Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1.C(N(CC)CC)C>CN1CCCC1=O>[NH:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:3]=2)[CH2:20][CH2:21]1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(Nc2cc(NCC3CCNCC3)ncn2)cn1
Temperature: 145 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
A mixture of 5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (124 mg, 0.533 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (228 mg, 1.066 mmol) and triethylamine (150 μL, 1.07 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated at 145° C. for 15 minutes using microwave irradiation. The mixture was concentrated in vacuo and the residue purified by preparative HPLC. The purified solid was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (3 mL) and was stirred for 1 hour at room temperature before being applied to a MP-TsOH cartridge. After washing with methanol, the pure product was eluted using 7M ammonia to give 5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile (10.3 mg, 6%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11]([C:34]2[C:29]([F:28])=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1F
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cccnc2F)nc1Cl

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=27%).
Reaction SMILES: CN(C)C=[CH:4][C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:16][CH2:17][CH3:18])[N:6]=1.O.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCCC1>[CH2:17]([O:16][C:7]1[N:6]=[C:5]([CH:4]=[O:22])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:18]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOc1nc(C=CN(C)C)c([N+](=O)[O-])cc1C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1nc(C=O)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a stirred solution of the compound prepared in Example 445 (1.07 g) in tetrahydrofuran (20 mL) at ambient temperature was added water (20 mL), and to the resulting mixture was added sodium periodate (2.62 g). The resulting mixture was stirred at ambient temperature for 18 hours. There was a significant amount of precipitate present in the reaction mixture, and it was collected by filtration and washed with 50% aqueous tetrahydrofuran. The combined filtrate and wash were concentrated to remove most of the tetrahydrofuran, and the residue was extracted with chloroform. The organic layers were combined and dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 1/1 hexanes/ethyl acetate, to provide the title compound (0.61 g) with the following physical data.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[CH:24]1([SH:29])[CH2:28][CH2:27][CH2:26][CH2:25]1.[H-].[Na+]>C1COCC1>[CH:24]1([S:29][C:5]2[C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:3]([CH:2]([F:23])[F:1])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Reactant: SC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1SC1CCCC1
Yield: 107.1 %

Procedure:
This compound was prepared as described in Example 108: 3 g (0.0083 mol) of product of Example 103, 1.02 g (0.01 mol) of cyclopentylmercaptan and 0.36 g (0.009 mol) of 60% NaH in 50 ml of dry THF were reacted affording 3.8 g of a red oil. Crude was purified by HPLC using 1% ethyl acetate/cyclohexane as eluting solvent to give 2.5 g of a light yellow oil which gas chromatography showed to be 94% pure. This material was passed through a spinning plate preparative chromatograph in two different portions of 1.25 g each (eluting solvent: 40% CH2Cl2 /cyclohexane) to give, after kugelrohr distillation at 105°-125° C./106 Pa, 1.95 g (55%) of product as a clear oil; nD25 1.4831.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>CO>[CH3:17][O:16][C:12]([CH2:13][CH2:14][N:1]([CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])[CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15])=[O:15]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(CCC[Si](OC)(OC)OC)CCC(=O)OC
Temperature: 30 °C
Yield: 99.1 %

Procedure:
3-Aminopropyltrimethoxysilane (11.05 g, 61.7 mmol) and methanol (20 ml) are stirred together for 30 minutes at room temperature. To the mixture is added 41.46 g (482 mmol) of methyl acrylate. The reaction mixture is heated overnight in a 30° C. oil bath. The reaction mixture is concentrated at reduced pressure to give 21.50 g of crude methyl 3-[(2-methoxycarbonylethyl)-(3-trimethoxysilylpropyl)amino]propionate, a yellow viscous oil. A mixture of the crude product, 1-[4-(2-hydroxyethyoxy)phenyl]-2-hydroxy-2-methylpropan-1-one (26.85 g, 119.7 mmol) and 1,2-dimethoxyethane (80 ml) is heated in an oil bath at 85° (bath temperature). Zirconium(IV) acetylacetonate (1.16 g, 2.38 mmol) is added, and the mixture is stirred at 85° C. overnight and then at room temperature for 24 hours. Solvent is evaporated, and approximately one-half of the crude product is passed through a silica gel column with 5:1 chloroform:methanol as eluent to obtain 15.74 g of the title compound, a yellow semisolid product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36](B(O)O)=[CH:35][CH:34]=[N:33]2)=[CH:28][CH:27]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[CH3:11][NH:10][C:8]([C:6]1[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]([CH3:23])=[C:2]([C:36]2[N:32]([C:29]3[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)[N:33]=[CH:34][CH:35]=2)[N:7]=1)=[O:9]
Reactant: CNC(=O)c1nc(Br)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: N#Cc1ccc(-n2nccc2B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CNC(=O)c1nc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 19.6 %

