Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:12]1[CH2:17][CH:16]=[CH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:12]1([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH:14]=[CH:15][CH2:16][CH2:17]1
Reactant: C1=CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=CCC1
Yield: 92.2 %

Procedure:
tert-Butyl dicarbonate (6.55 g) was added to a mixture of 1,2,3,6-tetrahydropyridine (2.50 g) and a 10% aqueous solution (3.0 ml) of sodium carbonate, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with 0.5N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound (5.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([Si:19]([O:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3,5-dichlorophenol (1.63 g, 10 mmol) and imidazole (1.50 g, 22 mmol) in DMF (10 mL) was cooled to 0° C. then TBDMSCl (1.66 g, 11 mmol) was added. After the addition, the solution was warmed up to ambient temperature and stirred for 10 min. The solution was re-cooled to 0° C. and the mixture was quenched with water. The aqueous layer was extracted with Et2O and the combined organic layers were washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (15:1) as eluent to give tert-butyl-(3,5-dichlorophenoxy)-dimethylsilane as a pale yellow solid.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][C:7]([OH:9])=O)(=[NH:4])[NH2:3].S(Cl)([Cl:12])=O>>[ClH:12].[C:2]([CH2:5][CH2:6][C:7]([Cl:1])=[O:9])(=[NH:4])[NH2:3]
Reactant: O=S(Cl)Cl
Reactant: N=C(N)CCC(=O)O
Agent: Cl
Product: N=C(N)CCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.52 g. (0.01 mole) of 3-amidinopropionic acid hydrochloride in 18 ml. of thionyl chloride is allowed to stir at room temperature overnight. The excess solvent - reactant is then removed under reduced pressure and the product is isolated as a yellow gum, which crystallizes on standing, 1.5 g.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[N:14]([O-])=O.[Na+].[OH-].[Na+].C(Cl)(Cl)Cl>O.Cl>[Cl:1][C:2]1[C:8]([O:9][CH:10]([F:11])[F:12])=[CH:7][C:5]([NH:6][NH2:14])=[C:4]([F:13])[CH:3]=1
Reactant: Nc1cc(OC(F)F)c(Cl)cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: NNc1cc(OC(F)F)c(Cl)cc1F
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A mixture of 13.3 g of 4-chloro-2-fluoro-5-difluoromethoxyaniline XIII-1 and 106 ml of hydrochloric acid was stirred at 0° C. A solution of 4.76 g of sodium nitrite in 35.4 ml of water was dropwise added in 10 minutes to the mixture, which was stirred at 0° to 5° C. for an hour. A solution of 35.4 g of stannous chloride dihydrate in 35.4 ml of hydrochloric acid was dropwise added in 15 minutes to the mixture, which was stirred at 0° to 5° C. for 2 hours. The reaction mixture was basified with 10% aqueous sodium hydroxide and shaken with chloroform. The chloroform layer was dried and concentrated, and 12.7 g of the titled compound XIV-1 thus obtained was used for the subsequent reaction without purification.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.[IH:33].O>C(OCC)C.CO>[IH:33].[O:25]=[C:23]([CH3:24])[CH2:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(=O)CCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)CCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane, ethylene ketal (0.9 g, 2.0 mmol) and dichloromethane (20 mL). Cool in an ice bath and add hydriodic acid (0.53 mL, 57%, 4.05 mmol). Warm to ambient temperature. After 0.5 hours, add water (0.5 mL) and heat to reflux. After 18 hours, cool to ambient temperature and evaporate in vacuo to give a residue. Combine the residue and methanol (45 mL) and add diethyl ether (250 mL) with stirring to give a solid. After 30 minutes, collect the solid by filtration to give, after drying the title compound. Elemental Analysis calculated for C17H24N4O.2 HI: C 36.71; H 4.71; N 10.07; Found: C 36.94; H 4.47; N 9.84.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([O:12]C)OC.Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>C1COCC1.C([Li])CCC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])=[C:3]([CH:4]=1)[CH:9]=[O:12]
Reactant: C=CCCCBr
Reactant: COC(OC)c1cc(C)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
Step AI (4): 1-Bromo-2-(dimethoxymethyl)-4-methylbenzene (615 mg, 2.51 mmol) was dissolved in THF (10 mL) under N2 atmosphere at −78° C. n-Butyllithium (1.6 M, 3.1 mL) was added and the reaction mixture was stirred for 30 min. 5-Bromopent-1-ene (0.31 mL, 2.64 mmol) was added. The reaction mixture was warmed to rt and stirred for 18 h. The reaction was quenched with the addition of HCl (1.0 N) and was further stirred at rt for 1 h. The reaction mixture was extracted with EtOAc and washed with brine. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 5-methyl-2-(pent-4-enyl)benzaldehyde (45 mg, 10%) as a colorless oil. LC-MS (M+H)+=189.41.
