Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][CH:19]=[C:18]1[C:13]=2[CH:14]([OH:23])[CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][CH:19]=[C:18]1[C:13]=2[CH:14]([O:23][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a suspension of Compound 224 (1.10 g, 3.60 mmol) in dry CH2Cl2 (10 mL) under ice-cooling was added successively 2,6-lutidine (0.59 mL, 5.07 mmol) and tert-butyldimethylsilyl trifluromethanesulfonate (0.99 mL, 4.31 mmol), the resultant homogeneous solution was then stirred at 25° C. for 30 minutes. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, ethyl ether-petroleum ether-benzene=1:2:2) to give Compound 225 (1.475 g, 98 percent): white solid; mp 123°-125° C.; Rf =0.50 (silica, 33 percent ethyl ether in benzene); IR (CHCl3) νmax 2952, 2933, 1621, 1506, 1336, 1295, 1256, 1240, 1174, 1151, 1090, 1025, 838 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1 H, H6), 7.98 (d, J=9.2 Hz, 1 H, H1), 7.55-7.48 (m, 3 H, H4 and aromatic), 7.46-7.34 (m, 3 H, aromatic), 7.27 (dd, J=9.2, 2.7 Hz, 1 H, H2), 5.42 (t, J=2.6 Hz, 1 H, H10), 5.20 (s, 2 H, benzylic), 3.04-2.93 (m, 1 H, H7), 2.87-2.72 (m, 1 H, H7), 2.26-2.05 (m, 2 H, H8 or H9), 1.92-1.76 (m, 2 H, H8 or H9), 0.84 (s, 9 H, SiC(CH3)3), 0.22 (s, 6 H, Si(CH3)2); MS (FAB+) m/e (rel intensity) 420 (M+H, 100), 362 (23), 330 (3), 288 (9); HRMS for C26H34NO2Si (M+H), calcd 420.2359, found 420.2360.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]3[C:16]=2[CH2:15][CH2:14][CH2:13]3)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][CH:31]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([C:4]2[CH:5]=[C:6]([CH:27]=[CH:28][C:3]=2[O:2][CH3:1])[O:7][C:8]2[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]3[C:16]=2[CH2:15][CH2:14][CH2:13]3)=[O:38])=[CH:32][CH:31]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(OC)cc2)c2c1CCC2
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(OC)c(C(=O)Cc3ccc(F)cc3)c2)c2c1CCC2
Yield: 54.6 %

Procedure:
Ethyl N-[7-(4-methoxyphenoxy)-6-methylindan-4-yl]malonamate (100 mg) and 4-fluorophenylacetic acid (60 mg) were dissolved in dichloromethane (261 μL). To the solution was added dropwise trifluoromethanesulfonic anhydride (66 μL) at room temperature with stirring. The mixture was stirred at room temperature for 15 hours. Adding water, the reaction mixture was extracted with diethyl ether. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (74 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:34]1([CH2:40][CH2:41][CH:42]([OH:44])[CH3:43])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[N:45]1[C:49]2([CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:48][O:47][C:46]=1[C:55]1[CH:60]=[CH:59][C:58](O)=[CH:57][CH:56]=1.Cl>O1CCCC1>[CH3:43][CH:42]([O:44][C:58]1[CH:59]=[CH:60][C:55]([C:46]2[O:47][CH2:48][C:49]3([CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[N:45]=2)=[CH:56][CH:57]=1)[CH2:41][CH2:40][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(O)CCN1CCCCC1
Reactant: Oc1ccc(C2=NC3(CCCCC3)CO2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCN1CCCCC1)Oc1ccc(C2=NC3(CCCCC3)CO2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
To a solution of triphenylphosphine (1.03 g, 3.92 mmol, 1.1 eq) in tetrahydrofuran (10 ml) at 0° C. is added dropwise diisopropylazodicarboxylate (0.776 ml, 3.92 mmol, 1.1 eq). The mixture is stirred for 5 minutes and 4-(1-piperidinyl)-2-butanol (0.56 g, 3.56 mmol, 1 eq) is added slowly. Then, a solution of 4-(3-oxa-1-azaspiro[4.5]dec-1-en-2-yl)phenol ax8 (0.82 g, 3.56 mmol, 1 eq) in tetrahydrofuran (5 ml) is added at 0° C. The mixture is allowed to warm at room temperature and stirred for 2 hours. It is then poured into 0.5 N hydrochloric acid and extracted with diethyl ether. The aqueous layer is treated with a 1 M aqueous solution of sodium hydroxide to reach pH 9 and extracted 3 times with diethyl ether. The combined organic layers are dried over magnesium sulfate and the solvent is removed under reduced pressure to give 1.18 g of an orange oil. The crude product is purified by chromatography over silica gel to give 0.41 g of 2-[4-(1-methyl-3-piperidin-1-ylpropoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-ene 37 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3C(C)=NC(C)=C[CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.[CH3:40][N:41]1C(C=O)=C[N:43]=[C:42]1[CH3:48]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:41]([CH3:40])[C:42]([CH3:48])=[N:43][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=1
Reactant: Cc1ncc(C=O)n1C
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.02 h

Procedure:
To a 50 mL flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2 g, 4.64 mmol, Intermediate 47: step d) was added THF (25 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-BuLi (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added drop wise. The color of the solution became a dark reddish-brown color. After 1 minute, 1,2-dimethyl-1H-imidazole-5-carbaldehyde (710 mg, 5.72 mmol in 4 mL THF) was introduced and the color of the mixture became greenish to light orange all within 1 minute. The mixture was allowed to warm to 0° C. over 45 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The reaction was diluted further with water and extracted with EtOAc (3×45 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a pale yellow solid. The solid was triturated with Et2O and collected by filtration and rinsed with additional Et2O and dried to afford the title compound as a white powder.
