Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:22]([CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[CH2:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N>CN(C=O)C>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:22]([CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:10][CH:11]=2)=[O:35])=[CH:32][CH:31]=1)[CH2:23][C:24]1[NH:28][CH:27]=[CH:26][N:25]=1
Reactant: CCCN(CCC)Cc1ccc(N)cc1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound (57.2 mg) obtained in Example 19-2, the compound (106 mg) obtained in Example 2-2, and HOBt (162 mg) were dissolved in anhydrous DMF (2.5 ml) and then added with PS-carbodiimide (manufactured by Argonaut Technologies, Inc.) (419 mg), followed by stirring at room temperature for 12 hours. After completion of the reaction, the solution was filtrated and the solvent was then distilled off. The residue was dissolved in chloroform and then washed with 1 mol/l sodium hydroxide and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (18.3 mg) of the subject compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)(=[O:9])=[O:8])=[O:5])[CH3:3]>[Pd].O.C(O)C>[CH3:3][C:2]([CH3:19])([C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)(=[O:9])=[O:8])=[O:5])[CH3:1]
Reactant: CC(C)(C)C(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)NS(=O)(=O)c1cccc(N)c1
Yield: 74.9 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(1,1-dimethylethylcarbonylaminosulphonyl)-3-nitrobenzene (5 g, 17.5 mmol), 10% palladium on carbon (0.5 g, 10% (w/w)) in water (4 ml) and ethanol (100 ml), the title compound (3.36 g, 75%) was afforded as a pale yellow solid after recrystallisation from ethanol. mp 147°-150° C. 1H NMR (360 MHz, D6-DMSO) δ 1.07 (9H, s), 5.62 (2H, brs), 6.78 (1H, dd, J=8.0 and 2.0 Hz), 6.94 (1H, d, J=8.0 Hz), 7.08 (1H, t, J=2.0 Hz), 7.19 (1H, t, J=7.9 Hz), 11.47 (1H, brs).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH2:30])[CH3:26].Cl.CCN(CC)CC>C1COCC1>[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH:30][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:26]
Reactant: O=C(O)CCCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
4-Phenylbutyric acid (2.46 g, 15 mmol) was dissolved in distilled THF (70 ml) in an argon atmosphere. After cooling in an ice bath, carbonyldiimidazole (CDI) (2.43 g, 1.5 mmol) was added and the mixture was stirred cold 1 hour and at room temperature 1 hour. The mixture was then cooled and glycine ethyl ester.HCl (2.09 g, 15 mmol) and distilled Et3N (2.1 ml, 15 mmol) were added. The mixture was left stirring overnight at room temperature. After removal of the solvent in vacuo, Et2O (200 ml) was added. The solution was washed with 1N HCl (70 ml), 0.5N NaOH (70 ml) and saturated NaCl solution (70 ml), dried (MgSO4) and freed of solvent in vacuo leaving title compound (3.13 g, 84%) as white crystalline material. TLC: silica gel, Et2O, UV; Rf : 0.58.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[C:18]([NH:23][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccccc1N
Product: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (4.78 g) and o-anisidine (2.96 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1F.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:14]([O:21][C:9]1[CH:8]=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[Cl:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Cl)c1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A 15.43 g (0.275 moles) portion of solid (pellets) potassium hydroxide was added to a solution of 43.89 g (0.25 moles) of 3-chloro-4-fluoro nitrobenzene and 32.34 ml (33.79 grams, 0.373 moles) of benzyl alcohol in 220 ml of acetonitrile. The reaction was vigorously stirred with a mechanical stirrer overnight. The resulting solid was filtered. Concentration of the filtrate gave a second crop, which was also filtered. On standing more solid came out of this filtrate. This mixture was treated with ether, and the solid filtered. All solids were washed thoroughly with water, and combined to give 49.71 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[OH:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[CH2:39][CH3:40].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:33][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([OH:9])[C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[CH:17]=2)[N:22]=[C:21]([O:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[CH2:39][CH3:40])[C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: CCC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(=O)NCCOc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Temperature: 25 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), N-(2-hydroxylethyl)propionamide (34.2 μL, 0.303 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 32.3 mg, 0.808 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight. The reaction solution was cooled to room temperature then transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/MeOH) then via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI): mass calcd. for C31H28Cl2N4O3, 574.2; m/z found, 575.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.14 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.78 (s, 1H), 7.68 (dd, J=8.8, 1.7 Hz, 1H), 7.47-7.41 (m, 2H), 7.41-7.37 (m, 1H), 7.38-7.34 (m, 4H), 7.34-7.30 (m, 2H), 6.32 (s, 1H), 4.52 (t, J=5.6 Hz, 2H), 3.53-3.44 (m, 5H), 2.11 (q, J=7.6 Hz, 2H), 1.04 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC(C)=C)=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[Cl-].[Mg+2].[Cl-]>C(OCC)C>[F:27][C:2]([F:26])([F:1])[S:3]([O:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:19][C:10]([CH3:24])([CH3:11])[CH2:9][C:17]=3[CH:18]=2)=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: C=C(C)COc1ccc(C(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC1(C)Cc2cc(C(=O)c3ccc(OS(=O)(=O)C(F)(F)F)cc3)ccc2O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.2 %

Procedure:
A mixture of 4.4 grams (0.011 mole) of 4-(trifluoromethylsulfonyloxy)-4'-(2-methyl-2-propenoxy)benzophenone and 0.05 gram (0.0005 mole) of magnesium chloride was stirred under a nitrogen atmosphere at 170°-175° C. for 20 hours. The reaction mixture was cooled to ambient temperature, and diethyl ether was added. The mixture was filtered through diatomaceous earth, and the filtrate was placed in a separatory funnel and washed with two portions of aqueous 0.5 N sodium hydroxide, three portions of water, and one portion of a saturated, aqueous, sodium chloride solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by centrifically accelerated, radial thin layer chromatography. Elution was accomplished using 3:1 methylene chloride:hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 1.7 grams of (4-trifluoromethylsulfonyloxyphenyl)(2,3-dihydro-2,2-dimethylbenzofuran-5-yl) ketone. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]12[CH2:33][CH:5]([C:6]3([CH3:32])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[CH:24]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[CH:22]=[CH:21]5)=[O:17])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[BH4-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]12[CH2:33][CH:5]([C:6]3([CH3:32])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([CH:16]([OH:17])[C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[CH:24]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[CH:22]=[CH:21]5)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc2cc(C(=O)c3ccc4c(c3)C3(C)C5(C)CCC(C5)C3(C)O4)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(C(O)c3ccc4c(c3)C3(C)C5(C)CCC(C5)C3(C)O4)ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
944 mg (2.14 mmol) of the ester obtained in Example 3, dissolved in 30 ml of a methanol/tetrahydrofuran (1/1) mixture, were treated with 81 mg of sodium borohydride. The reaction mixture was stirred for 5 hours at room temperature. Evaporation was carried out to dryness, the residue was taken up in ether and this phase was washed to neutral pH. After drying and evaporating, 905 mg (96%) of the expected compound, melting at 140°-141° C., were isolated.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1(C)C=CC=CC=1>[C:1]([C:3](=[C:28]1[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
Ethyl cyanoacetate (3.475 mL, 1.3 equiv), ammonium acetate (1.16 g, 0.6 equiv), acetic acid (1.725 mL, 1.2 equiv) were added to a solution of N-Boc-4-piperidone (5 g, 25.11 mmol) in toluene (55 mL). The mixture was heated at 110° C. for 2 h, 85° C. overnight, then at 135° C. for 4 h. The mixture was washed with 5% aq NaOH (15 mL), water (15 mL) and brine (10 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120-g silica gel cartridge, eluted with a 5 to 40% EtOAc in hexanes gradient, to afford tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (4.71 g, 64%) as an off-white solid.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][CH:16]([CH3:20])[CH2:17][CH:18]=[O:19]>>[CH3:3][C@H:2]([C@@H:18]([OH:19])[CH2:17][CH:16]([CH3:20])[CH3:15])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CC(C)CC=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: CC(C)C[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with 3-methylbutanal. 1H-NMR (CDCl3, 400 MHz): δ 8.06 (m, 1H); 7.25 (m, 3H); 4.17 (m, 1H); 3.91 (dq, 1H, J=3,7); 2.52 (br s, 1H); 1.82 (m, 1H); 1.56 (ddd, 1H, J=5,9,13); 1.31 (d, 3H, J=7); 1.25 (ddd, 1H, J=4,6,13); 0.95 (d, 3H, J=7); 0.94 (d, 3H, J=7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:12]([NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)Nc1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-aminoisoquinoline in DMF is added DMAP and benzyl isocyanate and the solution was stirred at room temperature for 4 hours. The mixture was poured into NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, 5% MeOH/CH2Cl2) provided 1-benzyl-3-(isoquinolin-6-yl)urea (E88).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[O:14][CH2:15][C:16](=[O:23])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[C:26]([CH:33]=O)=[CH:25]1.[OH-].[Na+]>C(O)C.Cl>[NH:24]1[C:32]2=[N:31][CH:30]=[CH:29][CH:28]=[C:27]2[C:26]([CH:33]=[C:15]2[O:14][C:13]([NH:12][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][OH:11])=[CH:7][C:2]=3[F:1])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:25]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCO)cc2F)OCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCCO)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 60.5 %

Procedure:
To a solution of ethyl 2-{[2-fluoro-4-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.017 g, 0.052 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0075 g, 0.051 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.052 mL, 0.10 mmol) was added at ambient temperature. The mixture was refluxed for 8.5 h. Cooled with ice bath, 2M sodium hydroxide solution (0.047 mL, 0.094 mmol) was added dropwise to neutralize, and ethanol (0.5 mL) was added and refluxed for further 16 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.014 g, y. 59%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:28])([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:28])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)CC(C)(N)C(N)=O
Product: CC(C)CC(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-amino-2,4-dimethylpentanamide (CAN 113509-60-7) as starting materials and isolated (41 mg, 32%) as a white solid; MS (ESI, m/z): 388.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[C:21]1([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=3[CH:16]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C1CCc2cc(O)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2cc(OCc3ccccc3)ccc2O1
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a stirred solution of 5.6 parts of ethyl 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylate in 90 parts of N,N-dimethylformamide were added portionwise 1.2 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 30 minutes. A solution of 3.1 parts of (chloromethyl)benzene in 18 parts of N,N-dimethylformamide was added dropwise. Upon completion, the whole was stirred for 22 hours at 70° C. The reaction mixture was evaporated. Water was added. The product was extracted with 1,1'-oxybisethane. The extract was washed with a sodium chloride solution 10%, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6 parts (76.9%) of ethyl 3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-carboxylate as a residue (intermediate 29).
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:13]([OH:21])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1>C(N(CC)CC)C>[C:25]([O:21][CH:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:26])[CH2:24][C:23]([CH3:22])=[O:27]
Reactant: C=C1CC(=O)O1
Reactant: OC(CN1CCCCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OC(CN1CCCCC1)c1ccccc1
Yield: 106.2 %

Procedure:
To 130 ml of benzene are added 14.7 g of 1-phenyl-2-piperidinoethanol, 7.1 g of diketene and 1 ml of triethylamine. The mixture is refluxed under heating for three hours. The reaction mixture is concentrated under reduced pressure to give 22 g of 1-phenyl-2-piperidinoethyl acetoacetate. A mixture of 22 of 1-phenyl-2-piperidinoethyl acetoacetate, 10.6 g of m-nitrobenzaldehyde and 12.7 g of (2-furyl)methyl β-aminocrotonate in 130 ml of isopropanol is refluxed under heating for 12 hours. The reaction mixture is concentrated under reduced pressure. To the viscous jelly-like oily substance thus obtaned is added an ethanol solution of hydrogen chloride and then the mixture is concentrated. The viscous jelly-like residue is crystallized from a mixture solvent of acetone-ether. The precipitated crystals are collected by filtration, and recrystallized from a mixture solvent of acetone-methanol to give α-diastereoisomer of 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(2-furyl)methylester-5-(1-phenyl-2-piperidinoethyl)ester in the form of hydrochloride as yellow crystals melting at 219°-221° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of 5-bromo-2-methylpyridine (5.00 g) in acetonitrile (30 mL) was added 70% m-chloroperbenzoic acid (10.8 g), and the mixture was stirred at room temperature for 30 min. The resulting white precipitate was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and recrystallized (ethyl acetate/hexane) to give the title compound (5.36 g) as a pale-yellow solid.
Reaction SMILES: [Si]([O:18][C:19]1[CH:67]=[CH:66][C:22]([O:23][CH2:24][C@@H:25]([OH:65])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:64]=[CH:63][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([N:43]4[CH2:48][CH2:47][CH:46]([C:49]5[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[C:51]([O:57][CH:58]6[CH2:62][CH2:61][CH2:60][CH2:59]6)[CH:50]=5)[CH2:45][CH2:44]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH:58]1([O:57][C:51]2[CH:50]=[C:49]([CH:46]3[CH2:45][CH2:44][N:43]([C:41]([N:38]4[CH2:39][CH2:40][CH:35]([NH:34][C:33]5[CH:63]=[CH:64][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:65])[CH2:24][O:23][C:22]6[CH:66]=[CH:67][C:19]([OH:18])=[CH:20][CH:21]=6)=[CH:31][CH:32]=5)[CH2:36][CH2:37]4)=[O:42])[CH2:48][CH2:47]3)[CH:54]=[CH:53][C:52]=2[O:55][CH3:56])[CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: COc1ccc(C2CCN(C(=O)N3CCC(Nc4ccc(CCNC[C@H](O)COc5ccc(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)cc5)cc4)CC3)CC2)cc1OC1CCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(C2CCN(C(=O)N3CCC(Nc4ccc(CCNC[C@H](O)COc5ccc(O)cc5)cc4)CC3)CC2)cc1OC1CCCC1
Yield: 68 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl}{4-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-piperidinyl}methanone (0.168 g, 0.181 mmol) was reacted according to Procedure H to yield (eluant: 5:1 chloroform-methanol) the title compound (0.085 g, 0.123 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:10][C:11]2[N:12]([C:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:15][N:16]=2)[N:13]=1.Cl>C(Cl)Cl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[CH:10][C:11]2[N:12]([C:14]([CH2:17][CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[N:15][N:16]=2)[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1ccc(-c2cc3nnc(CC4CCNCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 170.8 %

Procedure:
To a solution of tert-butyl 4-((6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)piperidine-1-carboxylate (Example 19) (0.6 g, 1.11 mmol) in CH2Cl2 (15 mL) was added 2 M HCl in diethyl ether (5 mL. The resulting mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The obtained residue was evaporated with CH2Cl2 three times, dried in high vacuum overnight to afford 450 mg (85%) of the title compound as an off-white powder. HPLC/MS (method A): retention time=3.01 min, (M+H)+=438.2.