Reaction SMILES: [C:1]([NH:5][CH3:6])([CH3:4])([CH3:3])[CH3:2].Cl[S:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])=[O:9]>>[CH3:15][O:14][C:12](=[O:13])[CH2:11][S:8](=[O:10])(=[O:9])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:6]
Reactant: CNC(C)(C)C
Reactant: COC(=O)CS(=O)(=O)Cl
Product: COC(=O)CS(=O)(=O)N(C)C(C)(C)C
Yield: 60296.7 %

Procedure:
The subtitle compound (14.81 g, 59%) was prepared as a yellow oil from tert-butylmethylamine (24.48 g, 0.28 mol) and methyl chlorosulfonylacetate (19.37 g, 0.11 mmol), using the method of Example 1(a).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:34]2)=CC=1.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[S:34]
Reactant: CNC(=O)c1cc(C(=O)OC(C)(C)C)cc(-c2ccc(C)cn2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CNC(=S)c1cc(C(=O)OC(C)(C)C)cc(-c2ccc(C)cn2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-[(methylamino)carbonyl]-5-(5-methylpyridin-2-yl)benzoate (1.0 g, 3.06 mmol) in dichloroethane (8 mL) was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (0.68 g, 1.69 mmol). The reaction mixture was heated to 50° C. After 3 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound. MS 343.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[F:14][C:15]1[CH:16]=[C:17]([NH:24][C:25](=[O:30])[O:26][CH:27]([CH3:29])[CH3:28])[CH:18]=[C:19]([F:23])[C:20]=1[CH:21]=O.Cl>CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([NH:24][C:25]([O:26][CH:27]([CH3:28])[CH3:29])=[O:30])[CH:18]=[C:19]([F:23])[C:20]=1/[CH:21]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)OC(=O)Nc1cc(F)c(C=O)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1c(F)cc(NC(=O)OC(C)C)cc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (1.4 g of 60% dispersion, 35 mmol) was placed in a flask and washed three times with hexane. The resulting solid was suspended in DMF (29 mL) and cooled to 0° C. Trimethyl phosphonoacetate (5.95 mL, 36.75 mmol) was added dropwise to this suspension to give a clear homogeneous solution. After stirring for another 15 minutes at 0° C., a solution of isopropyl 3,5-difluoro-4-formylphenylcarbamate (8.51 g, 35 mmol) in DMF (25 mL) was added dropwise. The resulting orange suspension was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture was then poured into 0.5 N HCl and extracted with three portions of dichloromethane. Combined organic phases were washed with saturated NaHCO3, H2O, brine, and dried (MgSO4) filtered and concentrated. The resulting orange solid was washed with hexane, 30% ethyl acetate-hexane, and then purified by column chromatography (15-30% ethyl acetate-hexane) to provide title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1C(O)=O.Cl.C(O)(C)C>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Nc1c(C(=O)O)cnn1-c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Nc1ccnn1-c1ncc(Cl)cc1Cl
Yield: 92.4 %

Procedure:
16.5 g (0.06 mole) of 5-amino-1-(3,5-dichloropyrid-2-yl)-pyrazole-4-carboxylic acid are slowly heated to 80° C. in a mixture of 150 ml of water, 75 ml of concentrated hydrochloric acid and 20 ml of isopropanol and the reaction mixture is stirred at this temperature until the evolution of gas has ended. The clear solution formed is evaporated to dryness, the residue is suspended in methylene chloride, the suspension is neutralized with aqueous sodium carbonate solution, the organic phase is separated off and the aqueous phase is extracted twice more with methylene chloride. The combined organic phases are dried over sodium sulphate and freed from the solvent in vacuo. 12.7 g (92% of theory) of 5-amino-1-(3,5-dichloropyrid-2-yl)-pyrazole are obtained as an oil. 1H-NMR (CDCl3 /TMS as the internal standard): δ=4.55; 5.55; 7.43; 7.88; and 8.30 ppm.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[N:33]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:39])[CH3:41])[N:33]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2N2CCOCC2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3N3CCOCC3)cc2=O)n1
Yield: 51 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2-morpholin-4-yl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 53) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (0.61 g, 51%); ES+-HRMS m/e calcd for C29H38N6O5 [M+H+] 551.2977 found 551.2976. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.24-1.76 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 2.83-3.05 (m, 4H), 3.46-3.59 (m, 4H), 3.89 (s, 2H), 4.67 (s, 1H), 5.51 (dd, J=4.1, J=11.0 Hz, 1H), 5.74 (d, J=3.0 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.09-7.18 (m, 2H), 7.25 (dd, Jo=7.8 Hz, Jm=1.5 Hz, 1H), 7.27-7.37 (m, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.02 (d, J=3.0 Hz, 1H), 10.77 (s, 1H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:25]([C:26](=[S:28])[NH2:27])[N:24]=[C:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[S:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:44]1[C:49](=O)[CH2:48][CH2:47][N:46]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:45]1.CCN(C(C)C)C(C)C>C(O)C>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:25]([C:26]2[S:28][C:44]3[CH2:45][N:46]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:48][C:49]=3[N:27]=2)[N:24]=[C:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[S:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.500 g, 0.809 mmol) in 20 mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.338 g, 1.21 mmol) followed by DIEA (0.423 mL, 2.43 mmol). The mixture was allowed to stir overnight at reflux then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (200 mg) and stirred at reflux for a further 3 hours. The cooled mixture was partitioned between saturated NaHCO3 solution (50 mL) and EtOAc (50 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (50 mL) dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a viscous yellow oil, 0.412 g, 64%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH2:9].CO[C:13]1[C:21](=[O:22])[C:17]2[N:18]=[CH:19][S:20][C:16]=2[C:15](=[O:23])[CH:14]=1>C(O)C>[CH3:10][N:5]([CH2:6][CH2:7][CH2:8][NH:9][C:13]1[C:21](=[O:22])[C:17]2[N:18]=[CH:19][S:20][C:16]=2[C:15](=[O:23])[CH:14]=1)[CH2:4][CH2:3][CH2:2][NH:1][C:13]1[C:21](=[O:22])[C:17]2[N:18]=[CH:19][S:20][C:16]=2[C:15](=[O:23])[CH:14]=1
Reactant: CN(CCCN)CCCN
Reactant: COC1=CC(=O)c2scnc2C1=O
Solvent: CCO
Product: CN(CCCNC1=CC(=O)c2scnc2C1=O)CCCNC1=CC(=O)c2scnc2C1=O
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 54.4 %

Procedure:
57 μl (0.37 mmol; 0.48 equivalent) of N-(3-aminopropyl)-N-methylpropane-1,3-diamine is added to 150 mg (0.77 mmol) of 5-methoxy-1,3-benzothiazol-4,7-dione in solution in 6 ml of ethanol. The reaction mixture is maintained under stirring at 85° C. for 90 minutes, then the solvent is evaporated off under reduced pressure and the expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol mixture 94/6) and 95 mg (yield=26%) of 5.5′-[(methylimino)bis(propane-3,1-diylimino)]bis(1,3-benzothiazole-4,7-dione) is obtained in the form of a red powder. Melting point: 223-224° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]>C(O)C>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Yield: 95.3 %

Procedure:
A solution of N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (253 mg, 0.575 mmol) in 10 mL of ethanol was hydrogenated at atmospheric pressure over 45 mg of 10% Pd(C) for 3 hours. The reaction mixture was filtered through a pad of celite and evaporated to dryness to give 4-amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (225 mg, 95%) as a white solid suitable for use in the next step, HR—FAB—MS: Obs mass, 410.2196. Calcd mass, 410.2200 (M+).
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CN(C=O)C>[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[O:37][CH3:36])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: COc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccccc1OCCOc1nccnc1N1CCNCC1
Reaction time: 15 h
Yield: 10.9 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (TMAD; 60 mg, 0.35 mmol) was dissolved in THF (1 mL) and DMF (0.5 mL) and added to a stirred solution of the product from Step 2 (100 mg, 0.31 mmol), 2-methoxyphenol (124 mg, 1.00 mmol) and triphenylphosphine (92 mg, 0.35 mmol) in THF (1 mL). The reaction mixture was stirred for 15 h and then concentrated under reduced pressure. The residue was passed through a bed of silica gel using toluene/EtOAc/MeOH (45:45:10) as eluent, and the pure fractions were combined, concentrated and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min. The mixture was concentrated and the residue was purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The combined product-containing fractions were concentrated and partitioned between 5% aqueous NaOH and CH2Cl2. The organic phase was concentrated, and the residue was purified by chromatography on silica gel using CH2Cl2/MeOH (8:2) as eluent to give 11.2 mg (11%) of the title product. HRMS m/z calcd for C17H22N4O3 (M)+ 330.1692, found 330.1707.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:20][NH:21][CH3:22]>C(Cl)Cl>[CH3:20][N:21]([CH3:22])[C:1](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1)c1ccccc1
Reactant: CNC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)C(=Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Into a slurry of 19.7 g of benzanilide (m.p. 162°-164° C.) in 200 ml of methylene chloride was added a solution of 12.0 g of thionylchloride in 50 ml of methylene chloride. After the addition was completed and the reaction mixture was stirred for one hour at room temperature, gaseous dimethylamine was introduced until the solution became saturated. Workup by filtration, waterwash, removal of the solvent and distillation afforded N,N-dimethyl-N'-phenylbenzamidine in 18.6 g or 83% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](N[Si](C)(C)C)(C)C.C(O[CH:25]1[O:47][C@H:46]([CH2:48][O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:36]([O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:26]1[O:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CCO.C(Cl)Cl.CC(C)=O.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:11])[N:8]([C@@H:25]3[O:47][C@H:46]([CH2:48][O:49][C:50](=[O:57])[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C@@H:36]([O:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@H:26]3[O:27][C:28](=[O:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]c(=O)sc12
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1ncnc2c1sc(=O)n2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 30 (1.22 g, 7.25 mmol) was glycosylated as described for the preparation of 6, requiring HMDS (35 mL), benzoyl-blocked sugar (5: 4.4 g, 8.7 mmol) and TMS-triflate (2.0 mL, 10.3 mmol). After stirring overnight at room temperature, the reaction mixture was refluxed for 2 days and then worked up in the usual manner. The crude mixture was subjected to flash silica gel column chromatography using a gradient of methylene chloride to methylene chloride-acetone 10:1 (v/v) and yielded two products. The first to elute from the column was assumed by 1H NMR to be a bis-glycoside which amounted to 660 mg. The second and major product off the column was obtained as a foam and assigned as the desired 3-ribosyl isomer by UV and 1H NMR: yield 1.04 g (24%): UV λmax (EtOH) 232 nm (ε), 283 (): 1H NMR (DMSO-d6) δ6.34 (t, 1H, C1,H), 7.39-7.98 (m, 17H, benzoyl aromatics and NH2, 8.19 (s, 1H, C5H), and other sugar protons. Anal. Calcd. for C, 60.78: H, 3.95: N, 9.15: S, 5.23. Found: 3.93: N, 8.13: S, 4.85.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1Cl)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:30])([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:20][CH2:21][SH:22]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[S:22][CH2:21][CH2:20][C:19]([F:30])([F:18])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:4]
Reactant: COC(=O)c1ccncc1Cl
Reactant: Fc1ccc(C(F)(F)CCS)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccncc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 3-chloro-pyridine-4-carboxylic acid methyl ester (0.28 g, 1.65 mmol) in DMF (10 ml) are added cesium carbonate (2.68 g, 8.25 mmol) and 3,3-difluoro-3-(4-fluorophenyl)-propane-1-thiol (synthesized according to the methods described in sections a) and b) of example 3) (0.34 g, 1.65 mmol) in a sealed tube. The reaction mixture is stirred at 90° C. for 1 h. After completion of the reaction, the mixture is diluted with water (15 ml) and extracted with EtOAc (3×20 ml). The organic layer is washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 10% acetone/hexane) to yield 3-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-pyridine-4-carboxylic acid methyl ester (0.19 g, 0.56 mmol, 34%).