Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(=O)CC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(CCCC2)CC3)CC1)C.C(Cl)(=O)C.[CH3:32][C@@H:33]([C@@H:39]1[C@@:43]2([CH3:60])[C@@H:44]([OH:59])[CH2:45][C@@H:46]3[C@@:51]4([CH3:57])[CH2:52][CH2:53][C@@H:54]([OH:56])[CH2:55][C@H:50]4[CH2:49][C@@H:48]([OH:58])[C@H:47]3[C@@H:42]2[CH2:41][CH2:40]1)[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>CO>[CH3:32][C@@H:33]([C@@H:39]1[C@@:43]2([CH3:60])[C@@H:44]([OH:59])[CH2:45][C@@H:46]3[C@@:51]4([CH3:57])[CH2:52][CH2:53][C@@H:54]([OH:56])[CH2:55][C@H:50]4[CH2:49][C@@H:48]([OH:58])[C@H:47]3[C@@H:42]2[CH2:41][CH2:40]1)[CH2:34][CH2:35][C:36]([O:38][CH3:1])=[O:37]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
Preparation of the starting compounds of the formula III using the example of methyl cholanate (Fieset et al., J. Am. Chem. Soc. 74, 1952, 3309) ##STR6## 450 ml of acetyl chloride are slowly added dropwise to 4.5 l of methanol, while cooling with ice, such that the temperature does not exceed 10° to 15° C. After the addition, the mixture is subsequently stirred at about 10° C. for a further 15 minutes. 600 g (1.47 mol) of cholic acid are then introduced at about 5° C. The ice-bath is removed, and after a further hour, while stirring, the reaction is ended. The reaction mixture is slowly added to 12 l of water. The mixture is stirred for a further 2 hours and then filtered with suction, and the residue is rinsed with 3 l of water. The crystalline substance is dried in vacuo at 50° C. 610 g (98%) of methyl cholate (melting point 154° C.) are obtained.
Reaction SMILES: [NH2:1][NH2:2].C[O:4][C:5]([CH:7]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1)[CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O>C(O)(=O)C>[O:4]=[C:5]1[CH:7]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:2][NH:1]1
Reactant: NN
Reactant: COC(=O)C(CC(=O)c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(=O)O
Product: O=C1NN=C(c2ccccc2)CC1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hydrazine (3.31 mL, 104 mmol) was added to a solution of benzyl 4-[1-(methoxycarbonyl)-3-oxo-3-phenylpropyl]piperidine-1-carboxylate (2.14 g, 5.22 mmol) in acetic acid (70 mL). The reaction mixture was heated at 50° C. After 1 h, the reaction mixture was concentrated. The residue was diluted with dichloromethane, neutralized by saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate and concentrated to give the title compound. MS 392.1 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(OC)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-methoxyphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:44][CH3:45])[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH3:45][O:44][C:37]1[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:36]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCC2
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 27 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 128 mg of [2-(7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH:20]=[CH:19][C:18]3[N:14]([C:15]4[N:29]=[CH:28][CH:27]=[CH:26][C:16]=4[C:17]=3[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:20][CH2:19][C:18]3[N:14]([C:15]4[N:29]=[CH:28][CH:27]=[CH:26][C:16]=4[C:17]=3[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c2n(c3ncccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)C=C2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Cc1c2n(c3ncccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Yield: 101 %

Procedure:
To a solution of methyl ((8R)-8-{[(4-fluorophenyl)sulfonyl]amino}-8,9-dihydropyrido[3,2-b]indolizin-5-yl)acetate (0.46 g, 1.1 mmol) in ethyl acetate (20 mL) was added under nitrogen Pd—C 10% (0.02 g, 0.19 mmol, 0.17 equiv.). After a period of 1 h under 1 atmosphere of H2, DCM was added to the reaction mixture which in turn was filtered over a micro filter and the solvents were evaporated to afford 464 mg of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25](=[O:27])[CH2:24][C:23]2=[O:28])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[C:30]1(C)[CH:35]=CC(S(O)(=O)=O)=C[CH:31]=1>C(O)CC>[CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][CH2:31][CH2:30][CH3:35])=[CH:24][C:23]2=[O:28])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(=O)CC2=O)n1
