Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][C:3]=1[NH:4][S:5]([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[O-2].[Ca+2].[CH2:25]([OH:28])[CH2:26]Br.O>CN(C=O)C>[NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][C:3]=1[N:4]([CH2:26][CH2:25][OH:28])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[CH:13][CH:14]=1)(=[O:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(C)cc([N+](=O)[O-])c2N)cc1
Reactant: OCCBr
Agent: [Ca+2]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CCO)c2cc(C)cc([N+](=O)[O-])c2N)cc1

Procedure:
0.087 mol (28 g) of 2-amino-3-nitro-5-methyl-N-tosylaniline is dissolved in 85 ml of DMF heated beforehand on a boiling water-bath. 9.7 g of quicklime are then added and 0.174 mol (21.75 g) of glycol bromohydrin is then introduced gradually, in the course of 30 minutes and whilst stirring, the heating on the boiling water-bath being maintained. After 11/2 hours, the reaction medium is filtered hot and the filtrate is then poured into 250 ml of iced water. The expected product precipitates. It is filtered off, washed with water and dried in vacuo. After recrystallisation from acetic acid and drying in vacuo, it melts at 201° C.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH:36]=O)[CH:33]=[C:32]([O:38][CH2:39][CH3:40])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16].[C:41]1([NH2:48])[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47].O>C(#N)C>[NH:47]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:48]=[C:36]1[C:34]1[CH:35]=[C:30]([CH:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:22][CH:21]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:31]=[C:32]([O:38][CH2:39][CH3:40])[CH:33]=1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C=O)cc(OCC)c1
Reactant: Nc1ccccc1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in acetonitrile (1.5 ml) was added dropwise very slowly (2 h.) to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-formyl-phenyl)-acetate (460 mg, 1.305 mmol) obtained in Example 244.1 and 1,2-phenylenediamine in acetonitrile (2 ml). The reaction mixture was stirred for 4 h. at room temperature. Water/saturated Na2CO3 solution (1:1) was added and the mixture was extracted with CH2Cl2. The organic phase was washed with H2O, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 3:2). There were obtained 173 mg (30%) of ethyl (RS)-[3-(1H-benzoimidazol-2-yl)-5-ethoxy-phenyl]-(4-cyano-phenylamino)-acetate as a colorless solid; MS: 441 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:42])[C:29]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=2)([OH:34])[C:30]([F:33])([F:32])[F:31])=[C:24]([Cl:43])[CH:23]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:42])[C:29]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=3)([OH:34])[C:30]([F:31])([F:32])[F:33])=[C:24]([Cl:43])[CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Nc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 18 h

Procedure:
Copper(II)acetate (60 mg), (4-methoxycarbonylphenyl)boronic acid (CAS Reg. No. 99768-12-4, 59 mg), and triethylamine (44 mg) were added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 68 step 4, 40 mg) in DCM (4 ml). The mixture was stirred with molecular sieves under air atmosphere for 18 h and then concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (10 mg) as a white foam. MS (m/e)=499.1 [M+H+].
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:14]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1cn[nH]c1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)n1cc(I)cn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a stirred solution of 4-iodopyrazole (10.30 g, 53.1 mmol) in toluene (50 mL) at r.t. was added triethylamine (8.10 mL, 58.1 mmol), followed by benzoyl chloride (8.20 g, 58.3 mmol). The reaction mixture was then heated to 100° C. and stirred for 4 h. The solid was filtered and washed with toluene (50 mL). The organic filtrate was diluted with EtOAc (100 mL), washed with water (3×50 ml), then brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Recrystallisation from hexanes gave the title compound (13.80 g, 87%) as a white solid. δH (DMSO-d6) 8.77 (1H, s), 8.05 (1H, s), 8.02-7.95 (2H, m), 7.74-7.67 (1H, m), 7.61-7.53 (2H, m).
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH3:22])[CH:8]([CH3:21])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH2:20])=[N:12]1.Br[CH2:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH3:22][N:7]([CH3:6])[CH:8]([CH3:21])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][CH2:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[N:12]1
Reactant: CC(CCn1nc(N)c2ccccc21)N(C)C
Reactant: CCN(CC)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nn(CCC(C)N(C)C)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.4 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 7.50 g of the 1-(3-dimethylaminobutyl)-3-aminoindazole, 8.98 g of 3-bromopropyldiethylamine hydr bromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochlor.ic acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 6.18 g of 1-(3-dimethylaminobutyl)-3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 52%.
Reaction SMILES: [Li].C[O:3][C:4](=O)[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:27])[CH2:7]1.O>C1COCC1>[F:26][C:22]1[CH:21]=[C:20]([S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH:8]3[CH2:9][CH2:10][N:6]([CH2:5][CH2:4][OH:3])[CH2:7]3)=[C:12]([CH3:27])[CH:13]=2)(=[O:19])=[O:18])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CN1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C)C1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(CCO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
Lithium alluminiumhydride (1.0 M in THF, 0.51 mL) was added to a solution of {3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetic acid methyl ester (100 mg, 0.2554 mmol) in THF (1 mL) and the resulting mixture was stirred at room temperature for 1 hour. Water was slowly added and the mixture was extracted with DCM. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 7 mg of 2-{3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-ethanol, MS (M+H)=364.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH2:21][O:22][CH3:23])=[C:4]([C:10]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([F:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[C:3]([O:20][CH2:21][O:22][CH3:23])=[C:4]([C:10]([N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:11]([F:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)Nc1c(F)cc(F)c(OCOC)c1C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCOC)c(F)cc(F)c1N(C(=O)OCC)C(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 80 %

Procedure:
The above ethyl 3,5-difluoro-6-(N-ethoxycarbonylamino)-2-methoxymethoxybenzoate was dissolved in 35 mL of tetrahydrofuran under ice-cooling, 792 mg of sodium hydride (60% oil dispersion) and 1.69 mL of pivaloyl chloride were added and the mixture was stirred at 0° C. for 25 minutes. 396 mg of sodium hydride (60% oil dispersion) and 0.85 mL of pivaloyl chloride were further added and the mixture was stirred at 0° C. for 20 minutes. 158 mg of sodium hydride (60% oil dispersion) and 0.34 mL of pivaloyl chloride were further added and the mixture was stirred 0 ° C. for 1.2 hours. An aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted with ether. The organic layer was washed with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 6.63 g of ethyl 3,5-difluoro-6-(N-ethoxycarbonyl-N-pivaloylamino)-2-methoxymethoxybenzoate (two stage yield: 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:11][C:12](=[CH2:15])[CH2:13]O.C(O)=O>C(OC(C)C)(C)C>[CH3:11][C:12]1([CH3:15])[CH2:13][C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[C:6]([CH3:9])=[CH:5][C:4]=2[O:10]1
Reactant: C=C(C)CO
Reactant: Cc1cc(O)cc(C)c1C
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: Cc1cc2c(c(C)c1C)CC(C)(C)O2
Yield: 41.5 %

Procedure:
3,4,5-Trimethylphenol (5.0 g, 36.7 mmol) and 2-methyl-2-propenol (3.2 g, 44.0 mmol) were added to formic acid (50 ml). The mixture was heated under reflux for 3 hours. The reaction mixture was diluted with isopropyl ether, washed with water and saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 97: 3 ) to obtain the desired compound (2.9 g, yield: 41.5% ) as oil.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:14][NH:15][O:16][CH3:17].O>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)O
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC(=O)N(C)OC
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
Decanoic acid (4 g, 23.2 mmol) was dissolved in an anhydrous dichloromethane solution (80 mL), and 1,1-carbonyldiimidazole (4.5 g, 27.9 mmol) was then added to the solution, followed by stirring for 1.5 hours. Subsequently, N,O-dimethylhydroxyamine hydrochloride (2.7 g, 27.9 mmol) was added to the reaction solution, and the obtained mixture was further stirred for 3 hours. After addition of distilled water, the reaction solution was extracted with dichloromethane two times. Anhydrous magnesium sulfate was added to the organic layer to dry it, and the resultant was filtrated and was then concentrated. The obtained residue was purified using column chromatography (hexane:ethyl acetate=8:1), so as to obtain N-methoxy-N-methyldecanamide (4.8 g, 97%) as an amide body in the form of a colorless transparent liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:12][N:11]=[N:10][C:9]=2[NH:21][NH2:22])=[CH:4][CH:3]=1.[OH2:23]>CC(O)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[N:11][N:10]3[C:2](=[O:23])[C:3]([CH2:4][CH:5]([CH3:8])[CH3:6])=[N:22][N:21]=[C:9]3[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:15][CH:16]=1
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: O
Solvent: CC(=O)O
Product: CC(C)Cc1nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine (50.0 mg, 0.15 mmol) in AcOH (1 mL) was added (CH3)2CH2COCO2H (40.0 mg, 0.3 mmol). The solution was stirred at RT for 30 min then was heated at 120° C. for 5 h. The reaction mixture was cooled to RT and then poured into water (20 mL). The resultant solution was extracted with EtOAc (20 mL). The organic laer was dried over Na2SO4, filered and concentrate to give the a brown solid. The solid was purified by reverse phase preparative HPLC to give the title compound 9-bis-(4-chloro-phenyl)-3-isobutyl-pyridazino[6,1-c][1,2,4]triazin-4-one, (23.0 mg, 0.054 mmol) as a solid. HPLC retention time=3.87 min; MS observed=425 (M+H); 1H NMR (CDCl3, 500 MHz) δ 8.72 (s, 1H), 7.37–7.33 (m, 4H), 7.24 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 2.96 (d, J=7.1 Hz, 2H), 2.34 (m, 1H), 0.99 (d, J=9.3 Hz, 6H).
Reaction SMILES: CCCCCC.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][N:22]=1>CN(C=O)C.CCOCC.O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)[C:18]#[N:19])=[N:22][CH:23]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C(C#N)c2ccc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a suspension of hexane washed 60% sodium hydride (2.65, 66.0 mmol) in DMF (30 mL) at 0° C. was added 3-methoxyphenyl acetonitrile (8.0 g, 54.3 mmol). The reaction mixture was stirred at 0° C. for 30 min. A solution of 2,5-dibromopyridine (15.45 g, 65.2 mmol) in DMF(20 mL) was added and the reaction was stirred at room temperature for 20 min and at 50° C. for 30 min. To the reaction mixture was added H2O (20 mL) and Et2O (200 mL). The organic layer was washed with brine (5×50 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (10:1) afforded 10.6 g of (5-Bromo-pyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile. 1HNMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.80 (dd, 1H), 7.27 (comp, 2H), 6.98 (d, 1H), 6.87 (s, 1H), 6.84 (m, 1H), 5.28 (s, 1H), 5.23 (s, 3H); MS (M+1) 303.0, 305.0.
Reaction SMILES: C(OC([CH2:6][CH2:7][N:8]([CH3:22])[CH2:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:13]CC)=O)=O)C.[H-].[Na+].[H][H]>C1(C)C=CC=CC=1>[CH3:22][N:8]1[CH2:7][CH2:6][C:11](=[O:13])[CH:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1
Reactant: CCOC(=O)CCN(C)CC(C(=O)OCC)c1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC(=O)C(c2ccccc2)C1

Procedure:
208.78 g of ethyl N-(2-ethoxycarbonylethyl)-3-methylamino-2-phenylpropionate, 10 ml of absolute alcohol and 500 ml of toluene are added to a suspension of 65.28 g of sodium hydride and 3.0 l of toluene. When hydrogen evolution slows (about 0.5 hour), the mixture is heated to reflux for 30 minutes. The reaction mixture is cooled and then extracted with 6 N hydrochloric acid. The resultant acid extracts are washed with 500 ml of hexane and heated to reflux under nitrogen for two hours. The mixture is then cooled, basified with 50 weight percent aqueous NaOH solution (1.6 l) and then extracted with ether. The ether extracts are dried over Na2SO4 and then filtered. The filtrate is concentrated in vacuo to yield an oil product of 1-methyl-3-phenyl-4-piperidone.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[N:3]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:3]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCCNC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCCN)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of tert-butyl (4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butyl)carbamate (515 mg, 1.316 mmol) in CH2Cl2 (4 mL) was treated with TFA (2 mL, 26.0 mmol) at 0° C. The mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ether to yield a white solid, which was collected by filtration to get 4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butan-1-amine, TFA (440 mg, 83% yield). LC-MS (M+H)+=292.4. 1H NMR (500 MHz, methanol-d4) δ 8.99 (s, 1H), 8.11 (d, J=1.5 Hz, 1H), 8.05 (dd, J=2.1, 1.3 Hz, 2H), 4.38 (t, J=6.2 Hz, 2H), 3.07-2.94 (m, 2H), 2.48 (s, 3H), 2.02 (dd, J=8.8, 6.3 Hz, 2H), 1.84 (d, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:10]=2[CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:18][O:17][C:14]1[CH:13]=[C:10]2[C:9]([CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N+:20]([O-:21])=[CH:11]2)=[CH:16][CH:15]=1
Reactant: NO
Reactant: COc1ccc(C#Cc2ccccc2)c(C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: COc1ccc2cc(-c3ccccc3)[n+]([O-])cc2c1
Yield: 58.8 %

