Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.CS(O)(=O)=O.C([O-])(=O)C.[K+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>O.O1CCCC1.C(O)C>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: CCOC(=O)Cl
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)N1C[C@@H](C)NC[C@@H]1C
Temperature: 20 °C
Yield: 74.2 %

Procedure:
A 12 L, 3-necked round bottom flask was charged with trans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had been recrystallized from toluene to mp=115-119° C., and 600 mL of water. The flask was cooled in an ice bath and a solution of methanesulfonic acid (1290 g, 13.4 mol) in 600 mL of water was added slowly with stirring and cooling to maintain the temperature below 40° C. The solution was cooled to 20° C. and 800 mL of ethanol was added. A 500 mL addition funnel was filled with 60% aqueous potassium acetate from a 2 L reservoir of the solution, and potassium acetate was added to the reaction flask to adjust the pH to 4.0. A second addition funnel was charged with a solution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL of tetrahydrofuran. The ethyl chloroformate and potassium acetate solutions were simultaneously added dropwise with adjustment of rate to maintain the reaction solution at pH 4.0±0.1, with cooling as necessary to maintain temperature at 25° C. After addition of the ethyl chloroformate was complete, the reaction was stirred for 1 hour with continued addition of potassium acetate solution to maintain a pH of 4.0. The organic solvents were removed by distillation under vacuum. The remaining aqueous solution was washed with 1500 mL of ethyl acetate to remove any bis-carbamate impurity. The ethyl acetate wash was extracted with two 500 mL portions of 1 M hydrochloric acid to recover desired product. The acid extracts were combined with the original aqueous solution and the pH was adjusted to 11 by addition of 10 M sodium hydroxide, with cooling to maintain temperature below 40° C. The aqueous solution was extracted with two 1500 mL portions of ethyl acetate, the combined extracts were dried over magnesium sulfate, and the solvent was removed to give 927 g (74%) ethyl trans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Si:20]([CH3:25])([CH3:24])[C:21]#[C:22][CH3:23]>>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:23][C:22]#[C:21][Si:20]([CH3:25])([CH3:24])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1nc2ccccc2n1Cc1ccccc1
Reactant: CC#C[Si](C)(C)C
Product: C[Si](C)(C)C#CCCc1nc2ccccc2n1Cc1ccccc1
Yield: 102.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(D), from of 1-benzyl-2-(chloromethyl)-1H-benzo[d]imidazole (500 mg, 1.9 mmol) and trimethyl(prop-1-ynyl)silane (262 mg, 2.34 mmol). 1-benzyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (647 mg, Yield: 100%) was obtained as a brown oil which was used in the next step without purification.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:35])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:69]1([O:73][C:74]([N:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)=[O:75])[CH2:72][CH2:71][CH2:70]1>CN(C=O)C.ClCCl>[CH:69]1([O:73][C:74]([N:76]2[CH2:81][CH2:80][N:79]([C:31](=[O:32])[C@@H:30]([NH:29][C:27]([C:18]3[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6](=[O:7])[NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:35])[N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:19]=3)=[O:28])[CH3:34])[CH2:78][CH2:77]2)=[O:75])[CH2:72][CH2:71][CH2:70]1
Reactant: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: O=C(OC1CCC1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 1 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid in 2 ml DMF were added 0.14 ml DIPEA, 78 mg HATU and 0.38 mg 1-cyclobutoxycarbonyl-piperazine. After stirring for 1 h it was diluted with dichloromethane and extracted with aqueous LiCl (4 w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:32][C:29]([CH3:30])([CH3:31])[C:28](=[O:33])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13]3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:34]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 55 °C
Yield: 87.6 %

Procedure:
Treat a solution of 6-{1-[4-(3,3-Dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-naphthalene-2-carboxylic acid methyl ester (0.53 g, 1.15 mmol) in THF (8 mL) and MeOH (16 mL) with 2N NaOH (2.9 mL, 5.8 mmol) and heat at 55° C. for 16 h. Concentrate the reaction mixture. Dilute the residue with in EtOAc (50 mL) and water (25 mL) and acidify the resulting mixture to pH 1 using 1N HCl. Discard the aqueous layer and wash the organic layer with brine, Dry the organic layer over Na2SO4, filter, and concentrate the filtrate to give the title compound as a yellow solid (0.45 g, 87%). MS (ES) m/e 447 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][CH:8]([C:12](=[O:14])[CH3:13])[C:9](=[O:11])[CH3:10])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][C:8]([C:9](=[O:11])[CH3:10])([CH3:16])[C:12](=[O:14])[CH3:13])[CH3:2]
Reactant: CCOC(=O)CCCC(C(C)=O)C(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)CCCC(C)(C(C)=O)C(C)=O
Yield: 87.2 %

Procedure:
5.5 g of 5-acetyl-6-oxo-heptanoic acid ethyl ester, 5.7 g of potassium carbonate, 15 g of iodo-methane, and 15 ml of acetone were refluxed for 18 hours. After cooling, petroleum ether was added, and the solid was filtered off and washed with acetone and petroleum ether. Fractional distillation and re-distillation yielded 5.11 g of 5-acetyl-5-methyl-6-oxo-heptanoic acid ethyl ester (boiling point: 151° C./20 mbar; purity: 82%; colorless).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:44][C@@:42]3([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]3[OH:45])[C@H:37]3[C@H:28]2[C:29]2[CH:30]=[CH:31][C:32]([OH:46])=[CH:33][C:34]=2[CH2:35][CH2:36]3)=[CH:23][CH:22]=1.I([O-])(=O)(=O)=[O:48]>O.CO>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]2[CH2:44][C@@:42]3([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]3[OH:45])[C@H:37]3[C@H:28]2[C:29]2[CH:30]=[CH:31][C:32]([OH:46])=[CH:33][C:34]=2[CH2:35][CH2:36]3)=[CH:25][CH:26]=1)=[O:48]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCSCc4ccccn4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)Cc4ccccn4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 0.5 h

Procedure:
3.7 cm3 of a 0.1M solution of sodium metaperiodate in water is added to a solution of 172 mg of the product obtained in Example 4 in 12 cm3 of methanol. The reaction medium is agitated for 1 hour 30 minutes and 3.4 cm3 of methanol and 0.6 cm3 of the metaperiodate solution are added, after 3 hours 30 minutes of agitation the reaction medium is poured into water, extracted with ethyl acetate, washed with salt water and evaporated to dryness under reduced pressure. 176 mg of residue is obtained which is chromatographed on silica twice (eluant methylene chloride-methanol (92.5-7.5)). 107 mg of desired product is collected.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.[CH:50]1([CH:53]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[CH2:54]O)[CH2:52][CH2:51]1>C1COCC1.CCOC(C)=O>[CH2:43]([O:42][C:40]([C:39]1[C:35]([I:34])=[N:36][N:37]([CH2:54][CH:53]([NH:56][C:57]([O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:63])[CH:50]2[CH2:51][CH2:52]2)[C:38]=1[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:41])[CH3:44]
Reactant: CC(C)(C)OC(=O)NC(CO)C1CC1
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn(CC(NC(=O)OC(C)(C)C)C2CC2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of PPh3 (15.52 g, 59.2 mmol) in THF (40.0 mL) cooled to −10° C. was added DIAD (11.50 mL, 59.2 mmol) and the resulting solution stirred at 0° C. for 0.5 h. Intermediate 104C (10 g, 29.6 mmol) was added as a solution in THF (10 mL) at 0° C. and stirred at RT for 45 min. A solution of Intermediate 348A (7.74 g, 38.5 mmol) in THF (10 mL) at was added at 0° C. and the reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with EtOAc (50 mL) washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (120 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 