Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH2:34]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)[CH2:35][CH2:36][CH2:37][CH3:38]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:42]3[CH:41]=[CH:40][C:39]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:44][CH:43]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: CCCCCc1ccc(B(O)O)cc1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: CCCCCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.8 g, 3.3 mmol) was coupled with 4-n-pentylbenzene boronic acid (769 m g, 4.0 mmol) according to general procedure G to give {4-[4-(2,4-dichloro-phenyl)-2-(4′-pentyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][O:26]CC2C=CC(OC)=CC=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].O>ClCCl>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(COC[C@@H]2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)cc1
Solvent: O
Solvent: ClCCl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.8 %

Procedure:
To a cold mixture of (1R,2R,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(4-methoxy-benzyloxymethyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 153, step 9, 171 mg) in dichloromethane (4 mL) was added water (0.2 mL) and dichlorodicyanoquinone (97 mg). The reaction mixture was stirred 90 min at room temperature. The suspension was filtered and the solid was washed with dichloromethane. The resulting liquor was partionned between dichloromethane and saturated aqueous solution of sodium hydrogenocarbonate. The aqueous layer was washed with dichloromethane. The combined organic layers were washed brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of dichlormethane:methanol (98:2 to 19:1 v/v) as eluant to afford the title compound (101 mg, 77%) as a white solid. MS (EI): 401.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(O)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=23)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1Nc1ccc(F)cc1
Temperature: 80 °C
Yield: 116.7 %

Procedure:
Intermediate 1 (0.051 g) and 4-fluoroaniline (0.024 g) were suspended in ethanol (2 ml) and triethylamine (0.14 ml) was added. The mixture was stirred under nitrogen and heated at 80° C. for 16 h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between DCM and water. The organic layer was loaded directly onto an SPE cartridge (silica, 5 g) and eluted sequentially with; (i) DCM, (ii) DCM: Et2O (2:1), (iii) DCM:Et2O (1:1), (iv) Et2O, (v) EtOAc, (vi) MeOH. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 6 (0.077 g). LCMS showed MH+=328; TRET=3.36 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:42]2[CH2:47][C@@H:46]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][C@@H:44]([NH:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:43]2)=[N:4][C:5]([N:20]2[CH2:25][C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C@@H:22]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21]2)=[C:6]([Cl:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[CH:11][CH:10]=1.NN>CO.CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:42]2[CH2:47][C@@H:46]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][C@@H:44]([NH:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:43]2)=[N:4][C:5]([N:20]2[CH2:25][C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C@@H:22]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21]2)=[C:6]([Cl:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: CC(=O)Nc1ccc(Nc2c(Cl)c(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2Cl)cc1
Agent: NN
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c(Cl)c(Nc3ccc(N)cc3)c2Cl)C1
Temperature: 80 °C
Reaction time: 120 h
Yield: 89.8 %

Procedure:
N-[4-(3,5-dichloro-2,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-pyridin-4-ylamino)-phenyl]-acetamide (139) (0.849 g, 0.92 mmol) was dissolved in MeOH (5 mL) and NMP (10 mL). Hydrazine (10 mL) was added and the mixture was heated at 80° C. with shaking in a 40 mL I-Chem vial for 5 days. LC-MS at this point indicated nearly complete deprotection. The mixture was diluted with EtOAc (50 mL), washed with water (4×25 mL) and brine (25 mL) via extraction, dried over MgSO4 and concentrated to give a yellow oil. Purification by flash chromatography using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc in hexane in 30 minutes) gave the desired product (140) as a beige powder upon concentration (0.728 g, 0.826 mmol, 89.8% yield). LC-MS (ESI): (exact mass: 879.42) m/e=880.5 [M+1]+ (100%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S([CH:28]([N+]#[C-])[N+:29]#[C-:30])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]2[O:13][CH:30]=[N:29][CH:28]=2)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [C-]#[N+]C([N+]#[C-])S(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(S(C)(=O)=O)c(-c2cnco2)c1Cl

Procedure:
