Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].C1(C)C=CC=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][C:34]=1[OH:35])[CH2:17][N:18]([N:27]1[CH:31]=[N:30][N:29]=[CH:28]1)[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>O.C(OCC)(=O)C.CN(C)C(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:17][N:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[N:27]2[CH:28]=[N:29][N:30]=[CH:31]2)[CH:32]=[CH:33][C:34]=1[O:35][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: N#Cc1ccc(N(Cc2ccc(O)c(Cl)c2)n2cnnc2)cc1
Reactant: NS(=O)(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(OS(N)(=O)=O)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sulphamoyl chloride solution in toluene (3 mL, 0.7 M, 2.1 mmol) was concentrated under reduced pressure (30° C. water bath temperature) to ca. 0.5 mL volume. The residue was cooled to 0° C. (ice bath) and N,N-dimethylacetamide (5 mL) was added. 4-[(3-Chloro-4-hydroxy-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02130, 163 mg, 0.50 mmol) was added to the colourless solution and the mixture was stirred for 18 h at room temperature. Ethyl acetate (50 mL) and water (30 mL) were added to the solution, the organic layer was separated, washed with water (2×30 mL) and brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in a small amount of acetone and precipitated by addition of hexane. The precipitate was filtered off and dried under high vacuum. Yield: 59 mg (29%) white powder. 1H-NMR (400 MHz, d6-DMSO) δ=5.11 (s, 2H), 6.72 (d, J=9.0 Hz, 2H), 7.38 (dd, J=8.2, 2.0 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 8.31 (s, 2H, —NH2), 8.91 (s, 2H). LRMS (FAB+): 405.0 (100, [M+H]+). HRMS (FAB+) 405.05349 C16H14N6O3SCl requires 405.053663
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]([C:20](=[O:24])[NH:21][CH2:22][CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][O:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:5])[CH3:2].[CH3:25][N:26]([CH3:55])[C:27]([C:29]1[CH:34]=[C:33](O)[CH:32]=[CH:31][C:30]=1[NH:36][C:37]([C:39]1[C:40]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:38])=[O:28].CCN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.CC(C)=O>[CH3:25][N:26]([CH3:55])[C:27]([C:29]1[CH:34]=[C:33]([O:12][C:11](=[O:13])[CH2:10][CH2:9][O:8][CH2:7][C:6]([C:20](=[O:24])[NH:21][CH2:22][CH3:23])([C:4](=[O:5])[NH:3][CH2:1][CH3:2])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:32]=[CH:31][C:30]=1[NH:36][C:37]([C:39]1[C:40]([C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:52])([F:53])[F:54])=[CH:49][CH:50]=2)=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:38])=[O:28]
Reactant: CN(C)C(=O)c1cc(O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCNC(=O)C(COCCC(=O)O)(C(=O)NCC)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Product: CCNC(=O)C(COCCC(=O)Oc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1)(C(=O)NCC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
4-Dimethylaminopyridine (55 mg), 3-(2,2′-bisethylcarbamoyl-2-phenylethoxy)propionic acid (115 mg) and 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-hydroxyphenyl)amide (161 mg) were dissolved in acetone (5 mL), and thereto was added WSC (86 mg). The mixture was stirred at room temperature for 3 hours and then concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=4:1→1:0) to give 3-(2,2′-bisethylcarbamoyl-2-phenylethoxy)propionic acid 3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl ester (150 mg).
