Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:15][C:14]3[C:13](=[O:16])[O:12][C:11](=[O:17])[NH:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(N(C)C)=O>[CH2:24]([N:10]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:15][C:14]=2[C:13](=[O:16])[O:12][C:11]1=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1[nH]c2cc(-c3ccccc3)sc2c(=O)o1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1oc(=O)n(Cc2ccccc2)c2cc(-c3ccccc3)sc12
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of 6-phenyl-1H-thieno[3,2-d][1,3]oxazine-2,4-dione (1 g, 4.1 mmol) and anhydrous sodium carbonate (477 mg, 4.5 mmol) diluted in 15 ml of anhydrous dimethylacetamide was stirred for one hour under nitrogen before adding benzyl bromide (785 mg, 4.5 mmol). The mixture was stirred overnight at room temperature. 912 mg (66.3%) of 1-benzyl-6-phenyl-1H-thieno[3,2-d][1,3]oxazine-2,4-dione were obtained as a pale yellow solid after filtration and washing the precipitate with acetone and pentane. NMR 1H (DMSO D6, 400 MHz): 7.8-7.76 ppm (m, 3H, Haro); 7.51-7.45 ppm (m, 3H, Haro); 7.43-7.41 ppm (m, 2H, Haro); 7.35-7.3 ppm (m, 2H, Haro); 7.28-7.24 ppm (m, 1H, Haro); 5.22 ppm (s, 1H, NCH2).
Reaction SMILES: [CH3:1][C:2]([CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:10]=1)([CH3:8])[CH3:7])([CH3:4])[CH3:3].[I-:22].[K+].[I:24]([O-])(=O)=O>O>[CH3:4][C:2]([CH2:5][C:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])=[CH:13][CH:14]=1)([CH3:7])[CH3:8])([CH3:1])[CH3:3].[I:22][I:24].[I-:24]
Reactant: [O-][I+2]([O-])[O-]
Agent: CC(C)(C)CC(C)(C)c1ccc(OCCOCCO)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: II

Procedure:
In a suitable glass container is placed 9.9 gm. of octylphenoxypoly(ethyleneoxy) ethanol, dissolved in 50 ml. of water to which is added 0.1 gm. of potassium iodide. The mixture is then acid to a pH of below 3 and 0.02 gm. of iodate ion added with stirring. After standing for twenty-four hours, the solvent is evaporated under vacuum and the formed octylphenoxypoly-(ethyleneoxy)ethanol-iodine is obtained in substantially pure form, without iodide ions.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:21])[CH2:19][CH3:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 103.6 %

Procedure:
Beginning with 2.0 gm (8.7 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.91 mL (10.4 mMol) propionyl chloride, 2.58 gm of the title compound were prepared as a crude brown foam essentially by the procedure described in Example 4. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 10% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. This residue was crystallized from ethanol:water to provide 1.74 gm (70%) of the title compound in two crops.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:16]=[N:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].[Cl:17][C:18]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:9]2[CH:16]=[N:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:21]=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: N#Cc1ccncc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccncc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.8 %

Procedure:
A flask was charged with sodium hydride (3.99 g, 158 mmol) and DMF (50 mL), and 3-hydroxyisonicotinonitrile (15.8 g, 132 mmol) was added. The reaction was stirred for 2 hours at ambient temperature. 2-Chloro-4-nitropyridine (21.9 g, 138 mmol) was added and the reaction was and stirred overnight. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried and concentrated. The crude product was purified by silica gel chromatography, eluting with DCM, 5% ammoniated methanol in DCM to give the desired product (0.250 g, 0.820% yield) as yellow solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Br-:24].[C:10]([C:9]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2)#[N:11]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCc1ccccc1
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 60.5 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)acetonitrile (0.0470 g, 0.155 mmol) and (2-bromoethyl)benzene (0.045 mL, 0.329 mmol) in 2CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0457 g, 60.9%). EI-MS m/z 407(M+) Rt (2.14 min).
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:21]2[O:25][CH:24]=[CH:23][C:22]=2[CH:26]=1>C(Cl)Cl>[ClH:10].[N:31]1[CH:32]=[CH:33][C:28]([NH:27][C:20]2[C:21]3[O:25][CH:24]=[CH:23][C:22]=3[CH:26]=[C:18]([NH:17][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:19]=2)=[CH:29][CH:30]=1
Reactant: Nc1cc(Nc2ccncc2)c2occc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cl
Product: O=S(=O)(Nc1cc(Nc2ccncc2)c2occc2c1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Benzenesulfonyl chloride (65 μL, 0.48 mmol) and pyridine (289 μL, 3.58 mmol) were added to (5-amino-1-benzofuran-7-yl)pyridin-4-yl-amine (90 mg, 0.40 mmol; Intermediate 33) in DCM (2 mL). The mixture was heated at 40° C. for 10 min, shaken at room temperature for 1 h, and solvent was removed in vacuo. The residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. The obtained TFA salt was converted into the hydrochloride salt by treatment with 2 M HCl in ether to afford 78.7 mg (45%) of the title product. HPLC 100%, RT: 1.560 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 6.91 (s, 1H) 7.04 (d, J=2.23 Hz, 2H) 7.36 (d, J=1.98 Hz, 1H) 7.51-7.65 (m, 3H) 7.74-7.77 (m, 2H) 8.03 (d, J=1.98 Hz, 1H) 8.32 (d, J=6.93 Hz, 2H) 10.43 (s, 1H) 10.84 (s, 1H). LC-MS 366 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(OCl)(C)(C)C.[CH3:22][S:23][CH:24]([CH3:30])[C:25](OCC)=[O:26].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:2]=1[NH:1][C:25](=[O:26])[C:24]2([CH3:30])[S:23][CH3:22])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CCOC(=O)C(C)SC
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1(C)C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 3.94 g. (0.02 mole) of 2-amino-benzophenone in methylene chloride at -65° C. was treated with 2.16 g. (0.02 mole) of t-butylhypochlorite. After 15 min. 2.96 g. ethyl α-(methylthio)propionate was added dropwise and stirring continued for 1 hr. At the end of this time 2.02 g. of triethylamine (0.02 mole) was added dropwise and the reaction solution was allowed to warm to room temperature. This was followed by treatment with 1 N hydrochloric acid and stirred for 15 min. The methylene chloride solution was then separated and stripped under vacuum. The yellow oil residue was triturated with isopropyl ether and 3 g. of a yellow solid was filtered off (51%). Recrystallization from absolute ethanol gave a cream color solid, m.p. 135°-137° C.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:23](O)=[O:24])[N:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1>>[CH3:1][NH:2][C:23]([C:12]1[N:13]([CH3:22])[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)[N:11]=1)=[O:24]
Reactant: CN
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: CNC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 9, Step B, but using methylamine (0.20 mL of 2N methylamine in THF), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[C:12]([CH3:21])[CH:11]=1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37](=[O:49])[N:38]([CH:46]1[CH2:48][CH2:47]1)[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:35])([CH3:34])[CH3:33]>ClCCl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([N:43]2[CH2:42][CH2:41][CH:40]([CH2:39][N:38]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:49])[CH:46]3[CH2:48][CH2:47]3)[CH2:45][CH2:44]2)=[O:20])=[C:12]([CH3:21])[CH:11]=1
Reactant: COC(=O)c1ccc(CCC(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N(CC1CCNCC1)C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CCC(=O)N2CCC(CN(C(=O)OC(C)(C)C)C3CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Oxalyl chloride (1.26 ml, 14.4 mmol) was added to a solution of 4-(2-carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (1.60 g, 7.2 mmol) in dichloromethane (50 ml) and few drops of DMF. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (50 ml) and DIEA (2.5 ml, 14.4 mmol) and cyclopropyl-piperidin-4-ylmethyl-carbamic acid tert-butyl ester from Example E38 (1.83 g, 7.2 mmol) in dichloromethane (5 ml) was added. The mixture was stirred for 2 h at room temperature, diluted with dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane) to yield the title compound (1.42 g, 43%).
Reaction SMILES: [H-].[Na+].C(N(CC)CC)C.[OH:10][CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[Br:22][C:23]1[CH:28]=[CH:27][C:26](F)=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=1>CN(C=O)C.CCOC(C)=O>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:10][CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(Br)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (247 mmol, 9.88 g) was stirred in DMF (100 ml) at room temperature. triethylamine (165 mmol, 22.88 ml, 16.66 g) was added. tert-butyl 2-hydroxyethyl(methyl)carbamate (173 mmol, 30.3 g) was added dropwise in DMF. 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (165 mmol, 40 g) was added in one portion and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water. The organic was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with heptane—60/40 heptane/EtOAc. Fractions were collected and combined to afford tert-butyl 2-(4-bromo-2-(trifluoromethyl)phenoxy)-ethyl(methyl)carbamate. (18.44 g)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14]OS(C)(=O)=O)[C:5]([CH2:8]OS(C)(=O)=O)=[N:6][CH:7]=1.CO.[NH3:22]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:14][NH:22][CH2:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)OCc1cc(Br)cnc1COS(C)(=O)=O
Reactant: N
Solvent: CO
Product: Brc1cnc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 58 (1 g, crude) in MeOH (5 mL) was added MeOH—NH3 (5 mL) at 0° C. and stirred at rt for overnight. The reaction mixture was evaporated to obtain the desired compound (600 mg, crude) as a brown liquid. Rf: 0.2 (10% MeOH/CHCl3). The crude compound was used in the next step without further purification; (m/z): 199, 201 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15](O)=[O:16])=[CH:9][CH:8]=1.S(Cl)(Cl)=O.[CH3:26][NH2:27]>ClCCl.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([NH:27][CH3:26])=[O:16])=[CH:9][CH:8]=1
Reactant: O=C(O)C=Cc1ccc(OCc2ccc(F)c(F)c2)cc1
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)C=Cc1ccc(OCc2ccc(F)c(F)c2)cc1
Temperature: 45 °C
Yield: 26 %

Procedure:
500 mg (1.72 mmol) 3-[4-(3,4-difluoro-benzyloxy)-phenyl]-acrylic acid is suspended in 5 ml dichloromethane. 0.62 ml (8.6 mmol) thionyl chloride is added and the reaction mixture heated overnight to 45° C. Concentration leaves a yellowish tar which is dissolved again in 10 ml dichloromethane and treated with 1.1 ml of a 33% solution of methylamine in ethanol. After heating at 45° C. for 3 hours, the reaction mixture is filtered and the filtrate concentrated. Chromatography (silica gel, dichloromethane/methanol) yields 136 mg (26%) of a colorless solid. MS: m/e=304.1 (M++H).
Reaction SMILES: CC(O[Hg][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:12]([O-:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B([O-])([O-])[O-].[Br-].[Cl-]>>[C:12]([O:20][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CC(=O)O[Hg]c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [O-]B([O-])[O-]
Product: O=C(Oc1ccccc1)c1ccccc1

Procedure:
Phenyl Mercuric Acetate, Benzoate, Borate, Bromide or Chloride
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].B(O)(O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CO>COCCOC.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>[F:10][C:9]([F:12])([F:11])[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: COCCOC
Product: FC(F)(F)Oc1ccccc1-c1ccncc1
Yield: 51 %

Procedure:
To a solution of (commercially available) (1-bromo-2-trifluoromethoxy-benzene) in DME (first degased with argon) under argon was added 3 mol % Pd(PPh3)4, pyridyl-4-boronic acid and 2N Na2CO3, the resulting reaction mixture was vigorously stirred under reflux. After 5 h at reflux, reaction as monitored by TLC showed completion. Two phases were separated, evaporation of most of the DME, redissolution of the residue in EtOAc and washing with aq. NaOH followed by evaporation gave a yellow oil. Flash Chromatography on SiO2 gel with a mixture of CH2Cl2/MeOH gave the title compound in 51% yield.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[O:23][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Reactant: Oc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(Oc2c(F)cccc2F)cnn1C1CCCCO1
Temperature: 120 °C
Yield: 48.3 %

Procedure:
A solution of 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (204 mg, 0.67 mmol) in anhydrous N,N-dimethylformamide (8.5 mL, 0.08M) was treated with 2,6-difluorophenol (0.09 g, 0.69 mmol) and potassium carbonate (0.20 g, 1.45 mmol). The reaction was heated at 120° C. overnight. At this time, the reaction was diluted with water (25 mL) and extracted with methylene chloride (3×25 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (25 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 24 g, 20% to 40% ethyl acetate/hexanes) afforded 5-(2,6-difluoro-phenoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (99.7 mg, 49%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.56 (m, 2H), 1.57-1.76 (m, 2H), 1.88-2.01 (m, 1H), 2.01-2.16 (m, 1H), 3.53-3.63 (m, 1H), 3.90-3.98 (m, 1H), 5.82 (dd, J=10.5, 1.6 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 7.34-7.43 (m, 2H), 7.43-7.55 (m, 1H), 8.23 (d, J=2.7 Hz, 1H).
Reaction SMILES: [Cl:1][N:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C@H:12]2[O:24][C@@H:23]([CH2:25][O:26]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@@H:13]2[O:14]C(=O)C)[CH:3]1[NH:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Cl:1][N:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C@H:12]2[O:24][C@@H:23]([CH2:25][OH:26])[C@H:18]([OH:19])[C@@H:13]2[OH:14])[CH:3]1[NH:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(=O)OC[C@@H]1O[C@H](N2c3cccc(Cl)c3N(Cl)C2NC(C)C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(C)NC1N(Cl)c2c(Cl)cccc2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O

Procedure:
3,4-Dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (2.06 g, 4.10 mmol), sodium carbonate (0.60 g, 5.66 mmol), water (12 mL), methanol (10 mL), and ethanol (24 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH2:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:24]([CH2:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH:23][C:32](=[O:33])[CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NC(=O)COc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A mixture of 1 g (3.1 mmol) 4-(3-amino-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, 0.793 g (4.65 mmol) phenoxyacetyl chloride and 2.2 g (21.7 mmol) triethylamine in 20 ml THF was stirred at room temperature for 30 min. The mixture was evaporated and 100 ml DCM were added. The organic phase was washed with 2×50 ml 0.1 M Na2CO3 aq. The combined aqueous phase was extracted with 2×100 ml DCM. The combined organic phases were dried with MgSO4 and evaporated to dryness. The residue was purified over silica eluting with ethyl acetate/hexane 1/1 to yield 1.15 g (81%) of the title compound as yellow solid. MS(ISP): 455.3 (M−H)−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15].[CH2:17]([O:19][C:20](=O)[O:21]CC)[CH3:18].[H-].[Na+].CC(O)=O>C1(C)C=CC=CC=1.O>[CH2:17]([O:19][C:20](=[O:21])[CH2:15][C:14](=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[CH3:18]
Reactant: CC(=O)c1ccccc1OCC1CCCO1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccccc1OCC1CCCO1
Yield: 63.3 %

Procedure:
A mixture of 1-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-ethanone (2.22 g, 0.01 mol) and diethylcarbonat (10 mL, 0.083 mol) in anhydrous toluene (20 mL) was added dropwise to a suspension NaH (1.0 g, 0.025 mol) in anhydrous toluene (20 mL). After addition, the mixture refluxed for 2 h, cooled and poured slowly into a solution AcOH (3 mL) and water (50 mL). After separated the organic layer, the aqueous layer was extracted with ethyl acetate (2×50 mL). Organic layers were combined, washed with water (20 mL), then dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (eluent hexane-ethylacetate, 1:5) to obtain 1.85 g (64%) 3-oxo-3-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-propionic acid ethyl ester as yellow oil.
Reaction SMILES: C(NC1C=C(C=C(C2OC=CN=2)C=1)[C:13]([NH:15][C@@H:16]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:17]([C@H:26]1[CH2:30][C@@H:29]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH2:28][N:27]1C(OC(C)(C)C)=O)[O:18][Si](C(C)(C)C)(C)C)=[O:14])(=O)C1C=CC=CC=1.[CH2:59]([N:62]([CH2:79][CH2:80][CH3:81])[C:63]([C:65]1[CH:66]=[C:67]([CH:71]=[C:72]([C:74]2[O:75][CH:76]=[CH:77][N:78]=2)[CH:73]=1)C(O)=O)=[O:64])[CH2:60][CH3:61].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Si](O[C@H]([C@H]1CC(O)(C2C=CC=CC=2)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C>C(Cl)Cl>[OH:18][C@H:17]([C@H:26]1[CH2:30][C@@H:29]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH2:28][NH:27]1)[C@@H:16]([NH:15][C:13](=[O:14])[C:67]1[CH:71]=[C:72]([C:74]2[O:75][CH:76]=[CH:77][N:78]=2)[CH:73]=[C:65]([C:63]([N:62]([CH2:59][CH2:60][CH3:61])[CH2:79][CH2:80][CH3:81])=[O:64])[CH:66]=1)[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCCS(=O)(=O)[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cc(F)cc(F)c1)NC(=O)c1cccc(C(N)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)[C@H]2C[C@@H](S(=O)(=O)CCC)CN2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
Step 17 (F): (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-(oxazol-2-yl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-phenylpropyl)-4-(propylsulfonyl)pyrrolidine-1-carboxylate. To a solution of 3-(dipropylcarbamoyl)-5-(oxazol-2-yl)benzoic acid (prepared as reported in WO 2002/02512, 20 mg, 0.062 mmol) in DCM is added HATU (28 mg, 0.073 mmol) and DIEA (33 mg, 0.26 mmol). After the solution is stirred at rt for 5 min, a 28 mg portion of the compounds of step 17 (E) (0.052 mmol) is added. The reaction solution was stirred 16 h at rt, and then the reaction solution was partitioned between ethyl acetate and water, the organic layer was concentrated, and the crude product was purified by chromatography eluting with a step gradient of 20% to 50% to 70% ethyl acetate in hexanes to provide 40 mg (98%) of the desired amide. MS (ESI) (M+H−Boc)+=739.34