25 g (0.09 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate (Ex. A.1.), 17.6 g (0.09 mol) of tosylmethylene isocyanide and 6.2 g (0.045 mol) of finely pulverulent potassium carbonate are stirred together with 450 ml of methanol at reflux temperature for 5 hours. The solvent was subsequently stripped off, the residue was taken up in ethyl acetate, and the mixture was extracted with water. The ethyl acetate phase was dried using sodium sulfate and concentrated.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]([CH2:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:20]=[CH:21][C:22]=1[Cl:23])[CH:13]1[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10](=[O:11])[N:12]([CH2:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][N:1]=[N+:2]=[N-:3])[CH:20]=[CH:21][C:22]=1[Cl:23])[CH:13]1[CH2:15][CH2:14]1)([CH3:7])([CH3:6])[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)c(CN(C(=O)OC(C)(C)C)C3CC3)c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cc(CCN=[N+]=[N-])ccc1Cl)C1CC1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
NaN3 (1.17 g, 18.0 mmol) was added to a sol. of toluene-4-sulfonic acid 2-{3-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-chloro-phenyl}-ethyl ester (2.16 g, 4.50 mmol) in DMF (45 mL). The mixture was heated to 65° C., and stirred at this temperature for 1.5 h. The mixture was allowed to cool to rt, and poured onto water. The mixture was extracted with TBME (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 95:5) yielded the title compound (1.49 g, 94%). LC-MS: tR=1.11 min; ES+: 336.43.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1>[S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc2ccccc2c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A 2 L four-necked round-bottomed flask equipped with a Teflon® coated magnetic stirring bar, dropping funnel, thermometer, and a gas inlet was evacuated and filled with nitrogen. 2-naphthol (51.8 g, 359.3 mmol, 1.0 equivalent), dehydrated toluene (800 mL), and triethylamine (52.6 mL, 377.3 mmol, 1.05 equivalents) were charged into the flask successively. Subsequently, to the solution was added p-toluenesulfonyl chloride (69.9 g, 366.5 mmol, 1.02 equivalents) in dehydrated toluene (140 mL) dropwise via the dropping funnel over 15 minutes at such a rate that the internal temperature was kept at 50° C. or lower, and the mixture was stirred for further 2 hours at room temperature. The thus-obtained white suspension was poured into water, and the aqueous layer was separated off. The organic layer was passed through a silica gel pad, and concentrated under reduced pressure to give solid residue, which was purified by recrystallization from toluene/methanol to afford 94.2 g of 2-naphthyl tosylate as a white powder. The mother liquor was concentrated under reduced pressure to give solid residue, which was recrystallized to recover further 9.2 g of 2-naphthyl tosylate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[C:19](I)=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=1.[CH3:22][I:23]>CCCCCC.C1COCC1.O>[F:13][C:14]1[C:19]([CH3:18])=[C:22]([I:23])[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: Cc1cnc(F)c(I)c1
Reactant: CI
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cnc(F)c(C)c1I
Temperature: -18 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (88 mL) was added to THF (1.2 L), and the mixture was cooled to −18° C. in a nitrogen atmosphere. A 2.69 M solution of n-butyllithium in hexane (215 mL) was added dropwise to the solution. After completion of the dropwise addition, the mixture was warmed to −5° C. with stirring over 30 minutes. The reaction mixture was cooled to −72° C. A solution of 2-fluoro-3-iodo-5-methylpyridine (109.69 g) in TIE (240 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at −74° C. for 1.5 hours. A solution of methyl iodide (36 mL) in THF (160 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at −70° C. to −74° C. for two hours. After completion of the reaction, water (200 mL) was added to the reaction mixture at the same temperature. The mixture was stirred at the same temperature for two minutes. The reaction mixture was returned to room temperature, and water (1.2 L) was then added. The mixed solution was stirred for three minutes. Water (300 mL) was further added. The mixture was extracted with MTBE (1.2 L). The organic layer was washed with brine (500 mL). The combined aqueous layers were extracted with MTBE (1 L). The combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. n-heptane (100 mL) was added to the residue, followed by cooling. The precipitated solid was collected by filtration. The residue was washed with n-heptane. The filtrate was cooled, and the precipitated solid was collected by filtration. This operation was repeated twice to give the title compound (86.9 g).
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([O:11][CH:10]2[CH2:9][N:8]([CH3:12])[CH2:7][CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(o1)CCN(C)CC2O
Product: Cc1cc2c(o1)CCN(C)CC2Oc1ccc(Cl)c(Cl)c1

Procedure:
The same method as in Example 1 was conducted using 2,6-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-d]azepin-4-ol (Reference Example 26) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][C:5]=1[CH2:6][NH:7][C:8](=[O:11])[O:9][CH3:10].C(O)C.[N:22](OC(C)(C)C)=[O:23]>C(OCC)(=O)C.O>[Cl:3][C:4]1[CH:15]=[CH:14][C:13]([C:16](=[N:22][OH:23])[C:17]#[N:18])=[CH:12][C:5]=1[CH2:6][NH:7][C:8]([O:9][CH3:10])=[O:11]
Reactant: COC(=O)NCc1cc(CC#N)ccc1Cl
Reactant: CC(C)(C)ON=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COC(=O)NCc1cc(C(C#N)=NO)ccc1Cl
Reaction time: 72 h
Yield: 68.4 %

Procedure:
0.15 g of sodium hydroxide and 0.60 g of methyl N-(2-chloro-5-cyanomethylbenzyl)carbamate were added to 5 ml of ethanol, and 0.40 g of t-butyl nitrite was added to the mixture at room temperature, followed by stirring for 72 hours. After completion of the reaction, the reaction solution was poured into water, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=3/1) to obtain 0.46 g of 2-[4-chloro-3-(methoxycarbonylaminomethyl)phenyl]-2-hydroxyiminoacetonitrile as a colorless viscous liquid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=2)[CH:2]=1.[H][H]>[Pd].CO>[NH:14]1[CH2:15][CH2:16][CH:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc3ccccc3c2)CC1
Agent: [Pd]
Solvent: CO
Product: c1ccc2ncc(C3CCNCC3)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
A catalytic amount of 50% wet 10% palladium on carbon was added to a mixture of tert-butyl 4-(quinolin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (260 mg, 0.84 mmol) in methanol (10 mL). Reaction vessel was placed on a Parr apparatus and charged with 10 psi of hydrogen gas. Reaction shook at room temperature for 4 hours. Mixture was filtered to removed catalyst. Filtrate was concentrated in vacuo. Residue was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1 mL) was added to the mixture. Reaction stirred at room temperature for 2 hours. Reaction mixture was concentrated in vacuo. Residue was dissolved in dichloromethane (20 mL). Mixture was washed with aqueous sodium bicarbonate (20 mL). Aqueous layer was back extracted with dichloromethane (30 mL). Organic layers were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as yellow oil in 45% yield. MS m/e (M+H)+=213.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Br)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-bromo-5-methyl benzoic acid (1.0 g, 0.00465 mole) in dry dichloromethane (10 mL) was added oxalylchloride (1.22 mL, 0.013 mole) dropwise at 0° C. followed by 1-2 drops of N,N-dimethyl formamide. The reaction mixture was then stirred for 2 hours at room temperature and the solvents were evaporated and the product dried under vacuum to yield 2-bromo-5-methylbenzoyl chloride which was used for the next step. To a precooled solution of 2-bromo-5-methyl benzoyl chloride in toluene (5 mL) was slowly added a pre-cooled solution of triethylphosphite (1.05 mL, 0.00604 mole) in toluene. The reaction was then left at room temperature for overnight. The solvents were then evaporated on a rotovap. The resultant product was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (NaHCO3, 25 mL), and then dried over magnesium sulfate (MgSO4). Filtration and solvent evaporation provided 1.1 g of product. Flash chromatography on silica gel using 0%-5% ethyl acetate/dichloromethane followed by drying of the product under high vacuum afforded 0.900 g of (2-bromo-5-methylbenzoyl)phosphonic acid diethyl ester. B. The material from A above was used to prepare [2-bromo-5-methylbenzoyl)difluoromethyl]phosphonic acid diethyl ester following a procedure similar to Example 80C. This material was used to prepare Compound 82 following a procedure similar to Example 40. 1H NMR: (DMSO-d6, 400 MHz) δ 7.56 (d, 1H, J=8.4 Hz), 7.40 (s, 1H), 7.19 (d, 1H, J=8.0 Hz), 2.28 (s, 3H). MS (ion spray): m/z 300.15/301.05 (M−H)
