Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH:8]1[CH:12]=[C:11]([CH2:13][C:14]([Cl:16])=O)[S:10][CH:9]=1.[O:17]1CCOCC1>>[Cl:16][CH2:14][C:13]([C:11]1[S:10][CH:9]=[CH:8][CH:12]=1)=[O:17]
Reactant: O=C(Cl)Cc1cccs1
Reactant: C1COCCO1
Agent: C[Si](C)(C)C=[N+]=[N-]
Product: O=C(CCl)c1cccs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
Trimethylsilyl diazomethane (TMSCHN2, 2M in hexanes, 100 ml, 0.200 mole) was added dropwise, over a period of 20 minutes, to an ice bath solution of thiophene-2-acetyl chloride (0.192 mole, 28.1 g) in 100 ml of dry 1,4-dioxane. The slush disappeared upon addition of TMSCHN2. The reaction mixture was slowly warmed to room temperature and stirred for 24 hours. The reaction mixture was cooled in an ice bath and HCl gas was bubbled for 0.5 hour and stirred at room temperature for 2 days. The solvent was removed under reduced pressure, the residue partitioned between 100 ml of aqueous saturated NaHCO3 solution and 250 ml of ethyl acetate and separated. The organic phase was washed with 100 ml of aqueous saturated NaHCO3 solution, dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was chromatographed on 200 g of silica packed with 2.5% EtOAc-hexanes and the column was eluted with increasing amounts of ethyl acetate in hexanes (2.5%, 1 L, 5%, 1 L; 7.5%, 1 L, 10%, 1 L; 12.5%, 1 L; 15%, 1 L) to give 12.8 g of the desired product which was slightly contaminated: 42% yield; 1H NMR (CDCl3) δ 7.80 (dd, 1H, J=0.9, 3.9 Hz), 7.74 (dd, 1H, J=0.9, 5.0 Hz average), 7.19 (dd, 1H, J=0.9, 5.0 Hz average), 4.61 (s, 2H). This product turned yellow and then brown over time and therefore was used in the formation of the 2-amino-1,3-thiazole derivatives as soon as possible.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CCCCCCCCCCCC)C(=O)C1C=CC(C(O)=O)=CC=1)CCCCCCCCCCC>CO>[CH2:15]([NH:27][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:13][CH3:14])=[O:12])=[CH:11][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCN
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: CCCCCCCCCCCCN(CCCCCCCCCCCC)C(=O)c1ccc(C(=O)O)cc1
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)c1ccc(C(=O)OC)cc1
Reaction time: 8 h
Yield: 91.2 %

Procedure:
19.4 g (0.1 mole) of dimethyl terephthalate and 18.5 g (0.1 mole) of dodecylamine are refluxed in 100 ml of methanol. After addition of 9 g (0.05 mole) of sodim methylate (30% strength in methanol) refluxing is continued for 8 hours, and the reaction batch is then worked up as described in Example 1, affording 31.7 g (91.2%) of 4-carbomethoxybenzoic acid dodecylamide having a 14% terephthalic acid bisdodecylamide content.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:16])=O)[CH:10]=2)[C:5]1=[O:17])[CH:2]=[CH2:3].Cl.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH2:28])=[CH:23][CH:22]=1>>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([NH:28][C@@H:27]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:40])([F:19])[F:39])=[CH:22][CH:23]=3)[C:29]3[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][N:30]=3)=[O:16])[CH:10]=2)[C:5]1=[O:17])[CH:2]=[CH2:3]
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Reactant: C=CCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Agent: Cl
Product: C=CCN1C(=O)c2ccc(C(=O)N[C@@H](c3ccc(C(F)(F)F)cc3)c3ncccc3C(F)(F)F)cc2C1=O

Procedure:
2-Allyl-1,3-dioxoisoindoline-5-carboxylic acid was then coupled with Intermediate 1 using the general methods described above for the amide coupling reaction (Table 2) to provide the title compound, (S)-2-allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.93 (d, J=3.9 Hz, 1H), 8.44 (d, J=7.6 Hz, 1H), 8.30-8.21 (m, 2H), 8.11-8.02 (m, 1H), 7.98-7.89 (m, 1H), 7.64-7.46 (m, 5H), 6.88 (d, J=7.6 Hz, 1H), 5.99-5.75 (m, 1H), 5.34-5.15 (m, 2H), 4.31 (d, J=5.7 Hz, 2H). MS (ESI pos. ion) m/z: 534.1 (M+H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:31]=[CH:32][CH:33]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:34]1([C:30]2[CH:29]=[C:28]([C:6]3[N:10]4[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]4=[N:8][CH:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-n2ccnc2)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1ccn2c(-c3cccc(-n4ccnc4)c3)cnc2n1
Yield: 21.3 %

Procedure:
To a degassed solution of 3-tributylstannyl-7-trifluoromethyl-imidazo[1,2-a]pyrimidine (1.4 mmol) was added 1-(3-bromophenyl)-1H-imidazole (0.60 g, 2.7 mmol) (prepared by the method of A. Johnson et al., J. Med. Chem., 1969, 12(5), 1024-8) and tetrakis(triphenylphosphine)-palladium(0) (218 mg, 0.18 mmol) and the mixture heated at reflux for 18 h. The crude reaction was adsorbed onto silica and chromatographed on silica, eluting on a gradient of 1 to 5% methanol in dichloromethane, to give a yellow oil. Crystallisation from ethyl acetatelisohexane afforded 3-[3-(imidazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.098 g) as a white solid: δH (400 MHz; DMSO) 7.15 (1H, s), 7.53 (1H, d, J 7.4), 7.73 (1H, dd, J 3.1 and 1.6), 7.74 (1H, d, J 0.8), 7.78-7.81 (1H, m), 7.89 (1H, t, J 1.4), 8.08 (1H, dd, J 1.6 and 1.2), 8.39 (2H, d, J 7.0), 9.44 (1H, d, J 6.7); m/z (ES+) 330 (M++H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.C1(C)C=CC(S(OOC[C@@H:27]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH3:28])(=O)=O)=CC=1.[CH3:37]N(C)C=O>>[O:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]1[O:29][CH2:27][CH2:28][CH2:37][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OOC[C@H](C)OC2CCCCO2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(OCCCO[C@H]2CCCCO2)cc1

Procedure:
1.0 g (0.021 mol) of 50% sodium hydride, 25 ml of dimethylformamide, 3.2 g (0.019 mol) of ethyl 4-hydroxybenzoate and 6.1 g (0.019 mol) of (S)-2-tetrahydropyranyloxypropoxy p-toluenesulfonate were reacted at 60° C. for 8 h. Then the same procedure as in Referential Example 1 was repeated to obtain 5.0 g of the crude product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH2:20].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:20][O:19][CH3:18])[CH2:10][CH:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 21 mmol) and O-methylhydroxylamine hydrochloride (2.7 g, 32.8 mmol) in chloroform (100 ml) containing triethyl-amine (5.5 g, 55 mmol). The reaction mixture was then stirred at ambient temperature over-night, prior to removal of solvent. The resultant crude reaction mixture was dissolved in ethyl acetate (150 ml) and washed rapidly with 1N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.3 g, 94%) was isolated as a pale yellow oil.
Reaction SMILES: [C:1]([CH:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:6])([CH3:4])([CH3:3])[CH3:2].[CH:11]([Li])(CC)C.C1OCCOCCOCCOCCOCCOC1.[N+:34]([C:37]([CH3:39])=[CH2:38])([O-:36])=[O:35]>C(#N)C.O1CCCC1>[N+:34]([C:37]([CH3:11])([CH3:39])[CH2:38][O:6][CH:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])([O-:36])=[O:35]
Reactant: [Li]C(C)CC
Reactant: CC(C)(C)C(O)C(C)(C)C
Reactant: C=C(C)[N+](=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)C(OCC(C)(C)[N+](=O)[O-])C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Di-t-butylmethanol is added to a dry flask under argon at 0° C. Dry tetrahydrofuran is added with a syringe. Sec-Butyl lithium (1.5M in Hexanes) is added quickly in one portion and the contents of the flask are stirred for one hour at room temperature. A 10 mM solution of 18-crown-6-ether in acetonitrile is added with a syringe and the flask cooled to 0° C. A tetrahydrofuran solution of 2-nitropropene is added with vigorous stirring over a 10 minute period. After completion of the reaction, as judged by thin layer chromatography, it is quenched with dimethyl sulfate, poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield 2-nitro-2-methyl-1-[di-(t-butyl)methoxy]propane.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:34])[NH:30][CH:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:34])=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@H](Cc1ccc(OC(=O)NC(C)C)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(OC(=O)NC(C)C)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6 mmol) was added to (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(isopropylcarbamoyloxy)phenyl)propanoate in methylene chloride (2 mL). The reaction was stirred for 1 h, and was concentrated under reduced pressure to give crude product, methyl (2S)-2-amino-3-(4-{[(isopropylamino)carbonyl]oxy}phenyl)propanoate (50 mg, 100%). Analytical LCMS (M+H)+: m/z=281.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][O:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:10]1([C:3]2[C:2]([NH:1][C:24](=[O:25])[CH2:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[C:6]([C:7]([NH2:9])=[O:8])[O:5][N:4]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: NC(=O)c1onc(C2CCCC2)c1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(CC(=O)Nc2c(C3CCCC3)noc2C(N)=O)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
12 g (61 mmol) of 4-amino-3-cyclopentyl-isoxazole-5-carboxamide (example VI) are dissolved in 50 ml of pyridine, and 12.48 g (67 mmol) of 4-methoxyphenylacetyl chloride and a spatula tip of DMAP are added. The reaction mixture is stirred at 60° C. for 5 hours and the solvent is then removed in vacuo. The residue is taken up in dichloromethane and the solution is shaken twice with 1N hydrochloric acid and twice with sodium hydrogencarbonate solution; it is then dried over sodium sulfate and the solvent is removed in vacuo. The residue is triturated with a little dichloromethane and then filtered; the filtrate is concentrated to dryness and the residue is purified by chromatography (cyclohexane/ethyl acetate=2:1).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([NH:7][N:8]([CH3:26])[C:9](=[O:25])[C:10]([O:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:12])[CH3:11])=[O:6])[CH3:3].O.NN>ClCCl>[CH3:3][C:2]([CH3:27])([O:4][C:5]([NH:7][N:8]([CH3:26])[C:9](=[O:25])[C:10]([O:13][NH2:14])([CH3:11])[CH3:12])=[O:6])[CH3:1]
Reactant: CN(NC(=O)OC(C)(C)C)C(=O)C(C)(C)ON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CN(NC(=O)OC(C)(C)C)C(=O)C(C)(C)ON

Procedure:
A stirred solution of 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-2-methylpropanoic acid, 2-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazide (7.10 g, 19 mmole) in 50 ml of dichloromethane at 0° C. was treated dropwise with hydrazine hydrate (1.80 ml, 38 mmole). After 30 minutes the resulting slurry was filtered and the filtrate evaporated. The residue was crystallized from ether/petroleum ether to give the title compound as 3.3 g of a colorless solid, m.p. 85°-90° C.
Reaction SMILES: [C:1]([O:9][CH:10]([C:16](=[O:18])[CH3:17])[C:11](=[O:15])[CH:12]=[CH:13]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC.C(O)(=O)C(O)=O.Cl.S(=O)(=O)(O)O>C(O)(=O)C.C(O)=O>[C:1]([O:9][C:10]1[C:11](=[O:15])[CH:12]=[CH:13][O:18][C:16]=1[CH3:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CO
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCC(=O)O
Solvent: CC(=O)O
Solvent: O=CO
Product: Cc1occc(=O)c1OC(=O)c1ccccc1

Procedure:
said 4-benzoyloxy-1-hydroxy-1-hexene-3,5-dione is heated in an acid chosen from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, dilute hydrochloric acid and dilute sulfuric acid to form 3-benzoyloxy-2-methyl-4-pyrone, and,
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[NH2:7][CH2:8][C:9]([NH:12][C:13]1[C:14]([CH3:33])=[N:15][C:16]2[C:21]([N:22]=1)=[C:20]([C:23]1[NH:31][C:30]3[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=3[CH:24]=1)[CH:19]=[CH:18][CH:17]=2)([CH3:11])[CH3:10]>C1COCC1.CC(O)C>[CH3:33][C:14]1[C:13]([NH:12][C:9]([CH3:11])([CH3:10])[CH2:8][NH:7][CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:23]2[NH:31][C:30]3[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=3[CH:24]=2)[N:15]=1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CN
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CNCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
A solution of methyl vinyl sulfone (0.016 mL, 0.178 mmol) (Sigma-Aldrich) in THF (1.0 mL) was added to a mixture of 2-(3-((1-amino-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (341) (65 mg, 0.18 mmol) in 2-Propanol (2.00 mL); the reaction mixture was stirred at RT for 16 h when only a small amount of product was observed via lcms. More methyl vinyl sulfone (0.16 mL, 1.78 mmol) was added to the reaction mixture before it was heated in the microwave at 110° C. for 75 min when mostly product was observed via lcms. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-6% of 2 M NH3 in MeOH/DCM to give 2-(2-methyl-3-((2-methyl-1-((2-(methylsulfonyl)ethyl)amino)propan-2-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (342, 58 mg, 0.12 mmol, 69% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.63 (s, 6H) 2.57 (s, 3H) 2.91 (s, 2H) 2.92 (s, 3H) 2.97 (t, J=6.94 Hz, 2H) 3.18-3.25 (m, 2H) 3.25-3.31 (m, 2H) 3.65 (td, J=6.85, 2.35 Hz, 2H) 5.52 (br. s., 1H) 5.92 (s, 1H) 7.09 (d, J=1.76 Hz, 1H) 7.36 (t, J=7.82 Hz, 1H) 7.64 (dd, J=8.12, 1.08 Hz, 1H) 7.91 (dd, J=7.63, 0.98 Hz, 1H) 12.49 (br. s., 1H). MS (ESI, pos. ion) m/z: 471.4 (M+1).
Reaction SMILES: [Cl-:1].[NH2:2][C:3]1[N:7]([C@@H:8]2[O:16][C@H:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]2[F:22])[CH:6]=[N:5][C:4]=1[C:23]([OH:25])=O>O1CCCC1>[C:12]([O:11][C@@H:10]1[C@@H:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[O:16][C@@H:8]([N:7]2[C:3]([N:2]=[CH:6][N:7]([CH3:8])[CH3:3])=[C:4]([C:23]([Cl:1])=[O:25])[N:5]=[CH:6]2)[C@H:9]1[F:22])(=[O:14])[CH3:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N)[C@@H](F)[C@@H]1OC(C)=O
Reactant: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O

Procedure:
In step f, compound (35) is dissolved in tetrahydrofuran and reacted with N,N-dimethylchloroforminium chloride under ice-cooling. This reaction may be carried out in the same manner as in the step 12 of SYNTHETIC PROCESS CHART (A). By this reaction, 1-(3,5-di-O-acetyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-(dimethylaminomethyleneamino)imidazole-4-carbonyl chloride [compound(36)] is produced.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CCN=C=NC[CH2:30][CH2:31]N(C)C.C1C=CC2N(O)N=NC=2C=1.C[O:46][CH2:47][C:48](O)=O>CN1C(=O)CCC1.C(OCC)C.CCN(CC)CC>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:48]1[CH2:47][O:46][CH2:30][CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Reactant: COCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOCc1nc2cnc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 15 h

Procedure:
The product from example 1 step (iii) (790 mg) was dissolved in NMP (5 mL), then EDCI (1.44 g), HOBt (1 g), methoxyacetic acid (0.71 mL) and Et3N (1 mL) were added. The mixture was stirred at 40° C. for 15 h then heated at 60° C. for 5 h. After cooling to rt, the crude mixture was dissolved in diethyl ether, washed with brine, dried and evaporated under reduced pressure, which afforded 600 mg of the subtitle product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(N(CC)CC)C>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 10.6 g (57 mmol) of N-tert.butoxycarbonyl-piperazine, 10.8 g (62.7 mmol) of 4-nitrobenzylchloride, 23.8 ml (171 mmol) of triethylamine in 100 ml of dichloromethane is stirred for 12 hours at 70° C. After diluting with water the organic phase is separated off, dried and evaporated down.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=O)[NH:5][CH2:4][C:3]1=[O:14].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:36]([SH:38])[CH3:37]>ClCCl>[CH2:36]([S:38][C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][N:5]=1)[CH3:37]
Reactant: CN1C(=O)CNC(=O)c2ccccc21
Reactant: CCS
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCSC1=NCC(=O)N(C)c2ccccc21
Temperature: -51 °C
Reaction time: 0.03 h

Procedure:
A solution of 1.0 mmol of 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Tett. Lett. 1994, 50(30), 9051) in 8mL dry dichloromethane (Aldrich Sure Seal), in an oven-dried round bottom flask under nitrogen cover, is treated with 1.1 equivalents of anhydrous pyridine (Mallinkrodt). The reaction is cooled to −51° C. in a dry ice/acetone bath and treated, dropwise via syringe over three minutes, with 1.1 equivalents of trifluoromethanesulfonic anhydride (Aldrich; sealed ampules). The reaction mixture is allowed to stir twenty minutes while maintaining a reaction temperature between −47 and −35° C. The temperature is brought to 0° C. over 1-2 minutes and then maintained at that temperature for one hour. Ethanethiol (3.4 equivalents) is introduced via syringe and the mixture allowed to stir overnight, still immersed in an ice water-filled Dewar. The temperature had risen to 16° C. by morning. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The aqueous portion is further extracted three times with methylene chloride and the combined extracts dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification is effected by flash chromatography (silica gel; gradient elution using methylene chloride/ethyl acetate in 100/1, 95/5, 90/10 and 85/15. The title compound is obtained as a colorless oil which crystallizes on standing.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].B.[H][H].[CH3:18][C:19]1[C:33](=[O:34])[N:32]=[C:31]2[N:21]([C@@H:22]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@@H:23]3[O:30]2)[CH:20]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.CO>[C:8]1(=[O:9])[N:4]([CH2:3][CH2:2][O:1][C@@H:23]2[C@H:24]([OH:29])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:22]2[N:21]2[CH:20]=[C:19]([CH3:18])[C:33](=[O:34])[NH:32][C:31]2=[O:30])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: Cc1cn2c(nc1=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
N-(2-Hydroxyethyl)phthalimide (277 g, 1.45 mol) was slowly added to a solution of borane in tetrahydrofuran (1 M, 600 mL), with stirring. Hydrogen gas evolved as the solid dissolved. Once the rate of gas evolution subsided, the solution was placed in a 2 L stainless steel bomb. 2,2′-Anhydro-5-methyluridine (60 g, 0.25 mol) and sodium bicarbonate (120 mg) were added and the bomb was sealed. After 30 minutes, the bomb was vented and placed in an oil bath and heated to 150° C. internal temperature for 24 h. The bomb was cooled to room temperature and opened. TLC (ethyl acetate-methanol; 95:5) revealed the disappearance of starting material. The crude solution was concentrated and the residue was purified by chromatography on silica gel starting with ethyl acetate to remove the excess phthalimide reagent, followed by ethyl acetate-methanol (95:5) to elute 2 (22.2 g, 20.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:32][C:33]1[O:37][C:36]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:44][CH:43]([NH2:59])[C:42]2=[O:60])=[O:39])=[CH:35][CH:34]=1>O1CCCC1.O>[CH3:32][C:33]1[O:37][C:36]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[C:54]([CH3:56])([CH3:57])[CH3:55])[CH2:44][CH:43]([NH:59][C:14]([NH:1][C:2]3[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=3)=[O:16])[C:42]2=[O:60])=[O:39])=[CH:35][CH:34]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccc(C)o1)C(=O)C(N)CN2C(=O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccc(C)o3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 196.8 %

Procedure:
Ethyl 3-aminobenzoate (0.33 g) was dissolved in tetrahydrofuran (10 ml), the solution was cooled on ice, triphosgene (0.21 g) was added at internal temperature 8° C., triethylamine (0.72 g) was added thereto over 15 minutes interval, the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of 1-(5-methylfuran-2-yl)carbonylmethyl-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.71 g) in tetrahydrofuran (10 ml) was added to the mixture. The resultant mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1), to thereby obtain 0.82 g of the title compound as a light brown crystal (Yield: 78%).