Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:13](O)(=[O:17])[C:14]([CH3:16])=[CH2:15].COC1C=CC(O)=CC=1.S(=O)(=O)(O)O.O=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:13]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: C=C(C)C(=O)O
Agent: COc1ccc(O)cc1
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 2 L jacket-equipped separable flask provided with a stirrer, a thermometer, a Dean-Stark water separator, a Dimroth condenser and a gas blowing tube, 84.0 g of 1,3-adamantanediol, 124.1 g of methacrylic acid, 0.38 g of p-methoxyphenol as a polymerization inhibitor, 1.2 g of concentrated sulfuric acid as an acid catalyst, and 750 ml of toluene as a solvent were put. Prepared gas diluted with nitrogen so as to have an oxygen concentration of about 5% by volume was supplied at a rate of 0.2 L/min. The reaction operation was performed as follows. While the solution was heated and water generated as a secondary product was removed by the Dean-Stark water separator, the reflux state was continued for 5 hours. Thus, a reaction solution containing 3-hydroxy-1-adamantyl methacrylate was obtained. The obtained reaction solution was cooled down to room temperature, and then a 10% by weight of aqueous solution of sodium hydroxide was added while stirring to neutralize the residual methacrylic acid and sulfuric acid. Then, the neutralized water phase was drawn out from the two-phase solution. To the residual organic phase, 0.85 g of p-methoxyphenol was added as a polymerization inhibitor. The resultant solution was washed with 5% by weight of dilute sulfuric acid and with 500 ml of ion exchange water, twice for each. After the washing, precise filtration was performed by use of a Teflon® filter having a pore diameter of 0.1 μm. Then, concentration-crystallization was performed by use of an evaporator while the temperature of the solution was kept at 40° C., until the weight of the solution became 110 g. After the concentration was finished, cooling crystallization was performed at a temperature of an ice water bath to separate the crystal by filtration. The crystal was rinsed with heptane twice, and then dried at a reduced pressure at 35° C. for 24 hours. During the process from the dehydration esterification reaction to the solid-liquid separation and until the termination of rinsing performed by use of ion exchange water, the prepared gas was kept blown into the solution. Table 1 shows the analysis results of the obtained 3-hydroxy-1-adamantyl methacrylate. Methylethylketone was used as the solvent for measuring the turbidity.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12](=[O:14])[CH3:13].Cl.C([O-])(O)=O.[Na+].[CH3:21][O:22][C:23](=O)[O:24]C>>[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12](=[O:14])[CH2:13][C:23]([O:22][CH3:21])=[O:24]
Reactant: COCCn1ccnc1C(C)=O
Reactant: COC(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Product: COCCn1ccnc1C(=O)CC(=O)OC
Temperature: 90 °C

Procedure:
NaH (7.84 g, 196 mmol of a 60% dispersion in oil) was added portionwise to a solution of 6.18 g (Intermediate 57, 34.5 mmol) of 1-[1-(2-methoxyethyl)-1H-imidazol-2-yl]ethanone in 100 ml dimethylcarbonate. The mixture was heated to 90° C. for 2 hour forming a thick slurry. After cooling to room temperature, the mixture was slowly transferred to 1N HCl over ice. The mixture was brought to about pH 7 with NaHCO3, then saturated with NaCl and extracted 4 times with EtOAc. The EtOAc was dried over MgSO4, then concentrated to give an oil that was chromatographed on silica gel (100% DCM followed by gradient elution to 50% EtOAc in DCM) to yield the title compound. MS (ES) (M+H)+: 227 for C10H14N2O4; NMR: 3.18 (s, 3H), 3.61 (m, 5H), 4.07 (s, 2H), 4.52 (m, 2H), 7.24 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:10][CH2:11][CH2:12][Si:13]([O:17][CH3:18])([O:15][CH3:16])[CH3:14]>C(OCC)C>[CH3:1][C:2]1[CH:6]=[CH:5][CH:4]([CH2:10][CH2:11][CH2:12][Si:13]([O:17][CH3:18])([O:15][CH3:16])[CH3:14])[CH:3]=1
Reactant: CC1=CC=CC1
Reactant: CO[Si](C)(CCCCl)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CO[Si](C)(CCCC1C=CC(C)=C1)OC
Yield: 89 %

Procedure:
33.4 g (417 mmol) of freshly distilled methylcyclopentadiene are added dropwise to a suspension of 10 g (417 mmol) of sodium hydride in 250 ml of absolute diethyl ether at RT over a period of one hour. 76.1 g of (3-chloropropyl)dimethoxy-methylsilane are subsequently added dropwise over a period of 30 minutes. The solution becomes warm during this process. After taking off the solvent, the mixture is fractionally distilled in an oil pump vacuum to give 78.9 g of (3-methylcyclopentadienylpropyl)dimethoxy-methylsilane (yield: 89%).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH2:17]([C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][CH:23]2O)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:23]2[C:24]3[C:20](=[C:19]([CH2:17][CH3:18])[CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CCO[C@@H](CC(=O)OC)c1ccc(O)cc1
Reactant: CCc1cccc2c1CCC2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCO[C@@H](CC(=O)OC)c1ccc(OC2CCc3c(CC)cccc32)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.446 mmol) produced in Example 41 (41C) and 4-ethylindan-1-ol (109 mg, 0.669 mmol) synthesized in (44B) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=2[O:23]C)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=2[OH:23])[CH:4]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:8]=1
Reactant: COc1c(C)cc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(Cl)cc(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-methoxy-3-methylbenzamide (1 g, 2.43 mmol) prepared in step 1 was dissolved in CH2Cl2 (15 ml), to which boron tribromide (3.54 ml, 12.15 mmol) was added at −70° C., followed by stirring at room temperature for 3 hours. The mixture was dropped in 20 ml of cold ice water, followed by stirring for 30 more minutes. The mixture was cooled down at room temperature, to which aqueous sodium hydroxide was dropped 6˜7 drops. Extraction was performed with dichloromethane. The organic extract was mixed, dried over MgSO4, and concentrated under reduced pressure, followed by chromatography (ethylacetate:hexane=1:5) to give 930 mg of the target compound (yield: 96%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(Cl)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Br>CS(C)=O>[O:26]1[CH:24]([CH3:22])[CH:25]1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)n(C)c(=O)c2c1
Reactant: BrCC1CO1
Solvent: CS(C)=O
Product: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2c1
Temperature: 25 °C

Procedure:
2.8 gm (10 mmols) of 2-(4-hydroxyphenyl)-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one were dissolved in 20 ml of dimethylsulfoxide, and the solution was mixed, while stirring, with 1.35 gm (10 mmols+20%) of potassium tert. butylate. Subsequently, 2.8 ml of epibromohydrin were added, and the reaction mixture was stirred at room temperature until the reaction had gone to completion. After pouring the reaction mixture into ice water, the crystalline precipitate formed thereby was suction-filtered off, washed well with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22]([OH:24])=O.Cl.[OH:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][CH:35]=[CH:36][C:27]=2[OH:26])[CH2:32]1)=[O:24]
Reactant: Oc1cccc2c1CCNC2
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)N3CCc4c(O)cccc4C3)c2cc1OC
Yield: 27.4 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 113 (27.4% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.64 and 2.89 (2t, 2H), 3.47-4.09 (m, 8H), 4.42 and 4.94 (2s, 2H), 6.29-6.78 (m, 2H), 6.85-7.12 (m, 2H), 7.36-7.42 (m, 1H), 7.50-7.65 (m, 2H), 8.12-8.21 (m, 1H), 8.29-8.35 (m, 1H), 9.48 and 9.54 (2s, 1H); MS (ESI) m/z 460 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])=[N:11][C:10]=1[CH3:21])=[O:8].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:15]2=[O:20])=[N:11][C:10]=1[CH3:21])=[O:8]
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1cccc(F)c1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1nc(N2CCCC(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccc(F)c1
Yield: 46 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-(3-fluorobenzyl)-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-fluorobenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 46% yield: mp 173-175° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.15-6.88 (m, 7H), 6.12 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 4.29-4.21 (m, 1H), 3.98-3.86 (m, 1H), 3.40-3.27 (m, 1H), 2.86-2.69 (m, 2H), 2.62 (s, 3H), 2.08-1.95 (m, 1H), 1.93-1.73 (m, 2H), 1.61-1.44 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.9, 162.9, 162.6, 161.6, 156.9, 152.4, 140.6, 134.5, 130.5, 130.2, 123.2, 119.1, 115.3, 114.6, 114.4, 47.9, 44.1, 43.4, 36.6, 24.8, 21.2, 17.3; MS (ES+) m/z 456.3 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10].C(N(CC)C(C)C)(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>ClCCl>[Cl:14][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1cc(CN)ccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(CNC(=O)C(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a thermally controlled reactor, add methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (700 g, 3.51 mol, 1.0 equiv), dichloromethane (4.9 L), and N,N-diisopropylethylamine (1.71 L, 9.82 mol, 2.8 equiv). Add pivaloyl chloride (515 mL, 4.21 mol, 1.2 equiv) dropwise at such a rate that the internal temperature does not exceed 21° C. Upon completion of the addition, stir the reaction mixture at room temperature for one hour. Quench the reaction mixture with saturated aqueous sodium bicarbonate (10 L). Extract the mixture with dichloromethane (2×1 L), combine the organic extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give an oil, (1.1 kg) carried on crude without further purification. MS (m/z) (35Cl/37Cl) 284/286 (M+1)
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23](Cl)=[O:24]>C(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:24]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: NCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1ccc(F)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of phenethylamine (1.01 mL, 7.95 mmol) and DIEA (1.38 mL, 7.95 mmol) in 20 mL of DCM, 3,4-difluorobenzoyl chloride (1.00 mL, 7.95 mmol) was added dropwise. The clear solution was stirred for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.57 (ddd, J=10.63, 7.56, 2.12 Hz, 1H) 7.31-7.44 (m, 3H) 7.15-7.31 (m, 4H) 6.02 (br. s., 1H) 3.67-3.78 (m, 2H) 2.94 (t, J=6.87 Hz, 2H).
Reaction SMILES: CC1(C)C[O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[O:4]C1.[OH-].[Na+]>C(OCC)C>[B:5]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=1)([OH:6])[OH:4]
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CCCc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2A (343 mg, 1.24 mmol) was added to a mixture of diethyl ether (10 mL) and NaOH (2 mL, 2 N). The reaction mixture was stirred at rt for 10 min. The ether layer was separated and then treated with an additional portion of NaOH for 5 min. The combined aqueous layers were washed with diethyl ether (2×) and acidified to pH 4 with hydrochloric acid (6 N). The resulting solid precipitate was collected by filtration to afford 2B contaminated with 2A (212 mg, 1:1 2B/2A, 43% yield based on content of 2B) as a beige solid.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[C:7]4[N:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH:9]=[N:10][C:6]=4[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=3)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCCO
Solvent: COCCOC
Product: Cn1ccc2cc(-c3cc(C(F)(F)F)cc4ncn(-c5ccccc5)c34)ccc21
Yield: 83.8 %

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (1.0 g, 2.5 mmol), 1-methyl-5-indolyl boronic acid (0.65 g, 3.73 mmol), 1,3-propanediol (0.9 ml, 12.4 mmol), potassium carbonate (1.71 g, 12.4 mmol) and bis(triphenylphosphin)palladium dichloride (100 mg, 0.14 mmol) in a mixture of dimethoxyethane (20 ml) and water (10 ml) was stirred at reflux in a nitrogen atmosphere for 1 hour. The cooled reaction mixture was partitioned between ethyl acetate and water and the organic layer was dried over magnesium sulphate and evaporated under reduced pressure. The residue was triturated in ethanol to afford the title product as an off-white solid (0.82 g, 84%) m/z, 392.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NS(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A solution of 2-chloro-4-methylaniline (5.00 g) and triethylamine (3.57 g) in dichloromethane (100 ml) was cooled to 0° C. Methanesulphonyl chloride (4.04 g) was added dropwise and the mixture stirred at ambient temperature overnight. The mixture was then washed with 2N aqueous hydrochloric acid solution (50 ml) and the solvent removed by evaporation. The residue was dissolved in ethyl acetate (75 ml) extracted with 2N aqueous sodium hydroxide solution (2×50 ml). The aqueous phase was acidified with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×75 ml). This was subsequently dried (MgSO4) and the solvent evaporated. Thus was obtained N-(2-chloro-4-methylphenyl)methanesulphonamide (2.5 g, 32%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.N1C(C)=CC(C)=CC=1C.S([Cl:33])(C)(=O)=O.[Cl-].[Li+]>CN(C)C=O.O>[Cl:33][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=c1[nH]nc(-c2cccc(CO)c2)c2ccccc12
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]nc(-c2cccc(CCl)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound prepared in example 1 (2.52 g) in dimethylformamide (30 ml) were added 2,4,6-collidine (3.96 ml), mesyl chloride (929 μl) and lithium chloride (593 mg). The mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water and the precipitate was collected by filtration. The precipitate was washed with water, methanol and ether to give the title compound (2.50 g) having the following physical data.
