Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13]Cl)=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C(O)CCC>[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[N:21]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:16])[C:4]=3[N:3]=[C:2]([CH3:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1nc2c(C)cccc2c(Cl)c1CCCl
Reactant: Cc1ccccc1N
Agent: Cl
Solvent: CCCCO
Product: Cc1ccccc1N1CCc2c(C)nc3c(C)cccc3c21
Yield: 22.5 %

Procedure:
2,8-Dimethyl-3-(2-chloroethyl)-4-chloroquinoline (7.63 g, 30 mmol) and 2-methylaniline hydrochloride (4.31 g, 30 mmol) in 1-butanol (100 ml) wereheated at reflux for 4 days, then the solvent evaporated, the crude producttaken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from aqueous ethanol gave 1-(2-methylphenyl)-4,6-dimethyl-2,3-dihydropyrrolo-[3,2-c]quinoline (1.95 g, 23%), m.p. 126°-128°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][CH:9]([C:11]1[C:20]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1)[OH:10].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C:9]([C:11]1[C:20]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OCCO2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
Compound 178a (3.0 g) obtained in Step A was dissolved in acetone (30 ml), mixed with Jones reagent (2.6 M) (4.9 ml), and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was mixed with water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate anhydride, and evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound 178(3.0 g, 75%) as colorless crystals.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21]>CN(C)C=O.Cl[Cu]>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[C:14]=1[F:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cccc(F)c1F
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
Into a 500 mL, 4-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of sodium hydride (6.8 g, 170.00 mmol, 1.70 equiv, 60%) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14.1 g, 99.93 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 0° C. in 15 min. The resulting solution was stirred for 2 h at room temperature. CuCl (10 g, 101.01 mmol, 1.00 equiv) was added and a solution of 2,3-difluorophenol (15.6 g, 119.91 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100° C., in an oil bath. The resulting solution was extracted with ether and the organic layers combined. The organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8) to give 21.2 g (84%) of 1,2-difluoro-3-(4-nitrophenoxy)benzene as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=O>C(O)CC>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]3[CH:13]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCCO
Product: Cc1ccc(-c2cn3cc(C(F)(F)F)ccc3n2)cc1
Yield: 70.2 %

Procedure:
10 g (0.0616 mole) of 2-amino-5-trifluoromethylpyridine and 17.5 g (0.0616 mole) of 1-bromo-2-(4-methylphenyl)-2-ethanone are mixed in 200 ml of n-propanol and the solution is heated to reflux. At the end of the reaction, the reaction mixture is concentrated under reduced pressure and the evaporation residue taken up with water and treated with an excess of ammonia solution until the pH is basic. The imidazopyridine is extracted with dichloromethane and purified by chromatography. 11.95 g (56%) of white solid are obtained. M.p. 187°-188° C.
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:40][C:39]([C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3C(OC(C)(C)C)=O)=[N:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][C:16]([C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3C(OC(C)(C)C)=O)=[N:15][CH:14]=2)=[CH:9][CH:8]=1)=O.Cl.Cl.[N:55]1([C:61]2[N:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=2)[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[C:16]1[NH:15][CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:5]3[N:67]([C:64]4[CH:63]=[CH:62][C:61]([N:55]5[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]5)=[N:66][CH:65]=4)[C:2]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[N:40]=[C:39]([C@@H:41]6[CH2:45][CH2:44][CH2:43][NH:42]6)[NH:38][CH:37]=5)=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(C(=O)CCC(=O)c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Reactant: Nc1ccc(N2CCCCC2)nc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5)n4)cc3)n2-c2ccc(N3CCCCC3)nc2)ccc1-c1c[nH]c([C@@H]2CCCN2)n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 170.4 %

