Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(CO[C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[O:11])=CC=1)([O-])=O.[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CCOC(C)=O>[N:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][N:29]([CH3:28])[C:10](=[O:11])[NH:12][C:13]2[CH:25]=[CH:24][C:16]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[CH:33][CH:34]=1
Reactant: CNCCc1ccncc1
Reactant: O=C(Nc1ccc2sc3ccccc3c2c1)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: CN(CCc1ccncc1)C(=O)Nc1ccc2sc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Nitrobenzoxycarbonylamino)dibenzothiophene (Example 1; 501 mg, 1.35 mmol) was suspended in EtOAc (10 ml) and 4-[2-(methylamino)ethyl]pyridine (408 mg, 3.0 mol) added in one portion. The resulting mixture was stirred at ambient temperature for 16 hours then further EtOAc (50 ml) added. The solution was washed with 1 M sodium hydroxide (3×25 ml), water (2×25 ml) and brine (25 ml), dried and evaporated in vacuo. NMR 8.44 (m, 3H), 8.34 (d, 1H), 8.13 (m, 1H), 7.96 (m, 1H), 7.82 (d, 1H), 7.55 (dd, 1H), 7.47 (m, 2H), 7.28 (d, 2H), 3.61 (t, 2H), 2.96 (s, 3H), 2.86 (t, 2H); m/z 362.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[O:6][CH2:5][CH2:4][O:3]1.[O-2].[Ca+2].S1C=CC=C1>O1CCCC1.[Pt]>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2ccccc2[N+](=O)[O-])OCCO1
Agent: [Pt]
Agent: [Ca+2]
Agent: [O-2]
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: CC1(c2ccccc2N)OCCO1
Yield: 78.2 %

Procedure:
2-methyl-2-(2-nitrophenyl)-1,3-dioxolane (0.132mol) was dissolved in tetrahydrofuran (600 ml) and this solution was hydrogenated with platinum on activated carbon (4 g) as a catalyst in the presence of calcium oxide (10 g) and thiophene (3 ml). After uptake of H2 (3 equiv), the catalyst was filtered on celite and washed with tetrahydrofuran. The tiltrate was evaporated. The residue was recrystallized from n-hexane. The crystals were filtered off and dried, yielding 18.5 g (78%) of 2-(2-methyl-1,3-dioxolan-2-yl)benzenamine (interm. 27).
Reaction SMILES: [CH2:1]([CH:7]1[C:12](=[O:13])[CH:11]2[N:9]([C:10]2([CH3:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[C:8]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>O1CCCC1.[Pd]>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([CH3:23])[N:9]2[CH:11]1[C:12](=[O:13])[CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]2=[O:24]
Reactant: CCCCCCC1C(=O)C2N(C1=O)C2(C)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCC1C(=O)C2N(C1=O)C2(C)c1ccccc1N
Reaction time: 4 h
Yield: 38.8 %

Procedure:
To a solution of 3-hexyl-6-methyl-6-(2-nitrophenyl)azabicyclo[3.1.0]hexane-2,4-dione (Preparation 138, 880 mg, 2.66 mmol) in tetrahydrofuran (10 ml) was added 5% palladium on charcoal (Johnsson Matthey type 87, 50 mg) and the reaction mixture was placed under an atmosphere of hydrogen (60 psi) at room temperature for 4 h. The catalyst was removed by filtration through Celite™ and the filtrate was concentrated in vacuo. The residue was flushed through a small plug of silica gel (<1 g) eluting with dichloromethane to afford only the exo isomer of the title compound as a pale yellow oil (310 mg, 39%).
Reaction SMILES: O[C@H](C1C=CN=CC=1)[C@@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]>[OH-].[K+].CO.C1COCC1.O>[CH3:4][C@H:3]1[C@@H:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:7][C:6](=[O:15])[NH:5]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)[C@H](O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1

Procedure:
A solution of benzyl [(1S,2R)-2-hydroxy-1-methyl-2-pyridin-4-ylethyl]carbamate in 7.5N aq. KOH/MeOH/THF (1:2:4, 7 mL) was stirred at room temperature overnight. The reaction was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford (4S,5R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one. LCMS calc.=179.1; found=179.2 (M+1)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[CH:10]=[CH:9][N:8]=1.[CH:15](=[O:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>CCOCC>[O:20]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:15]([C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[CH:10]=[CH:9][N:8]=1)[OH:21]
Reactant: Cc1ccnc(Br)c1C
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccnc(C(O)c2ccco2)c1C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To 120 ml of a 0.74 M ether solution of butyl-lithium, there is slowly added under nitrogen atmosphere a solution of 10 g of 2-bromo-3,4-dimethylpyridine in 25 ml of anhydrous ether, the temperature being maintained at -40° C. Once the addition is concluded stirring is continued for one hour and 30 minutes, maintaining the same temperature. The temperature is increased to -25° C. and a solution of 5.3 ml of recently distilled furfural in 10 ml of anhydrous ether is added dropwise, following which the temperature is increased to -15° C. and the mixture is stirred for one hour. The reaction mixture is poured over 10% hydrochloric acid to acid pH, cooling from the exterior with ice. The aqueous layer is made alkaline with 10% sodium hydroxide, is cooled from the exterior and is extracted with ether. The ether layer is dried over anhydrous sodium sulphate, filtered and evaporated to dryness, the result being 4.9 g of an oil which is purified by filtration through a silica gel column. The fractions eluated with 95/5 and 70/30 proportions of benzene/chloroform, are collected to obtain 2.65 g (Yield 24%) of 2-furyl-(3,4-dimethyl-2-pyridyl)-carbinol (I). An analytical sample recrystallized from ethyl alcohol has a melting point of 61°-62° C. Calculated analysis for C12H13NO2 : C.70.91; H.6.45; N.6.89. Found: C.70.65; H.6.45; N. 6.88.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:28][CH2:29][CH3:30])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
A suspension of 1.85 g (4.74 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 30 ml of N,N-dimethylformamide was treated with 3.06 g (23.7 mmol) of dibutylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 19:1 as the eluent. There were obtained 2.15 g (94%) of (S)-8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepin-9-one as a pale yellow oil; [α]D20 =+28.7° (MeOH, c=1%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][OH:38])[CH2:32][CH2:31]2)[CH:24]=1>>[OH:38][CH2:37][CH2:36][N:33]1[CH2:32][CH2:31][N:30]([C:25]2[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([NH:1][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[C:13]([S:17]([NH:20][CH3:21])(=[O:18])=[O:19])[CH:14]=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)[CH:24]=2)[CH2:35][CH2:34]1
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Reactant: CNS(=O)(=O)c1cccc(-c2csc3cnc(N)nc23)c1
Product: CNS(=O)(=O)c1cccc(-c2csc3cnc(Nc4cc(N5CCN(CCO)CC5)nc(C)n4)nc23)c1
Yield: 53.7 %

Procedure:
3-(2-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thieno[3,2-d]pyrimidin-7-yl)-N-methylbenzenesulfonamide (18 mg, 53% yield) was prepared in the same manner as Step 10 of Example 1 using 3-(2-aminothieno[3,2-d]pyrimidin-7-yl)-N-methylbenzenesulfonamide (20 mg, 0.062 mmol) and 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol (17 mg, 0.062 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=2)[C:8]([CH3:21])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([Br:29])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=2)[C:8]([CH3:21])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1coc(-c2cc(NC(C)=O)ncc2C)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cc(NC(C)=O)ncc2C)oc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of ethyl 5-(2-acetamido-5-methylpyridin-4-yl)-3-furoate (20.0 g, 69.9 mmol) in DMF (90 mL) was added NBS (29.6 g, 168.1 mmol). The reaction mixture was allowed to stir at 80° C. overnight and then concentrated. The residue was washed with EtOH and filtered to give ethyl 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furoate (20 g, 60%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)(C(C)(C)C)(C)C.[F:15][C:16]([F:43])([F:42])[C:17]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[N:30]=[CH:29]2)(C1N=C(CO)SC=1)[OH:18]>>[F:43][C:16]([F:15])([F:42])[C:17]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[N:30]=[CH:29]2)([C:12]1[S:11][C:10]([CH2:9][OH:8])=[N:14][CH:13]=1)[OH:18]
Reactant: OCc1nc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cs1
Reactant: CC(C)(C)[Si](C)(C)OCc1nccs1
Product: OCc1ncc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)s1
Yield: 17 %

Procedure:
The title compound (73.1 mg, 17% overall yield) was prepared from 2-(tert-butyldimethylsilanyloxymethyl)thiazole (242 mg, 1.06 mmol) according to methods described for the synthesis of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(2-hydroxymethyl-thiazol-4-yl)ethanol (Example 84). MS m/z 424.48 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][Mg]Cl)([CH3:4])[CH3:3].[O:8]1[CH2:13][CH2:12][CH2:11][O:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[C:24]([C:29]([CH:31]2[CH2:34][CH2:33][CH2:32]2)=[O:30])[N:23]=3)=[C:16]([F:35])[CH:15]=1>C1COCC1>[O:10]1[CH2:11][CH2:12][CH2:13][O:8][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[C:24]([C:29]([CH:31]2[CH2:32][CH2:33][CH2:34]2)([OH:30])[CH2:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[N:23]=3)=[C:16]([F:35])[CH:15]=1
Reactant: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCC1
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)CC(O)(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trimethylsilylmethylmagnesium chloride (1.1M solution in THF; 1.12 mL, 1.23 mmol) was added to a solution of (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)(cyclobutyl)methanone (327.0 mg, 0.821 mmol) in THF (15 mL) at 25° C., and the resulting solution was stirred at 25° C. for 5 min. Excess Grignard reagent was quenched by the careful addition of sat. aq. NH4Cl (5 mL), water was added to dissolve precipitated salts, and THF was then removed in vacuo. The resulting solution was partitioned between EtOAc (100 mL) and sat. aq. NH4Cl (20 mL), and the organic layer was separated and washed with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1-(2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)-1-cyclobutyl-2-(trimethylsilyl)ethanol as a yellow oil. MS (ESI) m/z: Calculated: 486.2; Observed: 487.1 (M++1).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=1[F:18].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:67][C:68]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[C:69]=1[NH2:70]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:18][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[C:14]([F:15])[C:9]=1[C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[NH:70][C:69]1[C:68]([F:67])=[CH:74][C:73]([F:75])=[CH:72][C:71]=1[F:76]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: COc1cc(F)c(-c2c(C)nn(C)c2Br)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cc(F)c(-c2c(C)nn(C)c2Nc2c(F)cc(F)cc2F)c(F)c1

Procedure:
5-Bromo-4-(2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step D) (0.30 g, 0.94 mmol), palladium(II) acetate (20 mg, 0.090 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.11 g, 0.19 mmol) and powdered potassium carbonate (2.6 g, 19 mmol) were combined in anhydrous 1,4-dioxane (4 mL), and the resulting mixture was sparged with a subsurface stream of N2 gas for 10 min. 2,4,6-Trifluoroaniline (0.28 g, 1.9 mmol) was added in one portion, and the reaction mixture was heated at reflux under nitrogen for 22 h. The reaction mixture was cooled, then filtered through Celite® diatomaceous filter aid. The filter pad was washed with ethyl acetate (20 mL), and the filtrate was washed with water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated to leave a semisolid residue. The residue was purified by column chromatography through 12 g of silica gel eluted with a gradient of hexanes/ethyl acetate (20:1 to 1:3) to give the title compound as a semisolid (73 mg).
Reaction SMILES: CO.[CH2:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21](=[O:31])[CH2:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[C].[Pd].C(OCC)(=O)C>[CH2:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(C/C=C/c1ccccc1)Nc1cc(CCc2ccccc2)ccc1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CCCc1ccccc1)Nc1cc(CCc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 mg of 10% palladium-carbon was added to a mixed solution of 0.50 mL of methanol and 0.50 mL ethyl acetate containing 8.0 mg of 4-phenethyl-2-((E)-4-phenyl-3-butenamido)benzoic acid and stirred under hydrogen atmosphere at room temperature for 1 hour and 30 minutes. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified with silica gel column chromatography [Flash Tube 2003 manufactured by Trikonex Company, eluent; ethyl acetate] to obtain 4.6 mg of 4-phenethyl-2-(4-phenylbutanamido)benzoic acid as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH2:20]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[CH2:21][CH3:22].O>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2([OH:29])[CH2:27][CH2:28][CH:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]2)=[CH:3][CH:4]=1
Reactant: CCCC1CCC(=O)CC1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: -69 °C
Reaction time: 1 h
Yield: 105.5 %

Procedure:
37.7 g of 1,4-dibromobenzene (13) and 300 mL of THF were placed in a reactor under nitrogen atmosphere and stirred at −69° C. 100 mL of a 1.6M n-BuLi hexane solution was added dropwise thereto at a temperature range of from −69 to −62° C. over 1 hour, and then further stirred at −70° C. for 1 hour. 22.4 g of 4-propylcyclohexanone (14) dissolved in 20 mL of THF was slowly added dropwise to the reaction solution at a temperature range of from −70 to −60° C. After gradually warming the reaction solution to 0° C., the reaction solution was slowly poured into 1,000 mL of water and extracted with 500 mL of toluene. The resulting organic layer was washed with 1N hydrochloric acid, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 50.1 g of 1-(4-bromophenyl)-4-propylcyclohexanol (15). The resulting compound (15) was a yellow oily matter.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br.Br[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[N:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccncc1
Agent: Br
Product: CCOC(=O)C(Cc1ccncc1)C(=O)OCC
Yield: 38.5 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (6.41 g) and 4-(bromomethyl)pyridine hydrobromide (10.1 g). This was purified by silica gel column chromatography to give the title compound (3.86 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].S1C=CC=C1C(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([CH3:12])[CH:14]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: O=C(Cl)c1cccs1
Product: Cc1cccc(C(=O)Nc2ccc(F)c([N+](=O)[O-])c2)c1

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 3-methylbenzoyl chloride according to the procedure of Example 256a substituting 3-methylbenzoyl chloride for thiophene-2-carbonyl chloride to provide N-(4-Fluoro-3-nitro-phenyl)-3-methyl-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].S(C1C=CC(C)=CC=1)(OC)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reaction time: 16 h

Procedure:
A solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.1 g) in THF (5 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.23 ml), followed by methyl tosylate (0.206 g). The resultant solution was allowed to reach room temperature and stirred for a further 16 h. The mixture was quenched with sodium acetate (0.074 g), stirred for 1 h and partitioned between water and ethyl acetate. The separated organic layer was washed with water, dried (over magnesium sulphate), and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 10:1, 8:1, 5:1, 3:1, 2:1, 1:1) to give the title compound (0.101 g) as a colourless gum.
Reaction SMILES: [C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2].CN(C=O)C.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47]>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([N:4]([C@H:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:15](=[O:16])[C:17]3[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:28])([CH3:29])[C:25]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:27])=[CH:19][CH:18]=3)[C@@H:7]([CH3:32])[CH2:6]2)[C:1](=[O:3])[CH3:2])=[CH:34][CH:35]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Reactant: CS(N)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)NS(C)(=O)=O)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
(2S,4R)-4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-butyric acid (200 mg, 0.37 mmol) was dissolved in methylene chloride (5 mL) and oxalyl chloride (2 mL). A single drop of DMF was added, and the mixture was stirred at room temperature until gas evolution ceased. All volatiles were removed. The slurry was dissolved in methylene chloride (10 mL) and triethylamine (2 mL). Methanesulfonamide (200 mg, 2.10 mmol) was added and the reaction mixture was stirred for 3 hours. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparatory HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](Cl)(=[O:44])=[O:43])#[N:35].O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[C:34]#[N:35])(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccccc3C#N)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.12 mmol) and triethylamine (0.36 mmol) in DCM (6 ml) was added 2-cyanobenzene-1-sulfonyl chloride (0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound.