Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:12]=2[N:13]=[C:14](S(C)(=O)=O)[N:15]=1.[NH2:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[C:34]([NH:41][CH2:42][CH2:43][NH2:44])[N:33]=1>>[NH2:31][C:32]1[N:33]=[C:34]([NH:41][CH2:42][CH2:43][NH:44][C:14]2[N:15]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:11]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:12]=3[N:13]=2)[CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39]
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(Nc3ccc(Cl)cc3Cl)c2C1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Nc3ccc(Cl)cc3Cl)c2C1

Procedure:
Following Example 7, treatment of tert-butyl 4-[(2,4-dichlorophenyl)amino]-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate with 2-amino-3-nitro-6-(2-aminoethylamino)pyridine gave tert-butyl 2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-[(2,4-dichlorophenyl)amino]-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: Brc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 88 %

Procedure:
Under an atmosphere of argon, 2-bromoiodobenzene (7.9 g, 25 mmole), biphenylboronic acid (5.0 g, 25 mmole) and tetrakis(triphenyl-phosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (60 ml). To the obtained solution, an aqueous solution of sodium carbonate (8.0 g, 75 mmole, 3 eq/40 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and white needle crystals (6.8 g, 88%) were obtained.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20](=[O:27])[CH2:19]2.N1CCCCC1>C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20](=[O:27])[C:19]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 58.8 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 97 mg 5,6-dimethoxy-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 104 mg (58%) of the title compound as a brown solid.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:19])([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>>[CH3:19][C:3]([CH3:2])([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH:18][C:26](=[O:27])[C:25]2[CH:29]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=2[O:30][CH3:31])=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)C(C)(C)Cc1ccc(CCN)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(C)(C)C(=O)O)cc1

Procedure:
By the reaction of ethyl α,α-dimethyl-β-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride with 5-chloro-2-methoxybenzoyl chloride, there is obtained α,α-dimethyl-β-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-propionic acid; m.p. 138°-141° C., after recrystallization from ethyl acetate.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1>C(=S)=S>[Br:1][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: COc1ccc(O)cc1
Reactant: BrBr
Solvent: S=C=S
Product: COc1ccc(O)c(Br)c1
Yield: 57.1 %

Procedure:
A solution of 2.6 mL (100 mMol) bromine in 10 mL carbon disulfide was added dropwise over 30 minutes to a solution of 12.4 gm (100 mMol) 4-methoxyphenol in 20 mL carbon disulfide at 0° C. After 30 minutes an additional 1 mL of bromine in 10 mL carbon disulfide are added dropwise. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in diethyl ether. This solution was washed sequentially with 100 mL water and 100 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 11.6 gm (57%) of the desired compound as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.NC1C=CC=CC=1.[CH:37]1[N:41]=[CH:40][N:39]([C:42](N2C=NC=C2)=[NH:43])[CH:38]=1>C1COCC1>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:42]([N:39]3[CH:38]=[CH:37][N:41]=[CH:40]3)=[NH:43])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: N=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)n1ccnc1
Yield: 1.6 %

Procedure:
To imidazole (65 mg, 9.760 mmol) in CH2Cl2 (10 ml) at room temperature under nitrogen atmosphere bromonitrile (500 mg, 4.71 mmol) was added. The resulting mixture was heated at reflux for 1 hr. Cooling to room temperature, filtration and concentration in vacuo to a volume of approximately 10 ml. The resulting pale liquor was let stand at 0° C. for 15 hrs. Filtration afforded a pale white powder for C-(di-imidazol-1-yl)-methyleneamine (210 mg, 28% yield). To [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone (132 mg, 3.389 mmol), aniline (213 mg, 2.347 mmol) and C-(di-imidazol-1-yl)-methyleneamine (420 mg, 2.608 mmol) in THF (20 mg) was heated at reflux for 2.5 hrs. Concentration in vacuo and RP-HPLC (gradient water:acetonitrile) afforded the title compound as a yellow powder (20 mg, 14% yield). MS (ESI) m/z 486.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]=[CH:14][CH:15]([OH:20])[CH2:16][C:17](=[O:19])[CH3:18]>N1C=CC=CC=1>[C:1]([O:20][CH:15]([CH:14]=[CH:13][C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[Cl:5])[CH2:16][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)CC(O)C=Cc1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)CC(C=Cc1ccc(Cl)cc1Cl)OC(C)=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
Acetyl chloride (1.2 ml, 16.5 mmole) was added dropwise to a stirred solution of 6-(2,4-dichlorophenyl)-4-hydroxy-5-hexene-2-one (3.9 g, 15 mmole) in pyridine (60 ml) at 0° C. The ice bath was removed, and the reaction mixture was stirred at 20° C. for 2 hours and then diluted with ether (300 ml). The ether solution was washed with 1 N HCl (3×300 ml) and saturated NaHCO3, dried over MgSO4, filtered and evaporated. The residual pale amber oil (4.1 g) was chromatographed on a 50 mm column with 15 cm of silica gel (230-400 mesh). Elution with methylene chloride (2 L) provided the title compound as a pale yellow oil (3.95 g, 87%): pmr (CDCl3) δ2.03 (3H, s), 2.17 (3H, s), 2.83 (2H, dd).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.OP(O)(O)=O>O.CS(C)=O>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:18][CH:19]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
A solution of 1-fluoro-4-(methylsulfonyl)benzene (2.2 kg), KOH (906.3 g), 4-(trifluoromethoxy)phenol (2.364 kg) and DMSO (4.4 L) was heated to 90° C. and stirred until HPLC showed <0.5% starting material remained (about 10 hours). HPLC conditions: Zorbax SB-C8 4.6 mm×25 cm; mobile phase was a gradient of 70% water with 0.1% H3PO4/30% acetonitrile to 10% water with 0.1% H3PO4/90% acetonitrile over 15 minutes at a flow rate of 1.5 mL/min, followed by a five minute hold at 10/90; UV detection at 220 nM. Retention times: starting sulfone, 4.5 min; desired product, 7.8 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[C:7](=[NH:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:24](=[O:25])[C:23]2[CH:27]=[C:19]([Cl:18])[CH:20]=[CH:21][C:22]=2[O:28][CH3:29])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccn(C[C@H]2CCCO2)c(=N)c1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\cc(C(C)(C)C)ccn1C[C@H]1CCCO1
Temperature: 60 °C
Reaction time: 14 h
Yield: 8.8 %

