Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1NC(CCc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)NC(=O)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
7-Chloro-3-(2-chlorophenethyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.0 g, 1 eq), 1-(chloromethyl)-4-methoxybenzene (448 mg, 1 eq), and potassium carbonate (1.19 g, 3 eq) were suspended in DMF (11.5 mL), and the mixture was stirred at room temperature overnight. Water was then added and the mixture was stirred for 30 minutes. The solid was collected by filtration, and the solid was returned to a flask and concentrated from toluene to remove water. The crude material was purified by chromatography (gradient: 9:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) yielding a white solid (970 mg, 72% yield). 1H-NMR (300 MHz, DMSO-d6) δ 8.90 (d, 1H), 7.60-7.50 (m, 3H), 7.38-7.17 (m, 4H), 6.97 (d, 2H), 6.78 (d, 2H), 5.32 (d, 1H), 4.81 (d, 1H), 3.80 (m, 1H), 3.65 (s, 3H), 2.74 (t, 2H), 2.10 (m, 1H), 1.90 (m, 1H). MS (ES+) m/z 490.9 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[H-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[S:31](Cl)(=[O:33])=[O:32])[C:24]([O:26]C)=[O:25].O>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[S:31]([N:6]([CH2:5][C:4]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=1[O:2][CH3:1])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1)(=[O:33])=[O:32])[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2Cl)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 8.4 g, 33.4 mmol, 1 eq) in THF (80 ml) was added 60% sodium hydride (2.0 g, 50.2 mmol, 1.5 eq) portionwise. The mixture was stirred for 15 minutes before the addition of methyl 3-chloro-4-(chlorosulfonyl)benzoate (Preparation 5, 9 g, 33.4 mmol, 1 eq) then stirred for a further 30 minutes. The reaction mixture was added to water (20 ml) and the THF evaporated in vacuo. The residue was diluted with water (200 ml), extracted with ethyl acetate (2×200 ml) and DCM (100 ml). The combined organics were dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][C:12]1=[O:24])[CH2:5][C@H:6]1[CH2:9][C@H:8]([CH3:10])[CH2:7]1.O.O.[OH-].[Li+]>O1CCCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH2:15][N:11]([CH:4]([CH2:5][C@H:6]2[CH2:7][C@H:8]([CH3:10])[CH2:9]2)[C:3]([OH:25])=[O:2])[C:12](=[O:24])[CH:13]=1
Reactant: COC(=O)C(C[C@H]1C[C@H](C)C1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1C[C@H](CC(C(=O)O)N2CC(Oc3ccccc3Cl)=CC2=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
In a flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (107 mg, 0.29 mmol) dissolved in a 1:1 solution of tetrahydrofuran:water (8 mL). To this mixture was added lithium hydroxide monohydrate (25 mg, 0.58 mmol) and the resulting mixture stirred for 1.5 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and partioned between 1N aqueous hydrochloric acid (10 mL) and ethyl acetate (10 mL). The organic layer was separated and dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid (102 mg, 100%) as a light amber semi-solid: HR-ES-MS m/z calculated for C18H20NO4Cl [M+H]+ 350.1154, observed 350.1154.
Reaction SMILES: [Na].[Cl:2][CH2:3][C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.O.[O:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1(C)C(C)=CC=CC=1.C(O)CO>[Cl:2][CH2:3][C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[OH:23][CH2:28][CH2:27][O:26][CH2:25][C:24]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C1COCCO1
Agent: Cc1c(-c2ccccc2)oc2c(CCl)cccc2c1=O
Agent: [Na]
Solvent: O
Solvent: OCCO
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)oc2c(COCCO)cccc2c1=O
Temperature: 25 °C

Procedure:
A solution of 2.5 g of Intermediate XIX in 25 ml of xylene and 3 ml of dioxane was prepared. 0.15 g of sodium was dissolved in 3.10 ml of anhydrous ethylene glycol, and this solution was added dropwise at ambient temperature to the solution of Intermediate XIX. After refluxing for 5.5 hours, the reaction mixture was cooled to ambient temperature and poured into 50 ml of water. It was extracted with dichloromethane, and the extract was washed with sodium chloride solution, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. The solid residue was crystallized from ethanol, giving 2.1 g of the title compound, m.p. 132°-133° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.C1C[O:27]CC1>>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:27])=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccccc1Cc1ccc(F)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1

Procedure:
A 1 M solution of lithium aluminum hydride in THF (258 ml, 258 mmol) was added dropwise to a solution of the mixture of 2-(4-fluorobenzyl)benzoic acid and the starting material 2-(4-fluorobenzoyl)benzoic acid, which was isolated in step 1, in THF (200 ml). The reaction mixture was heated to reflux for 2 hours. It was cooled to 0° C. Carefully, methanol (100 ml) and water (50 ml) were added successively. A 10% aqueous solution of sodium hydrogensulphate (500 ml) and a 1 N solution of sodium chloride in water were added. The phases were separated. The aqueous phase was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (600 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. 5.23 g of [2-(4-fluorobenzyl)phenyl]methanol were isolated by flash chromatography on silica (200 g), using ethyl acetate/heptane 1:1 as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[S:15][CH:16]=[C:17](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])[N:18]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[S:15][CH:16]=[C:17](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])[N:18]=3)[CH2:9]2)=[O:7])=[CH:26][CH:27]=1
Reactant: CCOC(=O)/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
The mixture of ethyl (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylate (0.9 g) and 1N-NaOH (4.4 mL) in MeOH (14 mL) was stirred at 50° C. for 3 hours and the mixture was evaporated in vacuo. To the residue was added a solution of AcOEt, THF and water, and the mixture was adjusted to pH 4 with 1N-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)acrylic acid (0.64 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][CH2:14][OH:15])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CCCCCCCC(C([NH3+])(C(CCCCCCC)=O)C(CCCCCCC)=O)=O.[Cl-].[Cl-].C([N+](C(=O)CCCCCCC)(C(=O)CCCCCCC)C)(=O)CCCCCCC>CS(C)=O>[CH2:10]([N:12]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:13][CH2:14][OH:15])[CH3:11]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCNCCO
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: CCCCCCCC(=O)[N+](C)(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCN(CCO)c1ccc(C=O)cc1
Temperature: 95 °C
Reaction time: 0.17 h

Procedure:
A one liter three-neck flask, fitted with mechanical stirrer, thermometer, and condenser, was charged with 25 g (0.2 mol) of 4-fluorobenzaldehyde), 54 g (0.6 mol) of 2-(ethylamino)ethanol, 41.5 g (0.3 mol) of anhydrous potassium carbonate, and 0.5 ml ALIQUAT-336™ (tricaprylyl methylammonium chloride) (Henkel Corp.) in 250 ml dimethylsulfoxide ("DMSO"). The reaction mixture was heated at 95° C. for 72 hours, cooled to room temperature, and then poured into an ice water mixture. The water layer was extracted with dichloromethane, and the combined organics were washed twice with cold water. After solvent evaporation, the red-colored oil was dissolved in 200 ml of ether and poured into 800 ml of 1N aqueous HCl. After stirring for 10 minutes, the water layer was separated and neutralized using aqueous sodium carbonate. 200 ml dichloromethane were added, and the organic layer was separated and dried with anhydrous sodium sulfate. Removal of the solvent afforded 4-(N-ethyl-N-hydroxyethylamino)benzaldehyde as a pale yellow oil. Yield 25 g (65%); 1H-NMR (CDCl3) δ1.18 (t, 3H), 2.30 (s, 1H), 3.62 (m, 2H), 3.66 (t, 2H), 3.90 (t, 2H), 6.70 (d, 2H), 7.68 (d, 2H), 9.62 (s, 1H) ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][C:15]([CH3:23])=[C:16]([C:18](OCC)=[O:19])[CH:17]=1)=O)C.O>C(OCC)C>[OH:9][CH2:10][C:12]1[CH:17]=[C:16]([CH2:18][OH:19])[C:15]([CH3:23])=[N:14][C:13]=1[CH3:24]
Reactant: CCOC(=O)c1cc(C(=O)OCC)c(C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1nc(C)c(CO)cc1CO
Temperature: 40 °C

Procedure:
To a ice-cooled mixture of lithium aluminum hydride (95%) (6.7 g, 168 mmol) in anhydrous diethyl ether (750 mL) is added a solution of 2,6-dimethyl-pyridine-3,5-dicarboxylic acid diethyl ester (31.5 g, 125 mmol) in diethyl ether (250 mL) via cannula under a stream of nitrogen. After the addition is complete, the reaction mixture is warmed to 40° C. for 0.5 h. After cooling to 0° C., water (50 mL) is added slowly under a stream of nitrogen. The resulting solids are filtered, washed with diethyl ether (250 mL), suspended in methanol (700 mL) and warmed to a gentle reflux (1 h). The remaining aluminum salts are filtered hot and washed with hot methanol (200 mL). The filtrate is concentrated and dried in vacuo to afford 5-hydroxymethyl-2,6-dimethyl-pyridin-3-yl-methanol as a white solid and is used in the subsequent step without further purification: Rf 0.16 (10% methanol in chloroform); 1H NMR (DMSO-d6, 300 MHz) δ 7.62 (s, 1 H), 4.45 (s, 4 H), 2.34 (s, 6 H); ESI-LCMS m/z calcd for C9H13NO2: 167.1; found 168.0 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[C:24]([NH:29][CH2:30][C:31]([NH2:33])=[O:32])=[N:25][CH:26]=[CH:27][CH:28]=1.[N-]1C=CN=C1>O1CCCC1.C(#N)C>[NH2:33][C:31](=[O:32])[CH2:30][NH:29][C:24]1[C:23]([NH:22][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C(O)c1ccccn1
Reactant: NC(=O)CNc1ncccc1N
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CC#N
Solvent: C1CCOC1
Product: NC(=O)CNc1ncccc1NC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.2 %

Procedure:
While bubbling nitrogen through a solution of picolinic acid (1.23 g, 0.01 mole) in 100 ml of tetrahydrofuran, solid 1,1'-carbonyldiimidazole (1.62 g, 0.01 mole) was added in portions. The reaction mixture was allowed to stir at room temperature for 5 hours. Then, a solution of 2-[(3-amino-2-pyridinyl)amino]acetamide (1.66 g, 0.01 mole) in acetonitrile was added in portions to the imidazolide solution and the reaction mixture was allowed to stir at room temperature overnight. The solvents were evaporated. The residue completely solidified upon standing. The solid was washed with methylene chloride and the solid was filtered off. The solid was recrystallized from ethyl acetate to give several crops of crystals, which were combined and recrystallized from ethyl acetate to give 0.52 g of title compound, mp 188°-90° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[BH4-].[Na+]>CO>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]([OH:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
To a solution of 4-amino acetophenone (0.5 g, 3.7 mmol) in methanol (10 ml), was added sodium borohydride (0.27 g, 7.4 mmol, 2 eq) at 0° C. The reaction mixture was stirred for 3 hr at room temperature. The solvent was evaporated and water was added. The compound was extracted with ethyl acetate, then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to yield pure 1-(4-amino-phenyl)-ethanol (0.4 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7](=[CH2:12])C(OC)=O)[O:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[CH3:23][OH:24].O>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:12][CH2:23][OH:24])[O:4][N:3]=1
Reactant: C=C(C(=O)OC)c1cc(C)no1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C=CCO)on1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A 8 g quantity of methyl 3-methyl-5-isoxazolylacrylate was dissolved in 150 ml of dichloromethane. To the solution was added dropwise with cooling at -70° C. or lower 100 ml of a 25 % solution of di-isobutyl aluminum hydride in toluene. After the addition, the reaction was effected for 30 minutes and then the excess of the reducing agent was decomposed with methanol-water. The organic layer was separated and dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation, giving 4.5 g of 3-methyl-5-isoxazolyl-allyl alcohol (Compound 4a) as an oil in a yield of 67.6 %. MS, m/e : 139 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@H:8]2[OH:17])[CH2:4][O:3]1.C(OC(=O)C)(=O)C.[BH4-].[Na+]>CS(C)=O>[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@@H:8]2[OH:17])[CH2:4][O:3]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@@H](O)[C@H]2O1

Procedure:
In a preferred embodiment of the method according to the invention, 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose is reacted with a mixture of DMSO and acetic anhydride in a molar ratio of 1:3 to 1:9 at 20-25° C., for around 12-48 h, typically for around 24 h, followed by reaction with sodium borohydride at 20-25° C., for around 0.5-2 h, typically for around 1 h, in order to yield 1,2:5,6-di-O-isopropylidene-α-D-allofuranose. The two reactions are performed sequentially, i.e. without isolation or purification of the intermediate product, i.e. the ulose.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:13]([CH3:25])([CH3:24])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)=O>>[O:1]([C:8]1[C:9](=[O:11])[O:10][C:13]([CH3:25])([CH3:24])[C:14]=1[C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Reactant: O=C(O)COc1ccccc1
Product: CSc1ccc(C2=C(Oc3ccccc3)C(=O)OC2(C)C)cc1

