Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:1]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH2:3]1
Reactant: O=CC[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OCc1ccccc1
Product: OC[C@H]1O[C@@H](OCc2ccccc2)C[C@@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
2-deoxy-D-glucose (Compound 1a, 2.5 g, 15.2 mmol) was dissolved in benzyl alcohol (20 mL), and then Dowex® 50W-X8 (H+ form, 3.5 g) was added. The reaction solution was stirred at 60° C. for 24 hours. Then the resin was filtered off, and the product was purified by flash column chromatography with CHCl3—MeOH (15:1) to give Compound 1 (2.67 g, 10.5 mmol) in 69 percent yield.
Reaction SMILES: Cl.C[O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[C:10]([F:18])[CH:9]=1)[NH2:6].[CH:20]1([N:26]2[C:30]3[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=3[N:28]=[C:27]2[C:38]2[CH:42]=[CH:41][O:40][CH:39]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:4]([CH:5]([NH:6][C:35]([C:33]1[CH:32]=[CH:31][C:30]2[N:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:27]([C:38]3[CH:42]=[CH:41][O:40][CH:39]=3)=[N:28][C:29]=2[CH:34]=1)=[O:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([F:18])[CH:9]=1)([OH:3])=[O:19]
Reactant: COC(=O)c1ccc(C[C@H](N)C(=O)OC)cc1F
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: Cl
Product: O=C(NC(Cc1ccc(C(=O)O)c(F)c1)C(=O)O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
Racemic 3-fluoro-4-(carbomethoxy)phenylalanine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner and saponified to give the title compound of example 120.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([OH:24])[C:22]=1[OH:23])[C:16]([O:18][CH3:19])=[O:17]>CCCCCC>[OH:24][C:21]1[C:22]2[O:23][CH:1]=[N:12][C:13]=2[CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:20]=1
Reactant: COC(=O)c1cc(N)c(O)c(O)c1
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CCCCCC
Product: COC(=O)c1cc(O)c2ocnc2c1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To stirred triethyl orthoformate (35.0 mL, 210 mmol) was added methyl 3-amino-4,5-dihydroxybenzoate hydrochloride (6.30 g, 28.7 mmol). The stirred suspension was refluxed for 20 min (until a clear solution formed), cooled to room temperature, and poured into hexane (200 mL). The formed precipitate was separated by filtration and vacuum-dried to afford the desired benzoxazole (4.26 g, 22.05 mmol, 77% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (br. s, 1H), 8.79 (s, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.50 (d, J=1.3 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10](C)[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1C=CC=CC=1>[CH2:32]([O:31][C:29]([N:10]1[CH2:11][CH2:12][C@@H:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=2)[C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: CN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Reaction time: 1 h

Procedure:
A mixture of 3.49 g of trans-4-(4-fluorophenoxy)-1-methyl-3-phenylpiperidine of Example 30, 2.53 g of anhydrous potassium carbonate, and 28 ml of dry benzene are treated all at once under a nitrogen atmosphere with 1.75 ml of ethyl chloroformate. After 1 hour at ambient temperature, the mixture is refluxed 18 hours, then cooled and partitioned between ether and water. The phases are separated and the aqueous phase is extracted with ether. The combined ether extracts are washed with 2 N HCl solution, then with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a gum which eventually crystallizes to a solid of trans-1-ethoxycarbonyl-4-(4-fluorophenoxy)-3-phenylpiperidine, m.p. s 78°, 80°-82.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C@@H:14]([NH:16][C:17]2[N:22]=[C:21]([C:23]([O:25]C)=O)[CH:20]=[N:19][CH:18]=2)[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH3:30]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C@@H:14]([NH:16][C:17]2[N:22]=[C:21]([C:23]([NH2:30])=[O:25])[CH:20]=[N:19][CH:18]=2)[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: COC(=O)c1cncc(N[C@@H](C)c2cccc(NC(=O)c3cccc(C)c3)c2)n1
Reactant: N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(C(N)=O)n3)c2)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of (S)-methyl 6-(1-(3-(3-methylbenzamido)phenyl)ethylamino)pyrazine-2-carboxylate (40 mg, 0.1 mmol) and aqueous ammonia (4 mL, 28%) in dioxane (2 mL) was heated at 130° C. in a sealed tube for 18 hours. After this time the mixture was allowed to cool to room temperature and was diluted with ethyl acetate (20 mL). The two phases were separated and the aqueous phase extracted with ethyl acetate (10 mL). The combined organic solutions were washed with brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give (S)-6-(1-(3-(3-methylbenzamido)phenyl)ethylamino)pyrazine-2-carboxamide (37 mg, 98%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.N1CCCC1>CO>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15](/[C:16](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH3:10])/[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: Cc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: Cc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 92.5 %

Procedure:
5-Chloro-2-methyl-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.5 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as yellow solid (Yield: 4.5 g).
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])=[C:9]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:8]=1.Cl.[NH2:30]O>C(O)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]2[CH:20]=[N:30][O:16][C:15]=2[CH:17]2[CH2:19][CH2:18]2)=[O:24])=[C:9]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:8]=1
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(Cl)cc1S(C)(=O)=O)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1cc(Cl)ccc1C(=O)c1cnoc1C1CC1

Procedure:
Sodium acetate (1.93 g) was added to a mixture of 1-(4-chloro-2-methylsulphonylphenyl)-3-cyclopropyl-2-ethoxymethylenepropan 1,3-dione (84 g) and hydroxylamine hydrochloride (1.64 g) in ethanol with stirring. The mixture was stirred at room temperature overnight. It was evaporated and the residue was dissolved in ethyl acetate, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from ether to give 4-(4-chloro-2-methylsulphonylbenzoyl)-5-cyclopropylisoxazole, compound 260 (4.4 g) as an off-white solid, m.p. 183°-185° C.
Reaction SMILES: CI.CN([CH:6]=[O:7])C.[Br:8][C:9]1[C:18]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:8][C:9]1[C:18]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:7][CH3:6]
Reactant: COC(=O)c1cc(O)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 1-liter egg plant-type flask, methyl iodide (6.67 mL, 105 mmol) was added to a DMF (200 mL) solution of methyl 4-bromo-3-hydroxy-5-{[(trifluoromethyl)sulfonyl]oxy}benzoate (19.9 g) and potassium carbonate (14.5 g, 105 mmol), and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water, dried with sodium sulfate, filtered, and concentrated to obtain a crude product. This was purified through silica gel column chromatography (Biotage [SiO2, 40+M]) with a hexane/ethyl acetate developer system to obtain the title compound as a colorless solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[S:2]([O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:16])=[CH:9][CH:8]=1)([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2ccc(O)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2c(c1)C(=O)CC2
Yield: 99 %