Procedure:
6-Bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (SM2, 0.05 g, 0.128 mmol), 1-(4-cyanophenyl)-1H-pyrazol-5-boronic acid (SM4, 0.062 g, 0256 mmol), Cs2CO3 (0.125 g, 0.384 mmol) and DME (3 ml) were added to a glass tube for microwave synthesis. The mixture was degassed with nitrogen and Pd(PBut3)2 (0.010 g) was added. The tube was sealed and heated with stirring at 110° C. (150 W) in a microwave heater for 10 minutes. The mixture was diluted with EtOAc (5 ml), and filtered. The solution was concentrated in vacuo and was purified by chromatography on silica to give a reasonably pure material that was further purified by preparative HPLC to give 0.012 g (20%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@@H:10]([CH:25]=[CH2:26])[C@@H:11]([OH:24])[C@@H:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C>[CH2:3]([C@@H:10]([CH:25]=[CH2:26])[C@@H:11]([O:24][CH2:28][CH2:29][O:30][CH3:31])[C@@H:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCCBr
Reactant: C=C[C@H](Cc1ccccc1)[C@@H](O)[C@H](C)OCc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@H](Cc1ccccc1)[C@@H](OCCOC)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
To a suspension of NaH (0.088 g, 3.68 mmol) in DMF (10 mL) was added dropwise a solution of (2S,3R,4S)-4-benzyl-2-((4-methoxybenzyl)oxy)hex-5-en-3-ol (1 g, 3.06 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 20 min and then 1-bromo-2-methoxyethane (0.852 g, 6.13 mmol) was added. The reaction mixture was heated to 60° C. for 5 h. The reaction was cooled to room temperature and another portion of NaH (0.088 g, 3.68 mmol) and 1-bromo-2-methoxyethane (0.852 g, 6.13 mmol) were added, and the reaction mixture was heated to 60° C. and stirred overight. The reaction mixture was quenched with saturated NH4Cl and the phases were separated. The aqueous phase was extracted with EtOAc (2×40 mL), and the combined organic phases were dried over MgSO4, concentrated, and purified by column chromatography on SiO2 (EtOAc/hexanes) to furnish the title product as colorless oil (0.730 g, 62%): 1H NMR (400 MHz, CDCl3) δ 7.30-7.06 (m, 7H), 6.86 (dd, J=8.6, 0.9 Hz, 2H), 5.68-5.47 (m, 1H), 4.95-4.69 (m, 2H), 4.60-4.26 (m, 2H), 4.04-3.91 (m, 1H), 3.79 (s, 3H), 3.73-3.69 (m, 1H), 3.68-3.60 (m, 1H), 3.59-3.53 (m, 2H), 3.39 (d, J=0.8 Hz, 3H), 3.38-3.36 (m, 1H), 3.15 (d, J=10.4 Hz, 1H), 2.70-2.42 (m, 2H), 1.30-1.17 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 159.05, 140.67, 138.83, 130.95, 129.56, 129.11, 127.92, 125.60, 116.61, 113.74, 84.59, 76.46, 72.41, 71.76, 70.26, 58.96, 55.28, 48.55, 36.96, 14.01; ESIMS m/z 407.2 ([M+Na]+).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:25]=[CH:24][N:23]=[C:22]3[C:13]=2[CH:14]=[CH:15][C:16]2[C:21]3=[N:20][CH:19]=[CH:18][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1>CO.C(Cl)Cl>[C:1]([C:19]1[CH:18]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21](=[C:22]3[C:13](=[CH:14][CH:15]=2)[C:12]([C:9]2[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=2)=[CH:25][CH:24]=[N:23]3)[N:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Reactant: [Li]C(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)ccnc3c2n1
Yield: 70 %

Procedure:
This yellow compound was prepared in a process analogous to the synthesis of PBP in which 2 equivalents of t-butyllithium were used for each equivalent of bathophenanthroline. The clean product was obtained after running chromatography in a silica/mixture of methanol/CH2Cl2 (1:1) column with a yield of 70 percent. 1H NMR (500 MHz, CDCl3) ppm: 9.28 (m, 1H), 7.81-7.74 (m, 2H), 7.68 (s, 1H), 7.57-7.35 (m, 11H), 1.62 (s, 9H). Analysis for mono-t-BBP. Found: C, 86.19, H, 6.18, N, 7.19. Calculated: C, 86.56, H, 6.25, N, 7.21.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>CC(C)=O>[CH3:2][CH2:1][NH:3][C:4](=[O:5])[NH:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][C:13]([O:16][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])=[CH:12][C:10]=2[N:11]=1
Reactant: CCNC(=O)Nc1nc2ccc(O)cc2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2cc(OS(=O)(=O)c3cccs3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
A stirred solution of 1-ethyl-3-(6-hydroxy-1H-benzoimidazol-2-yl)-urea (35 mg, example 84-c) and thiophene-2-sulfonyl chloride (18 mg) in acetone (3 ml) was treated with triethylamine (25 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LCMS triggered purification to give thiophene-2-sulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester (14 mg) as a off-white solid Mass spectrum: 367 [M+H]+; retention time=7.88 minutes.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:10][C:11]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][CH:13]2[CH2:14][CH2:15][CH2:16][C:11]([CH3:18])([CH3:10])[CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: CC1(C)CCCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC1CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-2-methylaniline (1000 mg) and 3,3-dimethylcyclohexanone (780 mg) were added to dichloromethane (25 mL) and the mixture was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (1367 mg) was then added and the solution was stirred at room temperature for 16 hours. Additional 3,3-dimethylcyclohexanone (780 mg) and sodium triacetoxyborohydride (1367 mg) were added, and the mixture was stirred for another 16 hours. The mixture was then washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified on silica gel using 2.5% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [N+:1]([C:4]12[CH:11]3[CH:6]4[C:7]5([N+:12]([O-:14])=[O:13])C3C1[CH:8]5[CH:5]24)([O-:3])=[O:2].[C:15]([Cl:20])(=O)[C:16]([Cl:18])=O>>[Cl:18][C:16]12[CH:11]3[CH:6]4[CH:5]5[C:4]3([N+:1]([O-:3])=[O:2])[C:15]1([Cl:20])[CH:8]5[C:7]24[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])C12C3C4C1C1C2C3C41[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Product: O=[N+]([O-])C12C3C4C1C1(Cl)C4([N+](=O)[O-])C3C21Cl
Yield: 68 %

Procedure:
A solution of 1,4-dinitrocubane (Eaton, P.E.; et al; J. Org. Chem.; 1984, 49, 185; Eaton, P.E.; Wicks, G.E.; J. Org. Chem.; 1988, 53, 5353) in oxalyl chloride was irradiated under a sunlamp for 12 h at room temperature. After removing oxalyl chloride under reduced pressure, the reaction mixture was hydrolyzed and partioned between ethyl acetate and 5% aqueous NaOH. From the organic phase was isolated 2-chloro-1,4-dinitrocubane,3, and 2,5-dichloro-1,4-dinitrocubane, 4. After acidification of the alkaline layer with HCl and extraction with ethyl acetate, 2-carboxy-1,4-dinitrocubane, 5, was obtained in 68% yield. ##STR1##
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8](Cl)[CH:7]=1)([CH3:3])[CH3:2].[Br-].[CH2:16]([CH:18]([Zn+])[CH2:19][CH3:20])[CH3:17].C1COCC1>O1CCOCC1>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([CH:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CCC([Zn+])CC
Reactant: Cc1cc(C(=O)OC(C)C)cc(Cl)n1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCC(CC)c1cc(C(=O)OC(C)C)cc(C)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A a solution of 2-chloro-6-methyl-isonicotinic acid isopropyl ester (2.0 g, 9.36 mmol) in dioxane (75 mL) is degassed and put under argon before Pd(dppf) (229 mg, 0.281 mmol) is added. At rt, a 0.5 M solution of 1-ethyl-propylzinc bromide in THF (46.8 mL, 23.4 mmol) is added dropwise to the mixture. The mixture is stirred at 80° C. for 16 h before the reaction is quenched by adding ice-cold water (200 mL). A precipitate forms and the mixture is diluted with EA (200 mL) and filtered through celite. The filtrate is transferred into a separatory funnel. The org. phase is collected and the aq. phase is extracted with EA (120 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to 4:1 to give 2-(1-ethyl-propyl)-6-methyl-isonicotinic acid isopropyl ester (1.6 g) as a yellow oil; LC-MS: tR=0.79 min, [M+1]+=250.14; 1H NMR (D6-DMSO): δ 0.70 (t, J=7.3 Hz, 6H), 1.33 (d, J=6.3 Hz, 6H), 1.58-1.70 (m, 4H), 2.51 (s, 3H), 2.55-2.63 (m, 1H), 5.15 (hept, J=5.8 Hz), 7.39 (s, 1H), 7.49 (s, 1H).
Reaction SMILES: [Li]C(C)(C)C.[CH:6]([Si:9]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[C:10]1[O:11][CH:12]=[CH:13][N:14]=1)([CH3:8])[CH3:7].[Sn:21](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.C(OCC)(=O)C>[CH2:30]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[C:12]1[O:11][C:10]([Si:9]([CH:6]([CH3:8])[CH3:7])([CH:15]([CH3:17])[CH3:16])[CH:18]([CH3:20])[CH3:19])=[N:14][CH:13]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
tert-BuLi (1.7M, 8.4 mL, 14.3 mmol) was added dropwise over 30 min. to a stirred solution of 2-(triisopropylsilyl)-1,3-oxazole* (3 g, 13 mmol) in THF (75 mL) at −78° C. under argon. The solution was allowed to stir for 20 min. at −78° C. and Bu3SnCl (5.2 mL, 19.5 mmol) was then added over 20 min. The reaction mixture was warmed up to room temperature and stirred for an additional 16 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was dissolved in n-pentane, filtered through Celite and the solvent evaporated to give the title compound in quantitative yield as a pale-yellow oily residue, which was used without further purification in the next step. *Prepared according to Ross A, et al. Tetrahedron Letters 2002, 43, 935.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)CCC2O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC2Cl
Reaction time: 3 h

Procedure:
1-Hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (4.77 g, 30 mmol) was dissolved in 10 mL of methylene dichloride. While cooled on ice, thionyl chloride (6.6 ml, 90 mmol) was added dropwise within about 15 minutes. The solution was concentrated after being stirred for 3 hours. The residue was dissolved in ethyl acetate and the solution obtained was washed with cooled brine for 3 times, dried over anhydrous magnesium sulfate, and concentrated to obtain 1-chloro-2,3-dihydro-1H-indene-5-carbonitrile.
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[O:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH2:4]1.C([O-])([O-])=O.[K+].[K+].F[C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][CH:33]=1.O>CN(C=O)C>[F:2][C@@H:3]1[CH2:7][N:6]([C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][CH:33]=2)[C@@H:5]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[O:15][C@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH2:4]1
Reactant: Fc1ccc(OC2CCOC2)c([C@H]2C[C@H](F)CN2)c1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2C[C@@H](F)C[C@@H]2c2cc(F)ccc2O[C@H]2CCOC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a solution of (2R,4S)-4-fluoro-2-(5-fluoro-2-((tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidine hydrochloride (4.74 g, 15.49 mmol) in dry DMF (20 ml), was added K2CO3 (4.85 g, 35.2 mmol) and stirred for 5 min at room temperature, then added 5-fluoro-2-nitropyridine (2.0 g, 14.08 mmol) under N2 atmosphere and stirred for 16 h at 80° C. After completion of reaction, poured the reaction mixture in ice cooled water and stirred for 10 min, solid precipitated was collected by filtration. Solid was dried under high vacuum to afford 5-((2R,4S)-4-fluoro-2-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)-2-nitropyridine as yellow solid (5.1 g, yield: 93%) MS (ESI): 392.1 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:19][O:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([O:11][C:2]2[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=Cc1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(I)cc2C=O)cc1
Yield: 69.1 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (3.6 g, 14.4 mmol) (Aldrich) was reacted with methyl 4-hydroxybenzoate (2.62 g, 17.3 mmol) and K2CO3 in N,N-dimethylacetamide to give 4-(2-formyl-4-iodo-phenoxy)-benzoic acid methyl ester as a yellow oil (Yield 3.8 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:22][C:21]([F:24])([F:23])[CH2:20]2)=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.OO.S([O-])([O-:29])=S>CO>[Cl:1][C:2]1[CH:7]=[C:6]([OH:29])[CH:5]=[N:4][C:3]=1[O:17][CH2:18][CH:19]1[CH2:22][C:21]([F:24])([F:23])[CH2:20]1
Reactant: CC1(C)OB(c2cnc(OCC3CC(F)(F)C3)c(Cl)c2)OC1(C)C
Reactant: [O-]S([O-])=S
Agent: OO
Solvent: CO
Product: Oc1cnc(OCC2CC(F)(F)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
3-Chloro-2-[(3,3-difluorocyclobutyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 4, 4.5 g, 12.5 mmol) was suspended in methanol (30 mL). Hydrogen peroxide (1.6 mL, 21.3 mmol) was added and the mixture stirred at room temperature under nitrogen for 16 hours. An aqueous solution of thiosulfite (10%, 10 mL) was added and the mixture was extracted with EtOAc (2×200 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage®, gradient of 0-50% EtOAc in heptane) to afford the title compound (2.53 g, 81%):
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].CO>O>[C:12]1([C:11]2[N:10]=[C:9]([S:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[NH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)COc1cccc(CSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1cccc(CSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
A mixture of methyl [3-[[(4,5-diphenyl-1H-imidazol-2-yl)thio]methyl]phenoxy]acetate (2.00 g, 4.6 mmol), lithium hydroxide monohydrate (586 mg, 14 mmol), methanol (35 mL) and water (10 mL) was stirred at room temperature for 2 hours. The solvent was evaporated, the residue diluted with water and 2N HCl solution added to pH=7. A white solid was filtered off and recrystallized from aqueous DMF to give [3-[[(4,5-diphenyl-1H-imidazol-2-yl)thio]methyl]phenoxy]acetic acid (1.33 g, 69%), m.p. 233°-235° C.