Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.S1C2C=CC=CC=2N=C1S[C:32](=[O:41])[C:33]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)=[O:34].C(O)C>ClCCl>[NH2:40][C:37]1[S:38][CH:39]=[C:35]([C:33](=[O:34])[C:32]([NH:1][CH:2]2[C:20](=[O:21])[N:4]3[CH:3]2[S:8][CH2:7][C:6]([CH2:9][S:10][C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=[C:5]3[C:17]([OH:19])=[O:18])=[O:41])[N:36]=1
Reactant: Nc1nc(C(=O)C(=O)Sc2nc3ccccc3s2)cs1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: ClCCl
Solvent: CCO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)C2SC1
Reaction time: 0.25 h

Procedure:
3.29 g of 7-amino-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid are suspended in 25 ml of dichloromethane and mixed with 2.7 ml of N,O-bis-(trimethylsilyl)acetamide. After 15 minutes, a clear solution is present. This is cooled to -15°, and 3.9 g of 2-(2-aminothiazol-4-yl)-2-oxothioacetic-acid-S-benzothiazol-2-ylester are added. After stirring for four hours at -15°, the preparation is stirred into 100 ml of ethanol, whereby the end product precipitates. This is stirred for one hour at 0°, filtered, washed with ethanol and vacuum dried. Yield: 3.9 g, i.e. 80.7%. M.p.: from 145° (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH2:8]Br)[CH:7]=1.C(=O)(O)[O-:13].[Na+].O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH2:8][OH:13])[CH:7]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(Br)cc(CBr)c1F
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(CO)c1F
Temperature: 25 °C
Yield: 49 %

Procedure:
To a stirred solution of 5-bromo-1-(bromomethyl)-2-fluoro-3-methylbenzene (6.56 g, 23.3 mmol) in acetone (150.0 mL) was added sodium bicarbonate (2.44 g, 29.1 mmol) and water (250.0 mL). The reaction was refluxed overnight. The reaction was cooled to room temperature and extracted 3× with ethyl acetate. The organic extracts were combined and washed with brine, dried over sodium sulfate and concentrated. The resultant oil was flash chromatographed (80 g silica, 5-10% ethyl acetate/hexanes gradient) to yield 2.5 g of (5-bromo-2-fluoro-3-methylphenyl)methanol as a white solid.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([O:15]C)=O)[CH3:5].O>C1COCC1>[CH3:5][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([NH:2][CH3:1])=[O:15])[CH3:3]
Reactant: COC(=O)c1sccc1N=NN(C)C
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1sccc1N=NN(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 76 %

Procedure:
To an ice cold (0-5° C.) solution of methyl amine (3 mL) in THF (5 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 36 h. The solution was poured into ice cooled water and the solution was extracted with chloroform (3×100 mL). The combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product, which was recrystallized from chloroform-hexane gave the product as a pale orange color solid (380 mg, 76%), mp 98-102° C. IR (neat) νmax 3297, 3082, 2929, 1637, 1380, 1348, 1299, 1221, 1109, 1016, 882, 776 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.35 (1H, br s), 7.29 (1H, d, J=5.2 Hz), 7.27 (1H, d, J=5.2 Hz), 3.57 (3H, br s), 3.21 (3H, br s), 3.00 (3H, d, J=4.8 Hz); LC-MS (positive ion mode): m/z 213 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][C@@H:13]([OH:27])[C@:14]4([CH3:26])[C@@H:18]([C:19]5[CH2:24][O:23][C:21](=[O:22])[CH:20]=5)[CH2:17][CH2:16][C@:15]4([OH:25])[C@@H:10]3[CH2:9][CH2:8][C@@H:7]1[CH2:6][C@@H:5]([OH:28])[CH2:4][CH2:3]2.O=O>O.CC(C)=O.[Pt]>[CH3:1][C@@:2]12[CH:11]3[CH2:12][C@@H:13]([OH:27])[C@:14]4([CH3:26])[C@@H:18]([C:19]5[CH2:24][O:23][C:21](=[O:22])[CH:20]=5)[CH2:17][CH2:16][C@:15]4([OH:25])[CH:10]3[CH2:9][CH2:8][C@@H:7]1[CH2:6][C:5](=[O:28])[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Agent: [Pt]
Agent: O=O
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12[C@H](O)CC3C(CC[C@@H]4CC(=O)CC[C@]34C)[C@@]1(O)CC[C@@H]2C1=CC(=O)OC1
Yield: 101.5 %

