Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-])[C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:22]>CN(C=O)C>[C:1]([O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH2:17][OH:22])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(COC(=O)c2ccccc2)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(CO)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate in 38 ml of DMF was added 11 ml of trifluoroacetic anhydride, followed by stirring at room temperature overnight. After evaporating trifluoroacetic anhydride under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 3.675 g of [6-(hydroxymethyl)pyridin-3-yl]methyl benzoate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:21]4[N:22]=[C:23]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[N:24]=[C:20]4[N:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[S:31](=[O:35])(=[O:34])([OH:33])[OH:32]>C(Cl)Cl>[S:31](=[O:33])(=[O:32])([OH:35])[O-:34].[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:21]4[N:22]=[C:23]([C:25]5[CH:26]=[NH+:27][CH:28]=[CH:29][CH:30]=5)[N:24]=[C:20]4[N:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: FC(F)Oc1ccc(-c2ccnc3nc(-c4cccnc4)nn23)cc1OCC1CC1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: FC(F)Oc1ccc(-c2ccnc3nc(-c4ccc[nH+]c4)nn23)cc1OCC1CC1
Product: O=S(=O)([O-])O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
In methylene chloride, dissolved was 7-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyrimidine (Compound 101) (0.03 g, 0.73 mmol), and 95% sulfuric acid (0.008 g, 0.08 mmol) was added thereto. The mixture was stirred at room temperature for 1 hour. When the reaction was completed, the solid produced was filtered, washed with Et2O, and dried to obtain the desired compound, 3-[7-{3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl}-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-pyridinium bisulfate (Compound 111) (0.024 g, 64.7%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:1]([CH2:3][C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6])#[N:2]
Reactant: Nc1ccccn1
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: N#CCC(=O)Nc1ccccn1
Reaction time: 4 h

Procedure:
Cyanoacetic acid (4.5 g) and 5.0 g of 2-aminopyridine, each in acetonitrile, were combined, and the suspension (150 ml) treated rapidly with a solution of 12.0 g of dicyclohexylcarbodiimide (DCCI) in 60 ml of acetonitrile. After stirring 4 hrs. and filtering, the filtrate was evaporated and the residue triturated with ether to give 2-(cyanoacetylamino)pyridine, m.p. 159°-161°. Recrystallization from ethyl acetate raised melting point to 162°-3°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH:10]([CH2:13]Br)[O:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22]2=[O:30])[CH2:17][CH2:16]1.[I-].[Na+].[C:33](=[O:36])([O-:35])[O-].[K+].[K+]>CN(C)C=O.O>[C:8]([OH:30])(=[O:9])/[CH:12]=[CH:11]/[C:33]([OH:35])=[O:36].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22]4=[O:30])[CH2:19][CH2:20]3)[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Fc1ccc(C2CCC(CBr)O2)cc1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)/C=C/C(=O)O
Product: O=c1[nH]c2ccccc2n1C1CCN(CC2CCC(c3ccc(F)cc3)O2)CC1
Reaction time: 3 h

Procedure:
A mixture of 2.59 g of 2-(4-fluorophenyl)-5-(bromomethyl)tetrahydrofuran, 2.17 g of 1-(4-piperidyl)benzimidazolin-2-one, 1.5 g of sodium iodide and 1.38 g of potassium carbonate in 30 ml of dimethylformamide is heated with stirring at 50°-60° C. for 3 hours. The reaction mixture is then poured into water and extracted with chloroform. The extract is washed twice with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant. The thus obtained colorless oil is dissolved in ethanol, and fumaric acid is added thereto. The crystals precipitated are collected by filtration and recrystallized from ethanol to give 1-[1-(2-(4-fluorophenyl)-tetrahydro-5-furylmethyl)-4-piperidyl]benzimidazolin-2-one fumarate as colorless needles, melting at 200°-201° C.
Reaction SMILES: O=S(Cl)[Cl:3].CN(C=O)C.[CH3:10][O:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][N:17]2[CH:22]=[C:21]([CH2:23]O)[C:20]([C:25]([O:27][CH3:28])=[O:26])=[C:19]([Cl:29])[C:18]2=[O:30])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][N:17]2[CH:22]=[C:21]([CH2:23][Cl:3])[C:20]([C:25]([O:27][CH3:28])=[O:26])=[C:19]([Cl:29])[C:18]2=[O:30])=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1c(CO)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(CCl)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
SOCl2 (0.1 ml, 1.370 mmol) and DMF (0.1 ml, 1.291 mmol) were each slowly added in sequence to a suspension of compound (11) (360 mg, 1.066 mmol) in CHCl3 (10 ml) and the reaction was stirred at 70° C. for about 3 h. The solvent was removed and the resulting mixture was deposited onto silica gel, loaded onto a silica gel column and eluted with MeOH/DCM (1:100) to afford the title compound (110 mg, 0.309 mmol, 29.0% yield). 1H-NMR (CDCl3, 400 MHz): δ=3.80 (s, 3H), 3.98 (s, 3H), 4.37 (s, 2H), 5.09 (s, 2H), 6.89 (d, 2H, J=8.0 Hz), 7.28 (d, 2H, J=8.0 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[N:2].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>CCOCC.O.CCCCCC>[C:1]([C:3]1[CH:4]=[C:5]([N:6]=[N+:15]=[N-:16])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: N#Cc1cccc(N=[N+]=[N-])c1

Procedure:
A suspension of 9.44g. (0.08 mole) of 3-cyanoaniline in 50 ml. of water at 0° C. was treated with 20 ml. of concentrated HCl, with slow addition, maintaining the reaction mixture temperature at or below 5° C. There was then added a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water, and the reaction mixture was aged for 1/2 hour at 0°-5° C. Then to the clear reaction mixture solution was added 75 ml. of hexane, followed by a solution of 5.72g. (0.088 mole) of NaN3 in 20 ml. of water, which were added dropwise with stirring. A precipitate was observed to form, after which 100 ml. of ether was added. The organic and aqueous components of the reaction mixture was separated and the aqueous component was extracted with 100 ml. of ether. The organic component was dried over MgSO4 and concentrated to a volume of about 100 ml. An aliquot was blown down and the structure of the product confirmed for 3-cyanophenylazide.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[C:8]([CH2:10][C:11](O)=[O:12])#[N:9].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(OCC)C>[CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][O:5][C:11](=[O:12])[CH2:10][C:8]#[N:9]
Reactant: C[Si](C)(C)CCO
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOCC
Product: C[Si](C)(C)CCOC(=O)CC#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2000 mg (16.91 mmol) 2-(Trimethylsilyl)ethanol are dissolved in 160 ml diethylether. 1307 mg (15.38 mmol) cyanoacetic acid, 3489 mg (16.91 mmol) N,N′-dicyclohexylcarbodiimide and 227 mg (1.54 mmol) 4-(1-pyrrolidinyl)pyridine are added. The mixture is stirred at room temperature for 3 hours under an argon atmosphere and kept at room temperature overnight. The suspension is filtered and the filtrate is washed twice with 5% aqueous acetic acid and twice with water. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated in vacuo. The residue is re-dissolved in 10 ml hexane and the suspension is filtered over 1 g silica. After evaporation of the solvent, distillation at 0.51 mbar yields the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.[C:28]([C:31]1[N:32]=[C:33]([CH2:38][CH2:39][CH2:40][CH3:41])[NH:34][C:35]=1[C:36]#[N:37])(=[O:30])[CH3:29]>CN(C)C(=O)C.C(OCC)(=O)C>[C:28]([C:31]1[N:32]=[C:33]([CH2:38][CH2:39][CH2:40][CH3:41])[N:34]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=2)[C:35]=1[C:36]#[N:37])(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 45.6 %

Procedure:
0.87 g of potassium carbonate and 2.4 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate were added to a solution of 1.2 g of 4-acetyl-2-butyl-5-cyanoimidazole (prepared as described in Preparation 5) in 12 ml of N,N-dimethylacetamide, and the resulting mixture was shirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with 100 ml of ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The aqueous layer was once again extracted with 50 ml of ethyl acetate, and the combined extracts were washed with a saturated aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.31 g of the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:18][NH:19][CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)=[CH:14][CH:15]=2)[C:10]1=[O:26])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:18][N:19]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[CH2:36][C:32]3[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=3)=[CH:14][CH:15]=2)[C:10]1=[O:26])[CH2:28][CH3:29]
Reactant: CCCN(CCC)CCCCN1Cc2ccc(CNCc3ncc[nH]3)cc2C1=O
Reactant: Cn1ccnc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN1Cc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
The compound (15.1 mg) obtained in Example 8-1 was dissolved in methanol (1.5 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (5.0 mg) and sodium cyanoborohydride (4.8 mg). The solution was adjusted to pH 4 by addition of acetic acid, followed by stirring at room temperature for 2.5 hours. Then, the solution was added with a saturated aqueous sodium hydrogen carbonate solution to stop the reaction and then subjected to extraction with chloroform. After that, the organic layer was washed with water and a saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (16.5 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:32]=[C:33]([C@@H:36]4[CH2:40][CH2:39][CH2:38][N:37]4[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:34][CH:35]=3)=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)[CH:12]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[N:32]=[C:33]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:34][CH:35]=4)=[CH:27][CH:26]=3)[CH2:13][CH2:14]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Yield: 99.7 %

Procedure:
The product from example 40C (1.37 g, 2.153 mmol), in ethanol (10 mL) and THF (10 mL) then added platinum(IV) oxide (196 mg, 0.862 mmol) and a hydrogen balloon and stirred the solution at room temperature for 48 h. The reaction was then treated according to the procedure in Example 39G to provide the title compound (1.3 g, 100%) as a mixture of stereoisomers.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:8]([C:9]([O:11]C)=[O:10])[CH2:7][CH2:6][C:5]=12.[Li+].[OH-]>C1COCC1.O.CO>[N:1]1[N:2]=[N:3][N:4]2[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][C:5]=12
Reactant: COC(=O)C1CCc2nnnn21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCc2nnnn21
Temperature: 60 °C

Procedure:
To a solution of methyl 6,7-dihydro-5H-pyrrolo[1,2-d]tetrazole-5-carboxylate (300 mg, 1.78 mmol) in THF/water/MeOH was added LiOH (214 mg, 8.92 mmol) and the resulting solution was heated via oil bath to 60° C. for 16 h. (Round bottom was equipped with a condenser.) The solution was cooled to room temperature and concentrated to remove organic solvents. The aqueous layer was then acidified to pH of ˜5 using 2N HCl. The mixture was concentrated to dryness under vacuum, azeotroping with toluene (2×20 mL) to make sure all water was removed. The material was used without further purification with Lithium chloride as a by-product. LC-MS: m/z (ES)=155 (MH)+.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NC(=O)C1(c2ccc(Br)cn2)CCCCC1
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CCCCC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 58 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclohexanecarboxylic acid amide following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=2.08 min; Mass spectrum (ESI+): m/z=556 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[C:12]3[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][C:16]([O:28][CH3:25])=[CH:15][CH:14]=4)=[CH:16][CH:17]=3)[C:12]3[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(Br)cc2c2cc(Cl)cnc21
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(/C=C/c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 135.6 %

Procedure:
To a solution of 9-benzenesulfonyl-6-bromo-3-chloro-9H-pyrido[2,3-b]indole (250 mg, 0.59 mmol, 1 equiv.) in anhydrous dioxane (25 ml) under Argon, Pd(PPh3)4 (102 mg, 0.09 mmol, 0.15 equiv.), K2CO3 (244 mg, 1.77 mmol, 3 equiv.), (E)-2′-(4-methoxyphenyl)ethenylboronic acid (110 mg, 0.77 mmol, 1.3 equiv.) and H2O (5 ml) are added respectively. The mixture is stirred at 100° C. overnight and then filtered over celite which is washed with AcOEt (20 ml) and THF (10 ml). The filtrate is concentrated under reduced pressure and the crude residue is purified over silica gel column (eluant CH2Cl2/PE 7:3). The product is obtained as a white solid (212 mg, 0.40 mmol) in 68% yield.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH2:17])=[CH:12][C:11]=1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:24]1[CH:36]=[C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])[CH:34]=[CH:33][C:25]=1[O:26][CH:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])([CH2:22][CH3:23])([CH3:21])[CH3:20].N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:28](=[O:29])[CH:27]([O:26][C:25]2[CH:33]=[CH:34][C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:36][C:24]=2[C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH2:31][CH3:32])=[CH:12][C:11]=1[OH:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 100 of ethyl acetate was dissolved 15 g (57×10-3 mole) of 2-benzamido-4-chloro-5-aminophenol, and then 21 g of 2-(2,4-di-t-amylphenoxy)butanoic acid chloride and 5 g of pyridine were added thereto and the mixture was stirred at room temperature for 3 hours. After the reaction, a solvent was distilled off, and the residue was separated and purified through column chromatography and recrystallized from n-hexane to obtain the title compound. Yield: 14.1 g, FD-Mass: 564, melting point: 190° to 191° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O>ClCCl>[F:29][C:2]([F:1])([F:30])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:27][CH:28]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of tert-butyl 4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carboxylate (16.09 mmol, 7.12 g) in dichloromethane (30 mL) was added trifluoroacetic acid (5 mL) and the reaction stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to afford the title compound (3.5 g). MS (ESI) m/z 343.1 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]1)#[N:24]
Reactant: N#Cc1cc(N)ccc1N1CCC(CCO)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 9.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1 g) and 5-amino-2-[4-(2-hydroxyethyl)piperidin-1-yl]benzonitrile (1.6 g), the title compound (0.2 g) was obtained, melting point: 186° C.
Reaction SMILES: Br[C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[C:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.CO[CH2:26][CH2:27]OC.[C:30]1(OB(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:30]1([C:2]2[C:14]([C:15]([CH3:17])([CH3:18])[CH3:16])=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([C:27]5[CH:26]=[CH:4][CH:3]=[CH:2][CH:14]=5)=[C:9]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH:10]=4)[CH2:5][C:4]=3[CH:3]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)Oc1ccccc1
Reactant: CC(C)(C)c1cc2c(cc1Br)Cc1cc(Br)c(C(C)(C)C)cc1-2
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc2c(cc1-c1ccccc1)Cc1cc(-c3ccccc3)c(C(C)(C)C)cc1-2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, a 300-mL three-necked flask was charged with 8.15 g (18.7 mmol) of 2,7-dibromo-3,6-ditert-butyl-fluorene and 1.08 g (0.93 mmol) of Pd(PPh3), and further charged with 120 mL of dehydrated 1,2-dimethoxyethane. The mixture was stirred at room temperature for 20 minutes. To this solution, 20 mL of an ethanol solution in which 5.01 g (41.1 mmol) of phenylboric acid was dissolved was added, and the mixture was then stirred at room temperature for 20 minutes. Thereafter, 37.4 mL (74.8 mmol) of a 2.0 mol/L aqueous solution of sodium carbonate was added. Subsequently, the mixture was heated to reflux for 18 hours, left to be naturally cooled, and quenched with dilute hydrochloric acid in an ice bath. Thereafter, ether was added to extract the soluble fraction, and the organic layer was washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and two times with saturated brine, and then dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting solids were subjected to separation by column chromatography to obtain a target product (yield 4.36 g (54%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:14])=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:2].Cl.[C:16](Cl)(=O)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.CCN=C=NCCCN(C)C>O>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=2[N:14]=[C:16]1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCNc1ccc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCn1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
A mixture of 1.0 g of N1-ethyl-4-trifluoromethylbenzene-1,2-diamine, 1.05 g of isonicotinoyl chloride hydrochloride and 15 ml of pyridine was stirred for 4 hours at 60° C. Then, 0.94 g of WSC was added, and the mixture was stirred for 8 hours at 80° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline, then, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of 1-ethyl-2-(pyridin-4-yl)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 221).