348B along with impurities arising from the coupling reagents (8.01 g, 84%); the crude material was taken to the next step without further purification. MS(ES): m/z=522 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:28])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:28])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of anhydrous zinc chloride (7.4 g, 54.3 mmol) in diethyl ether (50 ml) was added sodium borohydride (4.11 g, 0.11 mol) and the mixture was stirred at room temperature for 2 hrs. The insoluble material was removed by filtration. To the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-(3-trifluoromethylbenzyl)propionate (10 g, 27.1 mmol) in diethyl ether (20 ml) and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added to the reaction solution to terminate the reaction. The reaction solution was extracted with ethyl acetate (100 ml). The extract was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1-5:1) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-trifluoromethylbenzyl)propionate (7.9 g, 79%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl.CCOC(C)=O>[C:24]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
2,3-Dihydro-6-hydroxy-3-phenylinden-1-one (22.5 g, 100 mmol) obtained in Step 2 was placed into a flask and dissolved in CH2Cl2 (300 mL). To the solution at 0° C., pyridine (40 mL, 5.0 eq) and acetic anhydride (47 mL, 5.0 eq) were added dropwise. The mixture was stirred for 8 h at room temperature. The reaction mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product (20.0 g, 77%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CS(OCC([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=O)(=O)=O.Cl.[OH-:19].[Na+]>O.CO.C1C=CC=CC=1>[C:16]1([CH2:15][C:14]([OH:13])=[O:19])[CH:17]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [OH-]
Reactant: CCCCOC(=O)COS(C)(=O)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccccc1
Yield: 158.2 %

Procedure:
19.15 g (0.144 mol) of aluminum chloride are first introduced into 70 ml of benzene at 40°-50° C., and 10 g (0.048 mol) of n-butyl methanesulfonyloxyacetate are then added. The mixture is additionally stirred overnight, hydrolyzed with 10% hydrochloric acid and worked up by the method of Examples 6 to 9. The crude product obtained is refluxed together with 6 g of NaOH in 15 ml of water and 50 ml of methanol for 5 hours. Further workup is carried out as in Examples 6 to 9. 5.17 g (90.3% of theory) of phenylacetic acid are isolated.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][N:9]=2)[CH2:3]1.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](I)[CH:27]=1.CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:21][C:22]1[CH:27]=[C:26]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]([N:4]3[CH2:3][C:2]([CH3:20])([CH3:1])[O:6][C:5]3=[O:7])=[N:9][CH:10]=2)[CH:25]=[N:24][CH:23]=1
Reactant: Fc1cncc(I)c1
Reactant: CC1(C)CN(c2ccc(C#C[Si](C)(C)C)cn2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2ccc(C#Cc3cncc(F)c3)cn2)C(=O)O1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
5,5-Dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one (Example 29, step 1) (100 mg, 0.35 mmol) was dissolved in THF (3 ml). 3-Fluoro-5-iodopyridine (100 mg, 0.45 mmol, 1.3 equiv.), Et3N (145 μl, 1.04 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (10 mg, 14 μmol, 0.05 equiv.), triphenylphosphine (11 mg, 17 μmol, 0.05 equiv.), triphenylphosphine (3 mg, 10 μmol, 0.03 equiv.) and copper(I)iodide (1 mg, 3.5 mmol, 0.01 equiv.) were added under nitrogen and the mixture was heated to 60° C. TBAF 1M in THF (520 μl, 0.52 mmol, 1.5 equiv.) was added dropwise in 20 minutes at 60° C. The reaction mixture was stirred for 3 hours at 60° C. Sat. NaHCO3 solution was added and the mixture was extracted with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol gradient 100:0 to 90:10). The desired 3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one was obtained as a white solid (55 mg, 51% yield), MS: m/e=312.3 