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:40])([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:25][CH:26](Cl)[CH3:27]>>[CH2:30]([O:29][C:24]([O:25][CH:26]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:27])=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CCCCCCCCCCOC(=O)OC(C)Cl
Product: CCCCCCCCCCOC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl decyl carbonate (4.79 g, 18.1 mmol) were converted to chromatographed title product, 4.46 g white foam (8.0 mmol, 88.0%) which gave white crystals from isopropyl alcohol: mp 84°-86° C.: IR (KBr) 1764, 1679 cm-1 ; 1H NMR (CDCl3) delta 0.89 (t, J=7 Hz, 3H), 1.09-1.41 (m, 14H), 1.41-1.60 (br m, 2H), 1.75 (d, J=6 Hz, 3H), 3.11 (s, 3H), 4.00 (t, J=7 Hz, 2H), 6.36 (q, J=6 Hz, 1H), 7.07-7.17 (m, 1H), 7.63-7.96 (m, 5H), 8.30-8.40 (m, 2H), 9.40 (br s, 1H); precise mass calcd for C28H37N3O7S m/e 559.2352, found 559.2346.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])=[O:7].[C:15]1(=O)NCCCCC1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:15][C:9]1=[O:14])=[O:7]
Reactant: O=C1CCCCN1C(=O)c1ccco1
Reactant: O=C1CCCCCN1
Product: O=C1CCCCCN1C(=O)c1ccco1

Procedure:
Synthesized as for N-(2-furoyl)valerolactam (Example IX) using caprolactam (Aldrich) in place of valerolactam.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:16])[N:15]=1)(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)(=[O:3])=[O:4])=[O:29])[N:22]=1
Reactant: Cn1nnc(-c2ccccc2S(N)(=O)=O)n1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2nnn(C)n2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To 25 mL of acetonitrile was added at ambient temperature and pressure 0.48 g of 5-(2-aminosulfonylphenyl)-2-methyl-2H-tetrazole and 0.54 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate followed by 0.3 mL of DBU. After being stirred for three hours the reaction mixture was added to 25 g of ice and acidified to pH 3 with hydrochloric acid. The precipitate thus obtained was filtered, washed with water and dried to yield 0.66 g of the desired product, m.p. 214°-222° C. Infrared absorptions at 1720, 1600 and 1580 cm-1 were consistent with the desired structure.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=3[C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:22][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[O:10][C:11]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: Cc1c(C(O)C2CCCCC2)oc2cc(F)ccc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)C2CCCCC2)oc2cc(F)ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution (20 mL) of cyclohexyl(6-fluoro-3-methyl-1-benzofuran-2-yl)methanol (931 mg) synthesized above in toluene was added thionyl chloride (311 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (945 mg, 95%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[C:20]([CH3:43])=[N:21][N:22](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:23]=4)[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[ClH:44]>C(OCC)(=O)C>[ClH:44].[ClH:44].[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[C:20]([CH3:43])=[N:21][NH:22][CH:23]=4)[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C)cc23)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccnc3ccc(-c4c[nH]nc4C)cc23)cn1

Procedure:
A free product obtained by the same procedure as in Example 1065 from 210 mg 4-(6-methoxypyridin-3-yl)-6-(3-methyl-1-trityl-1H-pyrazol-4-yl) quinoline obtained in Example 1064 was treated with 4 N hydrogen chloride solution in ethyl acetate to give 16 mg of the title compound as a pale yellow solid.