Procedure:
Platinum IV oxide (0.5 g) was added to 1.0 g of Digoxigenin and dissolved in 100 mls of water and 150 mls of acetone. The mixture was pressurized to 2 atmospheres of oxygen and shaken for catalyst was filtered off, and the solvent stripped off leaving 1.01 g of white solid. This was dissolved in 100 mls of methylene chloride and extracted with 70 mls of water. The water was back-washed with two volumes of 50 mls of methylene chloride. The organic fractions were collected, dried with anhydrous sodium sulfate and the solvent was stripped off leaving 0.75 g of white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16](Cl)=[O:17].Cl>O>[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])=[O:17]
Reactant: Cc1ccc(C)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C)c(C(=O)c2cc(Cl)ccc2Cl)c1
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
To p-xylene (120 ml, 0.98 mol) was added aluminum chloride (32 g, 0.24 mol) at room temperature. To this mixture 2,5-dichlorobenzoyl chloride (30 g, 0.14 mol) was added slowly. The reaction was exothermic and hydrogen chloride evolved from the reddish solution. After the addition, the mixture was stirred for 10 min and then hydrolysed by slow addition of water. The aqueous layer was extracted with ether. The organic layer was combined with ethereal extract and washed with water, saturated sodium bicarbonate, brine, respectively, and then dried with magnesium sulfate. After the removal of solvent, the residue was recrystallized from methanol twice and then from hexane to give 36.8 g (92%) crystals (mp 58°-61° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(S(=O)(=O)N(C)Cc2ccc(OC)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(S(=O)(=O)N(C)Cc2ccc(OC)cc2)cc1
Yield: 82.3 %

Procedure:
To a suspension of the sulfonamide of Example 331 (c) (2.1 g, 4.54 mmol) in ethanol (125 mL) under nitrogen was added 10% Pd/C (0.6 g). The mixture was placed on a Parr hydrogenator at 50 psi of hydrogen for 2 hours, the catalyst was removed by filtration and the solvent was removed in vacuo. The residue was recrystallized from Et2O/MeOH, extracted with CH2Cl2, washed with water, then brine and was dried over MgSO4. The solvent was removed in vacuo to afford 1.41 g (82%) of N-methyl-N-(4-methoxybenzyl)-4-(2-(methoxycarbonyl)ethyl)phenylsulfonamide as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl.[CH3:11]O>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:11])=[O:8]
Reactant: CO
Reactant: NCCCCCC(=O)O
Agent: Cl
Product: COC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To a suspension of 6-aminocaproic acid (3.00 g, 22.9 mmol) in anhydrous MeOH (60 mL), was introduced hydrogen chloride gas for 25 min., during which time the suspension became clear. The solution was then stirred at room temperature for 5 hours. MeOH was removed in vacuo. The residue was recrystallized from THF to give a white solid (1) (3.10 g). (Yield: 75%). The compound is better stored in hydrochloride form, because its free amino form tends to polymerize. 1HNMR (MeOH-d4, 300 MHz) δ 3.66 (s, 3H, OCH3), 2.92 (t, 2H, J=7.7 Hz, NCH2), 2.37 (t, 2H, J=7.2 Hz, CH2CO2), 1.74-1.60 (m, 4H, CH2CH2), 1.48-1.36 (m, 2H, CH2).
Reaction SMILES: C(O[CH2:6][CH2:7][O:8][CH2:9][CH:10]1[O:12][CH2:11]1)C1OC1>[OH-].[Na+]>[CH2:9]([O:8][CH:7]([O:8][CH2:9][CH:10]1[O:12][CH2:11]1)[CH2:6][CH2:7][CH3:6])[CH:10]1[O:12][CH2:11]1
Reactant: C(COCC1CO1)OCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCCC(OCC1CO1)OCC1CO1

Procedure:
Gels comprising agarose and ethyleneglycol diglycidylether prepared at different polymer/cross-linker ratios. A series of gel comprising 1% agarose polymer in 0.1 M NaOH and 0.05, 0.1, 0.2, 0.4 and 0.6 ml of ethyleneglycol diglycidylether in 10 ml was prepared by incubation at room temperature for 4 days. Electrophoresis showed reduced migration distances with increasing cross-linker concentration. Resolution was inferior to that obtained with butanediol diglycidylether.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:30]=1[CH2:31]Br>ClCCl>[F:27][C:28]([F:41])([F:42])[C:29]1[CH:36]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:34]=[CH:33][C:30]=1[CH2:31][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCN)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A solution of methyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate (Biochim. Biophys. Acta 1997, 1339 (2), 321–330) (2 g; 8.44 mmol) in dichloromethane (20 ml) was treated with DIEA (1.47 ml; 8.44 mmol) and 2,4-bis-trifluoromethyl-benzyl bromide (2.59 g; 8.44 mmol). After stirring at rt overnight, the reaction mixture was concentrated and partitioned between ethyl acetate and saturated Na2CO3 solution. The organic phase was washed with Na2CO3 solution and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography on silica gel using an ethyl acetate-hexane mixture (10–50%) afforded the title compound (2.0 g; 51% yield).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([NH:8][NH:9]C(=O)C(F)(F)F)=[N:6][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CCO.O>[Br:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1
Reactant: O=C(NNc1ncc(Br)nc1Cl)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NNc1ncc(Br)nc1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
N′-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide G-1 (1.59 g; 4.97 mmol) is dissolved in 30 ml EtOH and treated with 3 ml conc. HCl. It is stirred for 2 hours at 100° C. The reaction mixture is cooled down, diluted with water and then the pH adjusted to 8 with saturated NaHCO3 solution. The water phase is extracted with EtOAc, the organic layer dried over MgSO4 and evaporated to dryness.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2F)=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:31][O-:32].[Na+]>CO>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[O:32][CH3:31])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:25][CH2:26]2)[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(OC)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Temperature: 130 °C

