Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([NH:22][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:2](=[O:3])[CH3:1])[CH:23]=[CH:24][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1ccccc1Nc1cccc(OCc2ccccc2)c1

Procedure:
10 g of phenacyl bromide and 11 g of 3-benzyloxyaniline are stirred at 60° C. for 2 h in 100 ml of ethanol in the presence of 11.7 g of powdered Na2CO3. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated. The residue is slurried with ether and the crystals are filtered off, 2'-(3-benzyloxyphenylamino)acetophenone being obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:29])=[CH:4][C:5]([F:28])=[C:6]([N:8]2[C:17]3[C:12](=[C:13]([CH3:21])[C:14]([F:20])=[C:15]([F:19])[C:16]=3[Cl:18])[C:11](=[O:22])[C:10]([C:23]([O:25]CC)=[O:24])=[CH:9]2)[CH:7]=1>Cl>[NH2:1][C:2]1[C:3]([F:29])=[CH:4][C:5]([F:28])=[C:6]([N:8]2[C:17]3[C:12](=[C:13]([CH3:21])[C:14]([F:20])=[C:15]([F:19])[C:16]=3[Cl:18])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2c(Cl)c(F)c(F)c(C)c2c1=O
Agent: Cl
Product: Cc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Reaction time: 8 h
Yield: 61.5 %

Procedure:
12N Hydrochloric acid (10 ml) was added to ethyl 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (400 mg), and the mixture was stirred overnight while heating under reflux. After the reaction mixture was allowed to cool, solids deposited were collected by filtration and washed successively with water and ethanol to obtain the title compound (230 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([OH:15])[C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)C(Oc1cccc(Cl)n1)n1cncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(O)C(Oc1cccc(Cl)n1)n1cncn1
Yield: 44.6 %

Procedure:
11.8 g (0.04 mol) of 1-(6-chloropyridin-2-yl-oxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one (Example 1) were dissolved in 100 ml of methanol, and 1.8 g (0.04 mol) of sodium borohydride were added in portions at 20°-30° C., while stirring. After the exothermic reaction had ended, 5 ml of concentrated hydrochloric acid were added dropwise and the mixture was stirred at room temperature for 1 hour. Thereafter, 200 ml of water were added and the mixture was neutralised with sodium bicarbonate solution. The reaction mixture was extracted by shaking with ether and the organic phase was dried over sodium sulphate and concentrated. 5.3 g (54% of theory) of 1-(6-chloropyridin-2-yl-oxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-ol were obtained as a viscous oil in the form of a diastereomer mixture.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:29][CH2:30][CH3:31])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][O:27][CH3:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.N12CCCN=C1CCCCC2>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:29][CH2:30][CH3:31])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([O:27][CH3:28])[C:6]([NH2:5])=[O:7])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNOC
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(OC)C(N)=O
Temperature: -16 °C
Reaction time: 1.5 h

Procedure:
Trimethylsilyl isocyanate (0.250 mL, 1.85 mmol) was added dropwise to a solution of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-O-methyl-hydroxylamine in dichloromethane (10 mL) cooled to −16° C. The reaction temperature was cooled to −20° C. over 10 minutes. After stirring for 1.5 hours, the reaction was warmed to 0° C. and stirred for an additional hour. A drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.250 mL, 1.85 mmol) was added to the reaction mixture and stirred for 3 days. The reaction mixture was diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate and stirred for 30 minutes. The layers were separated, and the organic layer was dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford 0.82 g of 1-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-methoxyurea as off-white crystals, mp 179-181° C. MS (APCI) m/z 371 (M+H+); Anal. calcd for C19H26N6O2: C, 61.36; H, 7.09; N, 22.60. Found: C, 61.08; H, 7.41; N, 22.69.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.P(Br)(Br)[Br:11].O>C(Cl)(Cl)Cl>[Br:11][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccncc1F
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1cnccc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
To a solution of (3-fluoropyridin-4-yl)methanol (910 mg, 7.2 mmol) in anhydrous chloroform (25 mL) was added dropwise a solution of phosphorus tribromide (675 μL, 7.2 mmol) in anhydrous chloroform (10 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with dichloromethane. The organic phase was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 4-(bromomethyl)-3-fluoropyridine was obtained (260 mg, 19% yield) and used in the next step without further purification; 1H NMR (400 MHz, MeOd4): δ 0.81 (s, 2H), 8.25 (t, J=6.4 Hz, 1H). 8.76 (d, J=5.9 Hz, 1H), 9.05 (d, J=3.5 Hz, 1H).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C:15](=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C:15](=[CH2:1])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a suspension consisting of methyl triphenylphosphonium bromide (18 g, 51 mmol) and THF (200 mL) at 0° C. was added n-butyl lithium (1.6 M solution in hexanes, 32 mL). The resulting orange solution was stirred at 0° C. for 5 min, then a solution of 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (9.0 g, 48 mmol) in THF (40 mL) was added via cannula. The reaction mixture was stirred at 0° C. for 90 min, then warmed to rt and stirring was continued for 1 h. The reaction mixture was then cooled to 0° C., quenched with sat. NH4Cl, and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated. The crude residue was suspended in hot hexanes and filtered. The filtrate was concentrated and purified (FCC) to give the title compound (4.4 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[O:22]=[C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12](=[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]3=[CH:15][CH:16]=2)[NH:11]1
Reactant: Nc1cccc(-c2nc(=O)[nH]c3c2ccc2ccccc23)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=c1nc(-c2cccc(NS(=O)(=O)c3ccccc3)c2)c2ccc3ccccc3c2[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 15 %

Procedure:
To a solution of 4-(3-aminophenyl)-1H-benzo[h]quinazolin-2-one (20 mg, 0.07 mmol) in pyridine (3 mL) was added benzenesulfonyl chloride (127 μL, 0.99 mmol), and stirred at 80° C. for 5 hours. After the solution was cooled to room temperature, the solvent was removed under reduced pressure. The residue was diluted with chloroform, washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), to give the titled compound as a yellow amorphous form (5 mg, yield 15%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.[F-].[Cs+]>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:14][C:6]1[CH:5]=[C:4]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(Br)c2)CCC1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C)cc3)c2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of compound ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (500 mg, 1.2 mmol), 4-methyl phenylboronic acid (0.237 g, 1.68 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (325 mg) as thick oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.[OH-].[NH4+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: COc1ccc2c(c1)C(N1CCN(CCCO)CC1)=Cc1ccccc1S2
Reactant: CCCCCCCC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCC(=O)OCCCN1CCN(C2=Cc3ccccc3Sc3ccc(OC)cc32)CC1
Reaction time: 48 h

