Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)[CH:2]=[CH2:3].[F:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:3]=[CH:2][CH2:1][N:4]2[C:12]3[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=3[C:6]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]2=3)=[CH:22][CH:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC=Cc2ccc(F)cc2)C1
Temperature: 25 °C

Procedure:
5-Allyl-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 0.76 mmol, 1 equiv.) and 4-fluorobromobenzene (134 mg, 0.76 mmol, 1 equiv.) were heated to 100° C. with palladium acetate (5 mg, 0.023 mmol), triphenyl phosphine (12 mg, 0.046 mmol) and triethyl amine (0.22 mL, 2 equiv.) in THF (5 mL) for 14 h. The reaction mixture was cooled to RT and diluted with THF (10 mL), filtered over a Celite bed and concentrated. The concentrate was dissolved in EtOAc (20 mL) and washed with water (5 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product that was purified by HPLC. 1H NMR (DMSO-d6) δ (ppm): 10.0 (bs, 1H), 7.61-7.58 (d, 2H), 7.44-7.40 (dd, 2H), 7.20-7.11 (m, 3H), 6.4 (d, 1H), 6.3 (m, 1H), 5.0 (m, 2H), 4.62 (d, 1H), 4.29-4.25 (m, 1H), 3.78 (m, 1H), 3.5 (m, 1H), 3.18 (m, 2H), 2.98 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[NH:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A 4 N hydrochloric acid/1,4-dioxane solution (20 mL) was added to tert-butyl 4-benzyloxycarbonylaminopiperidine-1-carboxylate obtained in Example (192a) (1.5 g, 4.49 mmol). The mixture was stirred at room temperature for one hour, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in methanol. Amberlite IRA-400(Cl) ion exchange resin (20 g) was added, and the mixture was stirred at room temperature for one hour. Amberlite was filtered off, and then the solution was concentrated under reduced pressure to obtain 910 mg of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])C1C=CC=CC=1>>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][C:5]([O:27][CH3:20])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccc(OC)cc1
Yield: 59 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting p-anisoyl chloride for benzoyl chloride, the title compound was obtained as a light yellow solid in 59% yield: 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 4.12 (q, J=6.9 Hz, 2H), 3.87 (s, 3H), 2.91 (t, J=7.2 Hz, 2H), 2.30(t, J=7.5 Hz, 2H), 1.74 (m, 2H), 1.65 (m, 2H), 1.39 (m, 4H), 1.25 (t, J=6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 14.19, 24.29, 24.75, 28.91, 28.96, 34.21, 38.06, 55.37, 60.10, 113.58, 130.02, 130.21, 163.23, 173.71, 198.93.
Reaction SMILES: [CH2:1]1[C:10]2=[CH:11][CH:12]=[CH:13][C:8]3=[C:9]2[N:4]([C:5](=[O:14])[CH2:6][CH2:7]3)[C:3](=[O:15])[CH2:2]1.Cl.[C:17]1([CH2:23][OH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][O:24][C:3](=[O:15])[CH2:2][CH2:1][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]3[C:9]=2[NH:4][C:5](=[O:14])[CH2:6][CH2:7]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCc2cccc3c2N1C(=O)CC3
Reactant: OCc1ccccc1
Agent: Cl
Product: O=C1CCc2cccc(CCC(=O)OCc3ccccc3)c2N1

Procedure:
A solution of 1,2,6,7-tetrahydro-3H,5H-benzo[ij]-quinolizine-3,5-dione (20.1 g, 0.1 mole) in phenylmethanol (200 ml) is treated with a drop of concentrated hydrochloric acid. The mixture is refluxed 24 hours (or until the starting dione can no longer be detected by thin layer chromatography). The solution is cooled and concentrated at reduced pressure. The product is purified by flash chromatography to yield 1,2,3,4-tetrahydro-2-oxo-8-quinoline propanoic acid phenylmethyl ester.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][C:12](=O)[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].N1C=CC=CC=1>O>[C:1]1([C:7]2[CH2:13][C:12](=[S:20])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccccc2)=Nc2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: S=C1CC(c2ccccc2)=Nc2ccccc2N1

Procedure:
A mixture of 23.6 parts of 2,3-dihydro-4-phenyl-1H-1,5-benzodiazepin-2-one and 24.4 parts of phosphorus pentasulfide in 400 parts by volume of pyridine is stirred at reflux temperature for one hour. This solution is then added dropwise with stirring to about 2000 parts by volume of 60° C. warm water. The solid which forms is separated by filtration, washed with water and dried in air overnight. The product thus obtained is recrystallized from ethyl acetate to give, as beige crystals, 2,3-dihydro-4-phenyl-1H-1,5-benzodiazepine-2-thione. This product has the formula ##STR12##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8](=[O:14])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][OH:19].[H-].[Na+]>>[CH2:10]([N:9]([CH2:12][CH3:13])[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:19][CH2:18][CH2:17][CH2:16][NH2:15])[CH:7]=1)=[O:14])[CH3:11]
Reactant: NCCCO
Reactant: CCN(CC)C(=O)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)C(=O)c1ccnc(OCCCN)c1

Procedure:
2-Chloro-4-diethylcarbamoylpyridine is reacted with 3-aminopropanol and sodium hydride to give 3-(4-diethylcarbamoyl-2-pyridyloxy)propylamine, which is reduced with lithium aluminium hydride in tetrahydrofuran to give 3-(4-diethylaminomethyl-2-pyridyloxy)propylamine; this product is heated under reflux in pyridine with 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone to give 2-[3-(4-diethylaminomethyl-2-pyridyloxy)propylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[O:4][C:5]([C:8](OCC)=O)=[N:6][N:7]=1.B.[NH2:15][CH2:16][CH2:17][SH:18]>>[CH3:13][N:2]([CH3:1])[C:3]1[O:4][C:5]([CH2:8][S:18][CH2:17][CH2:16][NH2:15])=[N:6][N:7]=1
Reactant: NCCS
Reactant: CCOC(=O)c1nnc(N(C)C)o1
Agent: B
Product: CN(C)c1nnc(CSCCN)o1

Procedure:
When 2-dimethylamino-5-ethoxycarbonyl-1,3,4-oxadiazole [prepared according to the procedure described in Org. Magn. Resonance, 6, 144 (1974)] is hydrolyzed and reduced with borane as described in Example 58, Step A, and then is reacted with cysteamine according to the procedure described in Example 60, Step A, there is produced 2-[(2-dimethylamino-1,3,4-oxadiazol-5-yl)methylthio]ethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C=O)[CH:5]=[N:6][C:7]=1[CH3:8].[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13].Cl>CO>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:4]1[CH:3]=[C:2]([Br:1])[C:7]([CH3:8])=[N:6][CH:5]=1
Reactant: Cc1ncc(C=O)cc1Br
Reactant: COC(OC)OC
Agent: Cl
Solvent: CO
Product: COC(OC)c1cnc(C)c(Br)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
In a sealed tube charged with a solution of 5-bromo-6-methyl-3-pyridinecarbaldehyde (for a synthesis see PB62797 Intermediate 69) (191 mg, 0.955 mmol) in MeOH (15 ml) was added trimethyl orthoformate (1.045 ml, 9.55 mmol) and HCl (4M solution in 1,4-dioxane, 0.573 ml, 2.292 mmol). The reaction mixture was stirred at 70° C. for 2 h 30 min. The solution was concentrated under vacuum and the residue was diluted with saturated NaHCO3 and EtOAc. The organic phase was extracted, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a pale oil. The crude was purified by flash chromatography using a 5 g Merck silica gel cartridge, and EtOAc/Hexane 1/9 as eluent to give 5-[bis(methyloxy)methyl]-3-bromo-2-methylpyridine (129.5 mg, 52%) as a yellow oil pure enough to be used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:48]=[C:47]([O:49][CH3:50])[C:41]2[O:42][CH2:43][CH2:44][CH2:45][O:46][C:40]=2[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:21](=[O:20])[NH:22][C:23]([CH:24]([C:38]2[CH:48]=[C:47]([O:49][CH3:50])[C:41]3[O:42][CH2:43][CH2:44][CH2:45][O:46][C:40]=3[CH:39]=2)[NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:30][CH:31]=2)=[N:11]1)=[O:4]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)OCCCO2
Reactant: COC(=O)c1scnc1NN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c3c(c2)OCCCO3)[nH]c1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After adding 55 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example (162c)) and 300 μl of triethylamine to a solution of 160 mg of {2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example 30c) in 5 ml of THF, the mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The reaction mixture was then concentrated. The residue was dissolved in 5 ml of DMF, and then 0.3 ml of triethylamine was added and the mixture was stirred at 80° C. for 6 hours.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1>>[F:21][C:20]([F:22])([F:23])[C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(CCCBr)c1
Reactant: CCc1cnccc1C
Product: CCc1cnccc1CCCCc1cccc(C(F)(F)F)c1
Yield: 80.4 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 4.03 g (15.1 mmol) of 1-bromo-3-(3-trifluoromethylphenyl) propane were reacted in the same manner as in Example 26. The reaction compound was purified to obtain 3.73 g of the desired compound (yield: 80.5%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(O)C>CCCCCC>[CH2:23]([O:22][C:20]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:21])[CH3:24]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)OCC
Yield: 79.4 %