Procedure:
2-(2-Phenylethynyl)-5-methoxybenzaldehyde (0.48 g) was reacted with hydroxylamine hydrochloride (0.17 g) and sodium acetate (0.21 g) in ethanol (10 ml) at 60° C. for 2 hr. Potassium carbonate (0.3 g) and water (1 ml) were added to the reaction mixture, and it was heated under reflux for 12 hr. The reaction solution was evaporated. The resulting residue was extracted with methylene chloride, and then washed with brine and dried. The solvent was removed, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.30 g of the title compound as a yellowish brown amorphous.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([F:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:14][C:8]1([C:7]2[C:2]([O:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:16]4[S:15][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[N:17]=4)=[CH:30][CH:29]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: FC1(c2cccnc2Cl)CCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: FC1(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCOCC1
Temperature: 90 °C

Procedure:
To 2-chloro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyridine (0.11 g, 0.510 mmol) was added to 4-(benzo[d]thiazol-2-ylamino)phenol (0.124 g, 0.510 mmol) with cesium carbonate (0.332 g, 1.020 mmol) in DMSO (1 mL). The resulting mixture was heated to 90° C. overnight. Aqeuous work up and purification by prep-plate TLC (3% MeOH/DCM) produced desired product. MS (ESI, pos. ion) m/z: 422 (M+1). IC50 (uM) +++++.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C:7]=1[CH2:25][CH3:26])C.[NH2:28][NH2:29].O>C(O)C>[Cl:24][C:20]1[CH:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:6]([CH2:5][C:4]([NH:28][NH2:29])=[O:3])=[C:7]2[CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cc1c(CC)n(Cc2cccc(Cl)c2)c2ccc(OC)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1c(CC(=O)NN)c2cc(OC)ccc2n1Cc1cccc(Cl)c1
Yield: 62 %

Procedure:
A mixture of 1.93 g (5 mmol) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-methoxy-1H-indole-3-acetic acid ethyl ester and 5 mL of hydrazine in 20 mL of ethanol was heated to maintain reflux for 19 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated to give 1.144 g (62% yield) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-methoxy-1H-indole-3-acetic acid hydrazide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1.CCCCCC>CCOCC>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:17]=[C:18]([NH:22][C:23]([N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][C:6]2=3)=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc2c(c1)CCCCN2
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc2c(c1)CCCCN2C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.0 g (11.3 mMol) of 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine [Monatsheft Chemie, 97 (1966),150] and 2.28 g (97%; 11.8 mMol) of 3-trifluoromethyl-phenyl-isocyanate in 20 ml ether is stirred for 30 min in a icebath. After addition of hexane, the mixture is concentrated partially in vacuo and the crystallized product filtered off: m.p.: 108° C.; MS: [M+1]+=365; Anal.: C,H,N,F.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].[H-].[Na+]>[Cl-].[Na+].O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
After adding 4,6-dichloropyrimidine (750 mg) to a suspension of 4-nitrophenol (700 mg) and sodium hydride (60%) (200 mg) indimethylformamide (13 ml) at 0° C., the mixture was heated and stirred at 80° C. for 1.5 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The obtained residue was passed through an NH silica gel column (Fuji Silysia Chemical), eluted with a solvent (ethyl acetate-hexane=1-4) and concentrated to obtain 700 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>O1CCCC1>[C:2]1([NH:1][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 91 %

Procedure:
First, 26.2 g of aniline, 100 mL of tetrahydrofuran (THF), and 56.9 g of triethylamine (Et3N) were put in a 500 mL three-neck flask, and mixed. Then, under cooling in ice, a mixed solution of 30 g of isobutyryl chloride and 100 mL of THF was dripped through a 50 mL dropping funnel to the above mixed solution, and then the temperature was increased to room temperature and the solution was stirred for 19 hours to be reacted. After the reaction, this mixture was subjected to suction filtration to give a filtrate. The resulting filtrate was washed with water, and then saturated saline, and anhydrate magnesium sulfate was added for drying. After the drying, the mixture was subjected to gravity filtration, and the filtrate was concentrated, so that N-phenylisobutyramide was prepared (a white solid, yield: 91%). The synthetic scheme of Step 1 is shown by (a-10).