Procedure:
To a solution of 10.0 grams of 8-methoxy-10-[4-(3-hydroxypropyl)piperazino]dibenzo[b,f]thiepin in 50 milliliters of benzene was added 9.1 grams of caprylyl chloride (octanoyl chloride) and the mixture was allowed to stand for 48 hours. Thereafter 150 milliliters of water and 20 milliliters of concentrated aqueous ammonium hydroxide solution was added thereto and the resulting mixture was shaken with benzene. The benzene extract was separated form the aqueous solution, filtered, and the filtrate was washed with water, dried over anhydrous potassium carbonate, and the benzene was evaporated therefrom. The residue was dissolved in 30 milliliters of acetone and to this solution was added a solution of 2.9 grams of maleic acid in 10 milliliters of acetone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([C:8](=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1.CC(O)=O>CCO.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:23][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(=C(O)c1ccc(F)cc1)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
Iron powder (710 mg, 13 mmol) was added to a stirred solution of ethyl 2-(5-bromo-2-nitrophenyl)-3-(4-fluorophenyl)-3-hydroxyacrylate (1.0 g, 2.4 mmol) in EtOH (20 mL)/AcOH (16 mL) in a 250 mL round bottomed flask. The flask was immediated placed in a preheated (100° C.) oil bath under an air condenser and the slurry was stirred vigorously. After 1.5 h, the reaction was cooled to r.t., diluted with EtOAc (200 mL), and the solids were removed by filtration. The filtrate was washed with water repeatedly until the organic phase was no longer red. The organic phase was then washed with sat'd NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated (PhMe azeotrope to remove residual AcOH) to give an off-white solid. The crude product was triturated with 1:1 CH2Cl2/hexanes and the filtrate purified by silica gel chromatography with a Biotage 40+M cartridge (gradient elution 10% to 40% EtOAc/hexanes over 10 column volumes, fraction collection at λ=254 nm). The off-white ppt. from above was further triturated with CH2Cl2 to give a white solid, and the filtrate was concentrated to give an off-white solid. Both ppt. and filtrate were chromatographed separately with the same method as above, but with fraction collection at λ=320 nm. Each of the three columns afforded two major peaks. The combined first peaks elute were concentrated to give the title compound (335 mg, 38% yield). 1H NMR (300 MHz, CDCl3) δ ppm 8.67 (br. s., 1H) 8.36 (br. s., 1H) 7.54-7.70 (m, 2H) 7.36 (d, J=7.68 Hz, 1H) 7.25 (t, J=7.68 Hz, 1H) 7.11 (t, J=8.23 Hz, 2H) 4.31 (q, J=6.83 Hz, 2H) 1.33 (t, J=7.14 Hz, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column. XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.73, (ES+) m/z (MH+)=362, 364 (1:1 ratio).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][OH:13])=[CH:5]2.N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][O:13][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])=[CH:5]2
Reactant: OCCc1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To solution of 2-(5-bromo-1H-indol-2-yl)ethanol (11.37 g, 47.36 mmol) in DCM (150 mL) was added imidazole (4.0 g, 58.75 mmol). Reaction mixture was cooled to 0° C. before solution of TBSCl (8.60 g, 57.06 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was then diluted with DCM (150 mL), washed with H2O (100 mL) and NaCl (aqueous saturated, 100 mL) and the organic phase was dried over Na2SO4. The solvent was concentrated to afford 5-bromo-2-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-indole which was used directly in the next step. LC-MS 354.2/356.2 [M+H]+, RT 1.85 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:14][C:15]([F:16])([F:17])[F:18])[C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC)c(OC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Cl)cc(C(=O)O)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
Methyl 3-chloro-4-methoxy-5-trifluoromethoxybenzoate (1.70 g) was dissolved in tetrahydrofuran (12 mL) and water (6 mL), and lithium hydroxide monohydrate (1.00 g) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.51 g) as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[S:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1.[CH2:18]([N:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])[CH3:19]>N1C=CC=CC=1>[CH2:18]([N:20]([CH2:24][CH3:25])[C:21]([N:15]1[CH:16]=[N:17][C:13]([S:12][C:3]2[C:4]([O:10][CH3:11])=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[N:14]1)=[O:22])[CH3:19]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1c(C)c(C)cc(C)c1Sc1nc[nH]n1
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(Sc2c(C)cc(C)c(C)c2OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(2,4,5-Trimethyl-6-methoxyphenylthio)-1,2,4-triazole (2.5 g) is dissolved in pyridine (60 ml) and diethyl carbamoyl chloride (1.4 g) is added dropwise to the solution. The mixture is stirred at room temperature for 1 h, then at 70° C. for 2 h. After distilling off pyridine, the residue is extracted with chloroform and dried with magnesium sulfate to obtain a crude product of 1-(diethylcarbamoyl)-3-(2,4,5-trimethyl-6-methoxyphenylthio)-1,2,4-triazole. This crude product is cooled to 0° C. and m-chloroperbenzoic acid (4 g) is added, followed by stirring at room temperature for 2 h and at 60° C. for 2 h. Subsequently, the resulting product is washed with a 10% aqueous solution of potassium carbonate and dried with magnesium sulfate. After distilling off the solvent, the residue is recrystallized from n-hexane/ethyl acetate; yield, 2.6 g (74%); m.p. 138°-139° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[CH2:12]([O:14][C:15]([C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[C:19](Cl)[N:18]=1)=[O:16])[CH3:13].O>O1CCCC1>[CH2:12]([O:14][C:15]([C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[C:19]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([F:3])=[CH:5][CH:6]=2)[N:18]=1)=[O:16])[CH3:13]
Reactant: OCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(Cl)nc1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccc(F)cc2)nc1C(=O)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of sodium hydride (55% in mineral oil, 254 mg, 0.6 mmol) and 4-fluorobenzylalcohol in tetrahydrofuran (30 mL) was heated at 60° C. for 30 min and then after cooling at 0° C. a solution of 6-chloro-pyridine-2,3-dicarboxylic acid diethyl ester (1.3 g. 0.5 mmol) in tetrahydrofuran (20 mL) was added over 10 min. The resulting mixture was kept at 0° C. for 1 h and then water was added. The mixture was then extracted with ethylacetate and the combined organic extracts washed with water, brine and then dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, heptane-EtOAc 9:1 to 3:1) to afford the title compound (1.3 g, 74%) as a colorless oil. MS: m/e=348.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)=[O:16])([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Product: Cc1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 88.6 %

Procedure:
Using p-toluidine (1.19 g, 11.0 mmol) and 3-nitrobenzoic acid (1.76 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.27 g (88.3%) of the title compound in the form of colorless needle crystals.
Reaction SMILES: [CH2:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3].[OH-].[K+]>CO>[CH2:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cc(CC(=O)OC)ccc2o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2cc(CC(=O)O)ccc2o1
Yield: 0 %

Procedure:
The product from Step 3 (4.0 g, 0.01 72 mol) was dissolved in methanol (30 ml) and potassium hydroxide flakes (1.06 g, 0.0188 mol) were added. The mixture was heated at reflux for 2 hours, then cooled and the solvent was evaporated in vacuo. The residue was taken up in water and extracted with diethyl ether. The aqueous phase was collected, acidified to pH1 with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to afford (2-propyl-5-benzoxazolyl)acetic acid (2.9 g) as an off-white solid, mp. 67-68° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][C:21]1[C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][C:24]2[CH2:25][CH:26]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:23]=2[CH:22]=1.Cl>CN(C)C=O>[CH3:12][O:11][C:9](=[O:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][CH2:20][C:21]2[C:37]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:36][C:24]3[CH2:25][CH:26]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:23]=3[CH:22]=2)=[CH:7][CH:6]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)C(C)(C)c1ccc(O)cc1
Reactant: BrCCCc1cc2c(cc1OCc1ccccc1)CC(CCc1ccccc1)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1ccc(OCCCc2cc3c(cc2OCc2ccccc2)CC(CCc2ccccc2)O3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a stirring solution of methyl 2-(4-hydroxyphenyl)-2-methylpropionate (0.81 g; 4.19 mmol) in dry diemthylformamide (8 mL) was added sodium hydride (192 mg, 4 mmol) as a 50% dispersion in oil. The mixture was stirred at room temperature for 30 minutes. A solution of 6-(3-bromopropyl)-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E88, in dry dimethylformamide (2 mL) was added. The resulting mixture was stirred at room temperature for 20 hours. The mixture was poured into cold dilute HCl (1N, 25 mL) and extracted twice with ethylacetate (50 mL). The combined organic extracts were washed with 1N HCl (25 ml×2) and brine (25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel to give 500 mg (87% yield) methyl-2-[4-[3-[2,3-dihydro-5-benzyloxy-2-(2-phenylethyl)benzofuran-6-yl]propoxy]phenyl]- 2-methylpropanoate, E42.