Reaction SMILES: C1(C(=[N:14][CH:15]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:30]>C(OCC)C>[ClH:30].[NH2:14][CH:15]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CCCC(C)C[C@@H](C)C(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Product: C=CCCC(C)C[C@@H](C)C(N)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of (3R)-ethyl 2-((diphenylmethylene)amino)-3,5-dimethylnon-8-enoate (20 g) in diethyl ether (20 mL) was added aqueous 1.5 N HCl solution (200 mL) and the reaction mass was stirred at room temperature overnight. The reaction mass was washed with diethyl ether (100 mL). The aqueous solution was basified using saturated sodium bicarbonate solution and was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get crude compound (3R)-ethyl 2-amino-3,5-dimethylnon-8-enoate hydrochloride (4 g, 30%). The crude compound was taken to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[CH:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1.Cl>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:22][CH2:21][CH:18]2[CH2:20][CH2:19]2)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Temperature: 80 °C
Reaction time: 25 h
Yield: 57.2 %

Procedure:
To a solution of 5-chloro-4-iodo-pyridine-2-carboxylic acid (CAN 120643-06-3, 600 mg, 2.12 mmol) in THF (20 mL) and DMF (2 mL) was added with stirring potassium tert-butoxide (1.0 g, 8.91 mmol) and cyclopropanemethanol (1.5 mL, 18.8 mmol). The resulting mixture was stirred at 80° C. for 25 h, cooled, acidified with hydrochloric acid (25 mL, 1 N) and partitioned into ethyl acetate. The organic portions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by prep. HPLC (Gemini NX, acetonitrile/water gradient) to give the title compound (276 mg, 57%) as light yellow solid. MS (ESI, m/z): 228.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])(C)(C)C.Cl.[OH-].[Na+].ClC(OC)=O>O1CCOCC1>[CH3:17][O:16][C:13]([CH3:15])([CH3:14])[CH:9]([NH:8][C:6]([O:5][CH3:1])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)NC(C(=O)O)C(C)(C)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
2-tert-Butoxycarbonylamino-3-methoxy-3-methyl-butyric acid was dissolved in dioxane (40 mL) and HCl (4N in dioxane, 5.4 mL, 21.6 mmol) was added at room temperature. The resulting solution was stirred at room temperature for 18 hours and the concentrated to dryness. The solid was dissolved in THF (14 mL) and cooled to 0° C. in an external ice/brine bath. Aqueous sodium hydroxide (6.25M, 1.9 mL, 11.76 mmol) and methyl chloroformate (0.5 mL, 5.88 mmol) were added at 0° C. Upon completion of the addition, the solution was removed from the ice bath and allowed to warm to room temperature, and stirred. After 18 hours, the crude reaction mixture was adjusted to pH 1 with 1N HCl and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated to give 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid (0.653 g, 65%) as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([F:39])=[C:24]([NH:28]C(=O)OCC4C=CC=CC=4)[CH:25]=[CH:26][CH:27]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2]>C1COCC1.CO.[Pd]>[NH2:28][C:24]1[C:23]([F:39])=[C:22]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3F)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3F)c12
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of benzyl 3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-fluorophenylcarbamate (0.6318 g, 1.195 mmol) and 10% Pd/C (0.191 g, 0.179 mmol) in THF (31.9 mL) and MeOH (47.8 mL) was hydrogenated. After 2 hr, the reaction was filtered through a wad of CELITE® and rinsed with THF and MeOH. The filtrate was concentrated in vacuo, dissolved in EtOAc (100 mL) and brine (25 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give the desired product (0.4462 g, 1.007 mmol, 84% yield) as a tan solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(O[C:23]1[C:28]([C:29]2[NH:30][C:31](=[O:48])[C:32]3[C:33](=[C:35]([CH2:45][CH2:46][CH3:47])[N:36]([CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)[N:37]=3)[N:34]=2)=[CH:27][C:26]([S:49]([N:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH3:59])[CH2:54][CH2:53]2)(=[O:51])=[O:50])=[CH:25][N:24]=1)C>>[CH2:58]([N:55]1[CH2:56][CH2:57][N:52]([S:49]([C:26]2[CH:27]=[C:28]([C:29]3[NH:30][C:31](=[O:48])[C:32]4[C:33](=[C:35]([CH2:45][CH2:46][CH3:47])[N:36]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)[N:37]=4)[N:34]=3)[C:23]([O:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:24][CH:25]=2)(=[O:51])=[O:50])[CH2:53][CH2:54]1)[CH3:59]
