Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[F:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1.[F-].[K+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:18][C:14]1[CH:13]=[C:12]2[C:17](/[C:9](=[C:4]3\[O:5][C:6]([CH3:8])([CH3:7])[C:2]([C:25]4[CH:24]=[CH:23][N:22]=[C:21]([F:20])[CH:26]=4)=[CH:3]\3)/[C:10](=[O:19])[NH:11]2)=[CH:16][CH:15]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccnc(F)c1
Temperature: 80 °C
Yield: 57.8 %

Procedure:
To a mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (2.0 g, 6.1 mmol), 2-fluoropyridine-4-boronic acid (1.1 g, 8.0 mmol), potassium fluoride (1.8 g, 5 eq.) in dioxane (50 mL) and water (5 mL) under a nitrogen atmosphere, was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (250 mg, 5%). The mixture was heated at 80° C. for 20 hour. The reaction was allowed to cool to room temperature and ethyl acetate (350 mL) was added. The organic phase was washed with water (100 mL×2) and evaporated to provide the crude product. The crude product was purified by column chromatography (silica gel, 5% CH3OH/CH2Cl2 elution) and then recrystallized from ethyl acetate/hexanes (80/20) to provide (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow-orange solid (1.2 g, yield 57%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[N:9]3[CH2:20][C:21]4[C:26]([C:8]=23)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(O)C.[OH-].[Na+]>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]3[CH2:20][C:21]4[C:26]([C:8]=23)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)Cc1ccccc1-3
Temperature: 25 °C

Procedure:
A mixture of Example 6 in ethanol (8 mL) and 1N NaOH (2.0 mL) was stirred at reflux for 1 hour and cooled to room temperature. The solution was acidified with 1N HCl (2.1 mL) and partially concentrated. The precipitated solid was collected by filtration, washed with water, dissolved in methanol, and filtered. The filtrate was concentrated by boiling to about 0.4 mL, and diluted with diethyl ether. The resulting precipitate was collected by filtration to provide the desired product as a colorless solid. ESI-MS, both positive and negative ion consistent for MW 331, 1H NMR (500 MHz, CD3OD) δ 1.42 (m, 3H), 1.86 (m, 7H), 3.14 (m, J=12.05, 12.05 Hz, 1H), 5.01 (s, 2H), 7.21 (t, J=7.48 Hz, 1H), 7.32 (t, J=7.48 Hz, 1H), 7.44 (d, J=7.63 Hz, 1H), 7.58 (s, 2H), 7.73 (d, J=7.63 Hz, 1H), 7.89 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([SH:22])[CH2:20][CH3:21]>CN(C=O)C>[F:1][C:2]1[C:7]([S:22][CH2:19][CH2:20][CH3:21])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CCCS
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1cc(N)c([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 98.7 %

Procedure:
To a mixture of 4,5-difluoro-2-nitro-phenylamine (1.51 g, 8.67 mmol), potassium carbonate (2.40 g, 17.3 mmol), and DMF (43 mL) was added 1-propanethiol (0.865 mL, 9.54 mmol). The reaction mixture was heated at 90° C. for 1.5 h, and allowed to cool to 23° C. The mixture was poured into ice/brine (400 mL) and the resulting precipitate was collected to yield the titled compound (1.97 g, 98% yield). MS (ESI/CI): mass calcd. for C9H11FN2O2S, 230.1; m/z found, 231.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.78 (d, J=10.3 Hz, 1H), 6.52 (d, J=6.3 Hz, 1H), 6.04 (s, 2H), 2.93 (t, J=7.3 Hz, 2H), 1.84-1.70 (m, 2H), 1.09 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([N:10]([N+:29]([O-:31])=[O:30])[C@H:11]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[N+:29]([NH:10][C@H:33]([C:34]([CH:6]([NH2:7])[CH2:5][CH2:4][CH2:3][C@@H:2]([C:8]([N:10]([N+:29]([O-:31])=[O:30])[C@H:11]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])=[O:9])[NH2:1])=[O:36])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])([O-:31])=[O:30]
Reactant: N=C(N)NCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)O)N(C(=O)[C@@H](N)CCCCN)[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](N[N+](=O)[O-])C(=O)C(N)CCC[C@H](N)C(=O)N([C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)O)[N+](=O)[O-]

