Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.[H-].[Na+].Br[CH:13]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].N1C=CC=NC=1O>O1CCCC1>[O:18]([CH:13]([O:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)[C:14]([O:16][CH3:17])=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C(Br)Oc1ccccc1
Reactant: Cc1cc(C)nc(O)n1
Agent: Oc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccccc1)Oc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,6-Dimethyl-2-pyrimidinol (3.0 g, 24 mmol) and 60 mL of tetrahydrofuran were placed in a dry 250 mL flask and blanketed with argon. Sodium hydride (1.0 g of 60 percent, 24 mmol) was added carefully and the mixture was allowed to stir at ambient temperature for 0.5 hr. A solution of methyl 2-bromo-2-phenoxyacetate (7.2 g, 29 mmol) in a small amount of tetrahydrofuran was added dropwise with stirring and the mixture was then allowed to stir overnight under argon at ambient temperature. The resulting mixture was found by thin layer chromatography to contain only a trace of the starting pyrimidinol. The mixture was concentrated by evaporation under reduced pressure and the residue was diluted with water and ether. The phases that formed were separated and the aqueous phase was extracted twice with ether. The combined ethereal phase was extracted with water and then dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain the title compound in crude form as a reddish oil. This oil was column chromatographed on silica eluting with a 75:25 mixture of hexane and ethyl acetate to obtain 1.2 g (17 percent of theory) of the title compound as a pink oil of 93 percent purity, as determined by gas-liquid chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21](O)=[O:22].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[C@@H:26]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27]1)=[O:22]
Reactant: CN1CCNC[C@@H]1Cc1ccccc1
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Product: CN1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)n(C)c3ccc(Cl)cc23)C[C@@H]1Cc1ccccc1

Procedure:
Prepared from 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoic acid (Description 12) and (2S)-1-methyl-2-(phenylmethyl)piperazine (Description 35) according to the method of Description 25. 1H NMR (400 MHz, CDCl3) mixture of two amide rotamers; δ7.56-6.98 (12H, m), 4.09, 3.93 (total 1H, each d, J 13.1 Hz), 3.53, 3.47 (total 3H, each s), 3.20-1.98 (12H, m), and 2.39, 2.38 (total 3H, each s). m/z (ES+) 520, 522 (M+1).
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[N:17]1[CH:22]=[C:21]([C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25]([NH2:32])[CH:24]=2)[CH:20]=[N:19][CH:18]=1>ClCCl>[ClH:10].[N:17]1[CH:22]=[C:21]([C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25]([NH:32][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:24]=2)[CH:20]=[N:19][CH:18]=1
Reactant: Nc1cc(-c2cncnc2)c2occc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cl
Product: O=S(=O)(Nc1cc(-c2cncnc2)c2occc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzenesulfonyl chloride (0.093 g, 0.524 mmol) and pyridine (347 μL, 430 mmol) were added to 7-pyrimidin-5-yl-1-benzofuran-5-amine (0.100 g, 0.473 mmol; Intermediate 18) in dichloromethane (2 mL). The mixture was shaken at room temperature for 1 h and the solvent was removed. The crude product was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid and then converted into the hydrochloride salt by treatment with 2 M HCL in diethyl ether. This gave 0.071 g (43%) of the title compound as a yellow solid. HPLC 97%, RT: 1.863 min (System A; 10-97% over 3 min). 1H NMR (500 MHz, DMSO-d6) δ ppm 6.98 (d, J=2.20 Hz, 1H) 7.34 (d, J=2.20 Hz, 1H) 7.50-7.54 (m, 3H) 7.58-7.60 (m, 1H) 7.80-7.82 (m, 1H) 7.97 (d, J=2.20 Hz, 1H) 9.10 (s, 2H) 9.20 (s, 1H) 9.87 (s, 1H). GC-MS 351 (M+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:29])[N:17]([CH3:28])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:20]=2)=[CH:11][C:10]=1[F:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:30][C:10]1[CH:11]=[C:12]([C:15]2[C:16](=[O:29])[N:17]([CH3:28])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:20]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Yield: 100 %