Procedure:
To a solution of the product from Example 138B (0.20 g, 0.28 mmol) and the product from Example 144C (0.11 g, 0.42 mmol) in toluene (2.8 mL) was added TFA (22 μL, 0.28 mmol). The mixture was stirred at 110° C. for 3 hours. To the cooled mixture was added TFA (0.5 mL) and the mixture was stirred for 1 h at rt. The solvent was then removed under reduced pressure and triturated with diethylether and dried to provide 0.31 g of the desired compound as a TFA salt. 1HNMR (DMSO-d6; 400 MHz): δ 9.78 (br s, 2H), 7.84 (d, J=2.71 Hz, 1H), 7.75 (s, 2H), 7.67 (AA′XX′, J=8.34 Hz, 4H), 7.35 (dd, J=9.11, 2.71 Hz, 1H), 7.18 (AA′XX′, J=8.46 Hz, 4H), 6.79 (d, J=9.11 Hz, 1H), 6.53 (s, 2H), 4.79 (app t, J=7.81 Hz, 2H), 3.4-3.2 (m, 4H), 2.44-2.36 (m, 2H), 2.25-1.98 (m, 6H), 1.65-1.45 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:44]1[N:45]=[CH:46][S:47][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.CN(C)C=O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:44]3[N:45]=[CH:46][S:47][CH:48]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Brc1cscn1
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1n[nH]c2c(-c3cscn3)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (200 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (179 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (21.6 mg), potassium acetate (116 mg) and N,N-dimethylformamide (3.0 mL) was stirred overnight at 110° C. under argon atmosphere. The reaction mixture was cooled to room temperature, 4-bromo-1,3-thiazole (0.105 mL), aqueous sodium carbonate solution (2 M, 0.589 mL) and tetrakis(triphenylphosphine)palladium(0) (68.1 mg) were added thereto, and the reaction mixture was stirred overnight at 120° C. under argon atmosphere. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (20.0 mg).
Reaction SMILES: [OH:1]O.[CH2:3]([CH:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][C:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([S:20][CH2:21][CH3:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[CH2:4][CH2:5][CH2:6][CH3:7]>C(O)(=O)C>[CH2:3]([CH:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:15][CH2:16][C:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([S:20]([CH2:21][CH3:22])=[O:1])[CH2:18][CH2:19]2)[CH2:10][CH2:9]1)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: OO
Reactant: CCCCCCCC1(SCC)CCC(C2CCC(CCCCC)CC2)CC1
Solvent: CC(=O)O
Product: CCCCCCCC1(S(=O)CC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 ml of 30% H2O2 is added to 3.8 g of 4-pentyl-4'-heptyl-4'-ethylthiobicyclohexane in 25 ml of glacial acetic acid and the mixture is stirred at room temperature for 3 hours. After customary working up, 4-pentyl-4'-heptyl-4'-ethylsulfinylbicyclohexane is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:19][C:20]=1[CH3:21])[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:16]1[S:17][C:18]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)=[CH:19][C:20]=1[CH3:21])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(OC(CC(C)C)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(CC(C)C)Oc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 3-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}butan-1-ol (525 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (365 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.8 mL) and 1,1′-(azodicarbonyl)dipiperidine (807 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(3-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}butoxy)benzoate as an amorphous compound. The obtained methyl 4-(3-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}butoxy)benzoate was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (371 mg, 52%).
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:6])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[C:1]([S@@:5]([NH:7][C@@H:8]1[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[CH2:16][C@H:17]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCc1cccc(F)c1/C=N/[S@@](=O)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1Cc2cccc(F)c2[C@H]1N[S@@](=O)C(C)(C)C
Reaction time: 8.5 h
Yield: 34.8 %

Procedure:
To a solution of 1.122 g of tert-butyl 3-{2-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]-3-fluorophenyl}propanoate (compound of Preparation Example 129) in 26.7 ml of THF was added 9.5 ml of lithium bis(trimethylsilyl)amide (1 M THF solution) at −78° C., followed by stirring at the same temperature for 8.5 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 390 mg of tert-butyl (1S,2R)-1-{[(S)-tert-butylsulfinyl]amino}-7-fluoroindane-2-carboxylate (Preparation Example 113a), and 130 mg of each of tert-butyl (1R,2R)-1-{[(S)-tert-butylsulfinyl]amino}-7-fluoroindane-2-carboxylate and tert-butyl (1S,2S)-1-{[(S)-tert-butylsulfinyl]amino}-7-fluoroindane-2-carboxylate (Preparation Example 113b and Preparation Example 113c).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(F)cc2)cc1

Procedure:
A mixture of 2-(4-fluorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (10 mmol) and p-toluenesulfonic acid monohydrate (1 mmol) in toluene (100 mL) is heated to reflux for 72 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using toluene/ethyl acetate to give pure 2-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole.
Reaction SMILES: Cl.C1(N2CCN([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:27](=[O:28])[C:26]4[CH:29]=[CH:30][CH:31]=[C:24]5[C:25]=4[C:20](=[CH:21][CH:22]=[CH:23]5)[C:19]3=[O:32])CC2)C=CC=CC=1.[Br:33][CH2:34]CCCCBr.BrCCCCBr>>[Br:33][CH2:34][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:27](=[O:28])[C:26]2[CH:29]=[CH:30][CH:31]=[C:24]3[C:25]=2[C:20](=[CH:21][CH:22]=[CH:23]3)[C:19]1=[O:32]
Reactant: BrCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of example 34 but substituting 1,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: [CH2:1]([C@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH2:4]1)[CH3:2].[C:18](Cl)(=[O:20])[CH3:19].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[C:18]([C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:14])([CH3:13])[C@H:3]([CH2:1][CH3:2])[CH2:4][C:5]2([CH3:16])[CH3:17])=[CH:10][C:9]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC[C@@H]1CC(C)(C)c2ccc(C)cc2C1(C)C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC[C@@H]1CC(C)(C)c2cc(C(C)=O)c(C)cc2C1(C)C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of (R)-3-ethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene ([α]546 +2.2° (C=0.95 in ethanol)) (36.5 g; 0.159 mol) and acetyl chloride (13.7 g; 0.174 mol) in 1,2-dichloroethane (100 ml), anhydrous aluminum chloride (25.3 g; 0.190 mol) was added at 20° C., and the resulting mixture was stirred for 1 hour. The reaction mixture was treated with dilute hydrochloric acid while cooling with ice. The organic layer was washed with dilute hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution in order, dried over anhydrous sodium sulfate and concentrated t give (R)-7-acetyl-3-ethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (41.5 g; 0.153 mol; 96%). B.P., 120° C./0.1 mmHg. [α]365 -46.1° (C=0.97 in ethanol).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:13]3[N:17]4[CH:18]=[C:19]([C@@H:22]([N:27]5[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]5)[C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][C:16]4=[N:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:40][N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][C:43]([CH3:55])=[N:42]1>>[CH3:40][N:41]1[C:45]([C:2]2[C:11]([CH3:12])=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:13]4[N:17]5[CH:18]=[C:19]([C@@H:22]([N:27]6[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]6)[C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:21][C:16]5=[N:15][N:14]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:44][C:43]([CH3:55])=[N:42]1
Reactant: Cc1c(Br)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C)n1
Product: Cc1cc(-c2ccc3ccc(-c4nnc5ccc([C@@H](N6CC[C@H](NC(=O)OC(C)(C)C)C6)C(F)(F)F)cn45)nc3c2C)n(C)n1

