Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].C(O)(=O)C>C(O)C>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([CH2:4][N:5]2[C:9]3=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]3[N:7]=[C:6]2[CH3:18])=[C:2]([Cl:1])[CH:22]=1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc([N+](=O)[O-])cc3Cl)c2n1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Yield: 94.1 %

Procedure:
Methyl 3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (705 mg) was suspended in ethanol (6 ml) and reduced iron (655 mg) and acetic acid (2.11 ml) were added, which was followed by refluxing under heating for 3 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution to make the residue alkaline and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to give methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (608 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11](C(O)=O)=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[Cu]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][CH:11]=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc([N+](=O)[O-])cc2)c(-c2ccc(F)cc2)s1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Yield: 57.4 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-(4-nitrophenyl)thiophene-2-carboxylic acid (7.6 g) and copper powder (1.6 g) in quinoline (12 ml) was stirred and refluxed for 7 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, brine, dilute hydrochloric acid and brine, successively, dried and evaporated. The residue (7.3 g) was purified by column chromatography on silica gel (80 g) eluting with a mixture of hexane and toluene (2:1) to give yellow orange crystals of 2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (3.8 g).
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]([CH2:12][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C:20]#[CH:21].C(N(CC)CC)C.O>CN(C=O)C>[C:24]([O:23][C:19]([C:20]1[CH:21]=[C:12]([C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: C#CC(=O)OC(C)(C)C
Reactant: O=C(C[n+]1ccccc1)OCc1ccccc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C(=O)OCc2ccccc2)n2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 1-benzyloxycarbonylmethyl-pyridinium bromide (1.50 g, 9.74 mmol) and tert-butyl propiolate (1.34 mL, 9.74 mmol) in DMF (80 mL) was added a solution of triethylamine (4.1 mL, 29.2 mmol) in DMF (10 mL). The mixture was vigourously stirred 4 h at 60° C. under air atmosphere. The solution was allowed to cool to RT, poured into water and extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 8:2) to give the desired material. TLC, Rf (c-hexane/EtOAc 8:2)=0.6; MS (LC/MS): 725.3 [2M+Na]+; tR (HPLC conditions a): 4.84 min.
Reaction SMILES: [F:1][C:2]([F:22])([S:19]([O-:21])=[O:20])[C:3]([F:18])([F:17])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[Na+:23].[OH2:24].OO>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[F:22][C:2]([F:1])([S:19]([O-:24])(=[O:21])=[O:20])[C:3]([F:18])([F:17])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:10].[Na+:23]
Reactant: O
Reactant: O=C(OCCCCC(F)(F)C(F)(F)S(=O)[O-])C1CCCCC1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: O=C(OCCCCC(F)(F)C(F)(F)S(=O)(=O)[O-])C1CCCCC1
Reaction time: 1 h
Yield: 224.3 %

Procedure:
A glass flask equipped with a thermometer, a condenser and a dropping funnel was charged with 10.0 g (10.5 mmol) of sodium 1,1,2,2-tetrafluoro-6-cyclohexylcarbonyloxyhexane-1-sulfinate having a purity of 39% obtained by Comparative Example 1-2, a catalytic amount of sodium tungstate dihydrate, and 10 ml of water, followed by stirring. Then, 2.4 g (21.0 mmol) of 30% hydrogen peroxide water was added dropwise in an ice bath. After terminating the dropping, stirring was continued at room temperature for one hour. The reaction termination was confirmed by 19F NMR. After concentrating the reaction liquid, it was washed with 10 ml of diisopropyl ether, followed by filtration and drying the obtained solid matter. After that, there was obtained as a white-color solid matter 9.1 g (yield 90%, purity 40%) of sodium 1,1,2,2-tetrafluoro-6-cyclohexylcarbonyloxyhexane-1-sulfonate. Upon this, 7% of 6-bromo-5,5,6,6-tetrafluorohexane cyclohexanecarboxylate was produced as a by-product.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+]>C(#N)C>[F:15][CH:11]([F:16])[O:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=Cc1cccc(O)n1
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cccc(OC(F)F)n1
Temperature: 70 °C
Yield: 42.7 %

Procedure:
To a solution of 6-hydroxypicolinaldehyde (2 g, 16.24 mmol) in acetonitrile (20 mL) was added sodium 2-chloro-2,2-difluoroacetate (4.46 g, 29.24 mmol) at room temperature. The reaction mixture was heated at 70° C. for 18 h. The reaction mixture was cooled to room temperature and the solid was filtered off. Then the crude material was purified via flash chromatography (100-200 mesh silica gel, 10% ethyl acetate in hexane) to afford the title compound (1.2 g, 42.85%). MS (ES+) (M+H) 174.10
Reaction SMILES: CC(N(C)C)=O.Cl[C:8]1[S:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]=1>O>[N:22]1([C:8]2[S:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: c1ccc2[nH]cnc2c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1sc(-n2cnc3ccccc32)nc1C(F)(F)F
Temperature: 25 °C
Yield: 287.7 %

Procedure:
A reaction vessel was charged with 150 ml dimethylacetamide, 13.0 g (50 mmol) ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate and 11.8 g (100 mmol) benzimidazole. The reaction mixture was heated at a temperature of 115°-125° C. for 96 hours. The mixture was cooled to room temperature, diluted with water and extracted three times with ethyl ether. The combined ether extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to provide 49.1 g of a dark gold oil. This oil was subjected to Kugelrohr distillation (90° C. @0.5 mm Hg) to provide 31.7 g of a yellow oil product identified in Table I.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]3=[O:33])[C:10]([OH:17])([C:13]([F:14])([F:16])[F:15])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cn1ncc2c(N)cccc2c1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 4 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 114 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 3, 50 mg of imine is reacted by reaction with 0.23 ml of titanium tetrachloride, and 12 mg of the title compound is obtained.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][C:44]=1[F:52]>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([Cl:42])=[C:44]([F:52])[CH:45]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(Cl)c(F)c2)c1
Yield: 40 %

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 4-chloro-3-fluorophenylboronic acid. LC/MS indicated a purity of 92% as measured by UV 214 nM. Yield: 40% (after two steps)
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:15][C:16]1[CH2:20][CH:19]=[C:18]([CH3:21])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].Cl.C([O-])(O)=O.[Na+]>>[CH3:21][C:18]1[CH2:19][CH:20]=[C:16]([CH3:15])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1=CCC(C)=C1c1ccccc1N
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC1=CCC(C)=C1c1ccccc1NC(=O)C(C)(C)C
Yield: 102.2 %

Procedure:
0.130 g (1.29 mmol) of triethylamine and 0.155 g (1.29 mmol) of pivaloyl chloride were added to 0.263 g (1.42 mmol) of 2-(2,5-dimethylcyclopenta-1,4-dienyl)phenylamine solution melted in 10 mL of MC solvent, and then reacted at room temperature for 1 hour. 5 mL of 2N HCl was added to the reaction product and strongly stirred for a few minutes. The organic layer was neutralized using 5 mL of NaHCO3, and the product was filtered using a column chromatography with a hexane/ethyl acetate (v/v, 10:1) solvent. The refined product was dried in vacuum to remove the solvent therein, thereby obtaining while solid (0.355 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[CH:6]=[N:7]/[NH:8][C:9](=[O:19])[CH:10]([O:17][CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I[CH3:26].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[CH:6]=[N:7]/[N:8]([CH3:26])[C:9](=[O:19])[CH:10]([O:17][CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: COc1ccc(/C=N/NC(=O)C(OC)c2ccccc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(/C=N/N(C)C(=O)C(OC)c2ccccc2)cc1OC
Reaction time: 2 h
Yield: 70 %

Procedure:
(E)-N′-(3,4-Dimethoxybenzylidene)-2-methoxy-N-methyl-2-phenylacetohydrazide (12-70) was synthesized according to the method used for the preparation of Example 6. To a solution of (E)-N′-(3,4-dimethoxybenzylidene)-2-methoxy-2-phenylacetohydrazide (12-21) (0.56 g) in anhydrous DMF in an oven-dried flask under argon was added iodomethane (1 eq) then NaH (60% in oil; 1.1 eq) was added and the mixture stirred for 2 hours. The reaction was quenched with brine and further diluted with water. The aqueous mixture was extracted with EtOAc and the combined organics were washed with water three times, brine once, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography provided the product (12-70) (0.4 g, 70%).
Reaction SMILES: ClC1C=C(F)C=CC=1CN[C:11](=[O:20])[C@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[CH2:18][CH3:19].[F:21][C:22]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH2:18]([N:13]1[C:14](=[O:17])[CH2:15][CH2:16][C@H:12]1[C:11]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:31])([F:32])[F:33])[C:22]=1[F:21])=[O:20])[CH3:19]
Reactant: CCN1C(=O)CC[C@@H]1C(=O)NCc1ccc(F)cc1Cl
Reactant: NCc1cccc(C(F)(F)F)c1F
Product: CCN1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1F

Procedure:
1-ethyl-N-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-5-oxoprolinamide was prepared in a manner analogous to that described above (see example 70) for N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxo-D-prolinamide but using 2-fluoro-3-trifluoromethylbenzylamine in the place of 2-chloro-4-fluorobenzylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].[N:12](OCCC(C)C)=O.Cl.C(N)(=O)C>CCCCO.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[N:12][S:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Reactant: CC(C)CCON=O
Agent: CC(N)=O
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc2nnsc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.7 %

Procedure:
To a solution of 2-Amino-5-nitrobenzenethiol (5b) (6.0 g, 35.3 mmol) in n-BuOH (30 mL), cooled to 0° C., a solution of Isoamyl nitrite (5.0 mL, 37.1 mmol) in n-BuOH (30 mL) was added followed by conc. HCl (5.0 ml). The reaction mixture was warmed to room temperature and stirred for 5 h. To the resulting reaction mixture Acetamide (0.4 ml) was added and stirred for another 30 min at room temperature. After completion of reaction (by TLC), the reaction mixture was diluted with H2O (80 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine solution (100 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography to afford 6-Nitrobenzo[d][1,2,3]thiadiazole (5c) (3.5 g, 54%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[C:9]([NH:10][C:11]([NH:13][CH2:14][CH2:15]Cl)=[O:12])=[CH:8][S:7][CH:6]=1)([O:3]C)=O.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+].[I-].[Na+].[OH-].[Na+]>O1CCCC1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:15][CH2:14][N:13]2[C:1](=[O:3])[C:5]3=[CH:6][S:7][CH:8]=[C:9]3[NH:10][C:11]2=[O:12])[CH2:28][CH2:27]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COC(=O)c1cscc1NC(=O)NCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
A 500 ml tetrahydrofuran mixture containing 13.1 g (50 mmol) of N-(3-carbomethoxythien-4-yl)-N'-(2-chloroethyl)urea from (a), 35 g (150 mmol) of 1-(2-methoxyphenyl)piperazine hydrochloride, 21 g (250 mmol) of sodium bicarbonate and 3.75 g (25 mmol) of sodium iodide was heated to reflux under nitrogen for 4 days. The tetrahydrofuran was removed in vacuo and the residue was partitioned between H2O and CH2Cl2. The CH2Cl2 extracts were dried over MgSO4 and evaporated to dryness. This residue which contained the title compound of Example 2 was dissolved in 300 ml of methanol and treated with 4.5 g (56 mmol) of 50% NaOH. After the solution had been stirred at room temperature for 16 hours, the resulting precipitate was collected by filtration to afford 9.7 g of the title compound. The filtrate was purified by flash silica gel chromatography using 1-5% MeOH in CH2Cl2. There was obtained an additional 3.4 g of the title compound (13.1 g total, 68%) which was converted to its hydrochloride salt with isopropanolic hydrogen chloride, 9.1 g, mp 273°-275° C. (dec).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[N:21][CH:22]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][N:21]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)nc1
Temperature: 100 °C
Reaction time: 42 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.6 g, 2.419 mmol) in toluene (4.84 mL) was added 5-methyl-2-(tributylstannyl)pyridine (1.02 g, 2.66 mmol), and palladium tetrakistriphenylphosphine (0.280 g, 0.24 mmol). The reaction was stirred at 100° C. and stirring continued for 42 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-pyridinyl)-quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:32])[CH2:13][NH:14][C@H:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][C:19]([O:25][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:20][CH:21]=4)[CH2:16]3)=[CH:11][C:5]=2[CH2:4][O:3]1.Cl.C(=O)(O)[O-].[Na+]>COCCOC>[OH:32][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][C@H:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:20][CH:21]=2)[CH2:16]1
Reactant: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc3c(c1)COC(C)(C)O3)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(O)c(CO)c1)CC2
Yield: 81.1 %

Procedure:
(-)-2-[(2S)-2-[[(2R)-2-(2,2-Dimethylbenzo[1,2-d]-1,3dioxan-6-yl)-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (192 mg) was dissolved in 3.8 ml of 1,2-dimethoxyethane, 4.2 ml of 1 N hydrochloric acid was added to the solution with stirring under ice-cooling, and the mixture was subjected to 2 hours of reaction at room temperature. The reaction solution was neutralized by adding an aqueous saturated sodium bicarbonate solution and then concentrated to dryness under reduced pressure. Tetrahydrofuran and ethanol were added to the resulting residue and insoluble materials were removed by filtration. The resulting filtrate was concentrated under reduced pressure, and the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate/ethanol=5/1) and then recrystallized from methanol to give 142 mg of (-)-2-[(2S)-2-[[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (Compound 6) having a melting point of 175 to 176° C.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OCO1
Reactant: [H][H]
Agent: N
Solvent: CO
Solvent: O
Product: NCC[C@@H]1C[C@H](CC(=O)O)OCO1
Temperature: 45 °C
Yield: 60.6 %

Procedure:
A solution of 1.04 g (4.88 mmol) of (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45° C. and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (±)-cis-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=3Br)=[CH:11][CH:12]=2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:6][C:5]1([CH3:33])[CH3:32])(=[O:3])[CH3:2].[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:11][CH:12]=2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:6][C:5]1([CH3:33])[CH3:32])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)N1c2ccc(NC(=O)c3cccc(C)c3Br)cc2C(C)(c2ccccc2)CC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: CC(=O)N1c2ccc(NC(=O)c3cccc(C)c3-c3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Suzuki cross-coupling of 1-acetyl-4-phenyl-6-(2-bromo-3-methylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (16 mg), benzeneboronic acid (25 mg), cesium fluoride (21 mg), triphenylphosphine (7.0 mg) and tris(dibenzylideneacetone)dipalladium(0) (6.0 mg) in dimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performed according to the method described in example 13.
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]([CH:30]=[O:31])=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=[C:26]3[C:21]=2[C:22](=[O:37])[CH2:23][C:24]([CH3:36])([CH3:35])[O:25]3)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:30]([OH:31])[C:29]2[C:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[C:21]3[C:26](=[CH:27][C:28]=2[CH:32]([CH3:34])[CH3:33])[O:25][C:24]([CH3:35])([CH3:36])[CH2:23][C:22]3=[O:37])=[CH:4][CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC(C)(C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 2.12 ml (1.06 mmol) of a freshly prepared 0.5 M solution of bromo(4-tert-butylphenyl)magnesium in tetrahydrofuran are slowly added dropwise to a solution of 300 mg (880 μmol) of 5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 20A) in 7 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, the solvent is then removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1).