Reaction SMILES: [O-]CC.[K+:4].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([CH3:25])[CH:19]=[CH:18][N:17]=1>C(OCC)C>[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20](/[CH:25]=[C:6](\[O-:8])/[C:5]([O:12][CH2:13][CH3:14])=[O:11])[CH:19]=[CH:18][N:17]=1.[K+:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)/C([O-])=C/c1ccnc(Cl)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
To a heterogeneous solution of potassium ethoxide (6.56 g, 77.9 mmol) in diethyl ether (55 mL), was slowly added diethyl oxalate (10.6 mL, 77.9 mmol). A slight exotherm resulted. After stirring 5 min, a homogeneous yellow solution resulted, but after 10 min, a heterogeneous yellow slurry was observed. Addition of 2-chloro-4-methyl-3-nitropyridine (13.45 g, 77.9 mmol) as a solid, with a diethyl ether rinse (23 mL), resulted in a dark violet solution with a dark precipitate. The mixture was stirred at room temperature overnight (21 h). The solid precipitate was filtered, rinsed thoroughly with diethyl ether, and air-dried to give potassium (1Z)-1-(2-chloro-3-nitropyridin-4-yl)-3-ethoxy-3-oxoprop-1-en-2-olate (19.8 g, 63.6 mmol, yield 81%) as an orange solid. The crude product was used directly without further purification or identification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:24](=[O:31])[NH:25][C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[C:5]2[N:9]=[C:8]([NH:10][C:11]([C:13]3[N:14]=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:12])[NH:7][C:6]=2[CH:23]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.C(Cl)Cl.[Cl-].[Na+].O>[C:32]1([S:38]([NH:1][C:2]2[CH:3]=[C:4]([C:24](=[O:31])[NH:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)[C:5]3[NH:9][C:8]([NH:10][C:11]([C:13]4[N:14]=[CH:15][C:16]5[C:21]([CH:22]=4)=[CH:20][CH:19]=[CH:18][CH:17]=5)=[O:12])=[N:7][C:6]=3[CH:23]=2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nc2cc(NS(=O)(=O)c3ccccc3)cc(C(=O)Nc3ncc[nH]3)c2[nH]1)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
82 mg (0.2 mmol) of the isoquinoline-3-carboxylic acid [6-amino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (See Example 130) was dissolve in pyridine (0.6 mL). To this stirred solution at 0° C., 0.2 mmol of phenylsulfonyl chloride in 0.2 mL of DCM was added in one portion. The reaction mixture was stirred at r.t. for 2 h. Brine (5 mL) was added and stirred for 10 min. The resulting solid was collected, washed with water (3×2 mL) and ethyl acetate (3×3 mL) and dried to give 55 mg (50%) of isoquinoline-3-carboxylic acid [5-benzenesulfonylamino-7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide as a solid. LCMS: 553 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:30]NN.S(=O)(=O)(O)O>C(O)C>[CH3:30][N:9]1[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:11]=[N:10]1
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (1.72 g) in ethanol (20 ml) was added methyl hydrazine (3.5 ml, 1.5 eq.) and concentrated sulfuric acid (0.1 ml). The reaction mixture was stirred 1 h at ambient temperature and solvent evaporated. The reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer dried magnesium sulfate, filtered and concentrated. Preparative HPLC chromatography provided the title compound (minor isomer) as a white solid (0.30 g, 17%). 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=5.4 Hz, 2H), 8.21 (d, J=8.7 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.77 (s, 1H), 7.66 (m, 3H), 7.53 (m, 1H), 7.19 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 7.01 (d, J=6.2 Hz, 2H) 5.40 (s, 2H), 3.69 (s, 3H); MS: (M+H m/z=393.3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:25]([C:29]1[CH:30]=[N:31][CH:32]=[C:33](B(O)O)[CH:34]=1)(=[O:28])(=[O:27])[NH2:26]>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[C:29]([S:25]([NH2:26])(=[O:28])=[O:27])[CH:30]=[N:31][CH:32]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: NS(=O)(=O)c1cncc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cncc(S(N)(=O)=O)c3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (0.200 g, 0.51 mmol) and 3-sulfamoyl-pyridine-5-boronic acid (example F.3) (0.103 g, 0.51 mmol) according to the general procedure VI. Obtained as a white solid (0.015 g, 6%). MS (ISP) 470.3 [(M+H)+]; mp>250° C.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:5](=[O:6])[N:4]([CH:7]2[CH:14]3[CH2:15][C:10]4([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH:12]([CH2:16][CH:8]2[CH2:9]4)[CH2:13]3)[NH:3]1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:5](=[O:6])[N:4]1[CH:7]1[CH:8]2[CH2:9][C:10]3([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH:12]([CH2:13][CH:14]1[CH2:15]3)[CH2:16]2
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)C12CC3CC(C1)C(N1NC(C)(C)C1=O)C(C3)C2
Product: COC(=O)C12CC3CC(C1)C(N1C(=O)C(C)(C)N1Cc1ccccc1Cl)C(C3)C2

Procedure:
Methyl 4-(3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl)adamantane-1-carboxylate prepared in Process 5 of Example 90, and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and methyl 4-[2-(2-chlorobenzyl)-3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl]adamantane-1-carboxylate was obtained as a pale yellow oil.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CN(C)C=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1O.COS(OC)(=O)=O>O>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[O:4][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(F)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1c(F)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Potassium carbonate (59.25 g, 0.43 mol) is added slowly to a solution of dimethylformamide (200 mL) containing 2-fluoro-6-nitrophenol (10, 33.63 g, 0.21 mol) and dimethylsulfate (41.0 mL, 0.43 mol) at room temperature. The orange mixture is stirred at 80° C. for 6 h. The resulting yellow mixture is cooled to room temperature, diluted with water (500 mL), and extracted with hexanes (3×500 mL). The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure to give 1-fluoro-2-methoxy-3-nitrobenzene as a yellow oil. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (CDCl3): δ 4.08 (d, JH-F=2.0 Hz, 3H, OCH3), 7.13 (apparent t of d, JH-H=8.5 Hz, JH-F=5.0 Hz, 1H, H-5), 7.34 (d, JH-F=10.5 Hz, JH-H=8.5 Hz, JH-H=1.5 Hz, 1H, H-6), 7.58 (d of apparent t, JH-H=8.5 Hz, JH-H=1.5 Hz, JH-F=1.5 Hz, 1H, H-4). 19F{1H} NMR (CDCl3): 8-126.7 (s). 13C{1H} NMR (CDCl3): δ 62.6 (d, JC-F=5.5 Hz, OCH3), 120.2 (d, JC-F=3.5 Hz, C-4), 121.1 (d, JC-F=19.5 Hz, C-6), 123.2 (d, JC-F=8.0 Hz, C-5), 142.2 (d, JC-F=14.5 Hz, C-2), 144.8 (br, C-3), 156.2 (d, JC-F=251.5 Hz, C-1). LCMS m/z calcd for C7H6FNO3 ([M]+) 171. Found 183 ([M−CH2O+H+ CH3CN]+, 26%), 183 ([M-CH2O+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]O)=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([NH:30][O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:23]([O:27][C:28]([N:30]([O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:6]2[C:5]3[CH:20]=[C:21]([Cl:22])[C:2]([Cl:1])=[CH:3][C:4]=3[N:8]=[C:7]2[CH2:9][CH3:10])=[CH:16][CH:15]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (Example 96, 100 mg, 0.3 mmol), N,O-Bis-tert-butoxycarbonylhydroxylamine (Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 20, 3471, 140 mg, 0.6 mmol) and triphenylphosphine (158 mg, 0.6 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD) (0.1 mL, 0.6 mmol). The mixture was stirred under nitrogen atmosphere at room temperature for 2.5 h. The solvent was removed and the residue was purified by flash column chromatography on silica gel eluting with hexane/ehtyl acetate (1:1) to afford 174 mg (quant.) of the title compound as yellow amorphous: 1H-NMR (CDCl3) δ 7.84 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.16 (1H, s), 3.92 (2H, t, J=6.7 Hz), 3.05 (2H, t, J=6.7 Hz), 2.76 (2H, q, J=7.6 Hz), 1.56 (9H, s), 1.46 (9H, s), 1.33 (3H, t, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH2:43][CH2:42][C:41](=[O:44])[CH:40]=2)O1>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:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:39]4[CH2:43][CH2:42][C:41](=[O:44])[CH:40]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC1(C)OB(C2=CC(=O)CC2)OC1(C)C
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: [Cs+]
Product: O=C1C=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, Cesium carbonate, 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopent-2-enone and tetrakis(triphenylphosphine)palladium (0). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.89-8.92 (m, 1H), 8.12-8.24 (m, 2H), 7.88 (d, J=9.12 Hz, 1H), 7.11 (d, J=3.43 Hz, 1H), 3.28-3.32 (m, 2H), 3.19-3.21 (m, 2H), 2.54-2.56 (m, 2H), 1.98-2.05 (m, 2H), 1.75-1.87 (m, 4H), 1.15-1.34 (m, 2H). m/z: 423 [M+H]+
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][C@H:8]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:6]12[CH3:7])[C:22]1[CH:21]=[CH:20][C:19]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18][C:17]=1[CH2:16][CH2:15]3)(=[O:3])[CH3:2].B.C1C[O:38]CC1.C[N+]([O-])(C)C.O>COCCOCCOC.C1COCC1>[C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH2:12][CH2:13][OH:38])[CH2:9][C@H:8]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:6]12[CH3:7])[C:22]1[CH:21]=[CH:20][C:19]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18][C:17]=1[CH2:16][CH2:15]3)(=[O:3])[CH3:2]
Reactant: C=CC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1OC(C)=O
Reactant: C1CCOC1
Agent: B
Agent: C[N+](C)(C)[O-]
Solvent: COCCOCCOC
Solvent: O
Product: CC(=O)O[C@H]1[C@H](CCCO)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A solution of 629 mg (1.41 mmol) of 29 in anhydrous diglyme (21 mL) was stirred at 0° C. as 1.49 mmol of borane-THF (1.49 mL of a 1 M solution in THF) was added. Reaction was stirred at 0° C. for ½ h the allowed to warm to rt and stir for 2 h. To this was added 660 mg (5.96 mmol) of trimethylamine oxide and reaction was stirred and heated at 150° C. for 2 h, cooled to rt, poured into H2O (150 mL) and extracted with CH2Cl2 (3×, 100 mL). Combined organic extracts were washed with 10% sodium metabisulfite (70 mL), H2O (70 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on a 3×22 cm column of silica gel using hexanes/EtOAc (1.5:1) as eluent gave 530 mg (81%) of 30 as a white solid. Data for 30: TLC, T-6, Rf0.34. 1H NMR (500 MHz, CDCl3) δ 0.83 (s, 3H, H-18), 2.09 (s, 3H, Oac), 2.85 (m, 2H, H-6), 3.85 (t, 2H, J=5.7 Hz, —CH2O—), 4.63 (d, 1H, J=7.8 Hz, H-17α), 5.04 (s, 2H, benzylic), 6.72 (d, 1H, J=2.6 Hz, H-4), 6.78 (dd, 1H, J=8.2, 2.6 Hz, H-2), 7.19 (d, 1H, J=2.6 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H); HRMS (ES) calcd for C30H38O4Na (M+Na+) m/e 485.2668, found m/e 485.2679.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)C>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:20][CH:21]=1
Reactant: Clc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(Cl)nc1
Temperature: 70 °C
Yield: 60.5 %

Procedure:
In a dry, nitrogen-purged flask, tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (330 mg, 1.6 mmol), prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), in anhydrous toluene (6 mL) was treated with 2-chloro-5-iodopyridine (383 mg, 1.6 mmol), available as described in (Tetrahedron Lett., (1993), 34, 7493-7496), Pd2(dba)3 (156 mg, 0.16 mmol), BINAP (212 mg, 0.34 mmol), and sodium tert-butoxide (230 mg, 2.4 mmol). The mixture was heated at 70° C. for 24 hours. The reaction mixture was poured into diethyl ether (10 mL) and washed successively with 1N HCl, saturated NaHCO3, and brine. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified on SiO2, eluting with ethyl acetate:hexanes (1:1) to provide the title compound (300 mg, 58% yield) as a light brown solid. 1H NMR (CDCl3, 300 MHz) δ 1.41(s, 4.5H), 1.46(s, 4.5H), 1.93-2.05(m, 2H), 3.14 (d, J=14.7 Hz, 0.5H), 3.35(d, J=14.7 Hz, 0.5H), 3.42(m, 2H), 3.57 (d, 8.45 Hz, 1H), 4.37(s, 1H), 4.53(s, 0.5H), 4.65(s, 0.5H), 6.82(dd, J=2.94, 8.83Hz, 1H), 7.13(d, J=8.46 Hz, 1H), 7.71(s, 1H); MS (DCI/NH3) m/z 310 (M+H)+.