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[N:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:15][C:16]1[N:21]=[C:20]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:14])[N:19]=[C:18]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) (0.99 g, 5 mmol), tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (Lowik et al, Eur. J. Org. Chem., 2001, 2825) (2.0 g, 6 mmol), and 3.5 g (25 mmol) powdered K2CO3 in 40 mL DMF was stirred at room temperature for 1 hr. Water was added, and the product was collected by filtration and washed with water and cold ethanol to give 2.14 g (86% yield) of tert-butyl 4-(4-chloro-6-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate: mp (CH2Cl2/EtOH)>300° C.; 1H NMR (CDCl3) δ7.99 (d, J=8.3 Hz, 1H), 7.48 (t, JHF=53.4 Hz, 1H), 7.41 (t, J=8.3 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 4.06 (s, 3H), 3.95 (m, 4H), 3.58 (m, 4H), 1.50 (s, 9H); Anal. Calcd. for C21H24ClF2N7O3: C, 50.9; H, 4.9; N, 19.8. Found: C, 51.1; H, 4.9; N, 19.95%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1.C(OCC)(=O)C>[OH:29][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCCC1
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCCC2)cc1
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
1.83 g of 4-[1-(imidazolyl)methyl]benzonitrile is dissolved in 50 ml of tetrahydrofuran and combined at -50° with 7.3 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran; the mixture is stirred for 0.5 hour, further stirred with 1.05 g of cyclohexanone for 1 hour at -60°, and heated to 25°. Then water is added, the mixture is diluted with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, yielding 2.7 g of crude 4-[1-hydroxycyclohex1-yl-1-(imidazolyl)methyl]benzonitrile.
Reaction SMILES: CN(C)C=O.OC1C=CC(S([N:16]2[CH2:22][CH2:21][CH:20]3[CH2:23][CH:17]2[C:18](=[O:24])[O:19]3)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[CH:17]12[CH2:23][CH:20]([O:19][C:18]1=[O:24])[CH2:21][CH2:22][NH:16]2
Reactant: O=C1OC2CCN(S(=O)(=O)c3ccc(O)cc3)C1C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1OC2CCNC1C2
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a dimethylformamide (0.6 mL) solution of 2-(4-Hydroxy-benzenesulfonyl)-6-oxa-2-aza-bicyclo[3.2.1]octan-7-one (101.1 mg) and cesium carbonate (331.3 mg) is added the aryl halide (2.5 equiv). The reaction is heated to 50° C. with shaking for 12-24 hours. The sample is cooled, diluted with water and ethyl acetate, and extracted two times with ethyl acetate. The organic layers are combined, dried over sodium sulfate and concentrated. The product is precipitated from diethyl ether to give the Aryloxy-benzenesulfonyl)-6-oxa-2-aza-bicyclo[3.2.1]octan-7-one.
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:12]=[CH:11][C:10]([CH2:13][C@@H:14]([NH:23]C(OC(C)(C)C)=O)[CH2:15][C@:16]([CH2:21][OH:22])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1.CCN(CC)CC>CC(C)=O>[C:1]([O:4][CH2:5][O:19][C:17](=[O:18])[C@@:16]([CH2:21][OH:22])([CH3:20])[CH2:15][C@H:14]([NH2:23])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCBr
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Bromomethyl acetate (38 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid acetoxymethyl ester.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][N:23]=1>O1CCOCC1.CCOC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:27]2[C:22]([CH3:21])=[N:23][CH:24]=[CH:25][CH:26]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: Cc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ncccc1-c1nc2cc(F)ccc2c(Cl)c1C

Procedure:
To a stirred solution of 2,4-dichloro-7-fluoro-3-methylquinoline (400 mg, 1.74 mmol) in 1,4-dioxane:water (5 mL:1 mL) was added PdCl2(PPh3)2 (122 mg, 0.17 mmol), sodium carbonate (553 mg, 5.22 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The reaction was heated at reflux overnight. After this time the reaction was diluted with EtOAc (100 mL) and water (50 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (hexane:EtOAc, 1:0 to 1:1) gave 4-chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline.