N:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)=[CH:13][CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:29]>CO>[ClH:29].[ClH:29].[N:16]1([C:12]2[CH:11]=[C:10]3[C:15]([C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[N:7][CH:8]=[N:9]3)=[CH:14][CH:13]=2)[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(N4CCCC4)ncnc3c2)CC1
Agent: Cl
Solvent: CO
Product: c1nc(N2CCCC2)c2ccc(N3CCNCC3)cc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-butyl 4-(4-(pyrrolidin-1-yl)quinazolin-7-yl)piperazine-1-carboxylate (B) (130 mg, 0.339 mmol) was dissolved at room temperature in methanol (2 ml), and then hydrogen chloride (2.71 ml, 3.39 mmol, 1.25 M solution in methanol) was added. The reaction mixture was refluxed for 1 h and then stirred for 15 h at room temperature. Concentration in vacuo was carried out, and the residue was taken up in a small amount of ethanol and heated. Diethyl ether was then added, the mixture was cooled in an ice bath, and finally the resulting solid was filtered off.
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[C:7]([O:18]CC2C=CC=CC=2)=[CH:6][C:5]=1[CH2:26][C:27]#[N:28])([O-])=O.C.C(O)C>[Pd].O>[OH:18][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][C:8]=1[OH:10])[NH:28][CH:27]=[CH:26]2
Reactant: N#CCc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Oc1cc2cc[nH]c2cc1O
Temperature: 80 °C

Procedure:
The reaction mixture is prepared in an autoclave by adding 0.04 mole (15 g) of 2-nitro-4,5-dibenzyloxyphenylacetonitrile, 1.5 g of palladium at a concentration of 10% on charcoal and 1.5 g of charcoal to 120 ml of ethanol containing 3 ml of water. These are heated to 80° C. for 2 hours, with stirring, under a hydrogen pressure of 4.105Pa. After cooling, the reaction mixture, which is treated in the same manner as previously, produces 5,6-dihydroxyindole in an equivalent yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].Cl.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33]Br)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:35])[CH2:33][N:15]2[CH2:14][CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Reactant: COc1cc(C2=CCNCC2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C2=CCN(CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-Neck round-bottom flask was added 4-(3-Methoxy-4-nitro-phenyl)-1,2,3,6-tetrahydro-pyridine; hydrochloride (364 mg, 1.34 mmol) (generated by 4N HCl treatment of the 450 mg of BOC precursor for 1 h), 4-(2-Bromo-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (413.0 mg, 1.345 mmol) and cesium carbonate (1095 mg, 3.362 mmol) in acetonitrile (10 mL, 200 mmol). The reaction was stirred overnight at reflux. The reaction mixture was cooled to RT, diluted with water and was extracted (twice) from EtOAc. Combined organic was washed with brine and was dried over MgSO4. After solvent evaporation and flash chromatography (ISCO, EtOAC: MeOH 98:2), the product, 4-{2-[4-(3-Methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester, was isolated as a gum/solid (301 mg, 49%). NMR 1H (DMSO-d6)-7.86 (d, 1H, J=8.54 Hz), 7.29 (s, 1H), 7.17 (d, 1H, J=8.58 Hz), 6.44 (s, 1H), 3.96 (s, 3H), 3.52 (br s, 2H), 3.44 (br s, 2H), 3.32 m with the water peak, 8H), 3.30 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH:28]([CH3:32])[NH:27]1>>[CH3:25][CH:26]1[NH:27][CH:28]([CH3:32])[CH2:29][N:30]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[S:8]2(=[O:24])=[O:23])[CH2:31]1
Reactant: CC1CNCC(C)N1
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccccc1F
Product: CC1CN(CCOCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC(C)N1
Yield: 86.7 %

Procedure:
In an analogous manner as described in general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.07 g, 0.18 mmol) was treated with 2,6-Dimethyl-piperazine (0.06 g, 0.54 mmol) to provide 0.07 g (92%) of 1-{2-[2-(3,5-dimethylpiperazin-1-yl)ethoxy]ethyl}-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:16][CH3:17])=[C:7]([Si:12](Cl)([CH3:14])[CH3:13])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[CH:23]([Li])[C:22]([CH3:25])=[C:21]([CH3:26])[C:20]=1[CH3:27]>O1CCCC1>[C:1]([C:5]1[C:6]([O:16][CH3:17])=[C:7]([Si:12]([CH3:14])([CH3:13])[C:22]2([CH3:25])[CH:23]=[C:19]([CH3:18])[C:20]([CH3:27])=[C:21]2[CH3:26])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Reactant: [Li]C1C(C)=C(C)C(C)=C1C
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)C1(C)C=C(C)C(C)=C1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution consisting of (3-tert-butyl-2-methoxy-5-methylphenyl)chlorodimethylsilane (5.24 g) synthesized in the above described (3) and tetrahydrofuran (50 ml) was added tetramethylcyclopentadienyl lithium (2.73 g) at −35° C., and the mixture was warmed to room temperature during 2 hours and stirred further at room temperature for 10 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=2)[CH:12]=1.[CH2:26]([Mg]Br)[CH3:27]>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([C:19](=[O:20])[CH2:26][CH3:27])=[CH:17][CH:18]=2)[CH:12]=1
Reactant: O=Cc1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Reactant: CC[Mg]Br
Product: CCC(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1

Procedure:
Following general procedures G and H, starting from [1-(5-formyl-furan-2-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester and ethylmagnesium bromide.
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[C:8]([CH3:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.CON(C)[C:34]([C:36]1([C:39]([F:42])([F:41])[F:40])[CH2:38][CH2:37]1)=[O:35].[Cl-].[NH4+]>C(Cl)Cl>[CH3:30][C:8]1[N:9]([C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[C:6]([C:34]([C:36]2([C:39]([F:42])([F:41])[F:40])[CH2:38][CH2:37]2)=[O:35])[N:7]=1
Reactant: CON(C)C(=O)C1(C(F)(F)F)CC1
Reactant: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1nc(C(=O)C2(C(F)(F)F)CC2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether) (633 mL, 1.9 mol) was added over 1 h to a 5° C. solution of 4-iodo-2-methyl-1-trityl-1H-imidazole (855 g, 1.9 mol) in methylene chloride (8 L). After stirring at 5° C. for 30 min, the reaction mixture was allowed to warm to ca. 12° C. and a solution of N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (355 g, 1.8 mol) in methylene chloride (2 L) was added over 1 h. After stirring at ambient temperature overnight, the reaction mixture was poured into saturated aqueous ammonium chloride. The organic phase was washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate) and concentrated in vacuo. The residue was dissolved in a minimal volume of ether and crashed out with heptane. After stirring in heptane (ca. 3 L) for 1 h, solid was collected by filtration, washing with heptane to afford (2-methyl-1-trityl-1H-imidazol-4-yl)[1-(trifluoromethyl)cyclopropyl]methanone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:23][O-:24].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([O:24][CH3:23])[C:11]=2[CH2:10][CH2:9]1
Reactant: C[O-]
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(C)cccc2c2c1CCN2c1ccccc1C
Yield: 49.3 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (0.62 g, 2 mmol), sodium methoxide (1.0 g, 18.5 mmol) and methanol (30 ml)were heated to 170° C. in a pressure vessel for 18 hours, then the solvent evaporated in vacuo. Conversion to free base, chromatography (silica gel. 40:60 dichloromethane/petroleum ether) and recrystallisation from methanol yielded 1-(2-methylphenyl)-4-methoxy-6-methyl-2,3-dihydropyrrolo- [3,2-c]quinoline(0.30 g), m.p. 107°-108°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]2[C:14](=[O:32])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([F:31])[CH:19]=3)[O:17][C:12]=2[C:11]([F:33])=[CH:10][C:9]=1[F:34].Cl.[CH3:36][NH:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>>[CH3:36][N:37]([CH3:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]2[C:14](=[O:32])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([F:31])[CH:19]=3)[O:17][C:12]=2[C:11]([F:33])=[CH:10][C:9]=1[F:34]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCBr)c(F)cc(F)c3o2)cc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Yield: 74 %

Procedure:
Substantially the same manner as that in Example 130 (1) was repeated except that 1.47 g (2.73 mmol) of the above 5-(5-bromopentylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was reacted with 2.22 g (27.3 mmol) of dimethylamine hydrochloride and 3.77 g (27.3 mmol) of potassium carbonate and the resulting compound was purified by silica gel column chromatography (chloroform:methanol=9:1), to give 1.02 g. of 5-(5-dimethylaminopentylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 74%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Si:11]([CH3:22])([CH3:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:10][Si:11]([CH3:22])([CH3:21])[C:12]1[CH:17]=[C:16]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)c1cccc(B(O)O)c1
Reactant: O=Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[Si](C)(C)c1cccc(-c2cccc(C=O)n2)c1
Temperature: 80 °C
Yield: 85.9 %

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (25 mL) at ambient temperature was added 3-trimethylsilylphenylboronic acid (1.04 g, 5.38 mmol), cesium carbonate (2.7 mL, 5.4 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.088 g, 0.11 mmol). The solution was degassed (3× vacuum/purge N2) and heated to 80° C. overnight. The mixture was cooled to room temperature and partioned between water and CH2Cl2. The organic phase concentrated and purified by chromatography (10% EtOAc:hexanes) to provide 1.18 g (86%) of the title compound. MS (DCI30 ) m/z 256 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[NH:5][C:4](=[O:26])[CH2:3]1.Br[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C([O-])(=O)C.[K+]>CN(C=O)C.CCOC(C)=O.[Cu]>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:26])[CH2:3]1
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)Nc2ccccc21)c1ccccc1
Reactant: Brc1cccnc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2cccnc2)c2ccccc21)c1ccccc1
Temperature: 125 °C
Yield: 64.9 %

Procedure:
To a stirring solution of 3.3 g (9.39 mmol) of 2-(2,4-Dioxo-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 47, in 25 mL of DMF is added 2.97 g (18.78 mmol, 2 equiv.) of 3-bromopyridine, 1.84 g (18.78 mmol, 2 equiv.) of potassium acetate, and 1.19 g (18.78 mmol, 2 equiv.) of copper powder. The suspension is heated to 125° C. for 8 h and then cooled to RT. It is diluted with 500 mL EtOAc and filtered through a bed of celite. The filtrate is washed with H2O (2×500 mL), conc. NH4OH (2×350 mL) and then dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 2.61 g of the title compound as an oil: 1H NMR (CDCl3, 300 MHz) δ8.50 (m, 1H), 7.78 (d, 1H, J=9), 7.48-7.25 (m, 7H), 7.14 (t, 1H, J=8), 6.88 (d, 1H, J=10), 5.06-4.95 (m, 1H), 4.30-4.09 (m, 3H), 3.54 (q, 1H, J=13, 6), 1.7 (s, 1H), 1.42 (d, 2H, J=6), 1.10 (dd, 6H, J=9,2).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:14][C:15]([C:17]1[CH:45]=[C:20]2[N:21]=[C:22]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)[CH:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[N:19]2[N:18]=1)=[O:16])[CH2:8][O:9]C(C)(C)C)(C)(C)C.FC(F)(F)C(O)=O>O>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:22]2[CH:23]=[C:24]([C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:29][CH:30]=3)[N:19]3[N:18]=[C:17]([C:15]([NH:14][CH:7]([CH2:8][OH:9])[C:6]([OH:46])=[O:5])=[O:16])[CH:45]=[C:20]3[N:21]=2)=[CH:39][CH:40]=1
Reactant: CC(C)(C)OCC(NC(=O)c1cc2nc(-c3ccc(Cl)cc3)cc(-c3ccc(Oc4ccccc4)cc3)n2n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NC(CO)C(=O)O)c1cc2nc(-c3ccc(Cl)cc3)cc(-c3ccc(Oc4ccccc4)cc3)n2n1
Yield: 93 %

Procedure:
A sample of 3-tert-butoxy-2-{[5-(4-chloro-phenyl)-7-(4-phenoxy-phenyl)-pyrazolo[1,5-α]pyrimidine-2-carbonyl]-amino}-propionic acid tert-butyl ester was treated with 1 mL of 95:5 trifluoroacetic acid (TFA):H2O, and the resulting solution was stirred at rt for 1.5 h, after which time it was quenched by the addition of 2 mL of 1:1 acetonitrile:water. The mixture was then concentrated and lyophilized to afford 11.2 mg (93% yield over 2 steps) of desired 2-{[5-(4-chloro-phenyl)-7-(4-phenoxy-phenyl)-pyrazolo[1,5-α]pyrimidine-2-carbonyl]-amino}-3-hydroxy-propionic acid, as a solid whose 1H NMR spectrum was consistent with its structure. For entry 260: LC-MS calcd. for C28H21ClN4O5 [M+H]+: 529.12; found: 529.1.
Reaction SMILES: C1C=C(Cl)C(S[CH:9]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[CH:21]2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=C(Cl)C=1.[N+]([O-])(O)=O.[Cl:30]C1C=CC=CC=1CCC(O)CN1C=CN=C1.S(Cl)(Cl)=O>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH:9]([Cl:30])[CH2:19][N:20]2[CH:21]=[CH:22][N:23]=[CH:24]2)=[CH:17][CH:16]=1
Reactant: OC(CCc1ccccc1Cl)Cn1ccnc1
Reactant: Clc1ccc(CCC(Cn2ccnc2)Sc2c(Cl)cccc2Cl)cc1
Solvent: O=[N+]([O-])O
Solvent: O=S(Cl)Cl
Product: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1

