Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[C:17](=O)([O-:38])[O:18][C:19]1C(C)=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=CN=1.[C:40]1([C:46]2[CH:51]=[CH:50][C:49](C3C=CN(C([O-])=O)C(=O)C=3C)=[CH:48][CH:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O.C1COCC1>[OH:11][C@H:6]([C:7]([CH3:8])([CH3:10])[CH3:9])[C@H:2]([N:1]([C:49]1[CH:48]=[CH:47][C:46]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:51][CH:50]=1)[C:17]([O:18][CH3:19])=[O:38])[C:3]([OH:5])=[O:4]
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccnc1OC(=O)[O-]
Reactant: CC(C)(C)[C@@H](O)[C@H](N)C(=O)O
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccn(C(=O)[O-])c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@H](C(=O)O)[C@H](O)C(C)(C)C
Reaction time: 15 h
Yield: 21 %

Procedure:
To a stirred mixture of (2S*,3R*)-2-amino-3-hydroxy-4,4-dimethyl-pentanoic acid (0.353 g, 2.19 mmol) and NaHCO3 (0.184 g, 0.84 mmol) in H2O (15 mL), at rt, the isomeric mixture containing (4-phenylphenyl)-methyl-2-pyridyl carbonate and (4-phenylphenyl)-methyl-2-oxopyridine-1-carboxylate (0.815 g, 2.2 mmol) [prepared as for example 17, step 1] in THF (15 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×20 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.181 g, 21%), which was used in the next step without further purification. MS (ESI) m/z: 410 [M−K]+; (ESI) m/z: 370 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.C([O-])(O)=O.[Na+].[CH2:17](O)[CH3:18]>OS(O)(=O)=O>[CH2:17]([O:9][C:8]([C:5]1[CH:4]=[C:3]([CH3:11])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])[CH3:18]
Reactant: Cc1cc(C(=O)O)ncc1Br
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(C)c(Br)cn1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a suspension of crude 5-bromo-4-methyl-pyridine-2-carboxylic acid (10.9 g, as potassium salt, approximately 35.5 mmol) in ethanol (120 mL), H2SO4 (0.5 mL) is added. The mixture is stirred at 70° C. for 18 h. The pH of the clear solution is adjusted to pH 9 by adding sat. aq. NaHCO3-solution and the mixture was extracted with diethyl ether (3×300 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated to give 5-bromo-4-methyl-pyridine-2-carboxylic acid ethyl ester (8.20 g) as a green oil; LC-MS: tR=0.87 min, [M+1]+=243.91.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH3:22])[NH:6][C:5]2=[O:23].[N:24]([O-])=O.[Na+]>Cl.O>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:7]1[NH:6][C:5](=[O:23])[C:4]2[CH:3]=[C:2]3[NH:1][N:24]=[N:12][C:11]3=[CH:10][C:9]=2[N:8]=1)[CH2:21][CH3:22]
Reactant: O=N[O-]
Reactant: CCCOc1ccccc1-c1nc2cc(N)c(N)cc2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCOc1ccccc1-c1nc2cc3nn[nH]c3cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
6,7-diamino-2-(2-propoxyphenyl)-4(3H)-quinazolinone (0.15 g, 0.51 mmol) was suspended in 1N HCl (5 mL) and cooled in an ice-methanol bath. A solution of sodium nitrite (0.035 g) in water (1 mL) was added in one portion. The reaction was stirred in an ice bath for 30 minutes, then warmed to room temperature for 90 minutes. The precipitated solid was collected by filtration, washed with water, and dried to afford the title compound as a brown solid (0.42 mmol, 83%): mp dec>260° C.; LRMS [MH+] 308.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[Cl:10][CH2:11][C:12](Cl)=[O:13]>[OH-].[Na+].ClCCl>[Cl:10][CH2:11][C:12]([NH:5][C:4]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(C)cc(NC(=O)CCl)c1
Reaction time: 18 h
Yield: 94.1 %