Reactant: OCCN1CCOCC1
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCN3CCOCC3)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of potassium bis(trimethylsilyl)amide (180 mg, 0.88 mmol) and 4-(2-hydroxyethyl)morpholine (4 ml) was stirred at 100° C. for 1 hour, then the title compound of Example 26 (100 mg, 0.17 mmol) added and the reaction mixture stirred at 110° C. for 18 hours. The resulting, cool mixture was partitioned between water (10 ml) and dichloromethane (20 ml), the phases separated and the organic phase washed with water (10 ml), dried (MgSO4) and evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate:methanol (90:10 to 80:20), to yield the title compound (33 mg, 30%) as a white solid. δ (CDCl3): 0.95 (3H, t), 1.04 (3H, t), 1.74 (2H, m), 2.42 (2H, q), 2.56 (4H, m), 2.64 (4H, m), 2.90 (2H, t), 2.99 (2H, t), 3.15 (4H, m), 3.80 (4H, m), 4.75 (2H, t), 5.68 (2H, s), 7.12 (1H, d), 7.25 (1H, m), 7.63 (1H, m), 8.58 (1H, d), 8.62 (1H, s), 8.92 (1H, s), 11.16 (1H, s). LRMS: m/z 652 (M+1)+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:12][C@@H:11]([N:23]2[C:52]3[N:51]=[C:45]([NH:46][C:47](=[O:50])[NH:48][CH3:49])[N:44]=[C:27]([O:28][C:29](=[O:43])[N:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)(C(C)(C)C)(C)C.C(N(CC)CC)C.C1(C)C=CC=CC=1>O1CCCC1>[C:37]1([N:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:29]([O:28][C:27]2[C:26]3[N:25]=[CH:24][N:23]([C:52]=3[N:51]=[C:45]([NH:46][C:47](=[O:50])[NH:48][CH3:49])[N:44]=2)[C@@H:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:9]([OH:8])[CH2:10]2)=[O:43])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c2n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-6-O-diphenylcarbamoyl-2-N-methylcarbamoyldeoxyguanosine (1.13 g, 52 mmol) was azeotroped with anhydrous tetrahydrofuran three times and then dissolved in anhydrous tetrahydrofuran (15 mL), and triethylamine 3 hydrogen fluoride (743 μL, 4.56 mmol) was added thereto. The mixture was stirred at room temperature overnight. Then, after addition of toluene (5 mL), the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C200) with methanol/5% to 6% chloroform, and then ethyl acetate (5 mL) and diethyl ether (15 mL) were added thereto for precipitation. Then, the precipitate was purified by filtration to give 6-O-diphenylcarbamoyl-2-N-methylcarbamoyldeoxyguanosine (643 mg, 81%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[C:12]1[C:17]([F:18])=[N:16][C:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)=[CH:14][N:13]=1>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:17]1[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:13][CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)[N:16]=1
Reactant: CCCCCCCCOc1ccc(-c2cnc(Br)c(F)n2)cc1
Reactant: CCCCCCCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(CCCCCCCC)c(F)n2)cc1
Reaction time: 8 h

Procedure:
7.95 mmol of freshly prepared octylmagnesium bromide in 30 ml of tetrahydrofuran are added dropwise at -10° C. to 2.00 g (5.3 mmol) of 2-bromo-3-fluoro-5-(4-octyloxyphenyl)pyrazine and 0.03 g (0.06 mmol) of [1,3-bis-(diphenylphosphino)propane]nickel(II) chloride in 30 ml of tetrahydrofuran, and the reaction mixture is stirred overnight, during which it warms to room temperature. The reaction mixture is partitioned between aqueous ammonium chloride solution and ether, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and freed from the solvent, and the mixture is purified by chromatography (silica gel/dichloromethane: hexane = 7:3). 1.12 g of 2-fluoro-3-octyl-6-(4-octyloxyphenyl)pyrazine are obtained. ##STR17## The compound has the following phase sequence:
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:10](=[O:29])[N:9]1[CH2:30][C:31](=[O:47])[NH:32][CH:33]1[CH2:37][C:36](=[O:38])[O:35][CH:34]1[O:39]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(#N)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:10](=[O:29])[N:9]1[CH2:30][C:31]([NH:32][CH:33]([CH:34]=[O:39])[CH2:37][C:36]([OH:38])=[O:35])=[O:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1)NC1CC(=O)OC1OCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: O=CC(CC(=O)O)NC(=O)CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Isoquinoline-1-carboxylic acid {1-benzyl-2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-3,7-dioxo-[1,2]diazepan-4-yl}-amide (10a, diastereomers) (14 mg, 0.022 mmol) was stirred in the solution of 10% HCl (1.5 mL) and acetonitrile (1 mL) for 4 hours. The reaction mixture was diluted with water (30 mL), washed with ether (30 mL) twice. The aqueous solution was purged with nitrogen for 30 min then cooled in dry ice and lyophilized overnight to afford 10 mg (83% yield) of the title compound. 1H-NMR (500 MHz, CD3OD) δ 2.00-2.10 (m, 1H), 2.32-2.50 (m, 2H), 3.62-3.72 (m, 1H), 4.15-4.35 (m, 2H), 4.45-4.80 (m, 4H), 5.25-5.32 (m, 1H), 7.30-7.68 (m, 5H), 7.95-8.05 (m, 1H), 8.12-8.17 (m, 1H), 8.22-8.27 (m, 1H), 8.35-8.41 (d, 1H), 8.56 (s, 1H), 8.65-8.74 (d, 1H). Analytical HPLC: 9.40 min. LC-MS (ES+): m/e=546 (M+H+).
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([N:14]2[CH2:23][CH2:22][C:17]3([CH2:21][CH:20]=[CH:19][CH2:18]3)[O:16][C:15]2=[O:24])[CH3:13])=[CH:8][CH:7]=1.C([OH:28])(C)C>O1CCCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([N:14]2[CH2:23][CH2:22][C:17]3([CH2:21][CH:20]([OH:28])[CH2:19][CH2:18]3)[O:16][C:15]2=[O:24])[CH3:13])=[CH:8][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC2(CC=CC2)OC1=O
Reactant: CC(C)O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC(O)C2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Borane dimethyl sulfide complex (2 mol/L in diethyl ether, 4.64 mL) is added dropwise to a solution of 8-[(S)-1-(4-bromo-phenyl)-ethyl]-6-oxa-8-aza-spiro[4.5]dec-2-en-7-one (2.60 g) in tetrahydrofuran (30 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature overnight. The solution is then chilled again in an ice bath and 4 M aqueous NaOH solution (2.1 mL) is added followed by the dropwise addition of hydrogen peroxide (35% in water, 6 mL). The cooling bath is removed and the mixture is warmed to 40° C. and stirred at this temperature for 1 h. The mixture is diluted with water and extracted with diethyl ether. The combined extracts are washed with water, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (methanol/ethyl acetate 0:1→4:1) to afford a mixture of the four title compounds which is submitted to SFC (Supercritical Fluid Chromatography) on chiral phase (column: phenomenex LUX 2A, 250×20 mm, 5 μM; eluent: isopropanol containing 0.2% diethylamine/sc carbon dioxide 25:75; flow: 60 mL/min) to give the four isomers in separate fractions.
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=O.Cl.[NH2:24][OH:25].O.[Cl-].[Na+].O>O.C(O)C>[OH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[N:24][OH:25]
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(O)cc1)c1ccc(O)cc1O
Yield: 47.2 %

Procedure:
Sodium acetate (0.46 g, 5.57 mmol) in water (3 mL) was added into a mixture of (2,4-dihydroxyphenyl)(4-hydroxyphenyl)methanone (0.91 g, 3.97 mmol), hydroxylamine hydrochloride (0.36 g, 5.17 mmol), and ethanol (20 mL). The reaction mixture was refluxed for 2 days. The mixture was poured into water/brine and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography CH2Cl2/EtOAc/MeOH 20/10/1) gave a white solid (0.46 g, 48% yield); MS m/e 245 (M+).