Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:18][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=3)[CH2:10][C@@H:5]2[CH2:4]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:1][CH2:2][C@@H:3]2[CH2:18][N:6]3[CH2:7][CH2:8][N:9]([C:11]4[N:12]=[CH:13][C:14]([F:17])=[CH:15][N:16]=4)[CH2:10][C@@H:5]3[CH2:4]2)=[CH:22][CH:21]=1
Reactant: OC[C@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OC[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Yield: 53.9 %

Procedure:
A solution of 0.25 g (0.99 mmol) of (7S,8aS)-7-hydroxymethyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 13), 0.167 g (1.49 mmol) of 4-fluorophenol, 0.31 g (1.19 mmol) of triphenylphosphine and 0.19 mL (1.2 mmol) of diethyl azodicarboxylate (DEAD) in 10 mL of dry THF was stirred at ambient temperature for 16 h. The solvent was evaporated, the residue was dissolved in chloroform and washed with 1M sodium hydroxide. The organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 1:1 hexane:ethyl acetate and a second chromatography with 3:1 hexane:ethyl acetate gave 0.185 g (54%) of the title compound. mp (.HCl) 207.5°-208° C. 13C NMR (base, CDCl3) δ 31.7, 35.2, 43.8, 49.1, 51.4, 56.6, 62.3, 72.5, 115.5, 115.6, 115.9, 144.9, 145.2, 149.9, 153.2, 155.1, 155.6, 158.8, 158.9. m/z (MH+) 347.
Reaction SMILES: [NH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1C(OC)=O)[NH2:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([F:24])=[C:20]([F:23])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:25](OCC)=[O:26]>C(O)C>[F:24][C:19]1[C:20]([F:23])=[CH:21][C:22]2[C:13]3[C:14]([C:25](=[O:26])[N:1]([C:3]4[CH:7]=[CH:6][S:5][CH:4]=4)[N:2]=3)=[CH:15][NH:16][C:17]=2[CH:18]=1
Reactant: COC(=O)c1sccc1NN
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl
Solvent: CCO
Product: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccsc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.05 equiv. of methyl 3-hydrazinylthiophene-2-carboxylate was added to a solution of 3c in ethanol. After 1.5 hr of stirring at room temperature, the solution was concentrated in vacuo and residue was dissolved in chloroform and washed with aq. Sodium bicarbonate solution, dried and concentrated in vacuo. The resulting solid was suspended in ethanol and stirred with 1N sodium hydroxide solution for 30 minutes, acidified with acetic acid and concentrated in vacuo. The solid was filtered, washed with water, dried and suspended in ethanol. 1N sodium hydroxide was added and the reaction mixture was refluxed for 1 hr, acidified with acetic acid and the crystals were collected by filtration. The yellow solid was combined with copper powder and quinoline and stirred at 190° C. for 1 hour. The copper was removed by filtration and the filtrate was mixed with 1N sodium hydroxide solution, followed by extraction with ether. The separated aqueous layer was treated with active charcoal, acidified with acetic acid to yield compound 41 as yellow solid. 1H-NMR (DMSO-d6) δ (ppm):7.58 (1H, dd, J=5.22, 3.30 Hz), 7.69 (1H, dd, J=11.26, 7.14 Hz), 7.74 (1H, dd, J=5.22, 1.38 Hz), 7.80 (1H, m), 8.15 (1H, dd, J=10.7, 8.2 Hz), 8.77 (1H, d, J=6.2 Hz). m/z 304.2 (MH+).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[O:18]1[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22].[CH2:25]([OH:27])[CH3:26]>C(Cl)Cl>[CH2:25]([O:27][CH2:20][C@H:19]([OH:18])[C:21]([O:23][CH3:24])=[O:22])[CH3:26]
Reactant: COC(=O)[C@@H]1CO1
Reactant: CCO
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC[C@H](O)C(=O)OC
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
Magnesium trifluoromethanesulphonate (11.85 g, 36.73 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (15.0 g, 146.93 mmol) and ethanol (10.29 ml, 176.32 mmol) cooled to 10° C. The resulting suspension was stirred at 10° C. for 20 minutes, allowed to warm to ambient temperature and then warmed to 50° C. for 30 hours. The mixture was allowed to cool and diluted with 9:1 DCM:ether (75 mL), filtered through Celite and washed through with 9:1 DCM:ether (3×50 mL) and evaporated. The residue was purified by flash silica chromatography, elution gradient 10 to 50% Et2O in DCM to give methyl (2S)-3-ethoxy-2-hydroxypropanoate (11.6 g, 53%). 1H NMR (400 MHz, CDCl3) δ 1.19 (3H, t), 3.00 (1H, d), 3.47-3.58 (2H, m), 3.72 (2H, d), 3.81 (3H, s), 4.23-4.34 (1H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:11][OH:12])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.[H-].[Na+].[CH2:15](I)[CH3:16].O>CN(C)C=O>[CH3:10][C:6]1([CH3:9])[O:5][CH2:4][C:3]([CH2:11][O:12][CH2:15][CH3:16])([CH2:2][OH:1])[CH2:8][O:7]1
Reactant: CC1(C)OCC(CO)(CO)CO1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCC1(CO)COC(C)(C)OC1
Reaction time: 2 h

Procedure:
To a stirred solution of 5,5-di-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane (5.0 g) (Beilstein 19, II, 93) in dry dimethylformamide (50 ml) under nitrogen, at 20°, was added sodium hydride (0.68 g, 80% dispersion in oil). The mixture was stirred at 80° for 2 hours and cooled. Ethyl iodide (4.4 g) in dry dimethylformamide (40 ml) was added and the mixture was heated at 110° for 3 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with brine, dried over anhydrous magnesium sulphate and evaporated in vacuo. 2,2-Dimethyl-5-ethoxymethyl-5-hydroxymethyl-1,3-dioxane was obtained as a pale yellow oil (1.2 g) and was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26](=O)[CH2:27][C:28]([CH3:30])=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH3:33][NH:34][NH2:35]>>[CH3:33][N:34]1[C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:32])[S:12][CH:13]=2)=[CH:27][C:28]([CH3:30])=[N:35]1
Reactant: CNN
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)CC(C)=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cc(C)nn1C

Procedure:
A compound obtained using 2-[(4-{2-[acetoacetyl(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 446-1 and methylhydrazine, and by an operation similar to that of Example 446 was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: B(Br)(Br)Br.[ClH:5].[CH3:6][C:7]1[N:11]([C:12]2[N:17]=[C:16]([O:18]C)[CH:15]=[C:14]([CH3:20])[N:13]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:37])[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH2:25]1.O>C(Cl)Cl>[ClH:5].[CH3:6][C:7]1[N:11]([C:12]2[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:20])[N:13]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:37])[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH2:25]1
Reactant: COc1cc(C)nc(-n2ncc(C(=O)CCN3CCN(c4ccccc4C)CC3)c2C)n1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)nc(-n2ncc(C(=O)CCN3CCN(c4ccccc4C)CC3)c2C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.9 %

Procedure:
300 mg of boron tribromide was added to 3 ml of methylene chloride and the obtained solution was cooled. Into the solution was dropped a solution of 470 mg of 1-[5-methyl-1-(4-methoxy-6-methyl-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-methylphenyl)-1-piperazinyl]-1-propanone hydrochloride in 100 ml of methylene chloride. After stirring at room temperature for 72 hours, water was added and the mixture was extracted with methylene chloride twice. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (silica gel 800 g, chloroform:methanol=10:1-5:1). Then the obtained product was converted into hydrochloride by adding a 1N hydrochloric acid/ethanol solution and recrystallized from ethanol to thereby give 150 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[H-].[Na+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2[C:34](=CC=CC=2)[O:33][CH2:32]1.COCBr.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[CH:23]=[CH:22][N:21]([CH2:32][O:33][CH3:34])[N:20]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4cc[nH]n4)ccc3n(C)c21
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Agent: COCBr
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: COCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n1
Reaction time: 0.08 h

Procedure:
303 mg (0.81 mmol) of compound B 3-(4-fluorophenyl)-1,9-dimethyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one are dissolved in 8 ml of DMF. 50 mg (1.22 mmol) of 60% NaH and a spatula of dibenzo-18-crown-6 are added. After stirring for 5 minutes, 73 μl (0.89 mmol) of bromomethyl methyl ether are added. The mixture is left to stir for 4 h at ambient temperature. A saturated NaHCO3 solution is added, the mixture extracted with EtOAc, and the organic phase is dried over MgSO4, filtered, and concentrated to dryness, adsorbing onto silica. The mixture is enriched in beta isomer by chromatography on a silica column, elution being carried out with 70/30 EtOAc/cyclohexane (ratio obtained: 62/38 beta/alpha) and then by means of a second purification by chromatography on a silica column, elution being carried out with 60/40 EtOAc/cyclohexane.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.[C-:21]#[N:22].[K+].O>CS(C)=O>[C:21]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:22]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1CC#N
Temperature: 90 °C

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-(methylsulfonyloxymethyl)cyclohexyl]carbamate (1.8 g) in dry DMSO was added with potassium cyanide (0.52 g, 7.76 mL) and the mixture was then heated at 90° C. under N2 for 4 hours. The mixture was cooled and then poured on to water (50 mL) and extracted with ether (3×30 mL). The combined organic phases were washed with brine and concentrated in vacuo to provide the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[C:18]([Cl:20])=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[Cl:20][C:18]1[C:17]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:16][C:14]2[NH:15][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12][C:13]=2[CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)(=O)C(C)C)cc3[nH]2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)c1cc2[nH]c(-n3cc(C(=O)O)cn3)nc2cc1Cl
Temperature: 23 °C
Reaction time: 56 h
Yield: 87.8 %

Procedure:
To a solution of 1-[5-chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.179 mg, 0.451 mmol), THF (1.7 mL), and water (0.55 mL) was added LiOH.H2O (56.8 mg, 1.35 mmol). The mixture was sonicated briefly, and stirred at 23° C. for 56 h. The solvent was evaporated, water was added, and the resulting solution was acidified to pH 1 with 1M aq. HCl. The precipitate was collected to yield the titled compound (0.146 g, 86% yield). MS (ESI/CI): mass calcd. for C14H13ClN4O4S, 368.0; m/z found, 369.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6, tautomeric broadening): 14.07 (s, 1H), 13.03 (s, 1H), 8.95 (d, J=0.4 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 8.09-7.64 (m, 1H), 3.88-3.76 (m, 1H), 1.22 (d, J=7.9 Hz, 6H).
Reaction SMILES: C([NH:4][CH2:5][C:6]1[C:17]2=[C:18]3[N:13]([CH:14]([CH3:19])[CH2:15][CH2:16]2)[CH:12]=[C:11]([C:20]([O:22]CC)=[O:21])[C:10](=[O:25])[C:9]3=[CH:8][CH:7]=1)(=[O:3])C.Cl.C([O-])(=O)C.[Na+].C>O>[OH2:3].[NH2:4][CH2:5][C:6]1[C:17]2=[C:18]3[N:13]([CH:14]([CH3:19])[CH2:15][CH2:16]2)[CH:12]=[C:11]([C:20]([OH:22])=[O:21])[C:10](=[O:25])[C:9]3=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cn2c3c(c(CNC(C)=O)ccc3c1=O)CCC2C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1CCc2c(CN)ccc3c(=O)c(C(=O)O)cn1c23

Procedure:
The product ethyl 8-acetamidomethyl-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate (1.0 g) from Example 6 was mixed with 25 ml of 6 N hydrochloric acid, and the mixture was heated at reflux for two hours. The mixture was evaporated to dryness, and the residue was triturated with isopropyl alcohol. The solid obtained was dissolved in 20 ml of water. One gram of sodium acetate was added, and the mixture was treated with decolorizing charcoal and filtered. The volume of the solution was reduced to 5 ml, and 5 ml of isopropyl alcohol was added. Seeding was used to provide white crystals of 8-aminomethyl-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrate, m.p. 228°-250° C. (dec.). Analysis: Calculated for C15H16N2O3.1/2H2O: %C, 64.0; %H, 6.1; %N, 10.0; Found: %C, 63.9, %H, 5.9; %N, 9.7. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 10 g of 4-hydroxybenzoic acid in 100 ml of N,N-dimethylformamide were added 29.1 g of 4-chlorobenzyl chloride and 25 g of potassium carbonate. The mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was treated with ethyl acetate-water. The resulting ethyl acetate layer was separated, washed with water, dried with anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent. The resulting residue was washed with n-hexane, then collected by filtration, and suspended in 50 ml of ethanol. To the suspension was added 100 ml of a 2N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 4 days and then neutralized with concentrated hydrochloric acid. The resulting crystals were collected by filtration and recrystallized from chloroform to obtain 16.7 g of 4-(4-chlorobenzyloxy)benzoic acid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([NH2:42])([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C[O-].[Na+].Cl>O.CC(N(C)C)=O>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][C:35]([CH2:38][C:39]([OH:41])=[O:40])([NH:42][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CC(=O)O)CC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)O)(NC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CC1
Temperature: 150 °C
Yield: 51.6 %

Procedure:
A 20-mL scintillation vial was charged with 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol), 4-amino-4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (322 mg, 1.25 mmol), NaOMe (59 mg, 1.09 mmol) and dimethylacetamide (3 mL). It was close-capped and heated in a 150° C. oil bath for 4 h. Reaction mixture was diluted with water (70 mL) and acidified by 1 N HCl to pH=4-5. Precipitate was collected, rinsed with water and dried. Crude product was purified by silica gel chromatography, eluting with 10-100% EtOAc/hexanes, to provide the title compound 92 mg (0.16 mmol) in 54% yield. LC-MS ESI−: 545.08 (M−1)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si:28]([CH3:33])([CH3:32])[CH2:29][CH2:30]O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][Si:28]([CH3:33])([CH3:32])[CH2:29][CH2:30][O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: C[Si](C)(C)CCO
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a solution of 5-benzyloxy-2-(2-tert-butoxycarbonyl-vinyl)-benzoic acid (5.50 g, 15.5 mmol) in CH2Cl2 (100 mL) was added 2-trimethylsilyl-ethanol (3.67 g, 31.0 mmol), EDC (5.36 g, 27.9 mmol), and DMAP (3.67 g, 31.0 mmol). The resulting mixture was stirred at room temperature for 12 h, washed with aqueous NH4Cl (150 mL), and extracted with CH2Cl2 (100 mL). The combined organics were dried (Na2SO4) and concentrated. The residue was purified using silica gel chromatography (hexanes/EtOAc 9/1) to afford the title compound as an oil (5.90 g, 84%). 1H NMR (400 MHz, CDCl3): δ 0.07 (s, 9H), 1.14 (t, 2H, J=8.8 Hz), 1.52 (s, 9H), 4.41 (t, 2H, J=8.8 Hz), 5.10 (s, 2H), 6.20 (d, 1H, J=15.6 Hz), 7.13 (dd, 1H, J=3.0, 8.3 Hz), 7.34-7.44 (m, 5H), 7.50 (d, 1H, J=3.0 Hz), 7.53 (d, 1H, J=8.8 Hz), 8.41 (d, 1H, J=16.1 Hz).
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:30])[NH:25]2>>[OH:1][C:2]([C:15]([F:16])([F:17])[F:18])([CH2:5][C:6]([CH3:7])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:14])[CH:3]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:30])[NH:25]2
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Product: CC(C)(CC(O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccccc1

Procedure:
Analogously to Example 13, 600 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 337 mg of 5-aminoquinolin-2(1H)-one (52313) are converted into 570 mg of product.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C@H:7]1[CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:5].[C:29]([OH:37])(=[O:36])[C@H:30]([CH2:32][C:33]([OH:35])=[O:34])[OH:31]>CC(C)=O>[C:29]([OH:37])(=[O:36])[CH:30]([CH2:32][C:33]([OH:35])=[O:34])[OH:31].[NH2:1][C@H:2]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C@H:7]1[CH2:13][O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:5]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Solvent: CC(C)=O
Product: O=C(O)CC(O)C(=O)O
Reaction time: 0.5 h

Procedure:
498 mg of the compound obtained in Example 11 was dissolved in 4 mL of acetone to which a solution of 166 mg of L-malic acid in 1 mL of acetone was then slowly added followed by stirring for 30 min. The reaction mixture was concentrated, to which 2 mL of ethyl acetate and 1 mL of 2-propanol were then added followed by stirring. 15 mL of hexane was added thereto, and the resulting mixture was stirred for 10 min and filtered to afford 506 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][O:8][C:9]([O:19][CH3:20])([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.O>O1CCCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:7][O:8][C:9]([C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:1][CH3:2])([O:19][CH3:20])[CH3:18]
Reactant: COC(C)(OC)C(=O)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC=C(c1ccccc1)C(C)(OC)OC
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
At 5° C., a solution of 2.5 g of potassium tert-butoxide in 25 ml of tetrahydrofuran (THF) was added dropwise to 8.2 g of ethyltriphenylphosphonium bromide dissolved in 50 ml of THF. The mixture was then stirred at 5° C. for about 10 min, and a solution of 3.9 g of 2,2-dimethoxy-1-phenylpropan-1-one from Example 1 in 10 ml of THF was added dropwise. The reaction mixture was stirred at 20 to 25° C. for 72 h and then admixed with about 300 ml of water and extracted with methyl tert-butyl ether (MTBE). The organic phases were washed with water, dried and freed of the solvent. Silica gel chromatography (MTBE/cyclohexane 1:10) of the residue gave 2.2 g of product as an isomer mixture which can be further reacted without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.Br[CH:28]([CH2:36][CH3:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[O:11]=[C:10]([C:12]1[S:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:28]([CH2:36][CH3:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:3][CH:4]=1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: O=C(CCc1ccc(O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)C(=O)OC(C)(C)C

Procedure:
Tert-butyl 2-(4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)butanoate is prepared from 3-(4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)-phenyl)thien-2-yl)propan-1-one and tert-butyl 2-bromobutanoate according to general procedure D.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[C:10](/[CH:12]=[CH:13]/[CH2:14][O:15][CH3:16])[N:9]=[C:8](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])[CH:7]=2)[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:7]=[C:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[N:9]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:11]=2)[CH2:3][CH2:2]1
Reactant: COC/C=C/c1cc(C(=O)NC2CC2)cc(/C=C/COC)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1cc(C(=O)NC2CC2)cc(CCCOC)n1
Reaction time: 24 h

Procedure:
To a solution of N-cyclopropyl-2,6-bis[(1E)-3-methoxyprop-1-en-1-yl]isonicotinamide from the previous step (1 eq.) in EtOAc (0.2 M) was added palladium (10% w/w over activated carbon, 40% loading). The reaction vessel was evacuated and back-filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 24 h. The reaction was quenched with CH2Cl2, filtered through celite and the insolubles washed further with EtOAc. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO2, 1:1 (v/v) Hex:EtOAc→1:4 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.