Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[N:6]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)=[C:7]=[O:8]>ClCCl>[CH:1]1([NH:5][C:7](=[O:8])[NH:6][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)NC2CCC2)cc1
Reaction time: 0.67 h
Yield: 88.3 %

Procedure:
Cyclobutylamine (27.91 g, 392.4 mmol, 33.5 mL) was added dropwise to a stirred solution of ethyl 4-isocyanatobenzoate (25 g, 130.8 mmol) in dichloromethane. After 40 minutes stirring, the solid precipitate that had formed was filtered off and dried to afford the title compound (30.28 g). MS (ESI) m/z 263.1 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](N(OC)C)=[O:9])=[CH:6][C:5]([Cl:14])=[N:4][CH:3]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:9])=[CH:6][C:5]([Cl:14])=[N:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(Cl)ncc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cnc(Cl)cc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-Amino-2-chloro-N-methoxy-N-methyl-isonicotinamide (1.50 g, 6.608 mmol) in THF (25 mL) under argon is added phenylmagnesium bromide in diethyl ether (6.00 mL, 2M, 18 mmol) at 0° C. The mixture is stirred for 30 minutes at 0° C. Aqueous citric acid solution (1 M, 25 mL) is added to the reaction and the mixture is extracted with ethyl acetate, the organic phase is dried over magnesium sulfate. The drying agent is removed by filtration and the solvent is concentrated to dryness. This provides the desired compound which is used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:18][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)NCCc1ccc(C(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
In a round-bottomed flask, N-[2-(4-acetyl-phenyl)-ethyl]-acetamide (7.23 g, 35.2 mmol) was dissolved in methylene chloride (120 ml), and methanol (60 ml). Tetrabutylammonium tribromide (17.0 g, 35.2 mmol) was added to this solution in one portion, and the mixture was allowed to stir overnight at room temperature. The volatiles were then removed in vacuo to afford an oil, which was then resuspended in 100 ml of methylene chloride and extracted with 125 ml of saturated aqueous sodium bicarbonate. The aqueous extracts were reextracted with methylene chloride (3×100 ml), and the combined organic extracts were then washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by column chromatography (silica gel; methylene chloride to 7% methanol/methylene chloride), and the resulting material was washed with 110 ml of water to afford 8.27 g (83% yield) of pure product as a white solid. LRMS ([M−1]−)=283.0, 284.9.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.C([Li])CCC.[Cl-].[CH3:14][O:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.CCCCCC>[CH3:14][O:15][CH:16]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrahydro-4H-pyran-4-one (5.00 g, 50 mmol) was dissolved in tetrahydrofuran (250 ml) and cooled in an ice-water bath. To this solution was added n-butyl lithium (24 ml of a 2.5M solution in hexane, 60 mmol) and the reaction mixture was then allowed to warm to room temperature and stirred for 1 hour. This was then cooled to 0° C. and a solution of (methoxymethyl)triphenyl phosphonium chloride (25.6 g, 75 mmol) in tetrahydrofuran (10 ml) was added and the reaction stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the residue triturated with diethyl ether (10×), decanting the supernatant each time. The combined supernatants were then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (95:5 to 90:10) to provide the title compound, 1.80 g.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
In a preferred embodiment, the mixture fed onto the SMB comprises from about 5 wt. % to about 85 wt. % of a mixture of D-xylose and L-arabinose. Still further, the at least two components fed onto the SMB comprise D-xylose and L-arabinose. Still further, after the separation step L-arabinose is present in one eluent fraction at from about 85 wt. % to about 100 wt. %. Still further preferably, minor components, eg., galactose, are allowed to go into the D-xylose fraction, thereby providing an L-arabinose fraction comprised from about 85 wt % to about 100 wt % L-arabinose. In a separate embodiment, minor components, eg., galactose, are allowed to go with the L-arabinose fraction, thereby providing a D-xylose fraction comprised from about 85 wt. % to about 100 wt. % D-xylose. Still further, it is preferred that the D-xylose fraction is comprised of from about 85 wt. % to about 100 wt. % D-xylose. Those skilled in the art will recognize that these fractions can be additionally purified by crystallization.
Reaction SMILES: [CH2:1]([N:8]1CCC[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Mg]Br.[CH2:17]1C[O:20][CH2:19][CH2:18]1>>[CH2:1]([N:8]1[CH2:17][CH2:18][C:19]([CH3:14])([OH:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: C1CCOC1
Reactant: C[Mg]Br
Product: CC1(O)CCN(Cc2ccccc2)C1
Temperature: -20 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
1-benzylpyrrolidone (1.1 g, 6.3 mmol) was dissolved in 4 mL THF under stirring at −20° C. The resulting solution was dropwisely added to a solution of methyl magnesium bromide (13.2 mL, 12.2 mmol) in THF. The stirring was continued for 3 hours. After the completion of reaction, the reaction solution was dropwisely added to an ice water. The resulting mixture was washed with a saturated aqueous NaCl solution, dried over Na2SO4, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate=20:1 (volumetric ratio)) to produce the product of 1-benzyl-3-methylpyrrolidinyl-3-ol (0.7 g) in a yield of 58.1%.
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7].C(N)CCC.[C:15]([C@:17]1([O:35][Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])[CH2:18][C:19]2([C:24]3[C:25](/[C:29]/1=[CH:30]\[C:31]([O:33][CH3:34])=[O:32])=[CH:26][O:27][N:28]=3)[O:23][CH2:22][CH2:21][O:20]2)#[CH:16]>C1C=CC=CC=1.[Cl-].[Na+].O.[Cu]I>[CH2:41]([Si:36]([CH2:37][CH3:38])([CH2:39][CH3:40])[O:35][C@@:17]1([C:15]#[C:16]/[CH:2]=[CH:3]\[C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[CH2:18][C:19]2([C:24]3[C:25](/[C:29]/1=[CH:30]\[C:31]([O:33][CH3:34])=[O:32])=[CH:26][O:27][N:28]=3)[O:23][CH2:22][CH2:21][O:20]2)[CH3:42]
Reactant: C#C[C@]1(O[Si](CC)(CC)CC)CC2(OCCO2)c2nocc2/C1=C\C(=O)OC
Reactant: C[Si](C)(C)C#C/C=C\Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCCCN
Solvent: O
Product: CC[Si](CC)(CC)O[C@@]1(C#C/C=C\C#C[Si](C)(C)C)CC2(OCCO2)c2nocc2/C1=C\C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
(Z)-(4-chloro-3-buten-1-ynyl)trimethylsilane (1.41 mL, 8.16 mmol) and n-butylamine (0.81 mL, 8.16 mmol) were added to a solution of Pd(Ph3)4 (628 mg, 0.54 mmol) in benzene (25 mL). The solution was stirred at 25° C. for 15 minutes and then added to a mixture of Compound 61 (2.204 g, 5.44 mmol) and CuI (207 mg, 1.09 mmol) in benzene (25 mL) at zero degrees C. The solution was stirred two hours at zero degrees C, poured into brine (100 mL) and extracted with dichloromethane (3×100 mL). The organic extracts were dried (Na2SO4), concentrated and purified by flash chromatography (10 percent Et2O in petroleum ether) to give Compound 62 (2.606 g, 91 percent) as a colorless oil; Rf =0.46 (30% Et20 in petroleum ether); [a]D25 =+17.4° (c .2.7 , CH2Cl2); IR (thin film) νmax 1720 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1 H, C=CH--O), 6.65 (s, 1 H, C=CH--CO2), 5.86 (ABq, J =11.0 Hz, Dn =30 Hz, 2 H, CH=CH), 4.38-4.29 (m, 2 H, ethylene ketal), 4.15-4.09 (m, 2 H, ethylene ketal), 3.74 (s, 3 H, CO2Me), 2.67 (ABq, J =14.1 Hz, Dn =61 Hz, 2 H, CH2), 0.89 (t, J =7.3 Hz, 9 H, Si(CH2CH3)3), 0.66 (m, 6 H, Si(CH2CH3)3), 0.17 (s, 9 H, SiMe3); 13C NMR (125 MHz, CDCl3) δ 166.6, 161.2, 161.0, 143.7, 121.2, 118.6, 114.9, 112.0, 103.5, 101.3, 100.7, 95.5, 85.7, 72.1, 65.0, 64.6, 51.5, 50.0, 6.8, 5.9, -0.4; FAB HRMS (NBA/CsI) m/e 660.1213, M+Cs+ calcd for C27H37NO6Si2 660.1214.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:28]([O:32][C:33](=[O:42])[N:34]([CH3:41])[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:28]([O:32][C:33](=[O:42])[N:34]([CH:35]1[CH2:36][CH2:37][N:38]([S:17]([C:13]2[S:14][C:15]([Br:16])=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[CH:12]=2)(=[O:19])=[O:18])[CH2:39][CH2:40]1)[CH3:41])([CH3:31])([CH3:29])[CH3:30]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCC(N(C)C(=O)OC(C)(C)C)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction mixture is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and methyl-piperidine-4-yl-carbamic acid tert-butyl ester (773.2 mg; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 30 minutes at room temperature. It is then washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (470 mg; quantitative).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:14]([OH:16])=O)=[N:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1([C:23]2[C:24]([CH3:31])=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:14](=[O:16])[NH:30][C:25]2[CH:24]=[CH:31][C:28]([CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:27][C:26]=2[NH2:29])=[N:11][NH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N2CCOCC2)ccc(N)c1N
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (10.0 g, 44.1 mmol), 4-morpholin-4-yl methyl-benzene-1,2-diamine (10.0 g, 48.5 mmol), EDC (10.14 g, 52.9 mmol) and HOBt (7.15 g, 52.9 mmol) in DMF (150 mL) was stirred at ambient temperature for 20 h and then the majority of the solvent removed in vacuo. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL), the layers separated and the organic portion washed with brine, dried over MgSO4 and reduced in vacuo to give [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (17.6 g, 96%) as a brown solid. LC/MS analysis indicates product contains ˜15% of the di-amide. This shows at approx. 5% level in 1H NMR. Di-amide is cleaved in subsequent step.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(O)CCC>[C:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:2]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1Nc1cccc(-c2ccccc2)c1

Procedure:
[1,1′-biphenyl]-3-amine (8.49 g, 50.2 mmol), 2-chloro-3-nitropyridine (7.23 g, 45.6 mmol), triethylamine (6.99 mL, 50.2 mmol), and 200 mL of butanol were added to a 1 L round bottom flask. The mixture was refluxed overnight under nitrogen. The next day the solvent was evaporated, and the residue was taken up in dichloromethane and washed twice with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated leaving an orange oil. 14.61 g, assume quantitative yield (13.29 g).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:30][CH2:31][CH2:32][CH2:33][S:34](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:36])=[O:35]>>[C:26]([O:25][C:23]([NH:22][CH:19]([CH2:20][NH:21][S:34]([CH2:33][CH2:32][CH2:31][Cl:30])(=[O:36])=[O:35])[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)NC(=O)OC(C)(C)C
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)OC(C)(C)C

Procedure:
3-Hexadecylthio-2-tert-butoxycarbonylaminopropylamine IVe4 is allowed to react and worked up by the same procedure as described in (4). m.p. 100.5°-101.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[Cl:21].[CH3:22][Sn](C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>Cl.[Pd]>[NH3:7].[Cl:21][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:6]=[N:7][C:2]=1[CH3:22]
Reactant: C[Sn](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(Br)c(Cl)c2)CC1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ncc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Product: N
Temperature: 160 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-bromo-5-chloro-3-pyridyl)-4-tert-butoxycarbonyl-piperazine (2.0 g, 5.3 mmol), tetramethyltin (1.9 g, 10.6 mmol), palladium-di-(triphenylphosphine (0.19 g, 0.26 mmol) and dimethylformamide (2 ml) was stirred at 160° C. in a sealed vessel overnight. The mixture was stirred in conc. hydrochloric acid (30 ml) at reflux for 15 min. The mixture was evaporated. Aqueous sodium hydroxide (50 ml, 1 M) was added and the mixture was extracted with dichloromethane (3×50 ml). Chromatography of this crude mixture on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound. Yield 0.70 g (43%). The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp 178.1-180.5° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[BH3:42].[OH:43][C:44]([C:47]([OH:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>O1CCOCC1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][C:3]1[C:2]([B:42]2[O:50][C:47]([CH3:49])([CH3:48])[C:44]([CH3:46])([CH3:45])[O:43]2)=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5]
Reactant: B
Reactant: Cc1c(N)cccc1Br
Reactant: CC(C)(O)C(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C

Procedure:
To a solution of 3-bromo-2-methylaniline (1.00 g) in dioxane (15 mL) was added triethylamine (3.0 mL), Pd(OAc)2 (60 mg), 2-dicyclohexylphosphinobiphenyl (377 mg) and pinacol borane (2.34 mL) and the reaction mixture was heated to 80° C. for 1 hour. The reaction mixture was then cooled, diluted with ethyl acetate, and reduced in vacuo. The residue was purified using flash chromatography to yield 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.07 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:36][CH:35]([CH3:37])[C:34]([NH:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])[CH2:11]1)=[O:38]
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
212 μl of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from Example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), and 80 μl of isobutyryl chloride (0.76 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrochloric acid and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC(RP18 column; acetonitrile/water gradient). Yield: 142 mg (65% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:52][CH:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: CC(N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (83 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-fluorophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (36 mg, yield 29%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([O:17][CH3:18])=[N:11]2.[OH-].[Na+].C(O)(=O)C>CO.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:24][CH:25]=1)=[C:8]2[CH3:31]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A solution of [8-chloro-2-methoxy-4-methyl-3-(4-pyrazol-1-yl-benzyl)quinolin-5-yloxy]acetic acid methyl ester (0.37 g) in methanol (7.0 mL) and water (0.7 mL) was treated with 5.0M aqueous sodium hydroxide solution (0.32 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified by the addition of glacial acetic acid, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was crystallised from methanol to give title compound as a white solid (0.18 g).
Reaction SMILES: [OH:1][OH:2].FC(F)(F)C(F)(F)C([O:8][C:9](=O)[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=O>FC(F)(F)C(F)(F)C(O)=O>[F:15][C:10]([F:16])([C:11]([F:12])([F:13])[F:14])[C:9]([O:1][O:2][C:9](=[O:8])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: OO
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: O=C(O)C(F)(F)C(F)(F)F
Product: O=C(OOC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F

Procedure:
In a manner similar to that of Example 1, H2O2 (>95%) was combined with pentafluoropropionic anhydride to give bis(pentafluoropropanoyl) peroxide (δ−85.1, −121.3) in pentafluoropropionic acid.
Reaction SMILES: [H-].[Na+].[NH:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Cl[CH2:19][C:20]1[CH:21]=[C:22]([S:26][CH2:27][C:28]([OH:30])=[O:29])[CH:23]=[CH:24][CH:25]=1.O.[CH3:32]N(C)C=O>>[CH3:32][O:30][C:28](=[O:29])[CH2:27][S:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][N:3]([C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:21]=1
Reactant: O=C(O)CSc1cccc(CCl)c1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CSc1cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
44 mg (1.1 mmol) of a 60% dispersion of sodium hydride in oil are suspended in 8 ml of dimethylformamide (DMF), and 238 mg (1.1 mmol) of di-t-butyl iminodicarboxylate are added. The reaction mixture is stirred at 60° C. for 30 min and then cooled to room temperature. A solution of 230 mg (1 mmol) of the methyl ester of [3-(chloromethyl)phenylthio]acetic acid in 3 ml of DMF is then added. The reaction medium is stirred at 50° C. for 90 min and then cooled and poured into 30 ml of water. The aqueous phase obtained is extracted with ethyl acetate (twice) and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel using a toluene/ethyl acetate mixture (95/5; v/v) as the eluent to give 300 mg of the expected compound in the form of a colorless oil (yield=73%).