Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:24]2[CH2:25][CH2:26][S:27][CH2:28][CH2:29]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCSCC2)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCSCC2)c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 37 (0.16 g, 0.392 mmol) in dry CH2Cl2 (2 mL) was added TFA (2 mL) slowly. After stirring at 0° C. for 3 h, the reaction mixture was concentrated to give a yellow solid. The crude product was purified by flash column chromatography on silica gel using a CH2Cl2:MeOH gradient (100:0 to 0:100) to give compound 38 a yellow foam (0.074 g, 54%). 1H NMR (400 MHz, DMSO-d6): δ 2.42-2.46 (m, 4H), 2.63-2.66 (m, 4H), 6.46 (d, J=16 Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.2 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 9.39 (s, 1H), 12.38 (s, 1H). LRMS (ESI) m/z 353 (M+H)+. HRMS (ESI) Calcd for C21H21O3S: 353.1211 (M+H)+. Found: 353.1208.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@@H:58]([O:59][C:60](=[O:67])[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C@H:57]([O:68][C:69](=[O:76])[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C@@H:56]([CH2:77][O:78][C:79](=[O:86])[C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[O:55][C@@H:46]1[O:47]CC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@@H:58]([O:59][C:60](=[O:67])[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C@H:57]([O:68][C:69](=[O:76])[C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[C@@H:56]([CH2:77][O:78][C:79](=[O:86])[C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)[O:55][CH:46]1[OH:47])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@@H](OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2C(O)O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 98.5 %

Procedure:
The disaccharide 28 (670 mg, 0.577 mmol) was dissolved in MeOH (3 mL) and EtOAc (30 mL). Palladium on charcoal (5%, 80 mg) was added. The mixture was stirred under 50 psi of hydrogen at r.t. o/n. TLC indicated ˜60% conversion. More palladium on charcoal (5%, 80 mg) was added. Stirring was continued at 50 psi for 3 days. TLC indicated complete conversion. The mixture was filtered through a plug of Celite and rinsed with EtOAc (5×1 mL). The combined filtrate and washings were evaporated to dryness to give the title compound 29 as a colourless foam (609 mg, 99%). The product was used directly for the next step without purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:16])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: Cc1cc(-c2ccc(Cl)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (45 mg, 78%), MS (ISP) m/z=311.4 [(M+H)+], mp 269° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 10) (52 mg, 0.186 mmol) and commercially available 4-chloro-phenylboronic acid (37.9 mg, 0.24 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:17])=[N-]>C1COCC1.CCOCC>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(F)(F)F)cc1N

Procedure:
To a solution of 2-amino-4-(trifluoromethyl)benzoic acid (5 g) in THF (85 ml) was added diazomethane (48.7 ml) in ether until completion of the reaction. Nitrogen was bubbled into the reaction mixture for 15 minutes to remove the excess of diazomethane and the solvent was removed under reduced pressure to provide a light brown solid (5.34 g). The compound was used in the next without purification. LRMS (ES+) m/z 220.1 (M+H)+.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[N:9]=[C:8]([Zn+])[CH:7]=[CH:6][CH:5]=1.Br[C:12]1[C:13]([C:24]2[CH:32]=[CH:31][C:30]3[C:26](=[CH:27][N:28]([CH3:33])[N:29]=3)[CH:25]=2)=[N:14][S:15][C:16]=1[NH:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[CH3:23])=[O:19]>O1CCCC1.COCCOC>[CH3:2][O:3][C:4]1[N:9]=[C:8]([C:12]2[C:13]([C:24]3[CH:32]=[CH:31][C:30]4[C:26](=[CH:27][N:28]([CH3:33])[N:29]=4)[CH:25]=3)=[N:14][S:15][C:16]=2[NH:17][C:18]([C@@H:20]2[CH2:22][C@H:21]2[CH3:23])=[O:19])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc([Zn+])n1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3nn(C)cc3c2)c1Br