Procedure:
3,5-Dimethylaniline (Acros, 10.50 mL, 84.05 mmol) in 2N sodium hydroxide (200 mL) was treated with chloroacetyl chloride (Acros, 10.00 mL, 125.7 mmol) as a solution in dichloromethane (200 mL) drop wise. After 18 hours, the layers were separated. The organic phase was washed with 1N hydrochloric acid, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide 15.64 g (94%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 6H), 4.21 (s, 2H), 6.73 (s, 1H), 7.20 (s, 2H), 10.11 (br s, 1H); MS (DCI/NH3) m/e 198 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25]>C1COCC1.CCCCCC>[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH:24]=[O:25])=[CH:3][CH:4]=2)[CH2:11][CH2:12]1
Reactant: CN1CCN(CCc2ccc(Br)cc2)CC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCN(CCc2ccc(C=O)cc2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 87 mL of a solution of 8.7 g of 1-[2-(4-bromophenyl)ethyl]-4-methylpiperazine in THF cooled to −70° C. was added dropwise 21.1 mL of a solution of n-butyllithium (1.6 mol/L) in hexane, and the mixture was stirred at the same temperature for 30 minutes. While the reaction mixture was stirred at the same temperature, 3.6 mL of N,N-dimethylformamide was added dropwise. The mixture was stirred at the same temperature for 30 minutes. The cooling bath was removed, and the mixture was allowed to warm to −10° C., poured into a mixture of 12 mL of 1 N hydrochloric acid and 100 mL of cold water, and subjected to extraction with CHCl3. The obtained extract was dried over MgSO4 and concentrated to give 7.04 g of the title compound (98%).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.Cl[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CN>ClCCl>[CH3:1][NH:3][S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
2.8 ml (20 mmol) triethylamine was added to and dissolved in a suspension of 4.4 g (20 mmol) of 4-chlorosulfonylbenzoic acid in dichloromethane. To the solution 3.1 ml of 40% aqueous solution of methylamine was added and stirred at room temperature overnight. After the reaction solution was concentrated under vacuum, the residue was dissolved in ethyl acetate-5% sodium hydrogencarbonate aqueous solution. The water layer was washed with ethyl acetate and adjusted to 2-3 pH with citric acid. The organic layer obtained by extracting the water layer with ethyl acetate was washed with distilled water, then with saturated brine, dried over anhydrous magnesium sulfate. This solution was concentrated under vacuum and the residue was crystallized from ethyl acetate-hexane to obtain 2.9 g of 4-methylaminosulfonylbenzoic acid (yield 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[P:12]([O-:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].[F-].[K+]>C(Cl)Cl>[OH:8][CH:7]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CCOP([O-])OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(O)c1cccc([N+](=O)[O-])c1
Yield: 98.8 %

Procedure:
m-Nitrobenzaldehyde (4.53 g, 30 mmol) was dissolved in diethyl phosphite (4.14 g, 30 mmol) under gentle heating. The solution was brought to room temperature and KF (8.7 g, 0.15 mole) was added with rapid stirring. After 30 min the mixture was suspended in CH2Cl2 (150 ml). The resultant suspension was filtered and the filtrate was concentrated under reduced pressure furnishing 8.57 g (99%) of 17 as a yellow colored solid, mp 93-95° C., IR (neat): 3750-3040, 1540, 1355, 1205 and 1050; 1H NMR (200 MHz, CDCl3): δ1.23 (6H, m), 4.10 (4H, m), 5.14 (1H, d, J=12 Hz), 5.94 (1H, s, OH) and 7.93 (4H, m); 13C NMR (50 MHz, CDCl3): δ17.6, 64.2, 64.9, 72.1, 122.4, 123.1, 129.3, 133.4, 139.8 and 148.3; HR-MS (EI): m/e 289.0715 (M+C11H16NO6P requires 289.0714).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.C1C=CC=CC=1>CCCCCC>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1

Procedure:
In a later publication in Tetrahedron Asymmetry 11 (2000), 1729-1732 the inventors of the above mentioned Chinese patent application reported the resolution of omeprazole using (S)-BINOL. An inclusion complex of (S)-BINOL and (S)-omeprazole was obtained as a grey-blue complex with 90.3% e.e. by mixing racemate omeprazole and (S)-(−)-BINOL in the mole ratio 1:1.5, in a solvent mixture of benzene:hexane (v/v=4:1) at 110° C. The inclusion complex obtained was further purified by recrystallization in benzene:hexane (v/v, 1:1) and separated on a silica gel column to yield (S)-(−)-omeprazole with 98.9% e.e. and 84.1% overall yield. The (S)-(−)-omeprazole so obtained was recrystallized in water to obtain as a white powder with 99.2% e.e.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]1[C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1.NC(C(O)=O)CCSC.N>CS(O)(=O)=O>[OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[N:6]=[C:5]1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2nc(C(F)(F)F)cn2CCO)cc1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Agent: N
Product: OCCn1cc(C(F)(F)F)nc1-c1ccc(O)cc1

Procedure:
A solution of 14.6 g of 1-(2-hydroxyethyl)-2-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole and 8.7 g of DL-methionine in 90 ml of methanesulphonic acid is stirred for 24 hours at 110°, then cooled, poured onto ice and the pH is adjusted to 10 with ammonia. The mixture is extracted several times with ethyl acetate, the combined organic phases are dried over sodium sulphate, filtered and the filtrate is concentrated to a small volume. 1-(2-hydroxyethyl)-2-(4-hydroxyphenyl)-4-(trifluoromethyl)-1H-imidazole having a melting point of 186°-188° can be obtained in crystalline form by the addition of hexane.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCCCC(O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
TBSOTf (2.9 mL, 12.6 mmol) was added to an ice-cold solution of 4 (3.017 g, 11.7 mmol) and 2,6-lutidine (1.6 mL, 13.7 mmol) in dichloromethane (30 mL). The reaction was stirred for 2 h at room temperature and then 100 mL saturated sodium bicarbonate solution was added. The resulting mixture was extracted with dichloromethane (30 mL) and the dichloromethane layer was washed with 1 M HCl (2×50 mL) and brine (50 mL). The dichloromethane solution was then dried (MgSO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (hexanes) gave compound 5 (3.843 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1)=[O:4].[C:15]([O:19][C:20](=[O:33])[CH2:21][C@H:22]([NH2:32])[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)([CH3:18])([CH3:17])[CH3:16].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[C:15]([O:19][C:20](=[O:33])[CH2:21][C@@H:22]([C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)[NH:32][C:12]([C:10]1[S:11][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:8][CH:9]=1)=[O:14])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)CCc1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccc2c(c1)OCO2
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)N[C@@H](CC(=O)OC(C)(C)C)c2ccc3c(c2)OCO3)s1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 130 %

Procedure:
214 mg (1 mmol) of 5-(2-methoxycarbonyl-ethyl)-thiophene-2-carboxylic acid (example 1, step b) were dissolved in 5 ml of anhydrous dimethylformamide. 265 mg (1 mmol) of (3S)-3-amino-3-(benzo[1,3]dioxol-5-yl)-propionic acid tert-butyl ester and 328 mg (1 mmol) of TOTU were added, and 3 mmol (0.51 ml) of N,N-diisopropyl-N-ethylamine were added to keep the pH of the mixture at 7.5 to 8. The reaction mixture was stirred for 4.5 hours at room temperature. Solvents were removed under reduced pressure to give a dark brown oil. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, 10% citric acid and with water. Then the organic phase was dried with anhydrous magnesium sulfate. After filtration the solvents were removed in vacuo to give 600 mg of a brownish oil which was purified by chromatography (silica gel; ethyl acetate/heptane (1/2, v/v)). 425 mg of a resin were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[C:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH:14]=[CH:15][CH:16]=1.O.NN>CCO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]#[C:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][NH2:20])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(C)c1C#Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1C#Cc1cccc(CCCN)c1
Reaction time: 4 h