Procedure:
12.6 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 12.0 g of 6-hydroxy-1-indanone and 45.2 ml of triethylamine in 350 ml of dichloro-methane and the solution was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of dichloromethane, washed twice with 150 ml of saturated sodium hydrogen carbonate solution each time an the combined aqueous phases were extracted once with 100 ml of dichloromethane. The combined organic phases were washed with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. 18.3 g (99%) of 6-mesyloxy-1-indanone were obtained as a brown solid which was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]([NH:14][C:15]1[C:16](=[O:40])[N:17]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]3[CH2:29][CH2:28]3)[CH:21]=2)[CH:19]=1)([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]3[CH2:29][CH2:28]3)[CH:21]=2)[N:17]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=2)[C:16]1=[O:40])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)(NC1=C[C@H](c2cccc(OC3CC3)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccc(C(F)(F)F)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OC3CC3)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Add trifluoroacetic acid (1.5 mL, 20 mmol) to a mixture of (R)-3-((R)-1-phenyl-ethylamino)-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (1.92 g, 4.01 mmol) in toluene (10 mL) and water (4 mL). Stir at ambient temperature for 60 min. Observe significant formation of (R)-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. LCMS, Ret. time=4.14 min., Method 3, MS (m/z): 376.0 (M+), 374.0 (M−1). Add a solution of 1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (1.2 g, 5.9 mmol) in toluene (10 mL) to the reaction solution. Then add acetic acid (1.9 mL, 33 mmol). Heat at 50° C. for 14 hours. Concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-10% ethyl acetate-hexane) to obtain (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one as a tan foam. LCMS, Ret. time=5.40 min., Method 3, MS (m/z): 562.0 (M+), 560.0 (M−1). Dissolve (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (1.09 g, 1.94 mmol) in acetic acid (20 mL) and add sodium cyanoborohydride (240 mg. 3.8 mmol). Stir 1 hour at ambient temperature. Concentrate under reduced pressure. Dissolve the residue in dichloromethane and wash with saturated sodium bicarbonate solution, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-15% ethyl acetate-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (645 mg, 59%) as a white foam. LCMS, Ret. time=5.04 min, Method 3 MS (m/z): 564.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([NH:12][C:13](=[O:23])[N:14]3[CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:10]([C:24]([O:26]C)=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si](OC1C=C(C2N=C3C(NC(=O)N3C3CCOCC3)=C(C(OC)=O)[N:53]=2)C=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([NH:12][C:13](=[O:23])[N:14]3[CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:10]([C:24]([NH2:53])=[O:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCOCC1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc2c1[nH]c(=O)n2C1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Methyl 2-(3-hydroxyphenyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 2-(3-(tert-butyldiphenylsilyloxy)phenyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-6-carboxylate (0.270 g, 0.513 mmol) was dissolved in tetrahyrdrofuran (10 mL) and tetrabutylammonium fluoride on silica gel (0.410 g, 0.615 mmol) was added to the solution. The solution stirred at ambient temperature for two hours. LCMS confirms product and no starting materials. The solution was filtered and condensed to give the crude title compound (0.110 g, 58%) which is used in the next step without further purification or characterization.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][CH2:7][C:8](Br)=[O:9].[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>O>[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:8](=[O:9])[CH2:7][Br:6])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(CNc1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CN(C(=O)CBr)c1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
1.08 g of sodium bicarbonate (12.9 mmol) and 1.0 ml of bromoacetyl bromide (11.3 mmol) were added to a solution of 4.00 g of [2-(2-benzyloxyphenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester obtained in Example (10a) (10.7 mmol) in a mixed solvent of ethyl acetate (50 ml) and water (50 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=2/1) to obtain 4.86 g of the title compound (yield: 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([OH:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(O)c23)c1
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCCCC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 1, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-hydroxyquinazoline (0.53 g) was reacted with cyclohexanol to give 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-cyclohexyloxyquinazoline (0.25 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.3–1.4 (m, 1H), 1.4–1.55 (m, 2H), 1.55–1.65 (m, 1H), 1.7–1.85 (m, 4H), 2.15 (m, 2H), 3.82 (s, 3H), 4.95 (m, 1H), 5.4 (s, 2H), 7.0 (d, 1H), 7.05 (m, 1H), 7.2 (s, 1H), 7.4–7.65 (m, 7H), 8.9 (s, 1H); Mass Spectrum: M+H+ 490 and 492.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[C:16]([NH2:21])=[C:15]([CH2:22][CH3:23])[CH:14]=1)[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH2:10])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH2:24]([C:26]([CH3:28])=O)[CH3:25]>>[C:24](=[N:21][C:16]1[C:17]([CH2:19][CH3:20])=[CH:18][C:13]([CH2:1][C:2]2[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([N:10]=[C:1]([CH2:2][CH3:3])[CH3:13])=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:14][C:15]=1[CH2:22][CH3:23])([CH2:26][CH3:28])[CH3:25]
Reactant: CCC(C)=O
Reactant: CCc1cc(Cc2cc(CC)c(N)c(CC)c2)cc(CC)c1N
Product: CCC(C)=Nc1c(CC)cc(Cc2cc(CC)c(N=C(C)CC)c(CC)c2)cc1CC
Temperature: 40 °C
Yield: 94.7 %

Procedure:
A two-liter three neck round bottom flask was equipped with a magnetic stirrer, a heating mantle, a thermocouple, a glass stopper and a Dean Stark trap fitted with a condenser. 4,4′-Methylenebis(2,6-diethylbenzeneamine) (310.5 g, 1.00 mol) and methyl ethyl ketone (450 mL, 350 g, 4.85 mol) were added to the flask. This mixture was stirred at 40° C. to dissolve the 4,4′-methylenebis(2,6-diethylbenzeneamine). Hexanes (300 mL) and Amberlyst-15 (15.54 g) were added to the flask. The mixture was heated to reflux, and water was removed as an azeotrope in the Dean Stark trap. Samples were periodically taken and analyzed by gas chromatography (GC). N,N′-di-sec-butylidene-4,4′-methylenebis(2,6-diethylbenzeneamine) was formed in 94.7% yield. GC results are summarized in Table 1; units for the diamine, monoimine, and diimine are GC area percent.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4].[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([Cl:13])=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccn(C(F)F)n1
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C(F)F)cc1Cl
Temperature: 50 °C
Yield: 85.5 %

Procedure:
A mixture of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (535 mg, 3 mmol) and N-chloro-succinimide (1.22 g, 9.1 mmol) in N,N-dimethylformamide (5 ml) was heated at 50° C. overnight. The reaction mixture was cooled, partitioned between ethyl acetate and water, the organic layer was washed with water, dried, evaporated and the residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (3:1) as the eluent to give the title compound (540 mg) as a white solid. MS (ISP): m/z=209.9 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1.[OH-].[NH4+:20]>CC(C)=O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([NH2:20])(=[O:16])=[O:15])=[CH:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(-c2sc(S(=O)(=O)Cl)cc2C)cn1
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(-c2sc(S(N)(=O)=O)cc2C)cn1

Procedure:
5-(6-Methoxy-pyridin-3-yl)-4-methyl-thiophene-2-sulfonyl chloride (0.19 g, 0.63 mmol) was dissolved in acetone (6 ml) and added dropwise to an aqueous ammonium hydroxide solution (25%, 1.2 ml). After 1 hour the solvent was removed under reduced pressure, the residue diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried (MgSO4.2H2O), filtered and concentrated under reduced pressure to yield a crude that was purified over silica gel (n-heptane-ethyl acetate 1:2 to 2:1 v/v) to yield a beige solid: 0.12 g (62%), MS: m/e 283.0 (MH−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[C@H:16]([CH3:17])[CH2:15][O:14][C:13]1=[O:18])[C:6]([OH:8])=O.[ClH:19].[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[ClH:19].[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:6]([C:5]3[CH:9]=[CH:10][C:11]([N:12]4[C@H:16]([CH3:17])[CH2:15][O:14][C:13]4=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:8])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: COc1cc(C(=O)O)ccc1N1C(=O)OC[C@H]1C
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: COc1cc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)ccc1N1C(=O)OC[C@H]1C
Yield: 45.7 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-3-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (1 g) described in Preparation Example 46 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (956 mg) described in Preparation Example 64, the title compound (838 mg) was obtained.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30]C(=O)C)[CH:26]=4)[CH:21]=3)=[N:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.Cl>C(O)C>[CH2:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[CH:26]=4)[CH:21]=3)=[N:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(OC(C)=O)ccc4c3)s2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(O)ccc4c3)s2)cc1
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
0.62 g (9.39 mM) of potassium hydroxide was dissolved in 30 ml of ethanol at 60°-65° C. To the solution, 1.50 g (3.48 mM) of 2-(4-hexylphenyl)-5-(6-acetoxynaphthalene-2-yl)-1,3,4-thiadiazole was added, followed by stirring for 10 minutes at 60°-65° C. The reaction mixture was poured into 100 ml of iced water and 0.83 ml of concentrated hydrochloric acid was added thereto to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from acetone to obtain 1.19 g of 2-(4-hexylphenyl)-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 87.9%). ##STR35##
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:28][C:27]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:38][CH2:37][C:27]2[N:28]=[C:29]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[S:30][C:26]=2[CH3:25])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(N3CCOCC3)sc2C)cc1
Reactant: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Product: Cc1sc(N2CCOCC2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Yield: 87.7 %

Procedure:
3-[4-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (272 mg, 0.806 mmol) and toluene-4-sulfonic acid 2-(5-methyl-2-morpholin-4-yl-thiazol-4-yl)-ethyl ester (522 mg, 1.36 mmol) were reacted according to Standard procedure A. Purification using radial chromatography (CH2Cl2/EtOAc 98:2 to 75:25) gave the title compound as a white solid (387 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 1.14 (d, 6H, J=5.9 Hz), 1.32 (s, 9H), 2.16 (s, 3H), 2.39 (t, 2H, J=7.6 Hz), 2.77 (t, 2H, J=7.6 Hz), 2.84 (t, 2H, J=7.1 Hz), 3.28 (t, 4H, J=4.9 Hz), 3.70 (t, 4H, J=4.9 Hz), 4.08 (t, 2H, J=7.1 Hz), 4.25 (d, 2H, J=5.4 Hz), 4.83 (heptet, 1H, J=4.9 Hz), 6.66 (dd, 1H, J=2.4, 8.3 Hz), 6.72 (d, 1H, J=2.4 Hz), 6.98 (d, 1H, J=8.3 Hz). MS (ES) m/e 548.3 [M+1].