Procedure:
Following the procedure described for example 1, Step 4, the title compound was prepared from phenoxyacetic acid and 2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (example 1, Step 4).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:24][CH2:25][CH2:26][C:27]([O:29]CC3C=CC=CC=3)=[O:28])[CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:10])[CH2:4][CH2:3]1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: CN1CCC(OC(=O)Nc2cc(CCCC(=O)OCc3ccccc3)ccc2-c2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CN1CCC(OC(=O)Nc2cc(CCCC(=O)O)ccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 1013.6 %

Procedure:
Benzyl 4-[3-({[(1-methylpiperidin-4-yl)oxy]carbonyl}amino)-4-phenylphenyl]butyrate (25.8 g, 5.30 mmol) was dissolved in ethyl acetate (250 mL), 10% palladium hydroxide-carbon (5 g) was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 days and, thereafter, at 50° C. for 6 hours. After filtering the reaction solution through celite, the filtrate was concentrated under reduced pressure to obtain 4-[3-({[(1-methylpiperidin-4-yl)oxy]carbonyl}amino)-4-phenylphenyl]butyric acid (21.3 g).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[C:9]2[C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:20][N:21]1[C:25]([CH2:26]O)=[CH:24][C:23]([C:28]([F:31])([F:30])[F:29])=[N:22]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:20][N:21]1[C:25]([CH2:26][O:14][C:12]2[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[C:9]3[C:5]([CH2:4][C:3]([OH:2])=[O:19])=[CH:6][S:7][C:8]=3[CH:13]=2)=[CH:24][C:23]([C:28]([F:29])([F:31])[F:30])=[N:22]1
Reactant: COC(=O)Cc1csc2cc(O)cc(C(F)(F)F)c12
Reactant: Cn1nc(C(F)(F)F)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1COc1cc(C(F)(F)F)c2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.7 %

Procedure:
To a mixture of methyl(6-hydroxy-4-(trifluoromethyl)-1-benzothiophen-3-yl)acetate (60 mg) and THF (dry) (3 mL) were added (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (37.2 mg), ADDP (62.6 mg) and tri-n-butylphosphine (0.071 mL) at room temperature. The mixture was stirred at room temperature for 12 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane). To the mixture of the crude material and THF (1 mL) was added 1N NaOH (1 mL) at room temperature for 12 h. The mixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The solid was crystallized from EtOAc-hexane to give the title compound (64.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[C:22]([NH:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH2:36])[N:27]=1)(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH:36][CH2:11][C:10]([C:13]([F:14])([F:16])[F:15])([OH:17])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:20][CH3:21])([CH3:18])[CH3:19])[N:27]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccc2c(N)cccc2n1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(NC(C)=O)ccc12)C(F)(F)F
Yield: 46.4 %

Procedure:
Analogously to Example 20, 263 mg (0.86 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 205 mg (1.0 mmol) of 2-acetylamino-5-aminoquinoline are reacted to form 197 mg of product.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.C(O)=O.Cl>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[F:14][C:9]1[C:10]([O:12][CH3:13])=[N:11][CH:2]=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)c(OC)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC)c(F)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a solution of 1.5 g of methyl 2-chloro-5-fluoro-6-methoxynicotinate in 15 mL of N,N-dimethylformamide, 0.38 g of tetrakis(triphenylphosphine)palladium(0), 1.4 mL of triethylamine, and 0.38 mL of formic acid were added at room temperature, and the mixture was stirred at 50 to 60° C. for 1 hour under a nitrogen atmosphere, and then stirred at 90 to 100° C. for 2 hours 20 minutes. Thereto were further added 1.4 mL of triethylamine, 0.38 g of tetrakis(triphenylphosphine)palladium(0) and 0.38 mL of formic acid at room temperature, and the mixture was stirred at 90 to 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was charged with ethyl acetate and water, and adjusted to pH 4.8 with 2 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution. A mixed solvent of chloroform:methanol was added to the organic layer to dissolve the insoluble substance, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resultant residue, and the solid was filtered off to obtain 0.30 g of methyl 5-fluoro-6-methoxynicotinate as a yellow solid.