Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[F:15][CH:16]([F:36])[C:17]1[N:22]=[C:21]([C:23](O)=O)[N:20]=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:18]=1>>[F:36][CH:16]([F:15])[C:17]1[CH:18]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[N:20]=[C:21]([C:23]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=3)[N:14]=2)[N:22]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)F)n1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)n2)cc1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.75 mmol) and 6-difluoromethyl-4-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid (example D.3) (0.16 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.096 g, 39%). MS (ISP) 498.3 [(M+H)+]; mp 307° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(CC)CC.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[OH:8][C@H:7]1[C@@H:3]([CH2:2][NH:1][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])[CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)[C@@H](O)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Reaction time: 18 h
Yield: 94.9 %

Procedure:
To a solution of (±)-1,1-dimethylethyl cis-3-(aminomethyl)-4-hydroxy-1-pyrrolidinecarboxylate (10.0 g, 46.0 mmole) in DMF (50 mL) at RT was added Et3N (8.4 mL, 60.0 mmole) and N-(benzyloxycarbonyloxy)succinimide (14.95 g, 60.0 mmole). After 18 h, the DMF was removed under vacuum and the residue purified on silica (25-50% DCM/EtOAc) to give the title compound (15.3 g, 95%) as a white foam: LC-MS (ES) m/e 351 (M+H)+; and a small amount of an N-methylated byproduct [1,1-dimethylethyl (3S,4S)-3-hydroxy-4-[(methyl{[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate] (0.33 g, 2%): LC-MS (ES) m/e 365 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]/[C:10](=[N:13]/[H])/[NH:11][OH:12].[O:15]=[C:16]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][N:17]1[CH2:34][C:35](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[N:13]=[C:35]([CH2:34][N:17]2[CH2:18][CH2:19][CH2:20][C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]2=[O:15])[O:12][N:11]=1
Reactant: [H]/N=C(/CCc1ccccc1Cl)NO
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1N(Cc2nc(CCc3ccccc3Cl)no2)CCCC1(c1ccccc1)c1ccccc1

Procedure:
A mixture of the product of Example 262A (180 mg, 0.91 mmol), the product of Example 68E (280 mg, 0.901 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (347 mg, 1.81 mmol) in 1,2-dichloroethane (4 mL) was stirred at ambient temperature for 3.5 hours and then heated to reflux for 16 hours. The cooled reaction mixture was diluted with CH2Cl2, washed with 1 N aqueous HCl and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel twice using ethyl acetate/hexanes as eluant, then finally purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). The dried down fractions were taken up in CH2Cl2 and combined and concentrated in vacuo. Hexane was added to the residue, which caused the product to solidify. The resulting material was collected by vacuum filtration and dried in the vacuum oven at 50° C. for 4 hours to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.46-7.41 (m, 1H), 7.35-7.16 (m, 13H), 4.83 (s, 2H), 3.56 (t, J=6.3, 2H), 3.20-3.10 (m, 2H), 3.09-3.00 (m, 2H), 2.62-2.55 (m, 2H), 1.79-1.67 (m, 2H); MS (ESI+) m/z 472 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.C[S-].[Na+]>CN(C)C=O>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][N:8]=[CH:9]3)=[CH:4][C:3]=2[OH:2])[CH:14]=1
Reactant: COc1cc2ccncc2cc1-c1cccnc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cc2ccncc2cc1-c1cccnc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
6-Methoxy-7-pyridin-3-yl-isoquinoline (42 mg) and sodium thiomethoxide (126 mg) were suspended in N,N-dimethylformamide (1.5 ml), and the mixture was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give 7-pyridin-3-yl-isoquinolin-6-ol (7 mg, yield 17%).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[C:10]1(=[O:16])N[C:13](=[O:15])[CH2:12][CH2:11]1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[N:3]1[C:13](=[O:15])[CH2:12][CH2:11][C:10]1=[O:16]
Reactant: O=C1CCC(=O)N1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N1C(=O)CCC1=O
Reaction time: 2 h
Yield: 120823.5 %