Reaction SMILES: N1C2C(=CC=CC=2)C2(C3C(=CC4OCC(=O)OC=4C=3)OC2)C1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:25]2([C:43]3[C:34](=[CH:35][C:36]4[O:41][CH2:40][CH2:39][O:38][C:37]=4[CH:42]=3)[O:33][CH2:32]2)[C:24]1=[O:44].Br[CH2:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[C:49]([F:54])[CH:48]=1.BrCCCCC>>[F:53][C:51]1[CH:52]=[C:47]([CH:48]=[C:49]([F:54])[CH:50]=1)[CH2:46][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2([C:43]3[C:34](=[CH:35][C:36]4[O:41][CH2:40][CH2:39][O:38][C:37]=4[CH:42]=3)[O:33][CH2:32]2)[C:24]1=[O:44]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: O=C1COc2cc3c(cc2O1)C1(CNc2ccccc21)CO3
Solvent: CCCCCBr
Product: O=C1N(Cc2cc(F)cc(F)c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-3,5-difluorobenzene to replace 1-bromopentane, 1′-(3,5-difluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (72%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.22-7.32 (m, 1H), 7.24-7.14 (m, 2H), 7.13-7.00 (m, 4H), 6.53 (s, 1H), 6.11 (s, 1H), 4.96 (s, 2H), 4.77 (ABq, 2H), 4.23-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.6, 154.7, 144.2, 141.9, 137.8, 131.6, 128.9, 125.7, 125.6, 125.2, 124.4, 123.7, 123.2, 121.0, 116.9, 116.7, 111.1, 109.1, 98.8, 79.5, 64.2, 63.6, 57.2; MS (ES+) m/z 421.8 (M+1).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)c(CO)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 600 mg (3.48 mmol) of 2,6-difluoro-3-methoxybenzaldehyde (CAS 149949-30-4) in 8 ml of ethanol at 0° C. was admixed with 65.9 mg (1.74 mmol) of sodium borohydride in portions. After stirring at 0° C. for 30 min, the reaction mixture was quenched with water and extracted three times with methyl tert-butyl ether. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, and dried with a phase separation cartridge. The solvent was drawn off to dryness under reduced pressure, which gave 550 mg (89% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:18]1[C:19]2[N:20](C=NN=2)[C:21]2C(N=1)=CC=C[CH:22]=2.C(NCC)C.C(NCCC)CC>>[CH2:19]([N:20]([CH2:21][CH3:22])[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:18]
Reactant: Clc1nc2ccccc2n2cnnc12
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CCCNCCC
Solvent: CCNCC
Product: CCc1nnc2c(N(CC)CC)nc3ccccc3n12
Yield: 69 %

Procedure:
This compound was prepared by the method of Example 11, utilizing 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 4) as starting material in place of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 2) and diethylamine as reagent in place of di-n-propylamine. The crude product was recrystallized from cyclohexane to afford 3.54 g. (69% yield) of pure 4-diethylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline as a white solid (m.p. 98°-100° C.). Mass spectrum: m/e, 269 (P).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:60]\[H])/[C:50]1[C:55]([C:56]([F:59])([F:58])[F:57])=[CH:54][CH:53]=[N:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:13]1([C:6]2([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:22][N:60]=[C:49]([C:50]4[CH:51]=[N:52][CH:53]=[CH:54][C:55]=4[C:56]([F:59])([F:57])[F:58])[N:48]=3)[C:2]2=[O:1])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1cnccc1C(F)(F)F
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3cnccc3C(F)(F)F)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxy-4-(trifluoromethyl)nicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 9.09 (s, 1H), 8.97 (d, J=5.1, 1H), 7.73 (d, J=5.2, 1H), 7.42-7.18 (m, 10H), 4.95 (s, 2H), 3.59 (t, J=6.5, 2H), 2.89 (t, J=6.5, 2H); MS (DCI) m/z 465.1 (M+H)+.