Solvent: CCCO
Solvent: O
Product: CCCOC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 105.5 %

Procedure:
(S)-3-cyclohexyl-2-(2,4-dioxo-pyrrolidin-1-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (100 mg, 0.26 mmol) was added to n-propyl alcohol (3 mL), and toluene-4-sulfonic acid hydrate (10 mg). The mixture was stirred at 100° C. for 3 h. The reaction mixture was concentrated and the crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(2-oxo-4-propoxy-2,5-dihydro-pyrrol-1-yl)-propionamide (24 mg, 22%) as an off-white solid: LR-ES-MS m/z calculated for C22H34N4O4 [M]+ 432, observed [M+H]+ 433; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.82-0.95 (m, 5H), 0.96-1.14 (m, 2H), 1.27 (d, J=6.0 Hz, 6H), 1.37-1.89 (m, 11H), 3.90 (d, J=17.6 Hz, 1H), 3.88 (s, 2H), 4.28 (d, J=17.6 Hz, 1H), 4.44 (d, J=6.0 Hz, 2H), 4.67 (s, 1H), 4.76 (dd, J=10.3, 3.9 Hz, 1H), 5.12 (s, 1H), 6.42 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.5 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([O:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([OH:19])=[O:2])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid methyl ester (266 mg, 0.877 mmol) in ethanol (10 mL) was treated with a solution of potassium hydroxide (123 mg, 2.19 mmol) in water (1 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water (5 mL) and the ethanol was removed in vacuo. The aqueous layer was then acidified to pH 2 with 1 N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 chloroform/methanol plus 1% acetic acid) to afford rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (223 mg, 88% yield) as a white solid, mp 87.5-89.9 IC; EI-HRMS m/e calcd for C13H14Cl2O3 (M+) 288.0320, found 288.0332.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]([CH:21]3[CH2:23][CH2:22]3)[C:13]([C@@H:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:3]=1.C(N(C(C)C)CC)(C)C>C(O)C.[C].[Pd]>[CH:21]1([N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10]([CH:2]=[CH:3][N:4]3[CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:9][CH:8]=2)[C:13]([C@@H:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[O:14])[CH2:22][CH2:23]1
Reactant: COCCCn1cc(Cl)c2ccc(CN(C(=O)[C@H]3CNCCO3)C3CC3)cc21
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1ccc2ccc(CN(C(=O)[C@H]3CNCCO3)C3CC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
10% Palladium-carbon (20 mg) was added to a solution of (2R)—N-{[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]methyl}-N-cyclopropylmorpholin-2-carboxamide (67 mg) and diisopropylethylamine (43 mg) in ethanol (3 ml) and the mixture was stirred under hydrogen atmosphere at room temperature for 8 hours. Insoluble materials were filtered and the filtrate was concentrated in vacuo. The resulted residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with NH-silica gel column chromatography (eluting solvent: ethyl acetate to ethyl acetate/methanol=10/1) to give (2R)—N-cyclopropyl-N-{[1-(3-methoxypropyl)-1H-indol-6-yl]methyl}morpholin-2-carboxamide (53 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[O:6].[OH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(CC)CC.[OH-].[Na+].Cl>C(OCC)(=O)C>[OH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6])=[O:22]
Reactant: COC(=O)CCCNC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)CCCNC(=O)c1cccc(NC(=O)c2ccccc2O)c1

Procedure:
To a solution of 2.60 g (11.00 mmol) of methyl 4-(3-aminobenzoylamino)butanoate dissolved in 25 ml of ethyl acetate, very slowly add 1.40 g (10.00 mmol) of 2-hydroxybenzoyl chloride dissolved in 5 ml of ethyl acetate. Then add 1.00 g (10.00 mmol) of Et3N (triethylamine) and keep the reaction mixture at room temperature for 24 hours. Eliminate the solvent at low pressure, add 40 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water. Purify the reaction product by recrystallization (EtOH/H2O). This yields 1.60 g (48%) of 4-[3-(2-hydroxybenzoylamino) benzoylamino]butanoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:34]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1.CCOC(C)=O>[Br:34][C:15]1[N:14]([CH2:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:13]2[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:9][C:10]([C:25]#[N:26])=[CH:11][C:12]=2[N:16]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (1 g, 2.73 mmol) was dissolved in THF (10 mL). Disodium hydrogen phosphate (1.16 g, 8.20 mmol) was added and the reaction was warmed to 35° C. with stirring. 1,3-dibromo-5,5-dimethylhydantoin (0.938 g, 3.28 mmol) was added in 1 portion and the reaction was continued with stirring at 35° C. After 1 hour, the reaction was diluted with EtOAc (100 mL) and washed with aqueous NaHSO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column with 0 to 75% EtOAc/hexanes provided 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:26])([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>C(O)C>[CH3:14][C:4]1[CH:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:23])([F:24])([F:25])[F:26])=[CH:18][CH:17]=2)[N:7]2[N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: Cc1cc(Cl)n2nc(C(C)C)nc2n1
Solvent: CCO
Product: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)n2nc(C(C)C)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of Intermediate 18 (0.042 g, 0.199 mmol) in ethanol (5 mL), 4-aminophenylsulfur pentafluoride (MANCHESTER, 0.044 g, 0.199 mmol) was added and the mixture was stirred at room temperature overnight. Solvent was removed in vacuo and the crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 75:25 to 25:75%) to yield the title compound as a white solid.
Reaction SMILES: O1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].O1CCCC1.CC(C)([O-])C.[K+]>O>[F:17][C:12]([F:18])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:21][F:22])([CH2:19][F:20])[CH:2]=[C:7]([N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])[C:6]=2[CH:8]=1)[C:13]([F:15])([F:16])[F:14]
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Reactant: O=C1CCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Yield: 16.2 %

Procedure:
To a mixture of 0.41 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.18 g of 2-pyrrolidinone and 8 ml of tetrahydrofuran was added 0.22 g of potassium tert-butoxide with stirring under ice-cooling and the mixture was stirred for 3.5 hours under ice-cooling and then stirred at room temperature for 4 days. Water was added and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain from the first eluted fraction 0.08 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzopyran represented by the following formula having a melting point of 104-105° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Si:36]([O:43][C:44]1[C:45]([F:55])=[C:46]([CH:49]=[C:50]([O:52][CH2:53][CH3:54])[CH:51]=1)[CH:47]=[O:48])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Si:36]([O:43][C:44]1[C:45]([F:55])=[C:46]([CH:47]([C:9]2[N:10]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[OH:48])[CH:49]=[C:50]([O:52][CH2:53][CH3:54])[CH:51]=1)([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CCOc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of intermediate 8.1 (1.00 g, 2.59 mmol) in 20 mL THF at 0° C., was added BuLi (1.4 M, 2.03 mL, 2.85 mmol). The mixture was stirred for 30 min at 0° C., then a solution of 3-(tert-butyldimethylsilyloxy)-5-ethoxy-2-fluorobenzaldehyde (773 mg, 2.59 mmol) in 2 mL THF was added dropwise. The mixture was stirred at 0° C. for 30 min, quenced with sat. NH4Cl and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes, gradient) to afford 1.50 g (80%) of Intermediate 123.1 as a pale yellow solid.