Procedure:
in the presence of sodium hydride reagent in dimethylformamide solvent. This substitution reaction takes a long time and gives the (1-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) with a poor yield (51.7%). In the next step of the butoconazole nitrate synthesis (1-[4-(chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) is treated with thionyl chloride (which is at once a reagent and a solvent) at 65-70° C. to yield 1-[4-(4-chlorophenyl)-2-chloro-n-butyl]-imidazole of the formula (V).
Reaction SMILES: C(#N)C.Cl[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>C(N(CC)CC)C>[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:21][CH2:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(CCl)N1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(OCC(=O)N1CCCCC1)c1ccc(O)cc1
Yield: 83.9 %

Procedure:
To 100 ml of acetonitrile were added 7.75 g of N-(α-chloroacetyl)piperidine, 5.0 g of 4-hydroxybenzoic acid and 4.3 g (5.9 ml) of triethylamine, and the mixture was refluxed with heating for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added ice-water, and precipitated crystals were recrystallized from water to give 8.0 g of the title compound. Melting point: 160°-164° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8]([CH3:14])([CH3:13])[O:7][C:6]=2[CH:5]=[C:4]([O:15][CH3:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8]([CH3:13])([CH3:14])[O:7][C:6]=2[CH:5]=[C:4]([O:15][CH3:16])[CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(O)c2c(c1)OC(C)(C)OC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)c2c(c1)OC(C)(C)OC2=O
Reaction time: 0.17 h
Yield: 83.5 %

Procedure:
A solution of 5-hydroxy-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (30.00 g, 0.134 mol) in N,N-dimethylformamide (400 mL) was treated with powdered anhydrous potassium carbonate (19.41 g, 0.14 mol) added all at once. The resulting mixture was stirred in vacuo for 10 min. and then flushed with nitrogen. The reaction flask was placed in a water bath (22° C.) and treated with benzyl bromide (24.03 g, 0.14 mol) added dropwise over 15 min. The resulting mixture was then stirred at 22° C. for 18 h (no starting material left by tlc). The solid was filtered and washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (500 mL), washed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Crystallization form ethyl acetate (50 mL) and hexane (150 mL) gave 35.17 g of 5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one as large colorless prisms. Chromatography of the mother liquors on silica gel (4×13 cm, elution toluene-ethyl acetate 0-5%) gave 6.64 g of additional material to afford a total yield of 41.81 g (99%). HRMS (ESI) calcd for C18H19O5 [M+H]+ m/z 315.1227. found 315.1386. 1H NMR (CDCl3, 600 MHz) δ 1.68 (s, 6H), 3.77 (s, 3H), 5.19 (s, 2H), 5.19 (s, 2H), 6.04 (d, J=2.03 Hz, 1H), 6.15 (d, J=2.03 Hz, 1H), 7.27 (broad t, 1H), 7.36 (broad t, 2H), 7.52 (broad d, 2H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[C:13](OC(=O)C)(=O)C.Cl>>[C:5]([NH:6][C:7]1[C:1](=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:2]([OH:4])=[O:3])(=[O:12])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Product: CC(=O)Nc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 94 %

Procedure:
The isatoic anhydride and acetic anhydride were combined in a three necked, round bottomed flask equipped with a mechanical stirrer, dropping funnel, thermometer, reflux condenser and drying tube. The acetic anhydride was added to the mixture through the dropping funnel over a period of 30 minutes. The reaction was heated to 90°-100° C for 1.5 hours and then cooled to room temperature. The cooled reaction mixture was poured into a kilogram of ice containing 150 ml of concentrated hydrochloric acid. The white solid which precipitated was isolated, washed with 200 ml of water and dried to give 51.5 parts (94% yield) of N-acetylanthranilic acid having m.p. 183°-185° C.
Reaction SMILES: [CH3:1][Mg]Cl.[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1>>[Cl:4][C:5]1[N:6]=[C:7]([CH3:1])[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: C[Mg]Cl
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Product: Cc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12

Procedure:
The experimental procedure of example 5 was repeated, except for the use of methylmagnesium chloride instead of ethylmagnesium bromide and 2,4-dichloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine instead of N-[4-chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-yl]-acetamide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CC(C)=O>[Cl:28][CH2:27][CH2:26][CH2:25][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:13][CH2:14]1
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CCN(Cc2ccc3ccccc3n2)CC1
Reaction time: 20 h
Yield: 65.7 %

Procedure:
A mixture consisting of 1-(2-quinolylmethyl)piperazine (21.75 g, 95.7 mmol), potassium carbonate (19.90 g, 144 mmol), 1-bromo-3-chloropropane (16.57 g, 105 mmol) and acetone (250 ml) was heated under reflux and stirring for 20 hours, insoluble matter was removed and the solvent was distilled off. The oil residue was dissolved in chloroform and the resulting solution was then subjected to chromatography on a silica gel column (developer: chloroform/methanol=100/1), whereby 19.10 g of the title compound were obtained as a yellow oil (yield: 65.7%).