Procedure:
Into an appropriate reactor fitted with warming, cooling and stirring means, were poured 152.5 ml (1.5 mol) of 2,4-difluoroaniline and 425 ml (2.1 mol) of diethyl ethoxymethylenemalonate. The mixture was warmed at 90° to 100° C. for about three hours with evacuation of ethanol appearing in the condensation. This lead to a solid product which was treated with hexane, washed, crystallized from hexane and dried to give 356.5 g (yield 76.5%) of 1-(2,2-diethoxycarbonyl-vinylamino)-2,4-difluoro-benzene. Elemental analysis of the product showed a good correspondence with the formula C14H15NO4F2. 350 g (1.17 mol) of this product were poured into a reactor with 1 liter of diphenyloxide. The mixture was refluxed at 265°-270° C. for 11/2 hours with a subsequent evacuation of the ethanol produced during the cyclisation. After cooling to ambient temperature, there was obtained a residue which was treated with benzene and then with hexane, dried and recrystallized from methanol. This gave 239 g (yiel 80.7%) of 1,4-dihydro-3-ethoxycarbonyl-6,8-difluoro-4-oxo-quinoline, elemental analysis of which showed a good correspondence with the formula C12H9NO3F2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:12].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>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.CN(C=O)C>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:24]=[N:25][CH:26]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1cccnc1)c1n[nH]c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1n[nH]c2ccc(-c3cncc(F)c3)cc12
Temperature: 180 °C
Yield: 1.6 %

Procedure:
To a microwave vial was added 5-bromo-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (CXXXV) (0.200 g, 0.63 mmol), 5-fluoropyridine-3-boronic acid (CXXIX) (0.098 g, 0.694 mmol), tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.032 mmol), potassium phosphate (0.201 g, 0.947 mmol), water (1 mL), and DMF (5 mL) The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180° C. The solution was filtered through a pad of Celite and concentrated under vacuum. The crude product was purified by column chromatography (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to afford 5-(5-fluoropyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (13) (4 mg, 0.01 mmol, 2% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 14.02 (br s, 1H), 10.70 (s, 1H), 9.08 (d, J=2.5 Hz, 1H), 8.83 (t, J=1.8 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.53-8.52 (m, 1H), 8.34-8.29 (m, 2H), 8.14-8.09 (m, 1H), 7.89-7.81 (m, 2H), 7.42-7.38 (m, 1H). ESIMS found for C18H12FN5O m/z 334.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[S-:11][CH2:12][CH3:13].[Na+].CN(C)C=O>O.[Cl-].[Na+].O>[Br:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([S:11][CH2:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Br)cc(Br)c1
Reactant: CC[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cc(Br)cc(OC)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a mixture 1,3-dibromo-5-methoxy-benzene (2.65 g, 10 mmol) and sodium thioethoxide (1.01 g, 12 mmol) was added dimethylformamide (30 mL) at room temperature. Then, the resulting light yellow solution was heated to 105° C. and stirred for 2 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and diluted with water (50 mL) and brine solution (50 mL). Then, the organic compound was extracted into ethyl acetate (3×50 mL). The combined extracts were washed with brine solution (150 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 120 g column chromatography, eluting with 0-20% ethyl actetate in hexanes to obtain 1-bromo-3-ethylsulfanyl-5-methoxy-benzene (1.35 g, 55%) as a white solid: EI(+)-HRMS m/e calcd for C9H11BrOS (M)+ 245.9715, found 245.9713.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O.C([OH:42])C>C(OCC)(=O)C.O>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:42])[CH:7]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccnc(Cl)c3)cc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1cc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc([N+](=O)[O-])cc3)cc2)cc[nH]1

Procedure:
2-Chloro-4-{4-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-phenyl}-pyridine (1.6 g, 3 mmol) was refluxed with 6M NaOH in 1/1 water/ethanol (10 mL, 60 mmol) for 2 to 4 hours, followed by regular ethyl acetate/water workup and silica gel column chromatography to give the intermediate 4-{4-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-phenyl}-1H-pyridin-2-one, which was then treated as described in general procedure L [using iodocyclohexane (0.78 mL, 6 mmol)] to give 1-cyclohexyl-4-{4-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-phenyl}-1H-pyridin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: OCc1ccc(Cl)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Clc1ccc(COc2ccnc(Cl)c2)cc1
Temperature: 105 °C
Yield: 56.2 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (5.0 g, 21 mmol), 4-chlorobenzyl alcohol (3.3 g, 23 mmol), cesium carbonate (8.9 g, 27 mmol), CuI (4.0 g, 21 mmol) and phenanthronine (0.76 g, 4.2 mmol) in toluene (20.0 mL) was purged with nitrogen for 10 min. The reaction mixture was heated at 105° C. overnight and then cooled and diluted with EtOAc. The resulting solution was washed with brine, passed through a pad of celite and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (hexanes/EtOAc 100% to 70%) to give the title compound (3.0 g, 56%): 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=6.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 6.90 (d, J=2.0 Hz, 1H), 6.80 (dd, J=6.0, 2.0 Hz, 1H), 4.07 (s, 2H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl.[OH-].[Na+]>O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccccc1
Temperature: 5 °C
Yield: 91 %

Procedure:
To a 5 L round bottom flask, equipped with a mechanical stirrer, containing the 571 g of wet N'-tert-butyl-N-(4-chlorobenzoyl)hydrazine intermediate and equipped with a 500 mL addition funnel containing 371 g of benzoyl chloride, is charged 1500 mL of methylene chloride, 250 mL of water and lastly 223 g of 50% by weight aqueous sodium hydroxide. The flask contents are stirred and cooled to 5° C. and the benzoyl chloride is added dropwise during a one hour period so that the temperature of the flask contents does not exceed 10° C. After allowing the flask contents to warm to room temperature, stirring is stopped and the organic and aqueous phases are allowed to separate overnight. The upper aqueous phase is removed by suction and is replaced by 500 mL of fresh water, the heterogeneous mixture is stirred, the phases are allowed to separate and the upper aqueous phase again is removed by suction. This washing procedure is repeated two more times and then 500-800 mL of hexane is added to the organic remainder. The contents are briefly stirred and then are poured onto a glass flitted Buchner funnel. The filter cake is washed extensively with a total of 2 L of hexane followed by 10 L of water and then is dried in vacuo at 65° C. for two days to give 758.2 g of N'-tert-butyl-N-(4-chlorobenzoyl)-N'-benzoylhydrazine as a white powder melting at 197°-198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:22])[F:20])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccccc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 199.0-199.1° C. 1H NMR (acetone-d/300 MHz) 7.94 (s, 1H), 7.76 (s, 1H), 7.65 (m, 1H), 1.51 (m, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 6.44 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 13F NMR (acetone-d6 /28; MHz) -79.5 (d, J=6.5 Hz). ESHRMS m/z 402.9752 (M-H, Calc'd 402.9751). Anal. Calc'd for C17H9Cl2F3O4 : C, 50.40; H, 2.24; Cl, 17.50. Found: C, 50.42; H, 2.12; Cl, 17.72.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])=[CH:12][CH:11]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C@@H:18]([CH3:19])[NH2:20])=[CH:12][CH:11]=1
Reactant: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 110.3 %

Procedure:
1,1-dimethylethyl [(1R)-2-({6-[(2,5-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 35, 60 mg) was dissolved in 4 mL of dry dichloromethane. To this solution, at 0° C., were added dropwise 40 equivalents of TFA (0.480 mL). The reaction was stirred for 3 hours 30 at 0° C. The reaction mixture was evaporated and then purified by SCX on a 5 g cartridge. 3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with CV of methanolic ammonia (1N). Evaporation of the volatiles, afforded the title compound (49 mg)