Reaction SMILES: N1N[N:3]=[N:4][C:5]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.O>N1C=CC=CC=1>[N:11]1[C:6]([C:5]2[O:28][C:18]([C:19]3[CH:27]=[CH:26][C:22]([C:23]4[O:24][C:5]([C:6]5[N:11]=[C:10]([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=6)[CH:9]=[CH:8][CH:7]=5)=[N:4][N:3]=4)=[CH:21][CH:20]=3)=[N:3][N:4]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)nc1
Solvent: c1ccncc1
Solvent: O
Product: c1ccc(-c2cccc(-c3nnc(-c4ccc(-c5nnc(-c6cccc(-c7ccccn7)n6)o5)cc4)o3)n2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
0.67 g of 6-(2H-tetrazol-5-yl)-2,2′-bipyridine was dissolved in 10 ml of dehydrated pyridine, and 0.32 g of terephthaloyl dichloride was added. Temperature was elevated to 110° C., and stirring was conducted for 5 hours under reflux. After cooling to room temperature, the reaction solution was poured into water, and a precipitated white solid was taken out by suction filtration, and washed with water. The solid was vacuum dried at 80° C. for 20 hours to obtain a while crude product. By purifying with column chromatography, 0.58 g (yield 74%) of BpyOXDp was obtained. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 8.736 ppm (2H), 8.640 ppm (4H), 8.463 ppm (3H), 8.260-8.384 ppm (4H), 8.060 ppm (2H), 7.932 ppm (2H), 7.380 ppm (1H).
Reaction SMILES: C1(NC=CP(=O)(OCC)OCC)CCCCC1.[H-].[Na+].[CH:20]([C:23]1[C:28]([CH:29]=O)=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:26]([CH:38]=[N:39][O:40][CH3:41])=[C:25]([CH:42]([CH3:44])[CH3:43])[N:24]=1)([CH3:22])[CH3:21].O.O.[C:47]([OH:52])(=O)[C:48](O)=O>O1CCCC1.O>[CH:20]([C:23]1[C:28](/[CH:29]=[CH:48]/[CH:47]=[O:52])=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:26]([CH:38]=[N:39][O:40][CH3:41])=[C:25]([CH:42]([CH3:44])[CH3:43])[N:24]=1)([CH3:21])[CH3:22]
Reactant: O=C(O)C(=O)O
Reactant: CON=Cc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Agent: CCOP(=O)(C=CNC1CCCCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=Cc1c(C(C)C)nc(C(C)C)c(/C=C/C=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
750 mg (2.9 mmol) of diethyl 2-(cyclohexylamino)vinylphosphonate, dissolved in 30 ml of dried tetrahydrofuran, are added dropwise at -5° C. under nitrogen to a suspension of 110 mg (3.6 mmol) of 80% pure sodium hydride in 15 ml of dry tetrahydrofuran. After 30 minutes, 810 mg (2.4 mmol) of the compound from Example 3 in 40 ml of dry tetrahydrofuran are added dropwise at the same temperature and the mixture is heated to reflux for 30 minutes. After cooling to room temperature, the mixture is added to 200 ml of ice-cold water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulphate. After concentrating in vacuo, the residue is taken up in 70 ml of toluene, a solution of 4.5 g (3.5 mmol) of oxalic acid dihydrate in 30 ml of water is added and the mixture is heated to reflux for 30 minutes.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH2:33][CH2:34][C:35]5[N:36]([C:38]([C:41]([F:44])([F:43])[F:42])=[N:39][N:40]=5)[N:37]=4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:45](O)(=[O:47])[CH3:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:45]([N:13]1[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]4[CH2:33][CH2:34][C:35]5[N:36]([C:38]([C:41]([F:44])([F:43])[F:42])=[N:39][N:40]=5)[N:37]=4)[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)(=[O:47])[CH3:46]
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCCN4CCNCC4)cc3)CC1)CC2
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
DIPEA (0.159 mL, 0.92 mmol) was added to 6-[4-[4-[3-(piperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.31 mmol), acetic acid (0.021 mL, 0.37 mmol) and HATU (139 mg, 0.37 mmol) in DMF (2 mL). The resulting solution was stirred at ambient temperature for 16 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (75 mg, 46.1%) as a solid.