Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6](CC2C=CC(OC)=CC=2)[CH:7]=1.P([O-])([O-])([O-])=[O:25].[K+].[K+].[K+].[N+:32]([C:35]1[CH:43]=[C:42]2[C:38]([CH:39]=[CH:40][NH:41]2)=[CH:37][CH:36]=1)([O-:34])=[O:33].CNCCNC>C(Cl)Cl.[Cu]I.C1(C)C=CC=CC=1>[N+:32]([C:35]1[CH:43]=[C:42]2[C:38]([CH:39]=[CH:40][N:41]2[C:6]2[CH:7]=[C:2]([OH:25])[CH:3]=[C:4]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:5]=2)=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: COc1ccc(Cc2cc(Br)cc(Nc3cccnc3)c2)cc1
Reactant: O=P([O-])([O-])[O-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2ccn(-c3cc(O)cc(Nc4cccnc4)c3)c2c1
Temperature: 110 °C

Procedure:
The resin-bound (3-bromo-5-p-methoxybenzylphenyl)-3-pyridylamine described in Example 22 (200 mg, ca 0.12 mmol) was placed in a 50 mL glass reactor. Copper (I) iodide (0.6 mmol, 114 mg), potassium phosphate (127 mg, 0.6 mmol), toluene (5 mL), 6-nitroindole (0.6 mmol, 98 mg) and N,N′-dimethylethylenediamine (53 mg, 0.6 mmol) were added to the reactor, and the reactor was heated to 110° C. for 16 h under N2 atmosphere. After cooling the reaction mixture to room temperature, the resin was filtered, washed with THF (4×3 mL), MeOH (4×3 mL), H2O (4×3 mL), DMF (3×4 mL), THF (4×3 mL), methylene chloride (4×3 mL) and dried in vacuo. The resin was treated with 2% dimethylsulfide, 50% TFA/methylene chloride (2 mL) for 20 min in a 20 mL glass vial. The slurry of resin in cleavage cocktail was filtered through a fritted syringe to a 20 mL glass vial, washed with methylene chloride (2×1 mL), and the combined solution was evaporated by nitrogen blowing under mild heating to give the crude product which was confirmed by proton NMR and LC/MS analysis. The crude product was passed through a short pad of silica gel using 5% MeOH in methylene chloride. The combined fractions of product were concentrated, and the residue was further purified by prep SFC to obtain 3-(6-nitro-indol-1-yl)-5-(pyridin-3-ylamino)-phenol (4.3 mg, 0.012 mmol). 1H NMR (400 MHz, CD3OD) δ 8.49 (d, J=2.0, 1H), 8.01 (dd, J=8.8, 2.4, 1H), 7.7 (m, 1H), 7.33 (m, 1H), 6.80 (d, J=3.2, 1H), 6.70 (t, J=1.8, 1H), 6.66 (t, J=2.0, 1H), 6.53 (t, J=2.0, 1H).
Reaction SMILES: C([O:3][C:4](=O)[N:5]([C:13]1[CH:18]=[C:17]([Br:19])[N:16]=[C:15]([NH2:20])[C:14]=1[N+:21]([O-])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>CC(O)=O.CCOC(C)=O.O.[Fe]>[NH2:20][C:15]1[C:14]2[NH:21][C:4](=[O:3])[N:5]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:18]=[C:17]([Br:19])[N:16]=1
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(Br)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
(2-Amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (50 mg, 0.13 mmol) was dissolved in AcOH (3 ml). Fe powder (43 mg, 0.76 mmol) was added and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture diluted with EtOAc (20 ml) and water (10 ml). The mixture was filtered through celite, washing through with EtOAc (20 ml). The layers were separated and the organic layer was washed with water (10 ml), sat. NaHCO3 (aq) (2×10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. The crude was triturated in pentane, filtered and dried in vacuo at 40° C. to give the title compound (15 mg) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][CH:5]([CH2:7][O:8][CH2:9][CH:10]2[O:14][CH:13]([CH2:15][OH:16])[CH2:12][CH2:11]2)[CH2:4][O:3]1.Cl[CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21].[H-].[Na+].O>CS(C)=O>[CH3:1][C:2]1([CH3:17])[O:6][CH:5]([CH2:7][O:8][CH2:9][CH:10]2[O:14][CH:13]([CH2:15][O:16][CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21])[CH2:12][CH2:11]2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(COCC2CCC(CO)O2)O1
Reactant: CCCN(CCC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCC)C(=O)COCC1CCC(COCC2COC(C)(C)O2)O1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A mixture of 4.93 g of 5-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]methyl]tetrahydro-2-furan-methanol (0.02 mole) and 3.55 g of 2-chloro-N,N-dipropylacetamide (0.02 mole) are dissolved in 125 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly 0.50 g of sodium hydride (0.02 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4× 300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is then removed in vacuo yielding a pale yellow oil which is vacuum distilled through a 10 cm vigreux column and the fraction distilling at 91°-94° @ 0.4 mm is collected, yielding 4.86 g (63%) of the above compound.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CN(C)[CH2:25][CH2:26]N(C)C>CCOCC>[CH2:2]([C:18]1[CH:25]=[C:26]([C:21]2[S:20][CH:19]=[C:18]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:22]=2)[S:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: [Li]CCCC
Reactant: CN(C)CCN(C)C
Reactant: CCCCCCCCCCCCc1ccsc1
Solvent: CCOCC
Product: CCCCCCCCCCCCc1csc(-c2cc(CCCCCCCCCCCC)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
n-BuLi (7.04 mL, 2.5 M in hexanes) was added dropwise to a stirring solution of 3-dodecylthiophene (4.000 g, 15.8 mmol) and N,N,N′,N′-tetramethylethylenediamine (2.75 mL, 17.6 mmol) in 80.0 mL of dry ether at −78° C. The solution was then warmed to room temperature and refluxed for 1 hour. After the solution was cooled to −78° C., CuCl2 (2.640 g, 19.6 mmol) was added in one portion. The reaction mixture was stirred overnight, during which time the temperature rose to room temperature. The reaction mixture was quenched with water and the resulting mixture was extracted with chloroform. The combined organic layers were washed with water, dried over MgSO4 and filtered, and the filtrate was concentrated to dryness. The crude product was purified by column chromatography on silica gel with hexanes as the eluent to yield a mixture of 4,4′- and 3,3′-didodecylthiophene (˜15% of the mixture by 1H NMR). Recrystallization from an acetone:ethanol (1:1) mixture gave 4,4′-didodecyl-2,2′-bithiophene (25) as a white solid (2.200 g, 55% yield). 1H NMR (CDCl3): δ 0.91 (t, 6H), 1.33 (m, 36H), 1.66 (q, 4H), 2.60 (t, 4H), 6.80 (s, 2H), 7.01 (s, 2H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12][C:13]([F:19])([F:18])[C:14](Br)(Br)[Br:15]>>[Br:15][C:14]([C:13]([F:19])([F:18])[F:12])=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)C(Br)(Br)Br
Product: O=[N+]([O-])c1ccc(C=C(Br)C(F)(F)F)cc1