Reaction SMILES: CC1(C)CO[C:5]2([CH2:9][C@@H:8]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:7][CH2:6]2)[O:4]C1.Cl>C(O)C>[O:4]=[C:5]1[CH2:6][CH2:7][C@H:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:9]1
Reactant: CC1(C)COC2(CC[C@H](C(=O)OCc3ccccc3)C2)OC1
Agent: Cl
Solvent: CCO
Product: O=C1CC[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of (S)-benzyl 8,8-dimethyl-6,10-dioxaspiro[4.5]decane-2-carboxylate (3.5 g, 11.50 mmol) in ethanol (50 ml) at 0° C. was added 0.1 N hydrochloric acid (17.5 ml) drop wise. The reaction was stirred at 25° C. for overnight. Upon completion, the reaction mixture was concentrated under reduced pressure; the residue was dissolved in dichloromethane (50 ml) and diluted with water (25 ml). The organic mass was extracted using dichloromethane (2×50 ml) and the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain (S)-benzyl 3-oxocyclopentanecarboxylate (2 g, 80%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[NH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=[O:3])[CH3:2].[C:28](=O)([O-])[O-].[K+].[K+].CI.CCCCCC>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[N:9]([CH3:28])[C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc(CO[Si](C)(C)C(C)(C)C)[nH]c1Sc1cccc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(=O)OCc1nc(CO[Si](C)(C)C(C)(C)C)n(C)c1Sc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
In 12 ml of dry dimethylformamide was dissolved 600 mg (1.4 mmol)of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methyl acetate, followed by addition of anhydrous potassium carbonate (2.8 mmol). Then, 240 mg (1.7 mmol)of methyl iodide was added, and the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture, ice-water was added, extracted with diethyl ether, the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:2)to obtain 288 mg of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1-methyl-1H-imidazol-4-yl]methyl acetate (47)as oil (yield 46%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:14]2[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=[CH:16][CH:15]=2)=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
EX-41A) To a solution of p-cresol (5.76 g, 0.053 mol) and 1,3-dinitrobenzene (8.97 g, 0.053 mol) in 100 mL of dimethylsulfoxide was added cesium carbonate (43.4 g, 0.133 mol). The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature, quenched with water, and extracted with diethyl ether. The organic layers were combined, washed with 0.1 N HCl and water, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 8.0 g (66%) of the desired 3-(4-methylphenoxy)nitrobenzene product as ayellow oil. 1H NMR (CDCl3) δ 7.83 (s, 1H), 7.64 (t, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 6.8 (d, 2H), 2.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[C:22]([OH:24])=[CH:23][C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].C(OCC)(=O)C>CN(C=O)C.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[C:22]([O:24][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:23][C:4]=2[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1nc2cc(O)c(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1Cc1ccc(C#N)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc2nc(C)n(Cc3ccc(C#N)c4ccccc34)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-methyl-5-hydroxy-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole (1.11 g) in DMF (50 mL) was added NaH (0.15 g) at ambient temperature. After stirring at ambient for 30 minutes ethyl bromoacetate (0.4 mL) was added. The reaction was stirred at ambient temperature for 1 hour and was worked up between ethyl acetate and H2O. The organic layer was dried, concentrated and purified by silica gel chromatography (hexane/ethyl acetate/CH2Cl2 /methanol, gradient) to afford 2-methyl-5-(ethoxycarbonylmethoxy)-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole.