Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.[O:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(OCCCl)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C.O>[CH2:25]([O:24][CH2:28][CH2:27][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[CH3:26]
Reactant: C1CCOC1
Reactant: c1ccc(CN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOCCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CCOCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-benzylpiperidin-4-yl)amine (0.5 g, 1.6 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. Add dropwise, a solution of potassium bis(trimethylsilyl)amide (3.6 mL, 0.5 M in toluene, 1.8 mmol). After 30 minutes, add 2-chloroethyl ethyl ether (0.2 g, 1.8 mmol). Warm to ambient temperature and heat to reflux. After 4 hours, add 2-chloroethyl ethyl ether (0.2 g, 1.8 mmol) and tetrabutylammonium bromide (0.1 g). After 12 hours, cool to ambient temperature and add water. Separate the organic layer and extract the aqueous layer with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(1-benzylpiperidin-4-yl)amine: Rf=0.55 (2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[CH:27]=1>O1CCCC1.CN(C)C=O.O>[CH:34]1([C:32]([NH:31][C:29]2[N:30]=[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]4[CH:19]=[C:18]([NH:17][C:8]([C:3]5[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=5)=[O:10])[CH:39]=[CH:38][CH:37]=4)=[CH:27][N:26]3[CH:28]=2)=[O:33])[CH2:35][CH2:36]1
Reactant: Cc1cccnc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-methylpyridine-2-carboxylic acid (53.5 mg, 0.390 mmol) in tetrahydrofuran (3 mL) were added oxalyl chloride (68.0 μL, 0.780 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in N,N-dimethylacetamide (3 mL). N-[6-(3-Aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (60.0 mg, 0.195 mmol) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (58.0 mg, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[C:23]([OH:32])(=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:26].C(=O)(O)[O-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:23]([OH:32])=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(NCCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(F)cc1)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A solution of the title B compound, 4-[2-(4-fluoro-phenyl)-ethylcarbamoyl]-benzene-sulfonyl chloride (171 mg, 0.5 mmol) in THF (2 mL) is added dropwise over 10 min to a solution of the anthranilic acid (68.6 mg, 0.5 mmol) in water (1 mL) containing sodium bicarbonate (126 mg, 1.5 mmol). After stirring for 30 min, the solvent is evaporated under a stream of nitrogen, and water (8 mL) is added. The mixture is stirred for a few min, then filtered. The filtrate is added dropwise to an excess of 1 N aqueous HCl to precipitate a light tan solid. The solid is collected by filtration, washed with water, and dried under vacuum to give 2-{4-[2-(4-fluoro-phenyl)-ethylcarbamoyl]-benzenesulfonylamino}-benzoic acid: m.p. 85-86° C.; ESI-MS 441 [M−1]−.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:8]=2[CH:7]=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:30])C=1.O.[OH-].[Na+]>C(Cl)Cl>[Cl:20][C:6]1[C:5]2[O:21][CH:2]([CH2:3][OH:30])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:8]=2[CH:7]=1
Reactant: C=CCc1c(O)c(Cl)cc2c(-c3ccccc3F)noc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4F)noc23)O1
Temperature: 0 °C
Yield: 65 %

Procedure:
To the ice-cooled solution of 7-allyl-5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (9.5 g) in methylene chloride (200 ml), m-chloroperbenzoic acid (16.4 g) was added in small portions under agitaiton, and the solution was subsequently refluxed for 3 hours. After cooling the solution, water and 100 ml of an aqueous solution of 2N sodium hydroxide were added and the mixture was subjected to extraction with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 6.5 g of 5-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 136°-139° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 319.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N)CCCC>ClCCl>[CH2:18]([NH:17][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: CCCCCN
