Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:44])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][O:36]C3CCCCO3)[CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:44])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][OH:36])[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-chloro-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M261) (0.54 g, 0.83 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (170 mg, 46%).
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:4].[OH:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[C:30]([C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:34])[CH:29]=[CH:28]2>CC#N.O.C(Cl)Cl>[O:4]=[C:26]1[CH:25]=[CH:24][C:23](=[O:22])[C:32]2[N:31]=[C:30]([C:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:34])[CH:29]=[CH:28][C:27]1=2
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCCCCCCCOC(=O)c1ccc2cccc(O)c2n1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCCCCCCCOC(=O)c1ccc2c(n1)C(=O)C=CC2=O
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a stirred solution of [bis(trifluoroacetoxy)iodo]benzene (PIFA) (258 mg, 0.6 mmol) in MeCN/water 2:1 (3 ml) at 0° C. was added octyl 8-hydroxyquinoline-2-carboxylate (71 mg, 0.24 mmol) in CH2Cl2 (1 ml). The solution was stirred for 20 min, poured into CH2Cl2 (20 mL), washed with water and dried in vacuo to give octyl 5,8-dioxo-5,8-dihydroquinoline-2-carboxylate (69 mg, 90%).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:8]=[C:9]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH2:3]1.[C:24]1([C@H:34]([NH2:36])[CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[C:24]1([C@H:34]([NH:36][CH:2]2[CH2:6][CH2:5][C@@H:4]([C:7]3[CH:8]=[C:9]([CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=3)[O:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:3]2)[CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)COc1cc([C@@H]2CCC(=O)C2)cc(C(F)(F)F)c1
Reactant: C[C@@H](N)c1cccc2ccccc12
Product: C[C@@H](NC1CC[C@@H](c2cc(OCC(=O)O)cc(C(F)(F)F)c2)C1)c1cccc2ccccc12

Procedure:
General procedure A was followed using ethyl 2-[3-[(1R)-3-oxocyclopentyl]-5-(trifluoromethyl)phenoxy]acetate as the ketone and (R)-1-naphthalen-1-yl-ethylamine as the amine. The resulting mixture of isomeric esters was purified and separated by flash chromatography (gradient of 0-80% EtOAc in heptane containing 2.5% NEt3). The faster eluting peak was isolated and subjected to hydrolysis following general procedure B to afford the title compound. 1H NMR (300 MHz, DMSO) δ 8.26 (d, J=8.0 Hz, 1H), 7.98-7.91 (m, 1H), 7.83 (t, J=7.7 Hz, 2H), 7.60-7.47 (m, 3H), 7.10-7.03 (m, 2H), 6.94 (s, 1H), 4.90 (q, 1H), 4.51 (s, 2H), 3.21-3.07 (m, 1H), 3.00-2.83 (m, 1H), 2.29-2.15 (m, 1H), 1.93-1.51 (m, 5H), 1.49 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:19])[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]1([C:7]2[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:10]=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCCn1cncc1-c1ccccc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCCCCn1cncc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.9 %

Procedure:
To a stirred solution of 4-(5-phenyl-1H-imidazol-1-yl)butan-1-amine (0.278 mmol) in THF (3 mL) at 0° C. was added acetyl chloride (0.306 mmol) drop wise and the resulting white suspension was allowed to warm to rt and stir for 5 h. Saturated NaHCO3 (2 mL) was added and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford a yellowish oil. Preparative thin layer chromatography afforded the pure product as colorless oil (30 mg, 43% yield). 1H NMR: 1.36 (m, 2H), 1.60 (m, 2H), 1.91 (s, 3H), 2.38 (br s, 1H), 3.12 (m, 2H), 4.00 (t, 2H, J=7.1 Hz), 5.80 (br s, 1H), 7.04 (s, 1H), 7.32-7.46 (m, 5H), 7.55 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: NC=O
Product: Cc1ccc2c(=O)[nH]cnc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-amino-4-methylbenzoic acid (31.6 g, 206 mmol) in formamide (60 mL) is heated to 130° C. for 1 hour, then at 175° C. for 3 hours. The solution is poured into 500 mL of ice water. The resulting solid is collected by filtration and further dried under reduced pressure. The title compound (26.2 g, 170 mmol) is obtained as a white solid. MS (EI): m/z 159 (M+).
Reaction SMILES: Cl.[CH3:2][S:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:6](=[O:8])[CH2:5][CH2:4][S:3][CH3:2])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CSCCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CSCCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 28.1 %

Procedure:
Proceeding as in Example 1, but substituting 3-(methylthio)propanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 85, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3-(methylthio)propanoyl)pyrrolidine-2-carboxamide (8.3 mg, 28.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.91 (s, 1H), 7.54 (d, 2H), 7.27 (m, 2H), 7.22-7.15 (m, 7H), 6.93 (m, 2H), 4.46 (t, 1H), 3.66 (m, 1H), 3.23 (m, 1H), 2.65-2.59 (m, 6H), 2.56 (m, 1H), 2.04 (s, 3H), 1.90 (m, 2H). MS (EI) for C28H29FN2O3S: 493.6 (MH+).
Reaction SMILES: N1C=CN=C1.[F:6][C:7]1[CH:8]=[C:9]([C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][C:12]=1[OH:13].[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18].O>ClCCl>[Si:21]([O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[F:6])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)c1ccc(O)c(F)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of imidazole (7.29 g, 107.0 mmol) and 1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (15.0 g, 97.3 mmol) in anhydrous dichloromethane (500 mL) was added drop-wise a solution of t-butyldiphenylchlorosilane (28.09 g, 102.0 mmol) in anhydrous dichloromethane (100 mL). The solution was stirred overnight at room temperature. The mixture was poured into water (500 mL) and the organic layer separated and washed with saturated sodium hydrogen carbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to give the title compound which was used without further purification (37.9 g, 96.55 mmol). MS (APCI+, m/z): 393 [M+H]+.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[F:8][C:9]([F:23])([F:22])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[NH:17][O:18][C:19](=[O:21])[N:20]=2)[CH:11]=1.[Cl-].[NH4+].C[CH2:27][O:28][CH2:29]C>>[CH3:27][O:28][CH2:29][N:20]1[C:19](=[O:21])[O:18][N:17]=[C:16]1[C:12]1[CH:11]=[C:10]([C:9]([F:8])([F:22])[F:23])[CH:15]=[CH:14][N:13]=1
Reactant: CCOCC
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.05 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.11 g of chloromethyl=methyl=ether was added, the mixture was stirred at room temperature for 1 hour, and at 60° C. for 4 hours, and the reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.21 g of 4-(methoxymethyl)-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (9)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([NH:11][C:12](=[O:14])[CH:13]=1)=[O:10].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:14])[NH:11][C:9]1=[O:10]
Reactant: Nc1ccccc1
Reactant: O=C1C=C(c2ccccc2Cl)C(=O)N1
Solvent: CCO
Product: O=C1NC(=O)C(c2ccccc2Cl)C1Nc1ccccc1

Procedure:
A solution of 2-(2-chlorophenyl)maleimide (4.70 g) and aniline (3.069) in ethanol (50 ml) is refluxed for 38 hours. The reaction mixture is concentrated and the residue is subjected to silica gel chromatography, with elution being carried out with n-hexane-ethyl acetate (4:1-1:1) to give 2-(2-chlorophenyl)-3-anilinosuccinimide (oil) (3.71 g)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([OH:19])=O)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:32][CH:33]1[CH2:37][NH:36][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34]1>C(#N)C.C(OCC)(=O)C>[OH:32][CH:33]1[CH2:37][N:36]([C:17](=[O:19])[CH2:16][P:4]([O:3][CH2:1][CH3:2])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:5])[C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34]1
Reactant: COC(=O)[C@@H]1CC(O)CN1
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC(O)C[C@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid (1.71 g), acetonitrile and carbonyldiimidazole (0.97 g) is stirred under argon at 0° C. for 1 hour. (S)-4-hydroxyproline, methyl ester (0.006 mole) is suspended in acetonitrile, added to the mixture and stirred at room temperature 90 minutes. Solvent is stripped off, and the resulting oil is taken up in ethyl acetate, washed with 5% potassium bisulfate, washed with saturated sodium bicarbonate, washed with brine, dried over magnesium sulfate, and the solvent stripped to leave 2.23 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[C:5]([CH3:11])[N:4]=1.C1C(=O)N([Br:19])C(=O)C1.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:6]1[C:5]([CH3:11])=[N:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][OH:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(CO)cc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(CO)c(Br)c(C)n1
Yield: 79.2 %

Procedure:
A mixture of (2-methoxy-6-methylpyridin-4-yl)methanol (1.1 g) and NBS (1.34 g) was stirred in an acetic acid solvent (22 mL) at room temperature for 12 hours. A 5 M aqueous sodium hydroxide solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 50%) to give the title compound (1.32 g).
Reaction SMILES: [CH:1]([C:3]1(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2]>C[Re](=O)(=O)=O.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1)=[CH2:2]
Reactant: C=CC1(O)CCCCCCCCCCC1
Agent: C[Re](=O)(=O)=O
Solvent: Cc1ccccc1
Product: C=CC1=CCCCCCCCCCC1
Yield: 93 %

Procedure:
A solution of 1.20 grams of 1-vinylcyclododecanol, 10 ml of toluene, and 20 mg of methylrhenium trioxide was refluxed 4 hrs, by which time VPC and TLC analyses indicated complete consumption of the starting material. The mixture was cooled, washed with 5% aqueous sodium carbonate solution to remove catalyst, and the organic phase dried (magnesium sulfate) and stripped of volatiles at reduced pressure. There was obtained 1.02 gram (93%) of 1-vinylcyclododecene as ca. 2:1 trans:cis mixture (VPC); NMR spectrum was in good agreement with that expected for the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46](B(O)O)[CH:47]=2)[CH2:42][CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[C:48]4[C:43]([CH:42]=[CH:41][NH:40]4)=[CH:44][CH:45]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)NCC2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4cc[nH]c4c3)c2)c1CCC(=O)OCC
Yield: 38.8 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 6-indolineboronic acid (170 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-ethoxy-5-(1H-indol-6-yl)-phenoxy]-hexyl}-phenoxy]-butyric acid ethyl ester (125 mg, 39%) as a light yellow oil: ES(+)-HRMS m/e calcd for C39H49NO7 (M+Na)+ 666.3401. found 666.3396.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:7][NH2:8].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[C:26]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)=[N:27][O:28][C:29]=2[CH2:30][OH:31])=[N:19][CH:18]=1>O1CCOCC1>[F:39][C:34]1[CH:33]=[C:32]([C:26]2[C:25]([CH2:24][O:23][C:20]3[CH:21]=[CH:22][C:17]([C:16]([NH:8][CH2:7][C:6]([F:13])([F:5])[C:9]([F:12])([F:11])[F:10])=[O:15])=[CH:18][N:19]=3)=[C:29]([CH2:30][OH:31])[O:28][N:27]=2)[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)C(F)(F)F)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
Trimethylaluminium solution (2M in toluene, 0.80 mL, 1.60 mmol) was added to a solution of 2,2,3,3,3-pentafluoropropylamine (116 μL, 1.10 mmol) in dioxane (4 mL). The mixture was stirred for 45 min at 50° C. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (4 mL) was added and the reaction mixture was stirred overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=1:1) to afford the title compound (96 mg, 73%) as a white solid. MS: m/e=492.1 [M−H]−.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:20])[C:16](OC)=[O:17])=[CH:3][CH:2]=1.C1COCC1.[CH3:32][NH2:33].Cl>CO.O>[CH3:32][NH:33][C:16](=[O:17])[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][O:7][C:4]1[CH:5]=[CH:6][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:2][CH:3]=1)=[O:20]
Reactant: COC(=O)C(=O)c1ccccc1COc1ccc(-c2ccccc2)cc1
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=O)c1ccccc1COc1ccc(-c2ccccc2)cc1
Yield: 81.9 %

Procedure:
To methyl 2-[2-(biphenyl-4-yloxymethyl)phenyl]-2-oxoacetate (3.46 g, 0.01 mol), added were anhydrous methanol (10 ml), dry THF (10 ml) and a 40% solution (2.33 g) of methyl amine (0.03 mol) in methanol, and the reaction mixture was stirred at room temperature for 2 hour. After completion of the reaction, water (150 ml) was added to the reaction mixture which was then adjusted to below PH 2 by addition of conc. HCl and extracted with ethyl acetate (150 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals (3.42 g; yield, 99.1%) were recrystallized from ethyl acetate/n-hexane to give N-methyl-2-[2-(biphenyl-4-yloxymethyl)phenyl]-2-oxoacetamide (2.83 g) as colorless crystals (m.p.: 144°-145° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19](=[O:27])[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:24]2[CH2:25][CH2:26][CH:21]([NH:20][C:19](=[O:27])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:22][CH2:23]2)=[O:34])=[CH:31][CH:30]=1
Reactant: Cc1nc(OCC(=O)NC2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(F)cc1
Product: Cc1nc(OCC(=O)NC2CCN(C(=O)c3ccc(F)cc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 57 and 4-fluorobenzoyl chloride in the same manner as in Example 32.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH:7](Br)[C@H:6]1[F:21])(=[O:3])[CH3:2].C[Si](C)(C)[O:24][C:25]1[N:30]=[C:29]([O:31][Si](C)(C)C)[CH:28]=[CH:27][N:26]=1.N1C=CC(=O)NC1=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C[Si](C)(C)N[Si](C)(C)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:26]2[CH:27]=[CH:28][C:29](=[O:31])[NH:30][C:25]2=[O:24])[C@H:6]1[F:21])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](F)C(Br)O[C@@H]1COC(=O)c1ccccc1
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: O=c1cc[nH]c(=O)[nH]1
Product: CC(=O)O[C@H]1[C@H](F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (11.5 g) and 2,4-bis(trimethylsilyloxy)pyrimidine [prepared by refluxing a mixture of 5 g of uracil and 5-15 mg of ammonium sulfate in 25 ml of hexa-methyldisilazane until a clear solution is obtained followed by removal of the excess hexamethyldisilazane in vacuo] in 150 ml of methylene chloride is stirred for 5 days at room temperature. Methanol (5 ml) is added to the mixture and the suspension is filtered through a celite pad. The filtrate is evaporated in vacuo and the residue is triturated with diethyl ether to give a crude product which was recrystallized from ethanol to give pure 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)uracil, 5.8 g, m.p. 179°-180°.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>C(O)(=O)C>[F:1][S:2]([F:10])([F:11])([F:12])([F:13])[C:3]1[CH:4]=[C:5]([N:9]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cccc(S(F)(F)(F)(F)F)c1

Procedure:
15 g (68.44 mmol) of 3-pentafluorosulfanylphenylamine was suspended with 10.14 g (68.44 mmol) of phthalic anhydride in 40 ml of a acetic acid and boiled under reflux for 2 h. The cool reaction mixture was admixed with 400 ml of water, heated in an ultrasound bath for 30 min and filtered. The residue was washed with water and subsequently with a little ethanol and dried under reduced pressure. 2-(3-Pentafluorosulfanylphenyl)isoindole-1,3-dione was obtained with a melting point of 188-190° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH:18]=O)=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH:18]=[N:21][OH:22])=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1c[nH]c2cccc(OCc3ccccc3)c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: ON=Cc1c[nH]c2cccc(OCc3ccccc3)c12
Yield: 96 %

Procedure:
This compound is obtained in a yield of 96% of theory by reacting 4-benzyloxy-3-formylindole with hydroxylamine hydrochloride and sodium acetate in aqueous dimethylformamide solution; m.p. 206°-210° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[F:21][C:22]1[N:27]=[C:26](F)[CH:25]=[CH:24][N:23]=1.Cl>CS(C)=O.O>[F:21][C:22]1[N:27]=[C:26]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:25]=[CH:24][N:23]=1
Reactant: Fc1ccnc(F)n1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc2cc(Oc3ccnc(F)n3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-hydroxy-1-napthoic acid (3.23 g, 17.2 mmol) in DMSO (8 mL), Cs2CO3 (16.8 g, 57.6 mmol) was added and stirred at RT 10 min. 2,4-Difluoropyrimidine (2 g, 17.2 mmol) was added and the reaction was stirred at RT for 12 h. The mixture was diluted with water and made pH 7 using 1 N HCl, at which point it is a foamy emulsion. The mixture sat without stirring 2 days and the resulting solid was filtered and rinsed with water and Et2O to yield the title compound as a pink solid.