Procedure:
31.5 ml of hexamethyldisilazane (0.15 mmole) were added to a refluxing suspension of a mixture of 50 ml of toluene and 19.80 g (0.20 mole) of succinimide and 458 mg of saccharin (2.5 mmoles) and refluxing was continued for 2 hours. Fifteen minutes after the addition of the silylating agent, a clear, light yellow solution was obtained which turned brown when refluxing was continued. The reaction mixture was cooled, filtered and after evaporation of the solvent, the residue was vacuum distilled to obtain 31.04 g (90.8%) of N-trimethylsilylsuccinimide boiling at 86°-88° C. at 1.3 mm Hg.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH:34]3[CH2:36][CH2:35]3)[CH2:28][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[C:17](=[O:37])[C@:16]([CH2:39]C(O)=O)([CH3:38])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1.C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C.Cl>ClCCl.O.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH:34]3[CH2:36][CH2:35]3)[CH2:28][S:29]([CH2:32][CH3:33])(=[O:30])=[O:31])[C:17](=[O:37])[C@:16]([CH2:38][C:1](=[O:5])[CH2:2][OH:3])([CH3:39])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCS(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCS(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.063 ml, 0.715 mmol) was added to a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 349, 0.316 g, 0.572 mmol) in dichloromethane (1.9 ml). The reaction was stirred for 3 h at room temperature. The solvents were removed in vacuo. To the solids was added tris(trimethylsiloxy)ethylene (0.42 ml, 1.26 mmol) and the reaction was stirred at 90° C. After 2 h, the reaction was cooled, charged with THF (1 mL) and HCl (1.4 M, 0.982 ml, 1.375 mmol), and brought to reflux for 30 min. After cooling, the reaction was poured into water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography (step gradient elution 1 to 5% 2 M ammonia in MeOH in dichloromethane) afforded the title compound.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:8]([CH3:20])=[C:9]([C:13](OC(C)(C)C)=[O:14])[NH:10][C:11]=1[CH3:12])(=O)C.C(OC(OCC)OCC)C>C(O)(C(F)(F)F)=O>[CH3:20][C:8]1[C:7]([CH2:6][CH2:5][OH:4])=[C:11]([CH3:12])[NH:10][C:9]=1[CH:13]=[O:14]
Reactant: CC(=O)OCCc1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(C=O)c(C)c1CCO
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
tert-Butyl 4-(2-acetoxyethyl)-3,5-dimethylpyrrole-2-carboxylate (15 g, 53 mmol) was dissolved in TFA (40 ml) and the solution was stirred at 40° C. under nitrogen for 10 min. The reaction mixture was then cooled to 0° C. and triethylorthoformate (9.6 ml, 58 mmol) was added dropwise. The mixture was allowed to warm up to 20° C. and was stirred for 1 hr before being poured into ice water. This was extracted with dichloromethane and the extracts were washed successively with 10% aqueous ammonia and water and dried over MgSO4. 4-(2-acetoxyethyl)-3,5-dimethylpyrrole-2-carboxaldehyde was purified by silica gel chromatography using (7:3) ethyl acetate:hexane. Yield 45%, m.p. 125–27° C. (water).
Reaction SMILES: [CH:1]1[N:6]=[C:5]([Cl:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+].[P:27](OC)([O:31]C)([O:29]C)=[O:28]>O>[CH:1]1[N:6]=[C:5]([Cl:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][O:17][P:27]([OH:31])([OH:29])=[O:28])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: COP(=O)(OC)OC
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
6-Chloropurine riboside (100 mg, 0.35 mmol) was dissolved in 1.75 mL of trimethyl phosphate. Phosphoryl chloride (160 mg, 1.05 mmol) was dissolved in a mixture of 0.17 mL of trimethylphosphate and 6.3 μL of water. Both solutions were cooled to 0° C., mixed and stirred on a magnetic stirrer at 0° C. After 6 hours, ice was added to quench the reaction and the pH was adjusted to 7 by addition of ammonium hydroxide solution. The crude product was then concentrated and purified on a C18 reverse phase column using water as the mobile phase. The fractions containing desired product were combined and lyophilized to dryness to afford 6-chloropurine riboside 5′-phosphate (96 mg, 0.26 mmol, 75%) as a white solid. 1H NMR (D2O, 500 MHz) δ (ppm): 4.20 (m, 2H), 4.42 (m, 1H), 4.55 (t, J=4.6 Hz, 1H), 4.84 (m, 1H), 6.28 (d, J=5.1 Hz, 1H), 8.79 (s, 1H), 8.86 (s, 1H).
Reaction SMILES: Cl[CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH2:16])=[O:15]>C(OCC)(=O)C>[CH3:6][O:5][C:3]([C:2]1[O:15][C:14]([C:13]2[CH:12]=[C:11]([CH3:10])[CH:19]=[CH:18][CH:17]=2)=[N:16][C:7]=1[CH3:9])=[O:4]
Reactant: Cc1cccc(C(N)=O)c1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1oc(-c2cccc(C)c2)nc1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
Heat to 120° C. a neat mixture of methyl 2-chloroacetoacetate (914 mL, 7.5 mmol) and 3-methyl-benzamide (676 mg, 5 mmol) and stir at this temperature for 12 hrs. Cool the reaction mixture to room temperature and dilute it with ethyl acetate, wash with saturated sodium bicarbonate solution (3 times), water (twice) and brine, Dry the organic extract over MgSO4 and concentrate. Purify the resulting residue by flash chromatography (elute with 10% ethyl acetate in heptane) to give the title compound as a yellow oil (492 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3[F:22])[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:61][S:62](Cl)(=[O:64])=[O:63]>ClCCCl.C(Cl)Cl.O>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[CH2:7][C:6]3[CH:46]=[CH:47][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[CH:17][C:18]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([S:62]([CH3:61])(=[O:64])=[O:63])[CH2:26][CH2:25]2)=[CH:19][N:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
A glass microwave reaction vessel (80 mL) was charged with tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (3.000 g, 4.66 mmol) and trifluoroacetic acid (5.39 mL, 69.9 mmol) in 1,2-dichloroethane (20 mL). The reaction mixture was stirred and heated in a CEM Voyager Model (Large-Scale Unit) Microwave at 80° C. for 5 min (100 watts, Powermax feature on). The mixture was concentrated in vacuo to remove as much residual TFA as possible. The crude mixture (3.4 g) was dissolved in THF (30 mL), cooled to −20° C., then sodium carbonate (4.94 g, 46.6 mmol) was added to the mixture. After 10 min, methanesulfonyl chloride (3.63 mL, 46.6 mmol) was added dropwise. Following addition, the mixture was allowed to slowly warm to ambient temperature overnight. The mixture was diluted with DCM and water (30 ml). The reaction mixture was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4. The solution was filtered and concentrated in vacuo to give crude product as a tan oil. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (120 gram) eluting with a gradient of 10% to 100% EtOAc in hexane over 30 min, followed by a gradient of 1% to 15% MeOH in DCM over 20 minutes to give 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.702 g, 2.74 mmol, 58.7% yield) as light-yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=9.00, 2.15 Hz, 1H); 8.24 (d, J=1.37 Hz, 1H); 7.23 (dd, J=8.51, 6.94 Hz, 4H); 6.86 (t, J=8.71 Hz, 4H); 4.81 (d, J=1.96 Hz, 4H); 3.81 (d, J=6.26 Hz, 6H); 3.60 (s, 2H); 3.23 (s, 4H); 2.74-2.80 (m, 3H); 2.56-2.61 (m, 4H); 2.55 (s, 3H). m/z (ESI, +ve ion) 622.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:16][CH2:17]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 100 °C
Yield: 44.2 %

Procedure:
10 g of methyl 4-hydroxybenzoate and 20.5 g of 4-(2-chloroethyl)morpholine were dissolved in 100 ml of dimethylformamide and, after the addition of 38 g of potassium carbonate, heated to 100° C. for 1 hour. The reaction mixture obtained was poured on to ice-water. extracted with ethyl acetate, dried and evaporated. The oily, slightly brown residue was saponified with potassium hydroxide in water/ethanol and, after acidification and recrystallization from hexane/ethyl acetate, gave 7.3 g of p-(2-morpholinoethoxy)benzoic acid in beige crystals. m.p. 112° C.-114° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:7]2[CH2:18]CC[CH2:15][C:8]=2[S:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2]>C(C(C)=O)C>[CH3:18][C:7]1[C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:10]([Si:11]([CH3:13])([CH3:12])[CH3:14])[S:9][C:8]=1[CH3:15]
Reactant: CCNC(=O)c1c([Si](C)(C)C)sc2c1CCCC2
Solvent: CCC(C)=O
Product: CCNC(=O)c1c([Si](C)(C)C)sc(C)c1C

Procedure:
Using the procedures for the synthesis of the compound of Example 270 and methyl ethyl ketone as the starting material, the title compound was obtained as a white solid. m.p. 90-94° C.
Reaction SMILES: Cl.[C:2]1([CH:8]([SH:14])[CH:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](O)(=O)C>C=O>[C:2]1([CH:8]2[S:14][CH2:15][NH:10][CH:9]2[C:11]([OH:13])=[O:12])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: NC(C(=O)O)C(S)c1ccccc1
Agent: C=O
Agent: Cl
Product: O=C(O)C1NCSC1c1ccccc1
Reaction time: 2.5 h
Yield: 88 %

Procedure:
A mixture of β-phenyl-DL-cysteine hydrochloride [HT Nagasawa et al, J. Med. Chem (1987) 30, 1373] (1.32 g, 5.65 mmol) in acetic acid (11 ml) and formaldehyde (37 wt % aqueous solution, 0.43 ml) was heated to 80° to give a cloudy solution that was cooled to 30° and stirred for 2.5 h, then stood at room temperature for 16 h. The white precipitate was collected by filtration, washed with Et2O and dried in vacuo to give the title compound (1.04 g, 88%). δH (DMSO-d6) 7.57-7.54 (2 H, m, Ar—H), 7.40-7.29 (3 H, m, Ar—H), 4.90 (1 H, d, CHα-Thiopro), 4.59 (2 H, d, J 9.3 Hz, NCH2S), 4.46 (1 H, d, J 9.8 Hz, CHPh). m/z (ESI, 60 V) 210 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[OH:31][C:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:37]([C:36]1[C:32]([O:31][CH2:2][C:3]2[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=2)=[N:33][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=1)=[O:38]
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)c1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of ethyl (3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (7.20 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (3.01 g), potassium carbonate (2.21 g) and N,N-dimethylformamide (100 mL) was stirred at 80° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (6.84 g, yield 73%) from a fraction eluted with ethyl acetate-hexane (3:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 145-146° C.
Reaction SMILES: [I:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)CCCCCCCCCCOc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCCCCOc1ccc(I)cc1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
Methyl 11-(4-iodophenoxy)undecanoate (10 g, 23.9 mmmol), in methanol (100 ml) was treated with sodium hydroxide (2.4 g, 60 mmol). The stirred reaction was heated at 40 C for 60 h. The reaction contained a heavy white precipitate at the end of the reaction. The reaction was then cooled to room temperature and concentrated in vacuo. The resulting solid was then treated with 1N hydrochloric acid (250 ml) and ethyl acetate (250 ml) and stirred vigorously until the solid had dissolved. The organic phase was separated dried over sodium sulfate and concentrated in vacuo to give 11-(4-iodophenoxy)-undecanoic acid (9.55 g, 23.6 mmol, 98%) δH (CDCl3)1.29-1.78 (16H, m, 3,4,5,6,7,8,9,10-CH2), 2.35 (2H, t, 2-CH2), 3.90 (2H, t, 11-CH2), 6.66 (2H, dd, 2,6-ArH), 7.53 (2H, dd, 3,5,-ArH), δc(CDCl3) 24.61, 25.92, 28.98, 29.08, 29.16, 29.27, 29.41, 34.02, 68.08, 82.37, 116.90, 138.11, 158.97, and 180.18.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH:14]1[CH2:13][CH2:12][CH:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[CH:10]=3)[CH:6]=[N:7]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc(N)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2cnn(C3CCNCC3)c2c1
Yield: 73.1 %

Procedure:
tert-Butyl 4-(6-amino-1H-indazol-1-yl)piperidine-1-carboxylate (6.64 mmol, 2.1 g) was stirred at room temperature in dichloromethane (10 mL)/trifluoroacetic acid (10 mL) for 1 hour. The reaction mixture was concentrated under vacuum. The resulting residue was purified by SCX column to afford the title compound (1.05 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)Cc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1cccc(O)c1
Temperature: 25 °C

Procedure:
A solution of 3-hydroxyphenylacetic acid (15.5 g) in ethanol (200 mL) was added sulfuric acid (1 mL) and refluxed for 2.5 hours. The reaction mixture was cooled to room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. (18.2 g, 99.0%, pale brown oil)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:36][C:37]([C@H:39]1[NH:57][C:56](=[O:58])[C@H:55]([CH2:59][CH2:60][CH2:61][NH:62]C(OC(C)(C)C)=O)[NH:54][C:53](=[O:70])[C@@H:52]([NH:71]C(OC(C)(C)C)=O)[CH2:51][C:50]2[CH:79]=[C:46]([CH:47]=[CH:48][C:49]=2[OH:80])[C:45]2=[CH:81][C:41](=[C:42]([OH:82])[CH:43]=[CH:44]2)[CH2:40]1)=[O:38])[C:12]([NH:14][CH2:15][C@@H:16]([NH:28]C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])(C)(C)C.[ClH:84]>O1CCOCC1>[ClH:84].[ClH:84].[ClH:84].[ClH:84].[NH2:71][C@H:52]1[CH2:51][C:50]2[CH:79]=[C:46]([CH:47]=[CH:48][C:49]=2[OH:80])[C:45]2=[CH:81][C:41](=[C:42]([OH:82])[CH:43]=[CH:44]2)[CH2:40][C@@H:39]([C:37]([NH:36][C@H:11]([C:12]([NH:14][CH2:15][C@@H:16]([NH2:28])[CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH2:10][CH2:9][CH2:8][NH2:7])=[O:38])[NH:57][C:56](=[O:58])[C@H:55]([CH2:59][CH2:60][CH2:61][NH2:62])[NH:54][C:53]1=[O:70]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@H](N)CNC(=O)[C@H](CCCN)NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](N)C(=O)N[C@@H](CCCN)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 mg (0.034 mmol) of the compound from Example 177A are dissolved at 0° C. in 1 ml of dioxane. Then 0.5 ml of a 4N hydrogen chloride solution in dioxane are added and the mixture is stirred at RT for 2 h. The mixture is evaporated to dryness in vacuo and the residue is dried to constant weight under high vacuum.