Agent: [Br-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1cccc(-c2c(-c3ccc4nn(C)cc4c3)nsc2NC(=O)[C@@H]2C[C@H]2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add a 0.5M solution of 6-methoxy-2-pyridylzinc bromide in tetrahydrofuran (6.13 mL, 3.07; mmol) to a solution of (1R,2R)-2-methyl-cyclopropanecarboxylic acid [4-bromo-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide (0.24; g, 0.61; mmol) in anhydrous 1,2-dimethoxyethane (3.1; mL) and degas by bubbling with nitrogen for 20 min. Add bis(tri-t-butylphosphine)palladium (0) (0.01; g, 12.27; μmol), stir at room temperature under nitrogen overnight and then heat at 55° C. for 48; h. Dilute with brine and extract with ethyl acetate. Dry the ethyl acetate layers over magnesium sulfate, filter and concentrate. Purify by silica gel chromatography, gradient eluting from 0:100; to 30:70; eluting using ethyl acetate:chloroform and then further purify by reverse phase HPLC (water w/ammonium bicarbonate (pH=9)/acetonitrile) to give the title compound (29.6; mg). 1H NMR (CD3OD) δ 0.85; (m, 1H), 1.18; (d, 3H), 1.35; (m, 1H), 1.44 (m, 1H), 1.62; (m, 1H), 4.11; (s, 3H), 4.24; (s, 3H) 6.57; (d, 1H), 6.62; (d, 1H), 7.27; (m, 1H), 7.34; (t, 1H), 7.65; (d, 1H), 7.91; (d, 2H), 12.17; (bs, 1H).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+:26]>C(O)(C)(C)C>[C:1]([O-:24])(=[O:23])[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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
In an amount of 87.6 g of behenic acid (Edenor C22-85R, trade name, produced by Henkel Co.), 49.2 mL of 5 mol/L NaOH aqueous solution and 120 mL of tert-butyl alcohol were mixed and allowed to react at 75° C. to obtain a solution of sodium behenate. This sodium behenate solution and an aqueous silver nitrate solution were added to a reaction vessel containing 635 mL of distilled water and 30 mL of tert-butyl alcohol with stirring. At this time, the internal temperature of the reaction vessel was kept at 30° C. and controlled so that the temperature of the solution should not be raised. After finishing the addition, the solid content was recovered by suction filtration and the solid content was washed with water. Wet cake corresponding to 100 g of the dry solid content of the obtained silver behenate was added with 7.4 g of polyvinyl alcohol (PVA-217, trade name, average polymerization degree: about 1700) and water, pre-dispersed by a homomixer and then dispersed in a dispersing machine (Microfluidizer-M-110S-EH; trade name, produced by Microfluidex International Corporation, using G10Z interaction chamber) to obtain Silver behenate dispersion A.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[CH2:3][NH2:4].[CH:7]1([CH:13]=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:7]1([CH:13]2[NH:4][CH2:3][C:2]([CH3:5])([CH3:1])[O:6]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CC1CCCCC1
Reactant: CC(C)(O)CN
Product: CC1(C)CNC(C2CCCCC2)O1

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl-2-methyl-2-hydroxypropylamine. The propanolamine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-3-cyclohexyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[NH:12][CH:13]=[N:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Compound 8 (2.39 g, 10 mmol) was dissolved in dry DMF (100 mL), cooled to 0° C., sodium hydride (0.48 g, 20 mmol) was added, and the mixture stirred at room temperature for 30 min. Ethyl bromoacetate (1.22 mL, 11 mmol) was added dropwise for 1 h. Stirring was continued for 2 h at room temperature and the reaction was quenched with methanol (2 mL). The solvents were evaporated under reduced pressure. The residue was subjected to column chromatography (DCM/MeOH; 9.5/0.5) to obtain 9 as a white solid: yield 1.3 g (40%); MS(+ESI): m/z 326 [M+H]+; 1H NMR (400 MHz, CDCl3): δ9.02 (s, 1H), 8.83 (s, 1H), 8.11 (s, 1H), 8.05 (d, 2H, J=7.2 Hz), 7.62 (t, 1H, J=7.2 Hz), 7.54 (t, 2H, J=7.2 Hz), 5.06 (s, 2H), 4.31 (q, 2H, J=7.2 Hz), 1.38 (t, 3H, J=7.2 Hz); 13C NMR (400 MHz, CDCl3): δ=166.76, 164.53, 152.96, 152.50, 149.83, 143.22, 133.68, 132.80, 128.89, 127.85, 122.56, 62.53, 44.33, 14.09.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12]>O1CCCC1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:11]([N:10]([CH3:14])[CH3:9])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1cccc(O)c1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
