Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][O:15]C(=O)C.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CO.O>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1ccc(OCCCCO)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 908.7 %

Procedure:
In a 1 L three neck distillation flask, p-hydroxybenzaldehyde (24.4 g, 20 mmol), 4-chlorobutylacetate (36.1 g, 240 mmol), potassium carbonate (33.2 g, 240 mmol) and dimethylformamido (150 ml) were placed and stirred for 3 hours at 120° C. After the reaction mixture was cooled, water was added and the resulting mixture was extracted with ethyl acetate. The solvent was removed to obtain an oily product. The product was dissolved in methanol (100 ml), and potassium hydroxide (22.4 g, 0.4 mmol) dissolved in water (50 ml) was dropwise added to the solution. The mixture was refluxed for 2 hours, and then cooled. Water was added and the resulting mixture was extracted with ethyl acetate. The solvent was removed to obtain an oily product. The product was purified through column chromatography to prepare the titled compound (35.3 g, yield: 91%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[SH:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CC1C=CC(S(O[CH2:30][C:31]([F:34])([F:33])[F:32])(=O)=O)=CC=1>O>[F:32][C:31]([F:34])([F:33])[CH2:30][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCSCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
1.7 g of sodium hydride was added to 30 ml of dry dimethylformamide, and then 7.5 g of tert-butyl 2-mercaptoethylaminoformate. Upon the end of the addition, the mixture was stirred for 1 h, and then slowly added with 2,2,2-trifluoroethyl (4-methylphenyl)sulfonate. Upon the end of the addition, the mixture was warmed to room temperature, and stirred overnight. The mixture was poured to water, extracted with diethyl ether, washed with 0.5M sodium hydroxide aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, distilled to remove the solvent, and subjected to a column chromatography to obtain 5.4 g of light yellow oily liquid, yield 53.8%.
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[CH2:10][C:11]([OH:13])=[O:12].[OH-].[Na+].Cl>>[O:2]=[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCl
Reactant: Oc1ncccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1cccnc1=O
Temperature: 105 °C

Procedure:
To 2-hydroxypyrimidine hydrochloride (1.00 g, 7.54 mmol) and chloroacetic acid (0.713 g, 7.54 mmol) was added 5 N sodium hydroxide solution (4.5 mL). The reaction mixture was heated at 105° C. for 2 h. After cooled down to ambient temperature and neutralized with 2 M hydrochloric acid (3.8 mL), the title compound was collected by crystallization and filtration as a pale yellow solid. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.59 (dd, J=3.9, 3.0 Hz, 1H), 8.16 (dd, J=6.4, 2.8 Hz, 1H), 6.46 (dd, J=6.4, 4.1 Hz, 1H), 4.58 (s, 2H). LC/MS 155.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH2:27])[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH:27][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:26]=1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
3-Nitrobenzaldehyde (0.302 g, 2.0 mmol) was added to a stirred mixture of 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.476 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture was stirred for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give an orange oil. Recrystallization from ethyl acetate/hexane gave the product (115 mg), mp 160-162° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][OH:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].O>CS(C)=O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:17]=[O:18])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reaction time: 0.67 h

Procedure:
Triethylamine (17 ml) is added to a solution of (2S)-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propanol (5.00 g, Reference compound No. 1-1) in dimethyl sulfoxide (100 ml). Then, a sulfur trioxide-pyridine complex (11.1 g) is added to the mixture, and the whole is stirred for 40 minutes. Water is added to the reaction mixture, and the whole is extracted with diethyl ether. The extract is washed with a saturated aqueous ammonium chloride solution, water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (4.48 g).
