Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35](Br)[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1.[C:40]([O:44][C:45]([N:47]1[CH2:51][C@@H:50](COC)[CH2:49][C@H:48]1[C:55]([OH:57])=[O:56])=[O:46])([CH3:43])([CH3:42])[CH3:41].[C:58]([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35]([O:57][C:55]([C@@H:48]6[CH2:49][CH2:50][C@H:51]([CH3:58])[N:47]6[C:45]([O:44][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:46])=[O:56])[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(OC(=O)[C@@H]2CC[C@H](C)N2C(=O)OC(C)(C)C)C4=O)N1C(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 96.9 %

Procedure:
(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (800 mg, 1.34 mmol) was treated with a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (485 mg, 1.87 mmol) in acetone (6 mL) and Cs2CO3 (306 mg, 0.94 mmol). The stirred reaction mixture was heated to 40° C. for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (680 mg, 65%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([O:39][C@H:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:41][C:42]([OH:44])=O)(=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(Cl)CCl.CI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:24]([O:39][C@H:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:41][C:42]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[O:44])(=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: CC(C)(C)[Si](OCCCCN)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NCCCCO
Yield: 80.9 %

Procedure:
In the same manner as described in Example 20-(1), 4-amino-1-(t-butyldiphenylsilyloxy)butane (500 mg, 1.53 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (695 mg, 1.53 mmol) in the presence of EDC·MeI (595 mg, 2.0 mmol) and then deprotected with TBAF (1.0 M in THF, 2.5 mL, 2.5 mmol) in THF (15 mL) to afford 651 mg (81%) of 4-[(R)-3-tetradecanoyloxytetradecanoylamino]-1-butanol as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]2C=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([Cl:11])[N:3]=1.FC(F)(F)C(O)=O.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1.CC[N:35](C(C)C)C(C)C.O>CC(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=2)[N:7]2[N:35]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: Clc1cc2nccn2c(Cl)n1
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
194 mg (3.20 mmol) of 5,7-dichloroimidazo[1,2-c]pyrimidine are suspended in 8 ml of 2-propanol, and 403.9 mg (1.13 mmol) of N6-(2-aminoethyl)-3-nitropyridine-2,6-diamine trifluoroacetate and 331.7 mg (2.57 mmol) of DIPEA are added. The mixture is heated at 80° C. for 16 h. After this time, water is added, and the precipitate which separates out is filtered off with suction. It is washed with a little 2-propanol/water, and the resulting solid is dried under high vacuum. 265 mg (74% of theory) of the product are obtained as a solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:26][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)[CH3:25]
Reactant: CCOC(=O)CC(C)Br
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCOc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.2 g (0.030 mol) of 60% sodium hydride in 100 mL of toluene was added 6.12 g (0.030 mol) of 4(benzyloxy)phenol and the reaction was stirred at room temperature for 30 minutes followed by the addition of 5.85 g (0.030 mol) of ethyl 3-bromobutyrate. The resulting mixture was heated to reflux overnight and then filtered. The filtrate was washed with 0.5N sodium hydroxide solution, 3% sodium carbonate solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 5.45 g of the bis-ether as a white solid. Electrospray Mass Spec: 314.8 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.FC1C=C([N+]([O-])=O)C=CC=1OC1C=CN=C2C=C(C(N(C)C)=O)SC=12.[Cl:43][C:44]1[CH:49]=[C:48]([N+:50]([O-:52])=[O:51])[CH:47]=[C:46]([Cl:53])[C:45]=1[OH:54]>>[Cl:43][C:44]1[CH:49]=[C:48]([N+:50]([O-:52])=[O:51])[CH:47]=[C:46]([Cl:53])[C:45]=1[O:54][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Agent: CN(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: O=C(c1cc2nccc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)c2s1)N1CCCC1
Yield: 69 %

