Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[OH:15].[CH3:16]/[C:17](/[CH3:26])=[C:18](/[O:24][CH3:25])\[O:19][Si](C)(C)C.CN(C)C=O>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[F-].[Zn+2].[F-]>[C:8]([C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([OH:15])=[C:2]([C:17]([CH3:26])([CH3:16])[C:18]([O:24][CH3:25])=[O:19])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(C)(C)c1cc(Br)c(O)cc1[N+](=O)[O-]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)c1cc(C(C)(C)C)c([N+](=O)[O-])cc1O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-4-tert-butyl-5-nitrophenol (15.00 g, 54.72 mmol), bis(tri-tert-butylphospine)palladium(0) (1.422 g, 2.783 mmol), zinc fluoride (2.82 g, 27.27 mmol), methyl trimethylsilyl dimethylketene acetal (MTDA) (19.35 g, 111.0 mmol), and dimethylformamide (150 mL) was heated at 70° C. for 18 h. The mixture was cooled to room temperature and diluted with water. After stirring for one hour, the aqueous phase was extracted with MTBE. The organic layer was dried in vacuo to afford the crude product as a brown solid. Purification of the product was accomplished by trituration in n-heptane. 1H-NMR (400 MHZ, DMSO-d6) δ 10.38 (s, 1H); 7.37 (s, 1H); 6.79 (s, 1H); 3.54 (s, 3H); 1.45 (s, 6H); 1.32 (s, 9H)
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.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>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][S:13][CH:14]=2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1cc(I)cc([N+](=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: [K+]
Solvent: CCO
Product: COc1cc(-c2ccsc2)cc([N+](=O)[O-])c1
Temperature: 160 °C
Yield: 91.9 %

Procedure:
To a solution of 1-iodo-3-methoxy-5-nitro-benzene (1.0 g, 3.59 mmol) in ethanol (18 mL) in a microwave tube were added tetrakis(triphenylphosphine)palladium(0) (837 mg, 0.72 mmol), thiophen-3-ylboronic acid (748 mg, 5.55 mmol), and potassium carbonate (496 mg, 3.58 mmol) at room temperature. The mixture was heated to 160° C. under closed microwave conditions for 30 minutes. After cooling to room temperature, the colored mixture was filtered and the filter cake was washed with water. The filtrate was diluted with 1.0 N HCl and the organic compound was extracted into ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution (100 mL) and dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by using an ISCO 80 g column, eluting with 0-10% ethyl acetate in hexanes to obtain 3-(3-methoxy-5-nitro-phenyl)-thiophene (776 mg, 92%) as a light yellow oil: EI(+)-HRMS m/e calculated for C11H9NO3S (M+)+ 235.0303, found 235.0298.
Reaction SMILES: C(=O)([O-])O.[Na+].O.O.[Sn](Cl)Cl.[N+:11]([C:14]1[CH:15]=[C:16]([NH:28][C:29](=[O:43])[C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=2[Cl:42])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])([O-])=O.O>C(OCC)(=O)C>[NH2:11][C:14]1[CH:15]=[C:16]([NH:28][C:29](=[O:43])[C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][C:33]=2[Cl:42])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1N

Procedure:
870 mg (10.3 mmol) of sodium hydrogen carbonate and 1.17 g (5.17 mmol) of tin (II) chloride dihydrate are added at ambient temperature to a solution of 250 mg (0.52 mmol) of 3-(2-chloro-4-trifluoromethylphenyl)propynoic acid-[3-nitro-4-(2-diethylaminoethoxy)phenyl]amide in 50 mL of ethyl acetate. The mixture is refluxed for 12 hours. After cooling, water is added and the organic phase is separated off. The aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is eliminated. The purification of the residue is carried out by column chromatography on Alox (eluant: dichloromethane/methanol (39:1)). Yield: 100 mg (43% of theory); melting point: 127° C.-130° C.; C22H23ClF3N3O2 (M=453.89); calc.: molecular ion peak (M+H)+: 454/456; found: molecular ion peak (M+H)+: 454/456; Rf value: 0.60 (Alox, dichloromethane/methanol (39:1)).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.O1C[CH2:15][CH2:14][CH2:13]1.C([Mg]Br)CC.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:13][CH2:14][CH3:15])=[N:6][N:5]2[CH:11]=1
Reactant: Clc1cn2nc(Cl)ccc2n1
Reactant: C1CCOC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: CCC[Mg]Br
Agent: Cl
Solvent: O
Product: CCCc1ccc2nc(Cl)cn2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,6-Dichloroimidazo[1,2-b]pyridazine (10.0 g, 53.2 mmol) and [1,3-bis(diphenylphosphino)propane]nickel (II) dichloride (0.43 g, 0.80 mmol) were added to tetrahydrofuran (80.0 ml) under a nitrogen stream, and a solution of n-propylmagnesium bromide in tetrahydrofuran (2 M, 31.9 ml, 63.8 mmol) was added dropwise over 60 minutes to the mixture under ice-cooling. The mixture was stirred for 10 minutes under ice-cooling, and the reaction mixture was warmed to room temperature and stirred for 2 hours at room temperature. Cold water (700 ml) was added to the reaction mixture which was then acidified with conc. hydrochloric acid, and the precipitated solids were collected by filtration, and the insoluble solids were washed with dilute hydrochloric acid and then with water. On one hand, the filtrate was extracted with ethyl acetate, and the extracts were combined and washed with dilute hydrochloric acid, a saturated saline solution, an aqueous saturated sodium bicarbonate solution and a saturated saline solution in this order. The resulting organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The concentrated residues and the solids collected by filtration were purified by silica gel column chromatography (ethyl acetate:hexane=3:7), to give the title compound as white crystals. The yield was 9.21 g (88.5%).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(O[K])(C)(C)C.O>CN(C=O)C>[C:2]1([C:8]2[CH:13]=[C:12]([CH:14]=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([N:16]([CH3:25])[CH3:15])=[CH:18][CH:19]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1ccnc(-c2ccccc2)c1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=Cc2ccnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.5 %

Procedure:
To a mixture of 2-phenyl-4-methylpyridine hydrochloride (1 g, 4.86 mmol) and 4-dimethylaminobenzaldehyde (0.725 g, 4.86 mmol) in anhydrous DMF (30 ml) was added solid tBuOK and the resulting mixture was stirred 5 hours at room temperature under nitrogen. Water (200 ml) was then added, the resulting yellow precipitate was filtered off and successively washed with water and Et2O to afford 650 mg (44%) of the titled compound as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([O:19][CH3:20])[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[CH3:20][O:19][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[C:9]([O:11][CH3:12])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(OC)c(-c2ccccc2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(OC)c1-c1ccccc1
Yield: 70.4 %

Procedure:
To a solution of 2,6-dimethoxy-biphenyl-4-carboxylic acid methyl ester (0.9 g, 3.3 mmol) in 10% aq. THF, an aq. solution of 5 N NaOH (5 mL) was added and the reaction mixture was refluxed for 5 h. After the reaction is completed, THF was removed completely under the vacuum and acidified with an aq. solution of 50% HCl. The resulting precipitate was filtered and washed thoroughly with water and dried to obtain the title compound (0.6 g, 70.5%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCOc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCOc1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
To a mixture of 10.4 g. of 6-(2-naphthyloxy)-1-hexanol and 8.1 g. of triethylamine in 250 ml. of dichloromethane chilled to -8° C. under nitrogen is added dropwise 5.1 g. of methanesulfonyl chloride. After one hour at 0° to -6° C., the mixture is washed with cold water, 10% hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried (magnesium sulfate). The solvent is removed under vacuum to give the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C@H:43]1([NH:52][C:53]2[O:54][CH2:55][C:56]3[C:62]([NH2:63])=[CH:61][CH:60]=[CH:59][C:57]=3[N:58]=2)[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>ClCCl.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:63][C:62]2[C:56]3[CH2:55][O:54][C:53]([NH:52][C@H:43]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH2:45][CH2:44]4)=[N:58][C:57]=3[CH:59]=[CH:60][CH:61]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1)Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
4-Chlorophenylacetic acid (122 mg, 0.65 mmol), N,N-diisopropyl ethyl amine (245 mg, 1.9 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (254 mg, 0.79 mmol) were dissolved in dichloromethane (5 mL) and dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 30 minutes. (R)—N2-Indan-1-yl-4H-benzo[d][1,3]oxazine-2,5-diamine (example 2) (150 mg, 0.54 mmol) was added and stirring was continued overnight. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The crude product was recrystallized from isopropanol and diisopropylether. The title compound (95 mg, 41%) was obtained as a white solid; MS: m/e=430.5 (M−H+).
Reaction SMILES: [F:1]/[C:2](=[CH:5]\[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])/[CH:3]=[O:4].[C:16]([Mg]Br)#[CH:17].CCOCC.Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Si:9]([O:8][CH2:7][CH2:6][CH:5]=[C:2]([F:1])[CH:3]([OH:4])[C:16]#[CH:17])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OCC/C=C(\F)C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: C#CC(O)C(F)=CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
5.01 Grams of (Z)-2-fluoro-5-(tert-butyldimethylsilyloxy)-2-pentenal was dissolved in 20 ml of dry tetrahydrofuran, and to the resulting solution was added dropwise a tetrahydrofuran solution of ethynylmagnesium bromide (1.5 equivalents vs. the aldehyde) with ice-cooling. After addition, the solution was stirred at room temperature for 10 hours. The reaction solution was cooled with ice, and after adding 50 ml of ether, poured into 10% hydrochloric acid. The ether layer was separated, and the aqueous layer was extracted twice with ether. The ether extracts were combined with the above ether layer, and this mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure. The residue obtained was treated by column chromatography on silica gel with an ethyl acetate/hexane (1:5) mixture as an eluent to obtain 3.42 g of 7-(tert-butyldimethylsilyloxy)-4-fluoro-3-hydroxy-4-hepten-1-yne as a pale yellow oily product.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:28][O:27]1>>[C:33]([O:32][CH2:31][C@@H:29]1[CH2:28][O:27][C:26](=[O:25])[N:30]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3)CC2)c(C)c1
Yield: 95.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (2.18 g) described in Preparation Example 177 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.11 g), the title compound (2.53 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N+:12]([O-])=O)=[CH:5][C:4]=1[O:15][CH3:16]>CO>[CH3:16][O:15][C:4]1[CH:5]=[C:6]([NH2:12])[C:7]([NH2:9])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Solvent: CO
Product: COc1cc(N)c(N)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,2-dimethoxy-4,5-dinitrobenzene (500 mg, 2.19 mmol) in MeOH (10 mL) was degassed and put under N2 atmosphere. A catalytic amount of Pd on charcoal (10%) was quenched with MeOH (1 mL) and transferred in one shot as a suspension in MeOH into the solution. Acetic acid (1.5 mL) was added and the black mixture was put under H2 atmosphere (1 atm), stirred at rt for 16 h. The mixture was filtered through a celite pad and rinsed with MeOH. The filtrate was concentrated in vacuo at 80° C. to afford the title compound 182 (residual acetic acid could not be removed from the product). 1H NMR: (DMSO-d6) δ(ppm): 6.23 (s, 2H), 3.56 (s, 6H). m/z: 169.3. (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=2)[OH:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=2)=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(O)c2ccc(OC)c(OCc3ccccc3)c2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc(OC)c(OCc3ccccc3)c2)ccc1OC
Yield: 100.8 %

Procedure:
To a stirred solution of (3-benzyloxy-4-methoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol (7.22 g, 18.3 mmol) in CH2Cl2 (40 mL) at room temperature was added activated MnO2 powder (4.6 g, 53 mmol) and kept adding 2˜3 equivalents of MnO2 every 3˜5 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (3-benzyloxy-4-methoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone as a brown solid (7.24 g, 100% yield): 1H NMR (CDCl3) δ 1.49 (t, J=7 Hz, 3H, CH2CH3), 3.95 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 4.14 (q, J=7 Hz, 2H, CH2CH3), 5.20 (s, 2H, CH2), 6.83 (d, J=8 Hz, 1H, Ar), 6.94 (d, J=8 Hz, 1H, Ar), 7.23-7.47 (m, 9H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1.[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:32][CH:33]=1)[CH2:40][C:36]1[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=1
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)c1ccccc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
The compound (45.5 mg) obtained in Example 24-3 was dissolved in anhydrous methanol (1.8 ml) and added with 1-methyl-2-imidazole carboxaldehyde (16.5 mg) and sodium cyanoborohydride (18.9 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off and the resultant was added with a 1 mol/l sodium hydroxide aqueous solution and subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (32.7 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)(=O)[CH3:2].[N+:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15]2)([O-:11])=[O:10].N1CCCCC1>>[N+:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[C:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)[CH3:2])([O-:11])=[O:10]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Reactant: CC(=O)c1c[nH]cn1
Solvent: C1CCNCC1
Product: CC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
4-Acetylimidazole (0.7 g, 3.1 mmol) and 5-nitroindolin-2-one (0.56 g, 3.1 mmol) in sealed tube were heated in the presence of piperidine at 135° C. After 30 minutes, the reaction mixture was cooled to ambient temperature and concentrated. Recrystallization from ethanol afforded 0.66 g of 5-nitro-3-[1-(imidazol-4-yl)ethylidene]indolin-2-one.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:17]([O:16][C:14]([CH2:13][N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(CC(=O)OCc2ccccc2)CC1

Procedure:
Ethyl isonipecotate was reacted with benzyl bromoacetate in acetonitrile in the presence of cesium carbonate, and then the reaction mixture was worked up and purified in a usual manner to obtain ethyl 1-(benzyloxycarbonylmethyl)isonipecotate as a colorless oily substance. MS: 306.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Product: OC(c1ccccc1)c1cccc(Br)c1

Procedure:
Prepared according to the procedure described in Example 16, Step 1, using 3-bromobenzaldehyde and phenylmagnesium bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8](OS(C(F)(F)F)(=O)=O)=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:20].[I-:21].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([I:21])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:20]
Reactant: O=C1CCc2c(Cl)cc(Cl)c(OS(=O)(=O)C(F)(F)F)c21
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(Cl)cc(Cl)c(I)c21
Temperature: 25 °C
Yield: 60.8 %

Procedure:
4,6-Dichloro-7-trifluoromethylsulfonyloxyindan-1-one (56.0 g., 0.160 mole), sodium iodide (133.1 g., 0.8 mole), and DMF (320 ml) in a dry apparatus were stirred under nitrogen at a bath temperature at 130° C. for four days, cooled to room temperature, and poured into 1 L of ice-water. The crystals were collected, washed with water, dried overnight in a vacuum oven at 50° C., then sublimed at 170°-190° C. at 0.05 mm to give 38.3 g. of crude product which was recrystalized from toluene to give 31.8 g of the title compound, mp. 170°-172° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]1.[CH3:16][C:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:23]([C:17]2([CH3:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:24])[CH2:9][CH2:8]1
Reactant: NCCN1CCN(c2ncccn2)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Product: CC1(C(=O)NCCN2CCN(c3ncccn3)CC2)CCCCC1

Procedure:
The title compound was prepared from 2-(4-(2-pyrimidinyl)-1-piperazinyl)ethyl amine (1.50 g, 0.00724 mol), 1-methylcyclohexylcarboxylic acid chloride (1.16 g, 0.00722 mol) and triethylamine (1.1 mL, 0.80 g, 0.0079 mol) in the manner previously described to give 1.80 g (62%) of product, mp. 212°-220° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([N:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29])=[O:22])[N:9]=1
Reactant: OCCNCCO
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)N(CCO)CCO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 6.5 g of diethanolamine are boiled under reflux for 2 h in 5 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel. After concentration and drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N,N-bis(2-hydroxyethyl)acetamide is obtained as a colorless foam. Rf value: 0.28 (silica gel 60, methylene chloride/methanol=9/1). 1H-NMR (DMSO-d6): 3,2-3,6 (m, 8H) 4.4-5.1 (b, 2H), 5.35 (s, 2H), 7.0 (m, 4H), 7.4 (m. 3H), 7.95 (d, 1H), 10.4 (bs, 1H), 11.05 ppm (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O)#[N:2].Cl.[OH:13][NH2:14]>C(O)C.N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[N:14][OH:13])#[N:2]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#Cc1cc(C=NO)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.4 %

Procedure:
3-Cyano-4-fluorobenzaldehyde (5.00 g) and hydroxyamine hydrochloride (2.90 g, 1.25 Eq) were dissolved in ethanol (100 mL) and pyridine (100 mL). The mixture was stirred at RT under N2 for 45 minutes. The solvents were removed and the brown oil was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, and concentrated to give 3-cyano-4-fluorobenzaldehydeoxime (5.03 g). CI mass spectrum z (rel. intensity) 165 (M+H, 100).