Reaction SMILES: C([O:4][CH2:5][C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:21])[CH2:7][N:8]([S:10]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH3:20])(=[O:12])=[O:11])[CH3:9])(=O)C.C(N(CC)CC)C.O>CO>[CH3:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[S:10]([N:8]([CH2:7][C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:21])[CH2:5][OH:4])[CH3:9])(=[O:11])=[O:12]
Reactant: CC(=O)OCC(O)(CN(C)S(=O)(=O)c1cc(C)ccc1C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: Cc1ccc(C)c(S(=O)(=O)N(C)CC(O)(CO)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A mixture of 3.50 g of 1-acetoxy-3-[N-(2,5-dimethylphenylsulfonyl)-N-methylamino]-2-phenyl-2-propanol prepared in the above-described way, 3 ml of triethylamine, 3 ml of water and 6 ml of methanol was stirred at room temperature for 4 hours. After distilling off the solvent, the residue was purified by silica gel column chromatography (developing solvent: benzene-ethyl acetate (4:1)) to obtain 2.80 g of the titled compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][CH:6]1[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:4].[Li+].[OH-]>CO.O>[C:17]([O:16][C:14]([NH:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH2:8][CH:9]([CH3:10])[CH3:11])=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC1CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid methyl ester (9.1 g, 31.9 mmol) in MeOH (260 mL) was added a solution of LiOH (3.34 g, 79.7 mmol) in water (80 mL). The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. Excess of solvent was removed and the residue was dissolved in water (100 mL). The aqueous solution was washed with ether, acidified to pH=3 with 2N HCl and extracted with EtOAc (2×150 mL). The combined organic phase was washed with brine, dried (Na2SO4) and evaporation of the solvent gave 8.4 g (97%) of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 0.71 (dd, J=4.0, 6.4 Hz, 1H), 0.95 (t, J=6.4 Hz, 6H), 1.35 (m, 1H), 1.43 (s, 1H), 1.49–1.55 (m, 1H), 1.64–1.69 (m, 2H), 3.23 (d, J=14.2 Hz, 1H), 3.40 (d, J=14.2 Hz, 1H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]=[N:9][S:10][CH:11]=1)(=O)=O.[S:12]1C=CC=C1CC([O-])=O.[Na+].[O:22]1CC[CH2:24][CH2:23]1>CCOCC>[C:23]([S:12][CH2:6][C:7]1[N:8]=[N:9][S:10][CH:11]=1)(=[O:22])[CH3:24]
Reactant: C1CCOC1
Reactant: O=C([O-])Cc1cccs1
Reactant: CS(=O)(=O)OCc1csnn1
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)SCc1csnn1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of 1,2,3-thiadiazol-4-ylmethanol methanesulfonate (0.90 g, 4.6 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (2 mL) of sodium thiolacetate [prepared from thiolacetic acid (0.38 mL, 5.3 mmol) and sodium bicarbonate (0.445 g, 5.3 mmol)]. The resulting mixture was stirred at 23° C. for 1 h and diluted with ether (75 mL). The organic solution was washed with water (3×3 mL), dried (MgSO4) and concentrated. The crude mixture was purified by chromatography (silica gel column: 1.4×19 cm) with 50% ether in hexane as eluting solvent to give 0.60 g (75%);
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=CC=1)O.[OH-].[K+].[CH3:11][CH:12]([CH2:25][CH3:26])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.[CH2:27](O)C>O.CCCCCCC.CCCCCC>[CH3:11][CH:12]([CH2:25][CH3:26])[CH2:13][O:6][CH2:5][CH:7]([CH3:27])[CH2:8][CH3:1]
Reactant: CCC(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: CCO
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CCCCCC
Solvent: O
Product: CCC(C)COCC(C)CC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Next, into a solution obtained by dissolving hydroquinone (248 g) and potassium hydroxide (88 g) in water (30 ml) and ethanol (2 l) was added the above p-toluenesulfonic acid 2-methylbutyl ester (366 g) and the mixture was heated with stirring at 60° C. for 2 hours and then under reflux for 7 hours, followed by distilling off ethanol (1.7 l), adding water (1.9 l) and 6N hydrochloric acid for acidification to separate a brown oily substance, extracting this substance with heptane (150 ml), water-washing the resulting heptane layer, distilling it under reduced pressure to obtain a fraction of b.p. 115°~135° C.(2.5 mmHg) (176 g), dissolving this fraction in heptane (300 ml), subjecting the solution to extraction with 1N aqueous solution of KOH (1 l), washing the resulting extract liquid with heptane (100 ml), adding 6N hydrochloric acid to the alkaline aqueous layer for acidification to separate an oily substance, water-washing this substance, and distilling it under reduced pressure to obtain a fraction of b.p. 107°~111° C. (2 mmHg) (140 g), dissolving this fraction in hexane (200 ml), and keeping the solution at 0° C. for crystal deposition to obtain optically active hydroquinonemono (2-methylbutyl) ether (m.p. 41°~42° C.) (129 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[O:20][CH3:21])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:24])=[CH:6][C:7]([CH3:23])([CH3:22])[NH:8]2.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[S:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:3]([CH2:2][O:32][C:30](=[S:31])[C:29]3[CH:33]=[CH:34][C:26]([CH3:25])=[CH:27][CH:28]=3)=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([CH3:22])([CH3:23])[CH:6]=[C:5]3[CH3:24])=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Reactant: Cc1ccc(C(O)=S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1-c1ccc2c(c1COC(=S)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 48.4 %

Procedure:
5-Chloromethyl-6-(4-fluoro-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquino line (Reference Compound No. 5-2, 50.0 mg, 0.145 mmol), 4-methylthiobenzoic acid (73.2 mg, 0.435 mmol), and potassium carbonate (80.2 mg, 0.580 mmol) were suspended in anhydrous N,N-dimethylformamide (1 mL), and the reaction mixture was stirred at 80° C. for 2.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the whole was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (32.4 mg) as a colorless amorphous product. (Yield 47%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1.Cl.CCOCC>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(CO)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
as follows: To a solution of 2-chloro-4-methylbenzoic acid (2.18 g; 12.8 mmol) in THF (22 mL) was added dropwise a solution of BH3.THF in THF (25.6 ml; 1.00 mol/l; 25.6 mmol), at 0° C. Upon complete addition the resulting mixture was heated under reflux, for 3 hours. Subsequently, the mixture was cooled to 0° C., 1M aqueous HCl (30 mL) was added dropwise, and the mixture was stirred for 10 min. Et2O (100 mL) was added and the layers were separated. The organic layer was washed with 1M aqueous HCl (2×), 5% aqueous NaHCO3 (2×), and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford (2-chloro-4-methyl-phenyl)-methanol (1.80 g), which was used as such.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.C=O.CCN(C(C)C)C(C)C.[Cl-].[Li+]>O1CCCC1.C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (54.3 g, 118.8 mmol) is dissolved in 120 mL of anhydrous tetrahydrofuran, add paraformaldehyde (4.28 g, 142.6 mmol), iPr2NEt (20.0 g, 154.5 mmol) and anhydrous Lithium chloride (2.56 g, 59.4 mmol), reflux for 2 h under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 200 mL of toluene, wash with 5% HCl(aq), saturated Na2CO3 and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [H-].[Na+].[N:3]1[N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:6]2=[CH:5][CH:4]=1.CI.[C:14](OCC)(=O)C>CN(C)C=O>[CH3:14][N:11]1[CH2:10][CH2:9][CH2:8][N:7]2[N:3]=[CH:4][CH:5]=[C:6]12
Reactant: c1cc2n(n1)CCCN2
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCCn2nccc21
Reaction time: 1.5 h

Procedure:
To a suspension of 62% sodium hydride (1.41 g) in N,N-dimethylformamide (30 ml) was added 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (4.5 g) under ice-cooling. To this solution was added dropwise methyl iodide (2.27 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into ethyl acetate (50 ml), and the resulting precipitate was filtered off. The filtrate was evaporated to give 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.05 g).
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:66][C:67]([F:71])([F:70])[CH2:68][NH2:69]>CN(C=O)C>[F:66][C:67]([F:71])([F:70])[CH2:68][NH:69][C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:22])([F:23])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:3]1)=[O:8]
Reactant: NCC(F)(F)F
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 7, 0.1 g, 0.200 mmol) in DMF (3 mL) was added HOBt (0.026 g, 0.200 mmol), DIPEA (0.050 g, 0.392 mmol) followed by addition of EDCl.HCl (0.056 g, 0.294 mmol, 1.5 eq.) and 2,2,2-trifluoro-ethylamine hydrochloride (0.026 g, 0.200 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×20 mL). Combined organic layer was washed with water (5×30 mL), brine (50 mL), saturated NaHCO3 (50 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1% methanol in DCM to afford sticky mass, which was crystallized with pentane to afford white solid (0.065 g, 56%). 1H-NMR (400 MHz, CDCl3) δ: 2.77-2.83 (m, 3H), 2.96-3.08 (m, 2H), 3.68 (d, 1H, J=17.2 Hz), 3.92-4.00 (m, 2H), 4.08 (d, 1H, J=17.2 Hz), 5.70 (t, 1H, J=6.3 Hz), 7.52 (d, 2H, J=8.2 Hz), 7.64 (s, 2H), 7.70 (d, 2H, J=8.12 Hz); LC-MS (m/z): [M−H] 588.60.
Reaction SMILES: [F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][C:7]([C:15]3[O:16]C=CC=3)=[CH:6][C:5]=1[NH:4][C:3]2=[O:20].I([O-])(=O)(=O)=[O:22].[Na+]>C(#N)C.C(Cl)(Cl)(Cl)Cl.O.O.[Ru](=O)=O>[F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][C:7]([C:15]([OH:16])=[O:22])=[CH:6][C:5]=1[NH:4][C:3]2=[O:20]
Reactant: O=C1Nc2cc(-c3ccco3)ccc2C2CCCC12F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc2c(c1)NC(=O)C1(F)CCCC21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 0.5 g (1.8 mmol) of 3a-fluoro-7-(2-furanyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 63 ml of acetonitrile-carbon tetrachloride-water (2:1:2) is mixed with 5.9 g (27.6 mmol) of sodium periodate and 0.05 g (0.4 mmol) of ruthenium(IV) oxide, and it is stirred for 4 hours at room temperature. The batch is diluted with water and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is taken up in 0.5 M potassium hydroxide solution. This solution is washed with methyl-tert-butyl ether, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum: 0.31 g of product.
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.[CH2:8]=O.CO[C:12](=[O:29])[C:13]([OH:28])=[CH:14][C:15](=[O:27])[N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH3:17]>C(O)C>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[CH2:18][N:16]([CH3:17])[C:15]([C:14]1[CH2:1][N:2]([CH3:8])[C:12](=[O:29])[C:13]=1[OH:28])=[O:27]
Reactant: C=O
Reactant: CN
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Temperature: 60 °C
Yield: 54 %

Procedure:
A solution of 2 M methylamine in tetrahydrofuran (0.5 ml, 1.0 mmol) was added to a mixture of paraformaldehyde (0.3 g, 1.0 mmol, equivalent of formaldehyde) in anhydrous ethanol (1 ml) and the resulting mixture was heated at 60° C. for 5 min. Then a solution of 3-[(3,4-dichlorobenzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (0.318 g, 1.0 mmol) in ethanol (3 ml) was added all at once and the resulting mixture was maintained at 60° C. for another 20 min. The reaction mixture was then quenched by the addition of ethyl acetate and pH 2 phosphate buffer. The organic phase was washed with brine, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. Recrystallization of the solid residue from a mixture of ethyl acetate and hexane gave 0.180 g (54% yield) of the title material as a white solid: mp 148–150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][NH:29][CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([N:29]([CH3:30])[CH3:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CN(C)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Yield: 58.8 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (74 mg, 0.2 mmol), sodium hydride (8 mg, 0.3 mmol), N-phenyl(trifluoromethylsulfon)imide (101 mg, 0.28 mmol), and dimethylamine (2 M in THF, 2 mL, 4.0 mmol) are treated according to method E yielding 46 mg of the 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-dimethylaminoquinoline. This is treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (19 μL) and triethylamine (0.11 mL).
Reaction SMILES: [CH2:1]([CH:5]1[CH:9](O)[C:8]2[CH:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Oc2ccc(NC(C)=O)cc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCc1cc2cc(NC(C)=O)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of N-(2-butyl-3-hydroxy-2,3-dihydro-5-benzofuranyl)acetamide [9a] (2.50 g, 10.0 mmol), p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) and dichloromethane (30 mL) was stirred for 1 hour at room temperature and passed through short silica gel column. The column was washed with dichloromethane (300 mL). The solvent was evaporated under reduced pressure to give 2.11 g (91.3%) of N-(2-butyl-5-benzofuranyl)acetamide [10a] as off-white crystals with mp 71-73° C.