Procedure:
A solution of [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (49.7 mmol, 0.112 mmol, Example 105) in methanol (4 mL) was treated with sodium methoxide (25 wt % in methanol, 0.29 mL, Aldrich) and heated at 130° C. in microwave for 3 hours. The reaction was concentrated and the crude product was purified on silica gel (95:5 methylene chloride/methanol) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3-fluoro-2,6-dimethoxy-phenyl)-methanone as a white solid. MS (M+H)+, 454.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[C@@H:27]([CH2:38][O:39]C(=O)C)[O:26][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:16])[NH2:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[C:12]([C:14](=[O:16])[NH2:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[C@@H:6]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:5]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(C(N)=O)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Cc2ccc(C(N)=O)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 5-carbamoyl-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.13 g) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 0.043 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on benzenesulfonylpropyl silica gel (eluent: methanol). Diethyl ether was added to the obtained compound, and the resulting precipitated solid was collected by filtration and dried under reduced pressure to give 5-carbamoyl-2-(4-ethyl-benzyl)phenyl β-D-glucopyranoside (0.079 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26](C)([CH3:28])[CH3:27])=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].C(N(CC)CC)C.ClC(O[C:42]1[CH:47]=CC=C[CH:43]=1)=O>Cl.CO>[CH2:1]([C:3]1[N:4]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]3[CH:27]=[CH:47][CH:42]=[CH:43][CH:28]=3)=[CH:19][CH:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A solution of tert-butyl 2-{4-[2-ethyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate (1.1 g, 2.6 mmol) in 10% HCl-MeOH (20 mL) was heated at 50° C. for 2 h. After cooling, the volatile components were removed by evaporation and the resulting amorphous was dried under reduced pressure. Then, the amorphous was suspended in dichloromethane at 0° C. To the cooled mixture was added triethylamine (1.4 mL, 10 mmol) and phenyl chloroformate (380 μL, 3.0 mmol). After 1 h, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 3:1 to 2:1) afforded 924 mg (85%) of the title compound as colorless amorphous. MS (ESI) m/z 430 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1)=O>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[O:23][CH:22]=[N:21][CH:20]=4)=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccc(-c2cnco2)cc1
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc2nc(-c3ccc(-c4cnco4)cc3)cn2c1
Yield: 43.6 %