Procedure:
A solution of 2-(3-(3-((2,6-dimethylphenyl)ethynyl)phenyl)propyl)isoindoline-1,3-dione (13) (0.094 g, 0.24 mmol) and hydrazine hydrate (0.038 g, 0.75 mmol) in dry EtOH (5 mL) was heated under reflux for 3 h. Additional hydrazine hydrate (0.038 g, 0.75 mmol) was added and heating continued for a further 4 h. The solvent was removed under reduced pressure and the residue was sonicated in a mixture of hexanes and aqueous Na2SO4. The mixture was filtered through Celite and washed with hexanes. The organic layer was concentrated under reduced pressure. Purification by flash chromatography (10:1:9 EtOAc/7 M NH3 in MeOH/hexanes)gave 3-(3-((2,6-dimethylphenyl)ethynyl)phenyl)propan-1-amine as a colorless oil. Yield (0.015 g, 25%): 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.39 (m, 3H), 7.25 (m, 1H), 7.13-7.22 (m, 3H), 2.65 (t, J=7.6 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.46 (s, 6H), 1.61-1.69 (m, 2H), 1.40 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:8][CH2:9][C@@H:10]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH3:11])=[N:4][O:5][C:6]=1[CH3:7].BrN1C(=[O:29])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.FC(C1C=CC=CC=1)(F)F>O>[F:1][C:2]1[C:3]([O:8][CH2:9][C@@H:10]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH3:11])=[N:4][O:5][C:6]=1[CH2:7][OH:29]
Reactant: Cc1onc(OC[C@H](C)N2C(=O)c3ccccc3C2=O)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Solvent: O
Product: C[C@@H](COc1noc(CO)c1F)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A mixture of 2-{(1S)-2-[(4-fluoro-5-methylisoxazol-3-yl)oxy]-1-methylethyl}-1H-isoindole-1,3(2H)-dione (383 mg), N-bromosuccinimide (269 mg), 2,2′-azobis(2-methylpropionitrile) (20.7 mg) and (trifluoromethyl)benzene (5 mL) was stirred at 100° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). The obtained residue was mixed with 1-methylpyrrolidin-2-one (5 mL) and water (10 mL), and the mixture was stirred at 105° C. overnight. The reaction mixture was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (118 mg).
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=O.[CH:15]([C:17]([CH3:19])=[O:18])=[CH2:16].Cl>O.CO>[CH3:3][C:4]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6][C:5]1=[CH:19][C:17](=[O:18])[CH2:15][CH2:16]2
Reactant: CC1C(=O)CCc2ccccc21
Reactant: C=CC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC12CCC(=O)C=C1CCc1ccccc12
Temperature: -15 °C
Reaction time: 6 h
Yield: 90.3 %

Procedure:
Potassium hydroxide in the amount of 2.25 g (40 mmol) was dissolved in 4.5 g of water in 100-ml three-necked flask, and the obtained solution was then cooled with ice under agitation in a stream of nitrogen gas. A methanol solution (8 ml) containing 4.8 g (30 mmol) of 1-methyl-2-tetralone was added dropwisely to the above obtained solution. The reaction vessel was cooled to -15° C., then, 2.1 g (30 mmol) of methyl vinyl ketone was added dropwisely to the reaction vessel and 2 ml of methanol was further added thereto. The resulted mixture was agitated under cooling with ice for 1 hour and then at room temperature for 6 hours in a stream of nitrogen-gas. Then, the mixture had been allowed to react at 70° C. for 6 hours. The reaction mixture was then poured into iced water, made acidic with hydrochloric acid and extracted with ether. The ether layer was removed and washed with water, and then dried with sodium sulfate. The ether was distilled off to obtain 5.75 g of oily yellowish orange residue. A part of this residue was crystallized and resulted crystals were recrystallized twice from cyclohexane to obtain 2.8 g of colorless plate-like crystals. The oily portion was further allowed to crystallize to obtain 1.9 g of crystals. The total yield was 4.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]([F:18])([F:17])[C:4]([C:7]([C:9]([F:16])([F:15])[C:10]([F:14])([F:13])[O:11][CH3:12])=[O:8])([F:6])[F:5].Cl[CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+]>CCOCC>[CH3:12][O:11][C:10]([F:13])([F:14])[C:9]([F:15])([F:16])[C:7]1([C:4]([F:6])([F:5])[C:3]([F:17])([F:18])[O:2][CH3:1])[O:22][CH2:21][CH2:20][O:8]1
Reactant: OCCCl
Reactant: COC(F)(F)C(F)(F)C(=O)C(F)(F)C(F)(F)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(F)(F)C(F)(F)C1(C(F)(F)C(F)(F)OC)OCCO1
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of 58 g (about 0.2 mol) of crude bis(2-methoxytetrafluoroethyl) ketone, 16.9 g (0.21 mol) of 2-chloroethanol, and 50 mL of ether was stirred while 29.0 g (0.21 mol) of anhydrous K2CO3 were added in portions with cooling. The resulting reaction mixture was stirred overnight, filtered and distilled to give 40.7 g of 2,2-bis(2-methoxytetra- fluoroethyl)-1,3-dioxolane, b.p. 81° at 40 Pa (0.3 mm), m.p. 39°-40° . Dissolution of the resulting filter cake in water, filtration of the resulting mixture and drying gave another 8.5 g of product, m.p. 38.5°-40° , for a total yield of 49.2 g (74%). IR (CCl4) and NMR (CCl4) of the product were consistent with the assigned structure. Anal.: Calcd. for C9H10F8O4 : C, 32.35; H, 3.02; F, 45.48. Found: C, 32.14; H, 3.19; F, 45.22.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:40][CH2:41][C:42]1[C:43]([OH:50])=[N:44][C:45]([CH3:49])=[CH:46][C:47]=1[CH3:48]>O.ClCCl.C(N(CC)CC)C>[OH:50][C:43]1[C:42]([CH2:41][NH:40][C:8]([C:6]2[CH:5]=[CH:4][N:3]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:2](=[O:1])[CH:7]=2)=[O:10])=[C:47]([CH3:48])[CH:46]=[C:45]([CH3:49])[N:44]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(c1ccccc1)n1ccc(C(=O)O)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccn(C(C)c3ccccc3)c(=O)c2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.7 %

Procedure:
A mixture of 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid (60 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (95 mg, 0.5 mmol), N-hydroxybenzotriazole (67 mg, 0.5 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) were stirred at 25° C. for half an hour before 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.33 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, was added water (10 ml) and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxamide as a white solid (28 mg, 29%). LRMS (M+H+) m/z: cald. 377.17. found 377. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.55 (t, J=4.5 Hz, 1H), 7.67 (d, J=6.9 Hz, 1H), 7.38-7.27 (m, 5H), 6.79 (s, 1H), 6.54-6.51 (m, 1H), 6.14 (q, J=7.2 Hz, 1H), 5.85 (s, 1H), 4.23 (d, J=4.5 Hz, 2H), 2.12 (d, J=6.6 Hz, 6H), 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH3:4].[CH:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH2:28].O>O1CCCC1>[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:20][C:21]2([O:26][CH2:28][CH2:27][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH3:4]
Reactant: C=CS(C)(=O)=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 36 mg, 0.8 mmol) was added to a stirred solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (1.45 g, 4.50 mmol) and methyl vinyl sulfone (0.95 g, 8.9 mmol) in tetrahydrofuran (18 mL). The reaction mixture was stirred at room temperature for 1 hour and additional methyl vinyl sulfone (0.47 g) was added. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 1.2 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclopentyl}methyl)-1H-imidazo[4,5-c]quinoline as a colorless oil.