Procedure:
Prepared as described in Example 191, using tert-butyl (S)-1-((R)-1-(3-(7-bromo-8-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate in place of 7-bromo-2,8-dimethylquinoline and substituting 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step A. LCMS APCI (+) m/z 621 (M+H).
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][OH:29])[CH:18]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][OH:29])[CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=C(c3cn(CCCO)c4ccccc34)C(=O)NC2=O)c2occc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NC(=O)C(c2ccc(O)c3ccoc23)=C1c1cn(CCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
Dissolve 3-(4-methoxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione (0.1 g, 0.24 mmol) in 2.5 mL dichloromethane under nitrogen at −78° C. Add boron tribromide (0.11 mL, 1.16 mmol, 5 equiv) dropwise and stir at −78° C. for 1 hr, warm to room temperature and stir for 1 hr. Quench the reaction with ice and then extract with ethyl acetate. Washed the organics with brine, dry over sodium sulfate, filter, and concentrate in vacuo. Purification by column chromatography (25% ethyl acetate: hexanes to 50% ethyl acetate: hexanes) afforded 0.050 g (52%) of the title product. High Res. Mass Spec (m/z): Calcd 403.1301 Found 403.1294.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][CH:23]=O)=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][Cl:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.S(C)C.CO.Cl>C1COCC1>[Cl:1][C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][Cl:20])=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CCc1nc2cc(NC=O)c(Cl)cc2n1-c1ccc(CCCl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CCc1nc2cc(NC)c(Cl)cc2n1-c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of (6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylformamide, step 1, 112 mg, 0.3 mmol) in THF (15 ml) was added Me2S B3 (0.07 ml, 0.77 mmol) under nitrogen at room temperature. The mixture was refluxed for 1 h. Then the mixture was cooled to room temperature and was added methanol (3 ml) and 2N aqueous HCl (12 ml). The mixture was stirred at 70° C. for 30 min. The volatile component was removed under reduced pressure, and the residue was dissolved with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous NaHCO3 (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1:4) to afford 93 mg (87%) of the title compound as white solids.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[N:23][NH2:24])[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:18][CH2:17]1.[F:33][C:34]([F:40])([F:39])[CH2:35][C:36](O)=O.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:36]([CH2:35][C:34]([F:40])([F:39])[F:33])=[N:24][N:23]=[C:20]2[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:18][CH2:17]1
Reactant: O=C(O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=NN
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Reaction time: 18 h

Procedure:
Triethylamine (0.259 mL, 1.86 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-hydrazonoazepan-3-ylcarbamate from Step A (548 mg, 1.55 mmol), 3,3,3-trifluoropropionic acid (0.205 mL, 2.32 mmol), EDC (356 mg, 1.86 mmol), and 1-hydroxy-7-azabenzotriazole (253 mg, 1.86 mmol) in dichloromethane (55 mL). After 18 h, saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 96:4, to give the title compound. MS: m/z=447 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][S:21][CH3:22])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:3]=1[C:23]([NH:25][CH2:26][C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:24].ClC1C=C(C=CC=1)C(OO)=[O:42].[OH-].[Ca+2].[OH-].S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][S:21]([CH3:22])=[O:42])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:3]=1[C:23]([NH:25][CH2:26][C:27]12[CH2:28][CH:29]3[CH2:35][CH:33]([CH2:32][CH:31]([CH2:30]3)[CH2:36]1)[CH2:34]2)=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCN(CCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [Mg+2]
Solvent: ClCCl
Product: CS(=O)CCN(CCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C
Yield: 29.8 %

Procedure:
Prepared according to the method of Example 22 from [2-[[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]amino]ethyl][2-(methylthio)ethyl]-carbamic acid, 1,1-dimethylethyl ester (0.460 g, Example 30a), 3-chloroperoxybenzoic acid (0.315 g) and dichloromethane (20 ml). Excess calcium hydroxide was added, followed by excess magnesium sulfate. The mixture was filtered through celite and concentrated under reduced pressure. The crude material was purified on silica gel (19:1/dichloromethane:methanol) to afford the sub-title compound as a gum (0.141 g) and the corresponding sulfone (0.057 g).