Procedure:
The product was prepared from 4-nitro-benzaldehyde and from 1,1,1-trifluoro-tribromoethane (CF3 --CBr3) by operating according to the process of example 1. The obtained product has:
Reaction SMILES: C(OCC[C:7]1[CH:12]=[CH:11][C:10]([Sn](CCCC)(CCCC)CCCC)=[C:9]([F:26])[CH:8]=1)(=O)C.Br[C:28]1[N:29]=[C:30]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]2)[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2.[C:46]([O:49][CH2:50][CH3:51])(=[O:48])[CH3:47]>C1(C)C(C)=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:44]([N:41]1[CH2:42][CH2:43][N:38]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:37]=[C:28]([C:7]3[CH:12]=[CH:11][C:10]([CH2:51][CH2:50][O:49][C:46](=[O:48])[CH3:47])=[C:9]([F:26])[CH:8]=3)[N:29]=2)[CH2:39][CH2:40]1)[CH3:45]
Reactant: CCOC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CCOC(C)=O)cc1F
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(CCOC(C)=O)c(F)c3)cc3ccccc23)CC1

Procedure:
2-(3-Fluoro-4-tributylstannylphenyl)ethyl acetate (2.77 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.19 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.17 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.44 g) of 1-(4-ethylpiperazin-1-yl)-3-[3-fluoro-4-(2-acetoxyethyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>O1CCCC1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in tetrahydrofuran were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in tetrahydrofuran at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:25])[CH:12]=[CH:11][CH:10]=[CH:9]3.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH:22]([C:17]1[CH:16]=[C:15]([C:14]2[C:4]3[C:3]([CH3:25])=[C:2]([CH3:1])[S:6][C:5]=3[CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:20]=[CH:19][C:18]=1[O:21][C:26](=[O:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C(C)C)c3)c2c1C
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C(C)C
Reaction time: 5.5 h
Yield: 68.6 %

Procedure:
At 5° C., to a stirred solution of 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenol (0.500 g, 1.44 mmol) in pyridine (3.5 mL) was added acetic anhydride (0.167 mL, 1.78 mmol). After 5.5 h, the reaction was quenched with H2O, acidified and extracted with ether. The combined ethereal extracts were sequentially washed with H2O, brine and concentrated. Purification on silica gel, eluting with 5 & 7% EtOAc/pet. ether, step gradient gave 0.384 g (69%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.49 (s, 1 H), 8.00-7.96 (d, 1 H), 7.48-7.31 (m, 4 H), 7.20 (s, 2 H), 3.10 (septet, 1 H), 2.40 (s, 3 H), 2.37 (s, 3 H), 1.56 (s, 3 H), 1.16 (d, 6 H).
Reaction SMILES: [Cl-:1].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[F:16][C:17]1[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>Cl.C(O)C>[ClH:1].[ClH:1].[F:16][C:17]1[CH:22]=[C:21]([CH:23]=[C:6]2[CH2:5][CH2:4][CH2:3][N:2]=[C:7]2[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:20]=[CH:19][C:18]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Reactant: [Cl-]
Reactant: O=Cc1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Solvent: CCO
Product: Fc1cc(C=C2CCCN=C2c2cccnc2)ccc1-c1ccccc1
Temperature: 85 °C
Yield: 73.8 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (150 mg, 0.60 mmol) and 2-fluorobiphenyl-4-carboxaldehyde (155 mg, 0.78 mmol) were combined in a reaction vessel and treated with ethanol (10 mL) and concentrated HCl(aq) (5 drops). The vessel was then sealed and the reaction was heated to 85° C. overnight then cooled to room temperature. The reaction mixture was then concentrated under reduced pressure then partially dissolved into hot isopropanol. This mixture was left to cool and crystals formed. The crystals were recovered by vacuum filtration, washed with fresh isopropanol, and dried under vacuum giving 92 mg (36%) of a yellow solid. LC-MS: RT=5.88 min, [M+H]+=343.1.
Reaction SMILES: [NH:1]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[N:15]=[C:14]([C:24]([O:26]CC)=O)[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:31].[Cl-]>N.CO>[NH:1]([C:8]1[N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:16]2[N:15]=[C:14]([C:24]([NH2:31])=[O:26])[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (50 mg, 0.12 mmol), and NH4Cl (10 mg, 0.1 9 mmol) in concentrated NH3 (3 mL) and MeOH (8 drops) was stirred for 16 h at room temperature. The solid was collected by filtration washing with water. Trituration with Et2O, provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide as a yellow solid (32 mg, 71%): LCMS RT: 1.93 min, MH+: 375.3. This trasformation can to also be accomplished using EDCI/HOBT coupling with NH3.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].C(N(CC)CC)C.[C:36]1([CH2:42][C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.O1CCCC1>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:43](=[O:44])[CH2:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a mixture of 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 and triethylamine (0.35 ml) in water (10 ml) was dropped a solution of phenylacetyl chloride (0.171 g) in tetrahydrofuran (10 ml) under cooling in an ice bath and stirring, which was continued for 30 minutes at the same temperature. The mixture was evaporated to remove tetrahydrofuran and the remaining aqueous solution was washed with diethyl ether and acidified with 6N hydrochloric acid. The mixture was extracted with a mixture (80 ml) of ethanolchloroform (1:1) and the extract was dried over magnesium sulfate, evaporated and triturated with diethyl ether to give 1-(6-benzoylamino-9H-purin-9-yl)-3-(phenylacetylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (370 mg), mp. 135°-140° C. (dec.).
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[CH3:15]S(C)=O.CCCCCCC.C(OCC)(=O)C>O>[CH3:15][O:12][N:7]1[C:8]([CH3:10])([CH3:11])[CH2:9][CH:4]([OH:3])[CH2:5][C:6]1([CH3:14])[CH3:13]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CS(C)=O
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CON1C(C)(C)CC(O)CC1(C)C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 17.9 g (64.4 mmol) of ferrous sulfate heptahydrate in 80 ml of water and a solution of 9.7 g (86 mmol) of 30% aqueous hydrogen peroxide are simultaneously added, under nitrogen, over a 90-minute interval to a mixture of 10.0 g (58.1 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 100 ml of dimethyl sulfoxide which is initially at 23° C. The temperature increases to 29° C. during the peroxide addition. After the addition is complete, the reaction mixture is stirred for two hours. The mixture is extracted with methylene chloride (200 ml, then 100 ml), and the crude product is purified by flash chromatography on silica gel (10:1 heptane/ethyl acetate, then 5:1 heptane/ethyl acetate) to afford 6.9 g (63% yield) of the title compound.
Reaction SMILES: [C:1]1(=[O:10])[C@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.F[B-](F)(F)F.[CH3:16][O+](C)C>>[CH3:16][O:10][C:1]1[C@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]=1
Reactant: C[O+](C)C
Reactant: O=C1NC[C@@H]2CCCC[C@@H]12
Agent: F[B-](F)(F)F
Product: COC1=NC[C@@H]2CCCC[C@@H]12

Procedure:
A sample of the title compound of EXAMPLE 171 (1.39 g, 10 mmol) was reacted with trimethyloxonium tetrafluoroborate (1.78 g, 12 mmol) by the method of EXAMPLE 26 to yield, after chromatography, 1.05 g (69%) of the title material.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:17])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCCc2ccc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1CCCc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A solution of 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (134 mg, 0.57 mmol), HBTU (327 mg, 0.86 mmol), and diisopropylethylamine (150 μL, 0.86 mmol) was stirred in methylene chloride (3.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (EXAMPLE SP-272) (234 mg, 0.57 mmol) and diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (3.0 mL) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (10 mL), saturated sodium bicarbonate (10 mL), and brine. The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1,2,3,4-tetrahydroquinoline-7-carboxamide (130 mg): ESI MS m/z 550 [M+H]+
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][N:30]=2)[CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][N:30]=2)[CH2:27][N:26]([S:10]([CH2:9][C@@:2]2([CH3:1])[NH:3][C:4](=[O:8])[NH:5][C:6]2=[O:7])(=[O:12])=[O:11])[CH2:25][CH2:24]3)=[CH:19][CH:20]=1
Reactant: Clc1ccc(-c2cc3c(cn2)CNCC3)cc1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4ccc(Cl)cc4)ncc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.5 %

Procedure:
[(4S)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.086 g, 0.38 mmol) in anhydrous NMP (0.50 mL) was added dropwise to a stirred solution of 6-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,7-naphthyridine (0.046 g, 0.19 mmol), DIPEA (0.066 mL, 0.38 mmol) and anhydrous NMP (1.5 mL) at RT. After the addition was complete the solution was stirred at RT for 1.5 h, then diluted with water (1 mL) and purified by preparative HPLC to afford 0.0070 g (8%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:4]2[CH:3]=1.[N:16]1([C:20]([C:22]2[CH:23]=[N:24][N:25]([CH3:30])[C:26]=2[C:27](O)=[O:28])=[O:21])[CH2:19][CH2:18][CH2:17]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:14]([O:13][C:11]([C:9]1[N:10]=[C:4]2[CH:3]=[C:2]([NH:1][C:27]([C:26]3[N:25]([CH3:30])[N:24]=[CH:23][C:22]=3[C:20]([N:16]3[CH2:19][CH2:18][CH2:17]3)=[O:21])=[O:28])[CH:7]=[CH:6][N:5]2[N:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1nc2cc(N)ccn2n1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Yield: 63.9 %

Procedure:
A mixture of ethyl 7-amino-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (540 mg, 2.62 mmol), 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (548 mg, 2.62 mmol), propylphosphonic anhydride (50% in ethyl acetate, 3.86 ml, 6.55 mmol) and diisopropylethylamine (1.37 ml, 7.86 mmol) in tetrahydrofurane (10 ml) is refluxed for 18 hours. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed several times with water and dried affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (665 mg, 63.9%) as a light brown solid. mp.: 252-5° C. MS: m/z=398.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=1.Cl[CH2:13][C:14]1[O:15][C:16]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([CH3:24])[C:17]=2[N:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:24][C:19]1[C:17]2[N:18]=[C:14]([CH2:13][NH:1][C:2]3[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=3)[O:15][C:16]=2[C:22]([CH3:23])=[CH:21][CH:20]=1
Reactant: CCc1cc(N)c(=O)[nH]c1C
Reactant: Cc1ccc(C)c2oc(CCl)nc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(NCc2nc3c(C)ccc(C)c3o2)c(=O)[nH]c1C
Yield: 42.8 %

Procedure:
A mixture of 3-amino-5-ethyl-6-methyl-2-(1H)-pyridinone (0.23 g, 1.5 mmol), 2-chloromethyl-4,7-dimethylbenzoxazole (0.29 g, 1.5 mmol), diisopropylethylamine (0.39 g, 3 mmol) in acetonitrile (50 mL) was refluxed under an atmosphere of nitrogen for 12 hours. The resultant mixture was concentrated under reduced pressure (15 torr). The residue was then subjected to column chromatography on silica gel (100 g, elution with 4% methanol in chloroform). Collection and concentration of appropriate fractions provided 0.2 g (44%) of the benzoxazolylmethylaminopyridone. Anal. Calcd. for C18H21N3O2 : C, 69.43; H, 6.80; N, 13.49. Found: C, 69.32; H, 6.66; N, 13.47.