Procedure:
Starting from the compound 139 and following the procedure described above for the synthesis of compound 6 (scheme 1, example 1) but replacing 2-fluoro-4-nitrophenol with 2,6-dichloro-4-nitrophenol, title compound 140 was obtained in 69% yield. LRMS (M+1) 438.0 (100%), 439.1 (20%), 440.1 (70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[C:12]([Cl:20])=[N:13][C:14]([C:17](=O)[CH3:18])=[CH:15][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[CH:31]=[CH:30][C:26]([CH2:27][O:28][NH2:29])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33].[C:36](O)(=O)[CH3:37]>CO>[C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[C:12]([Cl:20])=[N:13][C:14]([C:17](=[N:29][O:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([CH:37]3[CH2:36][CH2:15][CH2:16][CH2:11][CH2:10]3)=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH3:18])=[CH:15][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(CNCCC(=O)OC(C)(C)C)c(Cl)n1
Reactant: NOCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)O
Solvent: CO
Product: CC(=NOCc1ccc(C2CCCCC2)c(C(F)(F)F)c1)c1ccc(CNCCC(=O)OC(C)(C)C)c(Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-[(6-acetyl-2-chloro-pyridin-3-ylmethyl)-amino]-propionic acid tert-butyl ester (1 eq) in methanol is added O-(4-chloro-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 5 hours. After concentration, the residue is purified by column chromatography to give 3-({2-chloro-6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionic acid tert-butyl ester. MS: (ES+) 568.3 (M+1)+. The tert-butyl group is subsequently removed by treatment with TFA/DCM (1/1) at room temperature. The final compound 3-({2-chloro-6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionic acid is purified by preparative LCMS. 1H NMR (400 MHz, CD3OD) δ 1.28-1.60 (m, 5H), 1.71-1.92 (m, 5H), 2.30 (s, 3H), 2.79 (t, 2H), 2.90 (m, 1H), 3.38 (t, 2H), 4.42 (s, 2H), 5.29 (s, 2H), 7.38 (d, 1H), 7.50-7.68 (m, 3H), 7.94 (s, 2H). MS: (ES+): 512.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2cc(Cl)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(Cl)nc(-c3ccccc3)nc2c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
7-Chloro-2-phenylquinazolin-4(3H)-one (3.11 g, 12.1 mmol) in POCl3 (40 mL) was heated with stirring at 90° C. under N2 for 2 d. The reaction was cooled to rt and evaporated to dryness under high vacuum. The residue was stirred for 30 min at 0° C. under Ar as a suspension in NH3/i-PrOH (2 M, 45 mL). Later DCM (˜100 mL) was added and stirring was continued for 1 h at it Aq NH4OH (conc, 50 mL) was added and layers were separated. The aqueous layer was extracted with DCM (2×). The organic phase was washed (satd NaHCO3, H2O, brine), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a light yellow solid; 1H NMR (400 MHz, CD2Cl2) δ 8.56-8.46 (m, 2H), 8.14 (d, J=9.2 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.56 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.52-7.45 (m, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Yield: 96.7 %

Procedure:
To a solution of 1.2 g (6.0 mmol) 4-amino-1-t-butoxycarbonylpiperidine from Step B in 40 mL of methylene chloride was added 3.15 mL (18 mmol) of DIPEA and 1.03 mL (7.2 mmol) of benzyl chloroformate while cooled in an ice bath. After 0.5 h the reaction was quenched with aqueous sodium carbonate and extracted three times with methylene chloride. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 25% ethyl acetate/hexanes to afford 1.94 g of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=O)[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.CN(C=O)C.[Br:20]N1C(=O)CCC1=O>ClCCl>[NH2:12][C:7]1[C:8]([C:9]([O:10][CH3:11])=[O:14])=[C:3]([O:2][CH3:1])[C:4]([Br:20])=[CH:5][CH:6]=1
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)ccc(Br)c1OC

Procedure:
A mixture of Example 470A (9.8 g, 50.7 mmol), DMF (50 mL), and dichloromethane (150 mL) was cooled to 0° C., treated portionwise with N-bromosuccinimide (12.6 g, 76 mmol), stirred until all the starting material was consumed, and filtered. The filter cake was washed with dichloromethane combined filtrates were concentrated, treated with anhydrous methanol (450 mL), and heated to reflux for 54 hours. Purification by flash column chromatography on silica gel with 15% ethyl acetate/hexanes provided the desired product. MS (ESI(+)) m/e 260, 262 (M+H)+, 277, 279 (M+NH4)+, 282, 284 (M+Na)+; (ESI(−)) m/e 258, 260 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.34 (d, 1H), 6.50 (d, 1H), 5.63 (s, 2H), 3.82 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[NH:9][C:8](=O)[N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:5]=1)[CH2:2][CH3:3].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:8]1[N:9]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(=O)[nH]1
Product: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(Cl)n1

Procedure:
A mixture of 6-propyl-4-(3-trifluoromethylphenyl)-1H-pyrimidin-2-one (204 mg) and phosphorus oxychloride (3 mL) was stirred and heated at reflux for 72 h, then allowed to cool and poured onto a mixture of ice/ether (20 mL). The ether layer was separated, washed with saturated sodium carbonate solution (20 mL), dried over sodium sulphate, and evaporated at reduced pressure to afford 2-chloro-4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine as a dark brown oil (239 mg).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1.COC1C(OCOC)=C(B2OC(C)(C)C(C)(C)O2)C=CC=1OC>S(=O)(=O)(O)O>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N+:1]([O-:4])=[O:2])[CH:10]=[N:9][CH:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cncc2ccccc12
Agent: COCOc1c(B2OC(C)(C)C(C)(C)O2)ccc(OC)c1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2cncc(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium nitrate (5.34 g; 0.052 mol) was added to 20 ml of concentrated sulfuric acid and slowly dissolved by careful heating. The resulting solution was added dropwise to a solution of 4-bromoisoquinoline (10 g; 0.048 mol) dissolved in 40 ml of the same acid at 0° C. After removal of the cooling bath, the solution was stirred for one hour at room temperature. The reaction mixture was then poured onto crushed ice (400 g) and made basic with ammonium hydroxide. The resulting yellow precipitate was collected by filtration and the filtrate was extracted with diethyl ether (3×500 ml), dried (Na2SO4), and concentrated to give a yellow solid that was combined with the initial precipitate. Recrystallization from methanol gave 12.1 g (89%) of slightly yellow crystals: mp 172-174° C.; 1H NMR: (300 MHz, CDCl3): 9.27 (s, 1H); 8.87 (s, 1H); 8.21 (dd, 1H, J=6.6, 1.2 Hz); 7.96 (dd, 1H, J=6.6, 1.2 Hz); 7.73 (t, 1H, J=7.5 Hz). CIMS m/z: 253 (M+H+, 100%); 255 (M+H++2, 100%). Anal. Calc'd for C9H5BrN2O2: C, 42.72; H, 1.99; N, 11.07. Found: C, 42.59; H, 1.76; N, 10.87.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[O:14]([C:21]1[CH:28]=[CH:27][C:24](CN)=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:29]1C=CC=C[C:30]=1OCC1C=CC(CNC(C2C(N)=NC(N)=CN=2)=O)=CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.FC(F)(F)C(O)=O>CN(C)C=O>[O:14]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:30][NH:29][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)=[O:13])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:27][CH:28]=1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: Nc1cnc(C(=O)NCc2ccc(COc3ccccn3)cc2)c(N)n1
Reactant: O=C(O)c1ccc2nccnc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(Oc2ccccc2)c1)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To a solution of quinoxaline-6-carboxylic acid described in Preparation Example I-1 (15 mg, 0.063 mmol) and 4-phenoxybenzylamine described in Preparation Example 3 (13 mg, 0.063 mmol) in N,N-dimethylformamide (2 mL) were added benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (36 mg, 0.069 mmol) and triethylamine (19 μl, 0.14 mmol), which was then stirred at room temperature for 24 hours. The reaction mixture was concentrated, the residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (12 mg, 0.025 mmol, 40%) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.C[Si]([CH:44](O[Si](C)(C)C)[C:45]([O-:47])=[O:46])(C)C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.C(Cl)Cl>C(OCC)(=O)C>[O:33]=[C:31]1[O:30][N:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][C:12]3[C:13](=[O:14])[N:8]([CH:5]4[CH2:6][CH2:7][C:2]5([O:47][C:45](=[O:46])[CH2:44][O:1]5)[CH2:3][CH2:4]4)[C:9]4[N:10]([N:37]=[CH:38][N:39]=4)[C:11]=3[CH2:34][CH2:35][CH3:36])=[CH:21][CH:20]=2)[NH:32]1
Reactant: C[Si](C)(C)OC(C(=O)[O-])[Si](C)(C)C
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCC(=O)O3)c2ncnn12
Temperature: -78 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), trimethylsilyl[(trimethylsilyl)oxy]acetate (0.16 mL), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.18 mL) and methylene chloride (5 mL) was stirred at −78° C. for 1 hr, and then at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.066 g, 26%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:12])[N:7]([C:24]2[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][CH2:35][CH2:36][OH:37].CCN(CC)CC>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:12])[N:7]([C:24]2[CH:25]=[C:26]([CH2:30][C:31]([NH:34][CH2:35][CH2:36][OH:37])=[O:32])[CH:27]=[CH:28][CH:29]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(=O)O)c2)n1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(=O)NCCO)c2)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 2-(3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)phenyl)acetic acid (200 mg, 0.43 mmol) in THF (10 mL) was added 2-amino-ethanol (260 mg, 4.3 mmol) and Et3N (0.5 mL), then this mixture was heated to 40° C. and stirred overnight. After removal of the solvent, this mixture was extracted with EtOAc and washed with 1N HCl aqueous solution and the organic layer was dried over Na2SO4. After removal of the solvent, a crude product was obtained, which was purified by preparative HPLC to afford 2-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)pyrazol-1-yl]phenyl}-N-(2-hydroxy-ethyl)acetamide (104 mg, 50% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.81 (s, 1H), 8.12 (m, 1H), 7.98 (d, J=9.3 Hz, 1H), 7.92-7.87 (m, 2H), 7.61 (d, J=8.1 Hz, 1H), 7.53-7.49 (m, 2H), 7.47-7.38 (m, 4H), 7.29 (d, J=7.5 Hz, 1H), 6.39 (s, 1H), 3.49 (s, 2H), 3.35 (t, J=6.0 Hz, 2H), 3.07 (q, J=6.0 Hz, 2H), 1.25 (s, 9H); MS (ESI) m/z: 487 (M+H+).
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.[OH-].[Na+]>C1COCC1>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 74.1 %

Procedure:
The hydrolysis conditions described for 191 were employed. Thus, ethyl 4-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)butanoate (217) (0.155 g, 0.39 mmol) was dissolved in THF and EtOH (1:1, 10 mL) and then treated with 1 N NaOH (2 ml) at 70° C. for 1 h. Upon acidification, work-up, and purification afforded 0.110 g (74%) of the title compound 218. 1H NMR (300 MHz, CD3OD): δ 7.02 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.1 Hz, 2H), 4.00 (t, J=6.3 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H), 2.31 (br s, 4H), 2.05 (quintet, J1=13.5 Hz, J2=6.9 Hz, 2H), 1.60 (s, 8H). LCMS (ESI): m/z 379 (M−H)−. Anal. Calcd for C24H28O4, C, 75.76; H, 7.42. Found: C, 75.81, H, 7.64.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Na].[C:10]([CH2:12][N:13]=[CH:14]OC)#[N:11]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:11]=[CH:14][NH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC=NCC#N
Reactant: Oc1ccc(Br)cc1
Agent: [Na]
Solvent: CO
Product: Brc1ccc(Oc2c[nH]cn2)cc1

Procedure:
To a mixture of liquid 4-bromophenol (25 g, mp 64-68° C.) at 100-110° C. and its sodium salt [Prepared from 3.5 g (20 mmol) 4-bromo-phenol and sodium metal (0.46 g, 20 mmol) in anhydrous methanol. The resultant solution was concentrated and the residual solvent removed under vacuum overnight], neat methyl N-(cyano-methyl)methanimidate (2 mL, 20 mmol; Hosmane, R. S. et al, J. Org. Chem., p. 1212, 1984) was added dropwise over a period of 10 minutes under a slow stream of dry argon. The resultant mixture was stirred at 100° C. for 2 h, and the reaction product partitioned between methylene chloride (250 mL) and aqueous sodium hydroxide (1M, 250 mL). The aqueous layer was separated and extracted with methylene chloride (3×50 mL). The organic extracts were combined, washed with brine (50 mL), dried over anhydrous potassium carbonate, filtered and concentrated. The residue was subjected to column chromatography on silica gel eluting with a mixture of 7:3 v/v chloroform and acetone. Collection and concentration of appropriate fractions provided the titled compound as white powder.