Procedure:
From compound 8, in a manner similar to the synthesis of compound 2 (except that instead of trifluoroacetic acid use is made of its mixture with methylene chloride in the volume ratio of (1:1) α-benzyloxycarbonyl, ε-(nitroarginyl)lysylnitroarginylproline trifluoroacetate (compound 9) is obtained. The yield is 96%. αD20 =-12.0° (c=1, dimethylformamide). Ehis =0.52 (1 N acetic acid), Rf ==0.16 (B), 0.52 (C), 0.54 (D).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:16]2[CH:15]=[CH:14][C:13]3[CH:17]=[CH:18][CH:19]=[C:20](I)[C:12]=3[C:11](=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)C.O.[NH2:24][NH2:25]>>[N:24]1[NH:25][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[C:16]3[CH:15]=[CH:14][C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[C:11]=1[C:10]=23
Reactant: NN
Reactant: CC(=O)OCc1cccc2c(=O)c3c(I)cccc3ccc12
Solvent: O
Product: OCc1ccc2[nH]nc3c2c1C=Cc1ccccc1-3

Procedure:
The mixture of (6-iodo-5-oxo-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate with its 4-iodo form prepared in Example 6-h was treated with hydrazine monohydrate by the procedure of Example 1-h, and purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to give 320 mg and 1.1 mg of the title compounds as yellow powders, respectively.
Reaction SMILES: [ClH:1].C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:43][O:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[C:11]([NH:13][CH:14]2[C:41](=[O:42])[N:16]3[C:17]([C:38]([OH:40])=[O:39])=[C:18]([CH2:21][S:22][C:23]4[N:27]([CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[N:26]=[N:25][N:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[ClH:1].[ClH:1].[ClH:1].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:43][O:44][CH2:45][CH2:46][NH2:47])[C:11]([NH:13][CH:14]2[C:41](=[O:42])[N:16]3[C:17]([C:38]([OH:40])=[O:39])=[C:18]([CH2:21][S:22][C:23]4[N:27]([CH2:28][CH2:29][NH2:30])[N:26]=[N:25][N:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCN)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Conc. hydrochloric acid (3.2 g.) was added to a solution of 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.5 g.) in methanol (50 ml.) and stirred at room temperature for 2 hours. After removing the solvent in vacuo, methanol was added to the residue. The mixture was concentrated in vacuo again. The precipitates were collected by filtration and washed with diethyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid trihydrochloride (syn isomer, 2.8 g.).
Reaction SMILES: [CH3:1][N:2]([O:12][CH3:13])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1)=[O:4].B([O-])([O-])O[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]([O:12][CH3:13])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:10]=1)=[O:4]
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CON(C)C(=O)c1cncc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Yield: 102.8 %

Procedure:
Under argon atmosphere, a solution of N-methyl-N-methoxy-5-bromopyridine-3-carboxamide (3.70 g), 4-methyl-phenyl borate (2.26 g) and potassium carbonate (4.17 g) in toluene-ethanol-water (100-10-10 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (0.52 g), and the mixture was refluxed for 16 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:2→1:1) to give N-methyl-N-methoxy-5-(4-methylphenyl)pyridine-3-carboxamide (3.97 g) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]2[C:12]([N:11]=1)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ncccc1Nc1ccccc1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ncccc2n1-c1ccccc1
Temperature: 75 °C
Yield: 98.9 %

Procedure:
A mixture of [(S)-1-(3-phenylaminopyridin-2-ylcarbamoyl)ethyl]carbamic acid tert-butyl ester (980 mg, 2.75 mmol) in AcOH (25 mL) was heated for 10 h at 75° C. under a nitrogen atmosphere. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light brown foam (920 mg, 99%). LCMS (Method C): RT 2.88 min [M+H]+ 339.3.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][C:15]1([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]2[OH:30])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13].Br[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[C:35]#[N:36]>>[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][C:15]1([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][N:27]([C:32]3[CH:33]=[C:34]([C:35]#[N:36])[CH:37]=[CH:38][C:39]=3[O:40][CH3:41])[CH2:26][C:25]2=[O:30])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:13]
Reactant: COc1ccc(C#N)cc1Br
Reactant: Cc1c(C(=O)NC2(C(=O)NC3CCNCC3O)CCCCC2)oc2ccccc12
Agent: Cl
Product: COc1ccc(C#N)cc1N1CCC(NC(=O)C2(NC(=O)c3oc4ccccc4c3C)CCCCC2)C(=O)C1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(3-methyl-benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 3-bromo-4-methoxybenzonitrile was used instead of 1-bromotoluene in Step 1 thereof, 270 mg of the titled compound was prepared.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([OH:23])(C1C=CC=CC=1)C1C=CC=CC=1.ON1C(=O)C2=CC=CC=C2C1=O.O.O.O.FC(F)(F)C(C(F)(F)F)=O.FC(C1C=CC=CC=1)(F)F>C([O-])(=O)C.[Co+2].C([O-])(=O)C>[O:23]1[CH:2]([CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:1]1
Reactant: C=CC(O)CCCCC
Reactant: OC(c1ccccc1)c1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C(C(F)(F)F)C(F)(F)F
Solvent: FC(F)(F)c1ccccc1
Solvent: O
Product: CCCCCC(O)C1CO1
Temperature: 60 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
A mixture of 3mmol of 1-octen-3-ol, 15mmol of benzhydrol, 0.3 mmol of N-hydroxyphthalimide, 0.0015 mmol of cobalt (II) acetate, 0.6 mmol of hexafluoroacetone trihydrate, and 3 ml of trifluoromethylbenzene was stirred at 60° C. under an oxygen atmosphere (1 atm) for 24 hours. Gas chromatographic analysis of products in a reaction mixture revealed that 1-octen-3-ol was converted, at a rate of 43%, into 1,2-epoxy-3-octanol (yield: 40%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.[O:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:37]3[CH2:36][CH2:35][N:34]([CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)[CH2:39][CH2:38]3)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(C4CCOCC4)CC3)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 320 mg (0.89 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 181 mg (1.06 mmoL) 1-tetrahydro-pyran-4-yl piperazine, 370 mg (0.97 mmol) HATU and 258 μL DIPEA in 3 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/MeOH-gradient. Yield: 90 mg (20%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1([F:35])[O:34][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23][CH2:24][C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=4)=[N:20][C:19]=3[CH:33]=[C:15]2[O:14]1.C(N(CC)CC)C.C(=O)(O)[O-].[K+]>C(Cl)Cl>[F:35][C:13]1([F:12])[O:34][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23]([CH2:24][C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=4)=[O:6])=[N:20][C:19]=3[CH:33]=[C:15]2[O:14]1
Reactant: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c1
Yield: 76.5 %

Procedure:
A solution of 0.91 g of approximately 85% pure m-chloroperoxybenzoic acid in 20 ml of methylene chloride is added dropwise to a solution of 1.5 g of 2,2-difluoro-6-[(4-methoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole in 50 ml of methylene chloride at -30° C. in the course of 5 min., with stirring, and the temperature is allowed to rise to -10° C. in the course of 30 min. 0.62 ml of triethylamine is added, followed by 20 ml of aqueous potassium bicarbonate solution, the title compound already crystallizing out in the cold. The mixture is filtered and the precipitate is washed with water to yield 1.2 g of the title compound. The organic phase is separated off from the filtrate, washed with water and dried with magnesium sulfate and the solution is concentrated completely, at 30° C. A further 0.25 g of the title compound is obtained from the residue by recrystallization from ethyl acetate; total yield: 92%, m.p.: 184°-185° C. (decompositon).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Cc1oc(-c2ccc(F)cc2)nc1CC(=O)O
Yield: 98.6 %

Procedure:
1.53 g of ethyl 2-[2-(4-fluorophenyl)-5-isobutyl-4-oxazolyl]acetate, 10 ml of methanol, 3 ml of water and 0.6 g of potassium hydroxide are treated in the same manner as described in Example 8. 1.37 g of 2-[2-(4-fluorophenyl)-5-isobutyl-4-oxazolyl]acetic acid are thereby obtained. Yield: 98.9%.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]2[N:13]=[C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=3)[S:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>>[OH:8][C:9]1[CH:31]=[CH:30][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:28][CH:29]=3)[S:15][C:11]=2[CH:10]=1
Reactant: CC(=O)N[C@@H](C)COc1ccc(-c2nc3ccc(OCc4ccccc4)cc3s2)cc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](C)COc1ccc(-c2nc3ccc(O)cc3s2)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
A mixture of N-[(1S)-2-{4-[6-(benzyloxy)-1,3-benzothiazol-2-yl]phenoxy}-1-methylethyl]acetamide (46 mg), trifluoroacetic acid (1 mL) and thioanisole (0.1 mL) was stirred at 55° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give N-{(1S)-2-[4-(6-hydroxy-1,3-benzothiazol-2-yl)phenoxy]-1-methylethyl}acetamide (38.6 mg) as a powder. Using the obtained powder, and in the same manner as in Example 1, step A, the title compound was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:28]=[C:27]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:28]=[C:27]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chloromethyl-2-methoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (2.25 g), ethyl 4-hydroxy-2-phenylpyrimidine-5-carboxylate (1.50 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 0.2N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were recrystallized from tetrahydrofuran-ethyl acetate to give ethyl 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carboxylate as colorless prism crystals (2.50 g, yield 75%). melting point: 142-143° C.
Reaction SMILES: O.[OH-].[Li+].[OH:4][C@H:5]([CH3:35])[C@H:6]([O:8][C:9]1[CH:10]=[C:11]([O:24][C:25]2[N:26]=[CH:27][C:28]([C:31]([O:33]C)=[O:32])=[N:29][CH:30]=2)[CH:12]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:14]=1)[CH3:7].O[C@@H](C)[C@@H](OC1C=C(OC2N=CC(C(OC)=O)=NC=2)C=C(C(NC2C=CN(C)N=2)=O)C=1)C>O.C1COCC1>[OH:4][C@@H:5]([CH3:35])[C@@H:6]([O:8][C:9]1[CH:10]=[C:11]([O:24][C:25]2[N:26]=[CH:27][C:28]([C:31]([OH:33])=[O:32])=[N:29][CH:30]=2)[CH:12]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:14]=1)[CH3:7]
Reactant: COC(=O)c1cnc(Oc2cc(O[C@H](C)[C@@H](C)O)cc(C(=O)Nc3ccn(C)n3)c2)cn1
Agent: COC(=O)c1cnc(Oc2cc(O[C@@H](C)[C@H](C)O)cc(C(=O)Nc3ccn(C)n3)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Lithium hydroxide monohydrate (38 mg, 0.88 mmol) in water (3 mL) was added to methyl 5-[(3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate and methyl 5-[(3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate (1:1) (0.26 g, 0.59 mmol) in THF (6 mL) and the mixture stirred at RT for 72 hours. The THF was removed in vacuo and the aqueous residue adjusted to pH3 with citric acid, then extracted into ethyl acetate, washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound as a white solid (0.16 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[C:13]=2[F:20])=[CH:8][C:7]=1[F:21])[CH2:2][CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH2:46]([CH:49]1[CH2:54][CH2:53][CH:52]([CH:55]2[CH2:60][CH2:59][CH:58]([C:61](O)=[O:62])[CH2:57][CH2:56]2)[CH2:51][CH2:50]1)[CH2:47][CH3:48]>C1(C)C=CC=CC=1>[CH2:46]([CH:49]1[CH2:54][CH2:53][CH:52]([CH:55]2[CH2:60][CH2:59][CH:58]([C:61]([O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([F:21])[CH:8]=4)=[C:13]([F:20])[C:14]=3[F:19])=[O:62])[CH2:57][CH2:56]2)[CH2:51][CH2:50]1)[CH2:47][CH3:48]
Reactant: CCCCOc1ccc(-c2ccc(O)c(F)c2F)cc1F
Reactant: CCCC1CCC(C2CCC(C(=O)O)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2ccc(OC(=O)C3CCC(C4CCC(CCC)CC4)CC3)c(F)c2F)cc1F
Reaction time: 16 h
Yield: 66.9 %

Procedure:
4′-Butoxy-2,3,3′-trifluorobiphenyl-4-ol (T-11) (2.00 g) prepared in Example 8, dicyclohexylcarbodiimide (DCC) (1.46 g) and dimethylaminopyridine (DMAP) (0.08 g) were dissolved in toluene (100 ml), and 4′-propylbicyclohexane-4-carboxylic acid (1.70 g) was added, and then the stirring was continued at room temperature for another 16 hours. After the completion of the reaction, the reaction mixture was filtered and the filtrate was extracted with toluene. The organic layer was washed with a 1N—HCl aqueous solution, a 1N-aqueous sodium hydroxide solution, a saturated aqueous solution of sodium hydrogencarbonate, water and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave pale brown solids. Silica gel chromatography (heptane:ethyl acetate=20:1 by volume) and recrystallization (heptane:toluene=4:1 by volume) gave 4′-butoxy-2,3,3′-trifluorobiphenyl-4-yl 4′-propylbicyclohexane-4-carboxylate (1-8-14) as colorless powders (2.39 g) in 67% yield.