m-Aminophenol (10 g) and N,N-dimethylcarbamoyl chloride (7.42 g) are dissolved in tetrahydrofuran (65 ml) and the solution is stirred at 30° C. for 4 hours. The solvent is evaporated under reduced pressure and the solid residue is suspended in water. The mixture is filtered, washed well with water, and dried in a desiccator to give N-(3-hydroxyphenyl)-N',N'-dimethylurea which melts at 198° C. (decomp.) as measured on a Kofler bench. (U.S. Pat. No. 3,488,376 reports m.pt. 194°-197° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].Cl[C:20](OCC)=[O:21]>C(O)C>[N:10]1([CH2:9][CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:1][C:20]2=[O:21])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: Nc1ccccc1C(=O)NCCCn1ccnc1
Reactant: CCOC(=O)Cl
Solvent: CCO
Product: O=c1[nH]c2ccccc2c(=O)n1CCCn1ccnc1

Procedure:
A mixture of 4.0 g of 2-amino-N-[3-(1H-imidazol-1-yl)propyl]benzamide and 15 ml of ethyl chloroformate was heated in an oil bath at 95°-105° C. for 1.5 hours, dissolved in 50 ml of ethanol, and concentrated. The residue was mixed with 100 ml of ethanol and 3.2 g of potassium hydroxide, heated at reflux temperature for 3 hours and concentrated. The residue was dissolved in water and acidified with acetic acid to pH 6-7. The white precipitate was separated by filtration and recrystallized from ethanol. The desired product melted at 197°-200° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]1([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1.Cl>CC#N>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:30]1[CH:29]=[CH:28][C:27]([C:16]2([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:32][CH:31]=1)(=[O:5])=[O:4]
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCC2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(Oc1ccc(C2(c3ccc(O)cc3)CCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Trifluoromethanesulfonic anhydride (0.350 mL) was added to a solution of 4,4′-(cyclobutane-1,1-diyl)diphenol (500 mg) and pyridine (0.505 mL) in MeCN (10 mL) at 0° C. The mixture was stirred at room temperature for 40 min. The mixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give 4-[1-(4-hydroxyphenyl)cyclobutyl]phenyl trifluoromethanesulfonate (160 mg) as colorless oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:21]([OH:29])[CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](=[O:29])[CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cnc2c(c1)cc(C(O)CC1CCCCC1)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cnc2c(c1)cc(C(=O)CC1CCCCC1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a 250 mL round bottomed flask charged with 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclohexyl-ethanol (240 mg, 0.58 mmol) was added a solution of Dess-Martin periodinane in dichloromethane (0.3 M, 3.86 mL, 1.16 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclohexyl-ethanone (240 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C22H24N2O4S [M+H]+ 413.51, observed 413.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C[O:12][C:13](=[O:42])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3Br)[CH:24]=2)=[CH:18][C:17]=1[CH3:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:31]2[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:30]=2[O:29][C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:42])=[O:12])=[C:17]([CH3:41])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccc(F)cc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 4-fluorophenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 129 mg (60%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H22O4F4 510, found 511 (M+1, 100%).
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][OH:22])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29]>>[CH3:1][N:2]([CH2:20][CH2:21][O:22][C:28]([C:24]1[O:23][CH:27]=[CH:26][CH:25]=1)=[O:29])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)c1ccco1
Reactant: CCCCCCCCCCCCCCCC(=O)N(C)CCO
Product: CCCCCCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccco1

Procedure:
N-methyl-N-(2-furoyloxyethyl)palmitamide was prepared by the procedure of example 1 from 31 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)palmitamide and 13 gms. (0.1 mole) of furoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][C:27]=5[O:29][C@H:30]([CH3:35])[C:31]([O:33]C)=[O:32])[N:22]=[CH:21][N:20]=4)=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[N:5]=[CH:4]1>C1COCC1.CO>[S:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][C:27]=5[O:29][C@H:30]([CH3:35])[C:31]([OH:33])=[O:32])[N:22]=[CH:21][N:20]=4)=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[N:5]=[CH:4]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
Aqueous sodium hydroxide (2N, 1 ml, 2 mmol) was added to a solution of methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (480 mg, 1 mmol) in THF (3 ml) and methanol (3 ml). The mixture was stirred at room temperature for 2 hours. After evaporation of the solvents, the pH of the mixture was adjusted to 3 by addition of 2N hydrochloric acid. The precipitate formed was filtered, washed with water and dried under high vacuum to give (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (435 mg, 97%); Mass spectrum MH+ 447.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].CO>C1COCC1>[CH3:22][O:23][CH2:24][C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:26]
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reactant: COCC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added methoxyacetyl chloride (0.08 g, 0.70 mmol). The mixture was heated to reflux for 6 hours. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.111 g (87%) of product as an off-white solid: mp 244-246° C.; 1H NMR (DMSO-d6) 11.07 (s, 1H), 10.26 (s, 1H), 8.68 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 4.10 (s, 2H), 3.47 (s, 3H), 2.77-2.51 (m, 3H), 2.09-2.04 (m, 1H), 1.90 (s, 3H); 13C NMR (DMSO-d6) 172.12, 171.99, 169.15, 168.99, 167.38, 136.22, 135.68, 131.06, 124.25, 117.90, 115.91, 71.43, 59.06, 58.88, 29.01, 28.53, 20.92; Anal. Calcd. For C17H17N3O6: C, 56.48; H, 4.81; N, 11.62. Found: C, 56.10; H, 4.55; N, 11.39+0.12H2O.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:13]1[CH2:12][C:11](=[O:15])[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:14]1
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CCCCCCC1=CC(Br)CC1=O
Temperature: 5 °C

Procedure:
A stirred mixture of 35.9 g. (0.171 moles) of 2-(6-carboxyhexyl) cyclopent-2-en-1-one [Bagli et al., Tetrahedron Letters, No. 5, 465 (1966)], 35.0 g. (0.197 moles) of N-bromosuccinimide, and 600 ml. of carbon tetrachloride is refluxed for 35 minutes. The mixture is cooled to 5°C. and filtered. The filtrate is washed with cold water, dried over magnesium sulfate, and taken to dryness to give an oil, λMeOHmax. = 225 mμ (8850); νmax. = 1705 (carbonyl groups) and 1625. cm-1 (olefin group).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH:25][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCc1cc(F)cc(F)c1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3cc(F)cc(F)c3)s2)c(C)[nH]c1=O
Yield: 26 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 3,5-difluorobenzylamine as described in Step 5, Example 24 to give the title compound as a solid (26% yield). LC/MS: RT 3.67 min; m/e 425 (M+H); 1H NMR (δ, ppm): 11.82 (1H, s), 8.58 (1H, t), 7.49 (1H, s); 7.25 (1H, s); 7.08 (2H, m), 6.96 (2H, m), 4.20 (2H, d), 2.49 (2H, q), 2.27 (3H, s), 1.10 (3H, t); 19F NMR −110.