Procedure:
To a solution of the crude product of Example 61A (0.8 g, 1.7 mmol) in tetrahydrofuran (10 mL) were added 5-chloro-2-methoxybenzoyl chloride (0.4 g, 1.9 mmol) and triethylamime (0.7 mL, 5.1 mmol). After stirring at 60° C. for 14 h, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-5% methanol in dichloromethane) to provide 60 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (s, 9H), 1.50-1.69 (m, 1H), 1.69-2.09 (m, 3H), 3.57-3.70 (m, 1H), 3.75 (s, 3H), 3.76-3.86 (m, 1H), 4.00 (dd, J=12.9, 8.5 Hz, 1H), 4.30 (dd, 1H), 4.57 (dd, J=12.7, 3.2 Hz, 1H), 6.87 (dd, J=7.0, 2.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.34 (dd, J=8.8, 2.7 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.95 (d, J=7.1 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H) MS (ESI+) m/z 403 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][S:14]([O-:16])=[O:15].[Na+]>>[CH3:13][S:14]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)(=[O:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Product: CS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1

Procedure:
This compound was prepared in a similar manner from 1-(2-bromoethyl)-4-nitrobenzene and sodium methanesulfinate.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22]1([CH:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:33]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:2]3([CH3:1])[CH2:6][C:5]4[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=4[O:3]3)[CH2:17][CH2:18]2)=[O:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 72 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 3,3-diphenylpropionic acid, the procedure of Example 10 was otherwise repeated to provide the title compound. Yield 72%.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.C(OC([N:31]1[CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH2:33][CH2:32]1)=O)(C)(C)C>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:33]3[CH2:32][NH:31][CH2:36][CH2:35][CH:34]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC=C(B2OC(C)(C)C(C)(C)O2)C1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCCNC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting materials 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine and 5-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester. MS (ES+): m/z 422.05 (MH+, 35Cl, 37Cl), 424.06 (MH+, 37Cl, 37Cl).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:51])=[C:9]([CH2:11][O:12][C:13]2[CH:50]=[CH:49][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[C:20]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]5[N:39]=[C:40]([C:44]6[O:45][CH:46]=[CH:47][CH:48]=6)[O:41][C:42]=5[CH3:43])=[CH:32][CH:31]=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:51])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[C:20]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]5[N:39]=[C:40]([C:44]6[O:45][CH:46]=[CH:47][CH:48]=6)[O:41][C:42]=5[CH3:43])=[CH:34][CH:35]=4)=[N:19]3)=[CH:49][CH:50]=2)[N:10]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccco5)oc4C)cc3)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
After a mixture of ethyl 1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazole-4-carboxylate (250 mg), 1N sodium hydroxide solution (1 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (1 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazole-4-carboxylic acid (230 mg, yield: 93%). This was recrystallized from acetone-hexane. Melting point: 144–145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[K+].[CH2:25]([O:32][C:33]([N:35]([CH2:37][CH2:38]Cl)[CH3:36])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:38][CH2:37][N:35]([C:33]([O:32][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:34])[CH3:36])[C:12]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(C)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A mixture of 2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy- 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.42 g of powdered potassium hydroxide and 15 ml of dimethylsulfoxide is stirred at 50° C. for 30 minutes. A solution of 2.64 g of 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride in 5 ml of dimethylsulfoxide is added to the mixture, and the mixture is stirred at 50° C. for 3 days. The mixture is poured into ice-water, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and evaporated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform: ethyl acetate=10:1). 2.95 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17](CO)([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O-])(O)=[O:25].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:19][CH2:18][C:17]([CH:16]=[O:15])([CH2:20][CH2:21]2)[O:25][CH2:24]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a mixture of (4-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-1-yl)methanol (5A; 182 mg, 0.586 mmol) and NaHCO3 (59 mg, 0.704 mmol) in CH2Cl2 (5 mL) at 0° C. was added Dess-Martin periodinane (298 mg, 0.70 mmol). The solution was warmed to rt and stirred for 1 h. The reaction was diluted with EtOAc, washed successively with sat'd aq NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 100% EtOAc:hexanes) to afford the title compound (123 mg, 68% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.65 (s, 1H), 7.41-7.28 (m, 3H), 7.12-7.16 (m, 1H), 7.06-6.89 (m, 4H), 6.88 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 4.12-4.09 (m, 2H), 2.17-1.90 (m, 8H).
Reaction SMILES: C([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]=[C:15]3[NH:20][CH2:21][CH2:22][N:14]3[C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]=[C:15]3[NH:20][CH2:21][CH2:22][N:14]3[C:13]=2[N:12]([CH3:23])[C:11]1=[O:24]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2nc3n(c2n(C)c1=O)CCN3
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2nc3n(c2n(C)c1=O)CCN3
Yield: 45.5 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1-methyl-1,6,7,8-tetrahydro-2H-imidazo[1,2-e]-purine-2,4(3H)-dione (100 mg, 0.286 mmol) and a 1.0 M solution of hydrogen chloride in diethyl ether (1 ml, 1.0 mmol) in methanol (25 ml) was stirred at room temperature overnight. After concentrating under reduced pressure, the residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol-chloroform (4:2:1) to provide (R)-3-(5-hydroxyhexyl)-1-methyl-1,6,7,8-tetrahydro-2H-imidazo[1,2-e]-purine-2,4(3H)-dione (CT-30268) (40 mg, 46% yield) as a white powder.
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][CH2:37][CH2:38]Br.C(Cl)Cl>C(C(C)=O)C>[CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:38][CH2:37][O:36][CH3:35])=[CH:25][CH:26]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(O)cc3)n2n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COCCOc1ccc(-c2ccnc3nc(NC(=O)N[C@@H](C)CCCC(C)C)nn23)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
(S)-1-(1,5-dimethylhexyl)-3-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]urea (the compound obtained in Example 255; 30 mg) and potassium carbonate (108 mg) were suspended in methyl ethyl ketone (3 ml). Thereafter, 2-methoxyethyl bromide (327 mg) was added to the obtained suspension, and the obtained mixture was stirred at 80° C. for 10 hours. Thereafter, the reaction solution was cooled to a room temperature, and methylene chloride (5 ml) was then added thereto. The obtained mixture was washed with an aqueous 1 M hydrochloric acid solution (5 ml×3), an aqueous saturated sodium bicarbonate solution (5 ml×2), and distilled water (5 ml×2). The organic layer was concentrated under a reduced pressure, and the obtained residue was purified by reverse phase liquid chromatography (Inertsil PREP-ODS; 20 Φ×250 mm; eluted with water-containing acetonitrile) to obtain the captioned compound (14 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@@H:14](/[CH:30]=[CH:31]/[CH2:32][C:33]([N:35]1[C@@H:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:38][O:37][C:36]1=[O:47])=[O:34])[C:15]([N:17]1[C@@H:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][O:19][C:18]1=[O:29])=[O:16])[CH:12]=[CH2:13].[CH2:48]([O:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62]Br)=[CH:58][CH:57]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1COCC1>[CH2:11]([C@@H:14](/[CH:30]=[CH:31]/[C@H:32]([CH2:62][C:59]1[CH:60]=[CH:61][C:56]([O:55][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:57][CH:58]=1)[C:33]([N:35]1[C@@H:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:38][O:37][C:36]1=[O:47])=[O:34])[C:15]([N:17]1[C@@H:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:20][O:19][C:18]1=[O:29])=[O:16])[CH:12]=[CH2:13]
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Reactant: C=CC[C@@H](/C=C/CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](/C=C/[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 28.5 %

Procedure:
A solution of NaHMDS (1.0 M in THF, 0.258 mL, 0.258 mmol) was added dropwise to a −78° C. solution of (S,E)-2-allyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)hex-3-ene-1,6-dione (118 mg, 0.235 mmol) in THF (1.0 mL). After stirring at −78° C. for 40 min, a solution of 1-(benzyloxy)-4-(bromomethyl)benzene (78 mg, 0.282 mmol) in THF (0.2 mL) was added dropwise. The reaction temperature was then slowly raised to 0° C. over 45 min. After 30 min at 0° C., the reaction temperature was allowed to reach rt. After 2 h at rt, the reaction mixture was quenched by addition of saturated NH4Cl. The mixture was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4 and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (2S,5S,E)-2-allyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-(4-(benzyloxy)benzyl)hex-3-ene-1,6-dione (47 mg, 0.067 mmol, 29%) as a white solid. Anal. Calcd. for C43H42N2O7 m/z 698.2. found: 699.2 (M+H)+.