Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[N:7]([C:16]([N:20]=[C:21]=[O:22])([CH2:18][CH3:19])[CH3:17])=[N:8][C:9]([N:13]=[C:14]=[O:15])([CH2:11][CH3:12])[CH3:10]>CCCCC>[N:7]([C:16]([NH:20][C:21]([NH:6][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])([CH2:18][CH3:19])[CH3:17])=[N:8][C:9]([NH:13][C:14]([NH:6][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])([CH2:11][CH3:12])[CH3:10]
Reactant: CC(C)(C)NN
Reactant: CCC(C)(N=C=O)N=NC(C)(CC)N=C=O
Solvent: CCCCC
Product: CCC(C)(N=NC(C)(CC)NC(=O)NNC(C)(C)C)NC(=O)NNC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5.8 grams (0.05 moles) of 76% t-butylhydrazine in 30 ml pentane in a 50 ml erlenmeyer flask cooled in a water bath was added 5.6 grams (0.025 moles) of 2,2'-azobis(2-isocyanatobutane) (from Example XXXVI) dropwise over 20 minutes while holding the reaction temperature below 30° C. After the addition was complete, the reaction was stirred for an additional 60 minutes at room temperature and filtered. The filter cake was washed with pentane and dried. The dry white solid weighed 3.3 grams (33% crude yield) and melted at 155°-160° C. with decomposition. The product had a broad strong carbonyl band at 1625- 1675 cm-1 and a broad strong NH band at 3300- 3450 cm-1 in its infrared spectrum and the isocyanate band at 2200 cm-1 was absent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[C:26]1([CH:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:34][CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:33])=[O:20]
Reactant: CC(N)c1ccccc1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), (±)-1-phenylethylamine (0.433 g, 3.57 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (1.069 g, 80.0% yield).
Reaction SMILES: C(O)C.[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[CH3:14])[C:10](=[O:15])[N:9]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:8]2[CH2:23][CH2:24]OS(C)(=O)=O.[C-:30]#[N:31].[K+]>O>[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[CH3:14])[C:10](=[O:15])[N:9]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:8]2[CH2:23][CH2:24][C:30]#[N:31]
Reactant: Cc1cc2c(cc1C)C(CCOS(C)(=O)=O)N(c1ccc(F)cc1)C2=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1C)C(CCC#N)N(c1ccc(F)cc1)C2=O
Yield: 97.8 %

Procedure:
To a 80% ethanol solution of the product of above-mentioned (4-b) (0.23 g, 0.63 mmol) was added potassium cyanide (0.12 g, 1.9 mmol) and heated under reflux for 4 hrs. To the reaction solution was added water, and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled away under reduced pressure to give 0.19 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-cyanoethylisoindolin-1-one [IUPAC name: 3-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propanenitrile].
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:34])[N:14]([CH3:35])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:36]1[N:45]=[CH:44][C:43]2[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=2)[C:37]1=[O:51])(=O)C.[OH-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][C:22]([CH:25]5[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]5)=[CH:23][CH:24]=4)[C:15](=[O:34])[N:14]([CH3:35])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:45]=[CH:44]2)([CH3:48])([CH3:49])[CH3:47]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C(C)C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)N1CCC(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-isopropylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (248 mg, 357 μmol, Eq: 1.00) in THF (5.0 ml) was added NaOH (4.29 ml, 4.29 mmol, Eq: 12.0). The reaction mixture heated at 60° C. for 18 h. The solution was cooled to room temperature, and then diluted with saturated NaHCO3 and DCM. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, and then dried over Na2SO4. Concentrated in vacuo. The solid was triturated with Et2O and dried under vacuum to give 6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one (202 mg, 87%). LC/MS-ESI observed [M+H]+ 652. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.42 Hz, 6H) 1.43 (s, 9H) 1.84 (br. m., 5H) 2.28 (br. m., 2H) 2.50 (br. m., 1H) 2.79 (br. s., 1H) 3.03 (d, J=10.20 Hz, 2H) 3.90 (s, 4H) 4.42 (d, J=6.80 Hz, 2H) 6.92 (s, 1H) 7.40-7.73 (m, 6H) 8.17-8.32 (m, 4H) 8.60 (s, 2H)
Reaction SMILES: CCOC(C)=O.O.[C:8]([C:10]1[C:11]([CH3:30])=[N:12][C:13]([N:16]([CH2:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)C(=O)C)=[N:14][CH:15]=1)#[N:9]>Cl>[CH3:30][C:11]1[C:10]([C:8]#[N:9])=[CH:15][N:14]=[C:13]([NH:16][CH2:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[N:12]=1
Reactant: CC(=O)N(CCCC1CCN(C)CC1)c1ncc(C#N)c(C)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resultant mixture was treated at 20-25° C. with a dilute HCl solution (37% HCl (4.80 g) diluted with water (15.00 g)), followed by EtOAc (9.02 g) and water (10.00 g). The resultant mixture was settled and the top organic layer was removed. The acidic aqueous layer was stirred at room temperature for 1 h to yield a mixture (which contained the hydrolysis product, N-(5-cyano-4-methyl-pyrimidin-2-yl)-N-[3-(1-methyl-piperidin-4-yl)-propyl]-acetamide). The aqueous layer was extracted one time with EtOAc (9.02 g). 2-Methyl-THF (8.60 g) was added and the pH of the biphasic mixture was adjusted to about pH=12 by addition of 6N NaOH (9.69 g). The aqueous layer was removed and the 2-Me-THF layer was diluted with 2-MeT-HF (8.60 g) and dried with MgSO4 (1.0 g). The pH of the dried 2-MeTHF solution was adjusted to about pH=1 by dropwise addition of 5-6N HCl/IPA, whereupon the HCl salt of the title compound precipitated. The solid was filtered, dissolved in EtOH (3.95 g) and the pH was adjusted to about pH=12 using 6N NaOH (4.85 g). The solid which precipitated during the addition was filtered, washed with water (10.00 g) and dried in a vacuum oven at 60-70° C. for 5 h to yield the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17](F)=[CH:18][N:19]=1)[C:5]([C:7](=[CH:13][N:14]([CH3:16])C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:21]1(N)[CH2:26][CH2:25]C[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][N:19]=1)[N:14]([CH:16]1[CH2:25][CH2:26][CH2:21][CH2:22][CH2:23]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)ncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2cnc(Br)cc2c1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 66, 1.14 g, 3.29 mmol, 1 equiv.) in DMF (6.5 mL) was added cyclohexanamine (592 mg, 3.29 mmol, 1 equiv.). This reaction mixture was stirred at 70° C. for 30 min. Potassium carbonate (1.36 g, 9.86 mmol, 3 equiv.) was added and stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature and quenched with water (2 mL). 1 N HCl was added until pH 4-5 was reached. The precipitate was washed with water and hexanes and dried to provide ethyl 6-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (1.15 g, 92%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CC(C)=O>[CH2:1]([O:24][C:22]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([F:15])[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Temperature: 60 °C
Yield: 97 %

Procedure:
Benzyl bromide (467 mL, 3.93 mol) and potassium carbonate (1.4 kg, 10.1 mol) were added to a solution of 2-fluoro-4-hydroxybenzonitrile (490 g, 3.57 mol) in acetone (3.4 L). The stirred mixture was heated at 60° C. for 20 h, then cooled and filtered. The filtrate was concentrated and the resulting solid was triturated with 10% ethyl acetate-hexane (5 L) and vacuum dried at 35° C. to give the desired product (787 g, 97%).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[C-]#N.[Na+].[CH:16](=[CH:23][C:24](=[O:26])[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[O:7]=[C:1]([C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:23][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)C=Cc1ccccc1
Reactant: OCc1ccco1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CC(C(=O)c1ccco1)c1ccccc1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A solution of 38.4 g (0.4 mol) of freshly distilled furfurol and 125 ml of absolute dimethylformamide is added dropwise to a mixture of 9.8 g (0.2 mol) of NaCN and 125 ml of absolute dimethylformamide at 35° C in the course of 45 minutes in a manner analogous to Example 3. Stirring is then continued for 1/2 hour at 35° C. A solution of 43.8 g (0.3 mol) of benzalacetone and 150 ml of absolute dimethylformamide is then added dropwise in the course of 11/2 hours. Stirring is continued at the same temperature for a further 11/2 hours and the reaction mixture is then treated with twice its quantity of water and worked up as described in Example 5. 32.1 g of 1,4-dioxo-1-furyl-2-phenyl-pentane (44% of theoretical) are isolated from 83.5 g of the crude product by distillation; b.p. 147°-148° C/0.4 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O>C(O)CCC>[CH2:3]([O:29][C:28](=[O:30])[CH2:27][CH2:26][C:25]([NH:24][C@H:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1)[CH2:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[O:18])=[O:31])[CH2:2][CH2:7][CH3:6]
Reactant: CS(=O)(=O)NC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Product: CCCCOC(=O)CCC(=O)N[C@@H](CC(=O)NS(C)(=O)=O)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 114.4 %

Procedure:
To a solution of N-[(R)-1-(3′-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-succinamic acid (50 mg, 0.107 mmol) in n-butanol (2 mL) is added thionyl chloride (9.38 μL, 0.128 mmol). The reaction mixture is warmed to 50° C. and stirred for 1 h. After cooling to room temperature, the reaction mixture is concentrated and purified by reverse phase HPLC (SunFire C18, 0.1% TFA in H2O/CH3CN) to give N-[(R)-1-(3′-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-succinamic acid butyl ester (32 mg). HPLC retentions time=1.56 minutes (condition A); MS (m+1)=523; 1H NMR (400 Mz, DMSO-d6) δ ppm 0.86 (t, 3H, J=7.33 Hz), 1.22-1.34 (m, 2H), 1.45-1.55 (m, 2H), 2.23-2.33 (m, 2H), 2.35-2.44 (m, 3H), 2.45-2.55 (m, 3H), 2.71-2.83 (m, 1H), 3.18 (s, 3H), 3.96 (t, 2H, J=6.57 Hz), 4.27-4.38 (m, 1H), 7.28 (d, 2H, J=8.08 Hz), 7.37-7.43 (m, 1H), 7.48 (t, 1H J=7.83 Hz), 7.62 (d, 3H, J=8.34 Hz), 7.70 (s, 1H), 7.91 (d, 1H, J=8.34 Hz), 11.71 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[O:15][CH2:16][CH3:17]>C(O)(C)C>[CH3:10][O:11][C:12]([C:13]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH:13]([C:12]([O:11][CH3:10])=[O:19])[C:14]([O:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(N)=CC(=O)OC
Solvent: CC(C)O
Product: CCOC1=NC(N)=C(C(=O)OC)C(c2cccc(Cl)c2)C1C(=O)OC
Yield: 78 %

Procedure:
Upon heating a solution of 7.1 g of 3-chlorobenzaldehyde and 14.5 g of 3-amino-3-ethoxyacrylic acid methyl ester in 50 ml of isopropanol for 6 hours, 2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid dimethyl ester of melting point 158° C (isopropanol) is obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[H-].[Na+].[C:16](=O)([O:20]CC)[O:17][CH2:18][CH3:19].Cl>O>[O:11]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)[CH2:10][C:16]([O:17][CH2:18][CH3:19])=[O:20]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4′-trifluoromethylacetophenone (10.0 g), sodium hydride (60%, oil, 2.13 g) and diethyl carbonate (80 ml) was stirred at 80° C. for 90 min. Water was added to the reaction mixture, and the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-oxo-3-(4-trifluoromethylphenyl)propionate was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). A mixture of this oil and N,N-dimethylformamide dimethylacetal (9.50 g) was refluxed for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). To the obtained solution was added hydroxylamine hydrochloride (7.39 g), and the mixture was refluxed for 2 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, the crystals obtained from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio) were recrystallized from hexane to give ethyl 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylate (8.42 g, yield 56%) as a colorless prism. melting point: 53–54° C.
Reaction SMILES: [SH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](=[NH:10])OCC)=[CH:4][CH:3]=1.[CH3:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH2:19][S:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH3:13][C:14]1[NH:15][CH:16]=[N:17][C:18]=1[CH2:19][S:20][CH2:21][CH2:22][NH:23][C:6](=[NH:10])[C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:12][CH:11]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCOC(=N)c1ccc(S)cc1
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=N)c1ccc(S)cc1

Procedure:
4-Cyanothiophenol was treated with hydrogen chloride in ether at 0° and the hydrochloride salt produced was treated with potassium carbonate to give ethyl 4-mercaptobenzimidate. Ethyl 4-mercaptobenzimidate was treated with 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole in dry ethanol at room temperature to give the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1([CH3:17])[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[C:14]3([CH3:17])[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:27]1)[CH3:23]
Reactant: CC1(n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)CC1
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4(C)CC4)c3c2F)C1
Yield: 72.9 %

Procedure:
To 0.75 g (2.57 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid in 15.0 ml of acetonitrile was added 0.38 g (2.57 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.32 g (2.57 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for two hours and was cooled and filtered. The solids were washed with ether to afford 0.76 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro 1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid, mp 261°-263° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[CH2:38]=[O:39].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClCCl>[OH:1][C:2]1[C:3]([C:11]2([CH2:38][OH:39])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: C=O
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2cccnc21
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2cccnc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2.75 g, 8.08 mmol) in anhydrous dichloromethane (40.0 mL) were added triethylamine (4.91 g, 48.5 mmol) and chlorotrimethylsilane (3.51 g, 32.3 mmol) under nitrogen at 0° C. The reaction mixture was stirred at 0° C. for 2 h and diluted with anhydrous dichloromethane (50.0 mL). The organic layer was washed with water (2×25.0 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The gummy brown residue was dissolved in THF (40.0 mL) followed by the addition of formaldehyde solution (2.20 mL, 80.8 mmol, 37 wt % in water) and ytterbium (III) trifluoromethanesulfonate (1.25 g, 2.02 mmol). The reaction mixture was stirred at ambient temperature for 36 h and diluted with dichloromethane (100 mL). The organic layer was washed with saturated NaHCO3 (50.0 mL), saturated ammonium chloride (50.0 mL) and water (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound (2.85 g, 98%): 1H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H), 8.29 (dd, 1H), 7.72 (dd, 1H), 7.13 (dd, 1H), 6.55 (s, 1H), 6.46 (s, 1H), 5.86 (dd, 2H), 4.37 (dd, 2H), 3.77-3.84 (m, 2H), 3.25 (br, 1H), 1.63-1.77 (m, 2H), 1.36-1.22 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 179.9, 156.6, 152.3, 148.4, 147.5, 141.5, 133.8, 124.3, 118.7, 111.3, 107.9, 101.9, 101.4, 64.3, 59.1, 39.9, 31.6, 27.2, 22.3, 13.9; MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 4-(4-benzyl-morpholin-2-yl)-benzaldehyde (1.19 g; 4.23 mmol) in MeOH (25 mL) was added NaBH4 (0.16 g; 4.23 mmol), in small portions, at 0° C. After the addition was complete the mixture was allowed to warm to RT and stirred for one hour. Subsequently, the mixture was cooled to 0° C., water was added, and the MeOH evaporated in vacuo. To the aqueous solution was added a 5% aqueous NaHCO3 solution and EtOAc. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-methanol (1.16 g) which was used as such.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[C:25]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:9]=1[C:10](=[O:21])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:5])C.[OH-].[K+].Cl>O1CCOCC1>[C:4]([CH2:6][O:7][C:8]1[C:25]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:9]=1[C:10](=[O:21])[CH:11]=[CH:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1c(CC=C(C)C)c(OC)cc(OC)c1C(=O)C=Cc1ccc(OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Then, 23.7 g of 2'-ethoxycarbonylmethoxy-4,4',6'-trimethoxy-3'-(3-methyl-2-butenyl)chalcone was dissolved in 100 ml of dioxane, and 100 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 30 minutes to effect a reaction. After the reaction, the reaction mixture was made acidic by hydrochloric acid to obtain a yellow precipitate. The precipitate was recovered by filtration, washed with water, dried and recrystallized from ethyl acetate to obtain 18.5 g (yield=83.0%) of 2'-carboxymethoxy-4,4'6'-trimethoxy-3'-(3-methyl-2-butenyl)chalcone in the form of a light-yellow prism.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26]>CCCCCCC.C(OCC)(=O)C>[F:21][C:22]([F:30])([F:29])[C:23]([C:24]1[C:25]([CH3:26])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)=[O:28]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 44 h
Yield: 63 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-phenyl-methanone [example A6] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the reaction time was of 44 h and heptane/ethyl acetate (10:1) was used. Yield: 63%; MS: m/z=399 (M).