Procedure:
A solution of 5-(4-(benzyloxy)-3-fluorophenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.133 g, 0.331 mmol) in TFA (1.5 mL) was stirred at 40° C. for 3.5 hours The reaction mixture was concentrated to dryness and then purified by flash column chromatography, eluting with 20:1 dichloromethane/MeOH. The desired product (0.103 g, 100%) was obtained as a foamy white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.81 (br s, 1H), 8.96 (br s, 1H), 7.86 (s, 1H), 7.56-7.45 (m, 3H), 7.37 (t, J=7.4 Hz, 2H), 7.27 (m, 1H), 7.15 (t, J=7.2 Hz, 1H), 6.92 (t, J=9.0 Hz, 1H), 3.54 (s, 3H). LRMS (APCI pos) m/e 312 (M+1).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[N:16]>>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCBr
Reactant: c1ccc(N2CCNCC2)cc1
Product: N#CCN1CCN(c2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Phenyl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=202.2: AtRet=1.95.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2.C(O)(=O)C>O>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]1[C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=2[C:17]1=[O:22]
Reactant: Nc1cc(OC2CCCCC2)c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 69.7 %

Procedure:
2-Fluoro-4-chloro-5-cyclohexyloxyaniline (213 mg, 0.874 mmol), 3,4,5,6-tetrahydrophthalic anhydride (134 mg, 0.874 mmol) and acetic acid (10 ml) were charged into a 50 cc round-bottom flask, and heated for 15 hours while refluxing. After completion of the reaction, the reaction solution was cooled to room temperature, water (50 ml) was added thereto, and extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the solvent was distilled off under reduced pressure to obtain a crude product (332 mg). The product was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=19/1) to obtain N-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl) 3,4,5,6-tetrahydrophthalimide as a white solid (230 mg, 0.609 mmol, 70% yield). By recrystallization of the product from hexane/chloroform, it was isolated as white needle crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][C:35](=[O:37])[CH3:36])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(=O)Cl
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide: hydrobromide salt (45 mg), triethylamine (71 μL) and acetyl chloride (20 μL) in dichloromethane (1.4 mL) was stirred at room temperature for 2 hours. All volatiles were removed in vacuo and the residue was purified using column chromatography (10% methanol in dichloromethane) to yield the title compound as a yellow solid (27 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:49])(=O)=O.B1(C=C)OB([CH:58]=[CH2:59])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH:58]([C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:37])[CH3:36])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:49])=[CH2:59]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: c1ccncc1
Product: C=Cc1ccc(-c2cc3cc(CN4CCN(CCO[Si](C)(C)C(C)(C)C)CC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 82 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (46.0 mg, 0.0611 mmol) was dissolved in dimethoxyethane (2.8 mL), and the solution was treated with 2,4,6-trivinylcyclotriboroxane-pyridine complex (32 mg, 0.13 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (4.4 mg, 0.0054 mmol), potassium carbonate (46 mg, 0.34 mmol) and water (0.024 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 4-vinyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (31.6 mg, yield 82%).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[CH3:16][NH:17][CH3:18].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:16][N:17]([CH3:18])[C:9](=[O:10])[C@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:12][CH:13]=[CH2:14]
Reactant: CNC
Reactant: C=CC[C@@H](CCCCCCC)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CC[C@@H](CCCCCCC)C(=O)N(C)C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a mixture of 5.00 g (0.025 mol) of the product of Example 5 and 2.27 g (0.028 mol) of dimethylamine hydrochloride in DMF at 0° C. was added 4.2 mL (0.028 mol) of diethyl cyanophosphonate followed by 7.38 mL (0.053 mol) of triethylamine. The reaction mixture was stirred at 0 degrees for 1 h and then at room temperature for 3 h. The resulting pale yellow suspension was diluted with 750 mL of EtOAc/Hex (2:1) and this solution was then washed with 5% aqueous HCl solution, water, saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:4) to provide 5.68 g (100%) of the title compound as a colorless oil. CI Mass Spec: 226.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([OH:43])=O)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C([N+:50]([O-])=O)=CC=C(O)C=1.C1CCC(N=C=NC2CCCCC2)CC1.N>CCOC(C)=O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH2:50])=[O:43])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)O)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(N)=O)cc1
Reaction time: 8 h
Yield: 0.4 %

Procedure:
A solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(2-thiophenesulfonyl)-L-phenylalanyl]-L-lysine (650 mg, 1.0 mmol, example 24) dissolved in EtOAc (10 mL) was treated with p-nitrophenol (139 mg, 1.0 mmol) and DCC (206 mg, 1.0 mmol) and was left in a refrigerator overnight. Afterwards, the precipitate was filtered off through celite and the solvent evaporated. The crude intermediate was used without further purification in the next step. A portion of the intermediate (25 mg, 0.03 mmol) was added to a solution of ammonia in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 2.6 mg, 11% of the desired material.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH3:10]>>[Br:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH2:10])[CH:7]=1
Reactant: N
Reactant: Cc1cc(Br)cc(Br)n1
Product: Cc1cc(Br)cc(N)n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 2,4-dibromo-6-methyl-pyridine (J. Bernstein et al., J. Amer. Chem. Soc., 1947, 69, 1147) (22.6 g, 90 mmol) and aqueous ammonia (25%, 260 ml) was stirred in an autoclave at 160° C. for 4 hr. The reaction mixture was cooled to rt and extracted with Et2O. The organic phase was dried (Na2SO4), concentrated and chromatographed (SiO2 with AcOEt/hexane/NEt3=10/30/1) to yield the title compound as a white crystalline material (4.0 g, 6%). NMR (250 MHz, DMSO): δ=3.33 (s, 3H, CH3), 6.13 (s, broad, 2H, NH2), 6.44 (s, 1H, arom-H), 6.54 (s, 1H, arom-H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(Cl)=[O:16].CN(C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:8]([N:7]([CH2:1][CH2:2][CH2:3][CH3:4])[C:15]([N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN(C)c1ccccc1
Reactant: O=C(Cl)Cl
Reactant: Clc1cccc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Product: CCCCN(Cc1ccccc1)C(=O)N(c1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 5.09 g. of N-phenyl-3-chloraniline in 20 ml. of toluene is added to a solution of 4.70 g. of phosgene and 3.64 g. of N,N-dimethylaniline in 55 ml. of toluene and the mixture is warmed to 400° C. and then stirred while cooling to room temperature during 45 minutes. The mixture is extracted with water and the organic layer is separateld and evaporated to about one-half its volume. To this solution is added 100 ml. of toluene followed by 9.80 g. of N-benzyl-n-butylamine. The resulting mixture is sitrred under reflux for 30 minutes and then washed with water, 1N hydrochloric acid, and saturated sodium bicarbonate solution. The organic layer is separated, dried over sodium sulfate, decolorized using activated charcoal, and evaporated. The residue is evaporatively distilled at 185°-190° C. under reduced pressure (105 microns) to yield 1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea as a viscous, pale-yellow liquid.
Reaction SMILES: [S:1]([CH2:5][C:6]([OH:8])=[O:7])([OH:4])(=[O:3])=[O:2].[CH3:9][CH2:10]O>>[S:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)CS(=O)(=O)O
Product: CCOC(=O)CS(=O)(=O)O

Procedure:
Sulfoacetic acid (52 g, 371 mM) and EtOH (500 mL) were heated under reflux for 20 hours. The reaction mixture was cooled, and the excess ethanol was removed under vacuum to give ethyl sulfoacetate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6]Cl.[C:8]([OH:19])(=[O:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1>>[CH3:6][O:19][C:8](=[O:18])[C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:15])=[CH:16][CH:17]=1
Reactant: CCl
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: COC(=O)c1ccc(C(=O)N2CCCC2)cc1

Procedure:
The method described in Referential Example 492 was performed by use of pyrrolidine and terephthalic acid monomethyl chloride, whereby the title compound was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[C:12](Cl)=[O:13].[OH-].[NH4+:16]>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[C:12]([NH2:16])=[O:13]
Reactant: [NH4+]
Reactant: O=C(Cl)c1coc2ccccc2c1=O
Agent: [OH-]
Product: NC(=O)c1coc2ccccc2c1=O
Yield: 48.8 %

Procedure:
A quantity of 0.9 g (0.0043 mol) of 4-oxo-4H-1-benzopyran-3-carbonylchloride was added gradually to a stirred quantity of 15 ml of conc. ammonium hydroxide at room temperature. All solid went into solution when crystals gradually separated. After 15 min. the solid was filtered and washed with water; wt 0.4 g (48.8% yield); mp 220°-225°. Two recrystallizations from 2-propanol gave pure material melting at 250°-252°C.
Reaction SMILES: C(OC(=O)[N:10]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:46])[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH2:40][C:41]3[NH:42][CH:43]=[CH:44][N:45]=3)[CH2:34][C:35]3[NH:36][CH:37]=[CH:38][N:39]=3)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CO.C(O)C.[C].[Pd]>[NH:36]1[CH:37]=[CH:38][N:39]=[C:35]1[CH2:34][N:33]([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][NH:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[CH:19][CH:20]=2)=[O:46])=[CH:27][CH:28]=1)[CH2:40][C:41]1[NH:45][CH:44]=[CH:43][N:42]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=C(Nc1ccc(CNC2CCCCC2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (282 mg) obtained in Example 88-1 was dissolved in methanol (14 ml). After having been cooled with ice, the solution was added with a suspension of 10% palladium-carbon (140 mg) in ethanol (3.0 ml). After having been subjected to hydrogen displacement, the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After the reaction, the reaction solution was filtrated through Celite and the solvent was then distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and treated with hydrochloric acid, thereby obtaining hydrochloride (47.1 mg) of the subject compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(O[C@H:14]1[O:26][C@@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=O)C>[N+](C1C=CC(OP([O-])(OC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O.O>[C:17]([O:16][C@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:26][C@@H:14]1[N:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1)(=[O:19])[CH3:18]
Reactant: COC(=O)c1nc[nH]n1
Reactant: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O
Product: COC(=O)c1ncn([C@H]2O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reaction time: 0.42 h
Yield: 66 %

Procedure:
A mixture of methyl 1,2,4-triazole-3-carboxylate (0.64 g, 5 mmol), 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose (2) (1.5 g, 4.72 mmol) and bis(p-nitrophenyl)-phosphate (20 mg) were placed in a pear shaped flask and placed in a preheated oil bath at (160-165° C.). The flask was connected to a water aspirator and kept at 160-165° C. (oil bath temperature) under reduced pressure with stirring for 25 min. The reaction mixture was removed, cooled and diluted with EtOAc (150 mL) and sat. NaHCO3 (100 mL). The product was extracted in EtOAc. The organic extract was washed with water (100 mL) and brine (50 mL), dried and evaporated to dryness. The residue that obtained was purified by flash column of silica gel using CHCl3 →EtOAc as the eluent. The pure fractions were collected and evaporated to dryness to give 1.2 g (66%) of pure product: 1H NMR (CDCl3) δ 2.10 (3s, 9H, 3 COCH3), 3.98 (s, 3H, OCH3), 4.22 (m, 1H), 4.46 (m, 2H), 5.54 (t, 1H), 5.76 (m, 1H), 6.04 (d, 1H, C1',), and 8.38 (s, 1H, C3H). Anal. Calc. for C15H19N3O9 (385.22): C, 46.75; H, 4.97; N,10.91. Found: C, 46.82; H, 4.57; N=10.71.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].[H-].[Na+].[H][H].[CH2:21](I)[CH3:22]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[O:16][CH2:21][CH3:22]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A solution of 13 g of 2-bromo-4,6-di-tert.butyl-phenol in 100 ml of dimethylformamide (DMF) was added dropwise to a suspension of 2.2 g of sodium hydride (50% in mineral oil) in 100 ml of DMF at 0° C. The reaction mixture was stirred at room temperature until hydrogen was no longer evolved (ca. 1 h), cooled again to 0° C. and treated with a solution of 22 g of ethyl iodide in 50 ml of DMF. After stirring for about 1 hour at room temperature, the reaction mixture was poured on icewater, extracted with ethyl acetate, washed (H2O), dried (Na2SO4) and evaporated to give 13.5 g of 1-bromo-2-ethoxy-3,5-di-tert.butyl-benzene as white crystals, m.p. 55-56° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH:42]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 100 mg, 0.193 mmol), 3-(methanesulfonyl)phenylboronic acid (58.1 mg, 0.290 mmol), K2CO3 (80.2 mg, 0.580 mmol) and Pd(PPh3), (22.4 mg, 0.0193 mmol) were diluted with dioxane (2 mL) and water (1 mL). The reaction was purged three times with nitrogen and stirred at 60° C. overnight. The reaction was cooled and loaded directly onto a silica gel column eluting with hexanes:ethyl acetate (2:1) to yield ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3′-(methylsulfonyl)biphenyl-3-yl)acetate (80 mg, 69.8% yield).