Procedure:
The procedure of Referential Example 1 was repeated, except that 2-amino-5-methylpyridine (54 mg) and 2-bromo-1-[4-(1,3-oxazol-5-yl)phenyl]-1-ethanone (133 mg), which had been produced in Referential Example 10, were used, to thereby yield the title compound (60 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18]COC)=[C:15]([O:22][CH3:23])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CC(C)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([O:22][CH3:23])[CH:14]=[CH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1c(OC)ccc2cccc(Cc3ccccc3)c12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2cccc(Cc3ccccc3)c2c1O
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
79.5 g of 8-benzyl-2-methoxy-1-methoxymethoxynaphthalene was dissolved in 300 ml of acetone to give a solution. 120 ml of 6N hydrochloric acid was added to the solution at room temperature. The obtained mixture was stirred for 1.5 hours, followed by the addition of 400 ml of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The obtained solid was washed with hexane/diisopropyl ether (1:1) to give 51 g of the title compound as a colorless crystal.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=1.[CH:16]1([CH:19]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[N:20]2[CH2:25][CH2:24][C:23]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22][C:21]2=[O:37])[CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([CH:19]([C:38]2[CH:43]=[CH:42][C:41]([C:8]3[CH:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=3)=[CH:40][CH:39]=2)[N:20]2[CH2:25][CH2:24][C:23]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22][C:21]2=[O:37])[CH2:17][CH2:18]1
Reactant: CC(C)(O)CC1(c2ccccc2)CCN(C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Reactant: Cn1ccc(Br)cc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ccc(C(C3CC3)N3CCC(CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2 M aqueous Na2CO3 solution (0.69 mL) was added to a mixture of 4-bromo-1-methyl-1H-pyridin-2-one (0.14 g) and 3-{cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methyl}-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (pure diastereomer; 0.35 g) in N,N-dimethylformamide (4 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (57 mg) was added. The mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling the mixture to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound. Yield: 0.36 g (52% of theory); LC-MS (Method 1): tR=3.31 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: [C:1]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][O:8][CH2:7][O:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][O:8][CH2:7][O:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)C1(C(C)=O)COCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(C)O)COCOC1
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Ethyl 5-acetyl-1,3-dioxane-5-carboxylate (2) (22.3 g, 0.11 mol) was dissolved in ethanol (100 mL) and sodium borohydride (2.08 g, 0.055 mol) was added at 0° C. in portions. The mixture was stirred at the same temperature for 1 h. The excess of sodium borohydride was destroyed with acetone and the solution was extracted with ethyl acetate (3×600 mL). The combined organic extracts were concentrated in vacuo to give the title compound (18.9 g, 84%) as colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([CH2:16]O)[CH:12]=[N:13]2)=[CH:8][CH:7]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:16][C:11]1[CH:12]=[N:13][C:14]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:15]=2
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc2cc(-c3cccs3)ccc2c1
Product: ClCc1cnc2cc(-c3cccs3)ccc2c1
Yield: 77 %

Procedure:
In substantially the same manner as in Reference Example 73, 7-(2-thienyl)-3-quinolylmethanol was reacted with thionyl chloride to obtain 3-chloromethyl-7-(2-thienyl)quinoline. The yield was 77%. Recrystallization from ethyl acetate-hexane gave colorless leaflets, 120-121° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(Cl)Cl>[I:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1
Reactant: O=c1c2ccccc2oc2ccccc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2ccccc2oc2ccc(I)cc12
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A solution of xanthen-9-one (1.96 g, 10.0 mmol; Aldrich) in trifluoroacetic acid-CH2Cl2 (1:1, 40 mL) was chilled to 0° C. and treated with N-iodosuccinimide (NIS; 2.25 g, 10.0 mmol; Lancaster), added portionwise over 1 h. After an additional 1 h at 0° C., the ice bath was removed and stirring continued for 8 h. Residual oxidant was quenched with aq. NaS2O3 and the mixture was extracted with CH2Cl2. The organic phase was washed with NaHCO3, dried over MgSO4, and the residue purified by flash chromatography (120 g silica gel, 10-100% CH2Cl2-hexanes) to afford the title compound (1.75 g, 5.43 mmol; 54% yield): 1H NMR (300 MHz, CDCl3) δ ppm 8.66 (d, J=2 Hz, 1H), 8.34 (dd, J=8, 2 Hz, 1H), 7.98 (dd, J=9, 2 Hz, 1H), 7.75 (ddd, J=9, 7, 2 Hz, 1H), 7.50 (dd, J=8, 1 Hz, 1H), 7.40 (ddd, J=8, 7, 1 Hz, 1H), 7.28 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 323 (M+H)+, 340 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=1[CH3:27])=[O:14])=[O:10])([CH3:7])[CH:3]=[N:4][O:5][CH3:6].BrN1C(=O)CCC1=O.[Cl:40]N1C(=O)CCC1=O>>[Cl:40][C:31]1[C:11]([C:9]([NH:8][C:2]([CH3:1])([CH3:7])[CH:3]=[N:4][O:5][CH3:6])=[O:10])=[C:12]([CH:28]=[CH:29][CH:30]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][C:17]=1[CH3:27])=[O:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CON=CC(C)(C)NC(=O)c1ccccc1C(=O)Nc1ccc(OC(F)(F)F)cc1C
Agent: O=C1CCC(=O)N1Br
Product: CON=CC(C)(C)NC(=O)c1c(Cl)cccc1C(=O)Nc1ccc(OC(F)(F)F)cc1C
Yield: 63 %

Procedure:
2-(1,1-Dimethyl-2-(N-methoxyimino)ethylaminocarbonyl)-2′-methyl-4′-trifluoromethoxybenzanilide was treated in the same manner as in Example 36, except that the N-bromosuccinimide was replaced with N-chlorosuccinimide, to obtain 3-chloro-2-(1,1-dimethyl-2-(N-methoxyimino)ethylaminocarbonyl)-2′-methyl-4′-trifluoromethoxybenzanilide (yield 63%, melting point 197° C.). Regioselectivity of chlorination into the 3-position was 100%.