Product: CCCCCNC(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution diphenylacetyl chloride (1.73 mmol) and pyridine (0.28 ml, 3.46 mmol) in dichloromethane (12 ml) was added pentylamine (0.39 ml, 2.60 mmol) and the reaction mixture was stirred at RT for 16 h. Aqueous work up and crystallization from ethyl acetate/hexane yielded the product as a light yellow solid, m.p. 101° C. and MS: m/e=281 (M+).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]([Mg]Br)#[CH:6].[F:9][C@H:10]1[CH2:27][C@@:25]2([CH3:26])[C@@H:21]([CH2:22][CH2:23][C:24]2=[O:28])[C@H:20]2[C@H:11]1[C@@H:12]1[C:17](=[CH:18][C@H:19]2[CH3:29])[CH:16]=[C:15]([O:30]C)[CH2:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1.O>[C:5]([C@:24]1([OH:28])[CH2:23][CH2:22][C@H:21]2[C@H:20]3[C@H:11]([C@@H:10]([F:9])[CH2:27][C@:25]12[CH3:26])[C@@H:12]1[C:17](=[CH:16][C:15](=[O:30])[CH2:14][CH2:13]1)[CH2:18][C@H:19]3[CH3:29])#[CH:6]
Reactant: C#C[Mg]Br
Reactant: COC1=CC2=C[C@@H](C)[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@]1(O)CC[C@H]2[C@H]3[C@H]([C@@H](F)C[C@@]21C)[C@H]1CCC(=O)C=C1C[C@H]3C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 9.17 g of cerium(III) chloride in 60 ml of tetrahydrofuran was mixed drop by drop at 0° C. with 74.2 ml of an ethinylmagnesium bromide solution (0.5 M in tetrahydrofuran) and stirred for 1 hour at 0° C. Then, a solution of 2 g of crude 11β-fluoro-3-methoxy-7α-methylestra-3,5-dien-17-one in 40 ml of tetrahydrofuran was added drop by drop and stirred for another 3.5 hours at 0° C. For working-up, a saturated ammonium chloride solution was added, added to water, extracted three times with ethyl acetate, washed with semiconcentrated hydrochloric acid, sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 1.15 g of pure 17α-ethinyl-11β-fluoro-17β-hydroxy-7α-methylestr-4-en-3-one with a melting point of 218-220° C. was obtained. [α]D=+19.2° (CHCl3).
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].CC#N.CCN(CC)CC.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=1>O>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH:5][CH2:4][C:3]([F:7])([F:6])[F:2])=[CH:21][CH:20]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)CNCc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 92.7 %

Procedure:
In 15 ml of water was dissolved 12.55 g of 2,2,2-trifluoroethylamine hydrochloride, followed by addition of 68 ml of CH3CN, and further 9.35 g of Et3N and then 3.00 g (0.0185 mole) of 6-chloro-3-pyridylmethyl chloride under cooling with ice-water and stirring. The mixture was stirred at room temperature for one hour, at 50° C. for one hour and at 70° C. for 90 hours. The CH3CN was distilled off, and the residue was followed by addition of NaHCO3 and then extracted with CH2Cl2 (100 ml×3). The extract was dried over MgSO4 and distilled to remove CH2 Cl2 . To the residue was added 100 ml of Et2O and the resulting unsoluble matter was filtered off. The filtrate was concentrated to give 3.85 g of the title compound as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:8][C:6]1[CH:7]=[C:2]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[F:9])[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)c(F)c1
Temperature: 80 °C
Yield: 96.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (Aldrich, 0.74 g, 5.0 mmol), 2-fluoro-4-nitrophenol (Aldrich, 0.79 g, 5.0 mmol) and DMF (10 ml) was treated with potassium carbonate (0.72 g, 5.2 mmol) and heated at 80° C. for 3 h. The mixture was cooled, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4), and concentrated to give the crude product as a yellow solid. The crude product was triturated with isopropyl ether to give 4-chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine as a yellow solid (1.3 g, 94%). 1H NMR (DMSO-d6) δ 8.80 (s, 1H), 8.51 (dd, 1H, J=8.6, 2.5 Hz), 8.31 (d, 1H, J=9.1 Hz), 7.87 (d, 1H, J=9.1 Hz), 7.84 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[S:35][C:34]([C:36](O)=[O:37])=[N:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:34]4[S:35][C:31]([CH3:30])=[CH:32][N:33]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1cnc(C(=O)O)s1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ncc(C)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 5-methylthiazole-2-carboxylic acid (30 mg, 0.21 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC=CC=1[C:62]([F:65])([F:64])[F:63])#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:62]([F:65])([F:64])[F:63])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Reactant: C#Cc1ccccc1C(F)(F)F
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1ccccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-2-(trifluoromethyl)benzene in quantitative yield.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[N:9][CH:10]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[N:9][CH:10]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(CCCO)cn1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)OC)c(CCCCl)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
370 mg of dimethyl 5-(3- hydroxypropyl)-pyridine-2,4-dicarboxylate (from Example 16) are dissolved in 10 ml of chloroform, the solution is cooled to 0° C. and 0.18 ml of thionyl chloride in 2 ml of chloroform are slowly added. The mixture is subsequently stirred at room temperature for one hour and then at 60° C. for one hour. After cooling, the mixture is evaporated and the residue is taken up in chloroform and water; the phases are separated and the organic phase is washed with sodium sulfate solution, dried over magnesium sulfate and evaporated. After chromatography on silica gel, 286 mg of a yellow oil remain.
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:49])[C@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.C(N)CCC>CO>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:49])[C@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C@H:20]1[OH:21]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Solvent: CO
Solvent: CCCCN
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)[C@H]1O
Yield: 73.3 %

Procedure:
A mixture of 1-(6-benzoylamino-9H-purin-9yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-L-phenylalanylamino)-β-D-ribofuranuronic acid (432 mg) prepared in Example 5 and n-butylamine (3.5 ml) in methanol (15 ml) was refluxed for 50 minutes and evaporated to dryness. The residue was dissolved in a mixture of water and diethyl ether and the aqueous layer was separated out. The aqueous solution was adjusted to pH 4 to 5 with 10% hydrochloric acid and the resulting precipitates were collected by filtration, washed with water and dried to give 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-L-phenylalanylamino)-β-D-ribofuranuronic acid (267 mg), mp. 195°-201° C. (dec.).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22].CN1CCOCC1>O.C(#N)C>[F:19][C:20]([F:26])([F:25])[S:21]([NH:2][C@@H:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])=[O:22]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Acetonitrile (100 ml) was added to hydrochloride (4.00 g, 14.6 mmol) of ethyl (S)-2-amino-3-(4-nitrophenyl)propionate and trifluoromethylsulfonyl chloride (2.5 ml, 23.5 mmol) and then N-methylmorpholine (3.2 ml, 29.1 mmol) were added. The mixture was stirred at room temperature for 2 hours. Water (100 ml) was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/n-hexane=2/1) to give 2.25 g of ethyl (S)-2-(trifluoromethylsulfonylamino)-3-(4-nitrophenyl)propionate as a yellow solid (42%). This solid (1.97 g, 5.32 mmol) was dissolved in acetic acid. (100 ml) and 10% palladium-carbon (750 mg) was added. The mixture was stirred at room temperature for 66 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite and acetic acid was distilled away from the filtrate under reduced pressure. The residue was washed with water to quantitatively give 1.81 g of ethyl (S)-3-(4-aminophenyl)-2-(trifluoromethylsulfonylamino)propionate as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(OCC)C)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]=[O:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:45](O)[CH2:46][OH:47].C([O-])(O)=O.[Na+].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]3[O:20][CH2:45][CH2:46][O:47]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3ccccc3)c(C=O)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCc1nc2cc(-c3ccccc3)c(C3OCCO3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 84.9 %

Procedure:
0.1 g(0.000169 mole) of the aldehyde compound obtained in step 11 of Example 1 and 0.032 g(0.000507 mole) of ethylene glycol were dissolved in 5 ml of benzene and to the resulting solution was added 0.01 mg of p-toluenesulfonic acid. The resultant was refluxed for 6 hours and thereto were added 1 ml of aqueous saturated NaHCO3 solution and 5 ml of water. The reaction solution was extracted with ethyl acetate(5 ml×3) and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resultant was recrystallized from hexane-methylene chloride to obtain 80 mg of the title compound(yield 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:12]2[CH:17]=[CH:16][C:15]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Na+].Cl>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:12]2[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CN(Cc2cccc([N+](=O)[O-])c2)c2ccc(S(=O)(=O)[O-])cc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccc(CN(Cc2cccc([N+](=O)[O-])c2)c2ccc(S(=O)(=O)O)cc2)c1
Temperature: 25 °C

Procedure:
A mixture of 25.75 grams (g) (0.15 mole) of sulfanilic acid in 450 milliliters (ml) of water, 37 g (0.46 mole) of 50 percent sodium hydroxideand 58.3 g (0.34 mole) of 3-nitrobenzyl chloride was stirred and heated to about 90° C. for 31/2 hours, during which time the reaction mixtureturned from a milky yellow to a reddish brown color. The solution was allowed to cool overnight and the resulting solid isolated by vacuum filtration. The solid was washed thoroughly with diethyl ether to remove excess 3-nitrobenzyl chloride, leaving 20.0 g of sodium 4-(bis((3-nitrophenyl)methyl)-amino)benzenesulfonate as shiny, yellow flakes having a melting point greater than 275° C. A 14.7 g portionof the sodium 4-(bis((3-nitrophenyl)methyl)amino)-benzenesulfonate was heated to 65° C. in approximately 350 ml of absolute ethanol and then acidified with concentrated hydrochloric acid. Upon cooling to room temperature, a solid crystallized which was recovered by vacuum filtrationto give 10.0 g of 4-(bis((3-nitrophenyl)methyl)amino)benzenesulfonic acid as light tan crystals which decomposed at 226°-228° C.
Reaction SMILES: C([N:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([CH3:20])[CH3:19])C1C=CC=CC=1>CC(O)=O.[Pd]>[CH3:17][C:16]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:20])([CH3:19])[NH:8]1
Reactant: CC1(C)c2ccccc2C(C)(C)N1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)NC(C)(C)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
(Griffiths, P. G. et al Synthesis of the radical scavenger 1,1,3,3-tetramethylisoindolin-2-yloxyl. Aust. J. Chem. 1983, 36, 397-401; Chan, K. S. et al. Reactions of nitroxides with metalloporphyrin alkyls bearing beta hydrogens: aliphatic carbon-carbon bond activation by metal centered radicals. J. Organomet. Chem. 2008, 693, 399-407). The protected benzyl-amine 16 (1.864 g, 7.02 mmol) was dissolved in AcOH (34 mL) in a Parr flask, and 10% Pd/C (169.5 mg) was added. (The reaction was splited in 3 batches.) The flask was placed in a high pressure reactor. The reactor was charged with H2 and purged for 5 cycles and was finally pressurized with H2 at 4 bars (60 psi). After stirring at rt for 3 h, the reaction mixture was filtered through Celite, and the solvent removed in vacuo. The resulting residue was dissolved in water (5 mL) and the solution neutralized with 2.5N NaOH (pH 11.5), and extracted with Et2O (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to yield 1.165 g (95%) of the crude title compound as slightly yellow crystals. mp 36.0-36.5° C. 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2 H), 7.18-7.11 (m, 2 H), 1.86 (bs, 1 H), 1.48 (s, 12 H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:19]([F:20])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(C(F)(F)F)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(c2ccc(C(F)(F)F)cn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of D1 (11.5 g, 0.04 mol) in DCM (80 ml) was cooled (ice-bath) and trifluoroacetic acid (excess, 50 ml) was added. Reaction was warmed to ambient temperature, stirred for 3 h and partitioned between ethyl acetate and aqueous sodium hydroxide. The organic phase was separated, dried (MgSO4) and filtered. Removal of solvent under reduced pressure afforded the crude product as a yellow oil. Bulb to bulb distillation under reduced pressure initially afforded the title compound as an oil which crystallised on standing.