Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]([O:20][CH3:21])[CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2.[C-]#N.[K+].[Cu][C:26]#[N:27]>>[C:26]([C:2]1[C:3]2[CH:4]=[C:5]([O:20][CH3:21])[CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2)#[N:27]
Reactant: N#C[Cu]
Reactant: COc1ccc2nc3cc4ccccc4cc3c(Cl)c2c1
Agent: [C-]#N
Agent: [K+]
Product: COc1ccc2nc3cc4ccccc4cc3c(C#N)c2c1

Procedure:
treating 12-chloro-2-methoxy-benz[b]acridine with potassium cyanide and copper (I) cyanide to produce 12-cyano-2-methoxy-benz[b]acridine;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.O.C(#N)C.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1Cl

Procedure:
2,4-dichlorophenol (3.0 g, 18.4 mmol), 2-fluoro-1-nitrobenzene (1.28 ml, 12.1 mmol) and potassium carbonate (3.0 g, 22.1 mmol) were mixed in DMF (10 ml) and heated at reflux for 3 h. DMF removed in-vacuo. NaOH (1M) added, and extracted with diethyl ether, organic layers dried over MgSO4 and evaporated to dryness, to afford a yellow solid. 3.7 g, >100%, m.p. 54-55° C., Rf. 0.80 (DCM), LCMS tr=5.02 min (50% MeOH and 50% water at 0.5 ml/min), m/z M+H 283.06, 285.07, HPLC tr=2.39 min (Isocratic 90% acetonitrile and 10% water at 1.0 ml/min), 99.75%, 1HNMR (CDCl3, 270 MHz) δ 6.86 (1H, dd, J=1.2, 8.4 Hz, ArH), 6.98 (1H, d, J=6.9 Hz, ArH), 7.23 (1H, m, ArH), 7.23 (1H, m, ArH), 7.50 (1H, m, ArH), 7.50 (1H, m, ArH), 7.98 (1H, dd, J=1.5, 8.2 Hz, ArH).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[CH3:13][O-:14].[Na+]>CO>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:3]([CH2:2][O:14][CH3:13])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc(Cl)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
To a suspension of 2-(bromomethyl)-4,6-dichlorobenzonitrile (1.04 mmol) (A.2.5.1) in 2.5 mL MeOH was added a solution of NaOMe (1.27 mmol, 0.5M in MeOH). The reaction mixture was heated to 50° C. for 1 h. The mixture was concentrated in vacuo, redissolved in EtOAc and it was then washed twice with an aqueous solution of KHSO4, twice with a sat. aq. NaHCO3 solution and once with brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product as orange oil.
Reaction SMILES: CCN(C(C)C)C(C)C.C(OC([NH:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([C:33](=[O:63])[C@H:34]([NH:43][C:44]([C@@H:46]2[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][N:47]2C(OC(C)(C)C)=O)=[O:45])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH2:29][CH2:28]1)=O)(C)(C)C.NC1C=CC=CC=1N1CCN(C(=O)[C@H](NC([C@@H]2CC3C(=CC=CC=3)CN2C(OC(C)(C)C)=O)=O)CC2C=CC(Cl)=CC=2)CC1.C(OC(=O)NCC=O)(C)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[NH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([C:33](=[O:63])[C@H:34]([NH:43][C:44]([C@@H:46]2[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][NH:47]2)=[O:45])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N)CC1
Agent: CC(C)(C)OC(=O)NCC=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NCCNc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
Following the procedure for the synthesis of Example 40 Step 3 (without DIEA), tert-butyl 3-[N-((1R)-2-{4-[2-({2-[(tert-butoxy)carbonylamino]ethyl}amino)phenyl]-piperazinyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)-carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperazinyl]-1-[(4-chlorophenyl)-methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate (Preparation IX) (630 mg, 1.0 mmol) in 2 mL of ClCH2CH2Cl, tert-butyl-N-(2-oxoethyl)carbamate (179 mg, 1.126 mmol) (Aldrich) in ClCH2CH2Cl (10 mL), and NaBH(OAc)3 (330 mg, 1.557 mmol) (Aldrich). The crude was purified by flash chromatography (SiO2, 2:1 hexane:EtOAc) to afford the desired compound (578 mg). MS (ESI, pos. ion) m/z: 761 (M+H), (ESI, neg. ion) m/z: 759 (M−H). Calc'd for C41H53ClN6O6: 761.35. Anal. Calc'd for C41H53ClN6O6-0.5 C4H8O2-0.5 H2O: C, 63.42; H, 7.18; N, 10.32; Cl, 4.35. Found C, 62.96 (+0.46); H, 7.14; N, 10.26; Cl, 4.06.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(C)cc2[N+](=O)[O-])sc2ccccc12
Yield: 100.9 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxlate (4.0 g), 4-fluoro-3-nitrotoluene (3.3 g) and dimethyl sulfoxide (55 ml), ethyl 2-(4-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate (6.5 g) was obtained.
Reaction SMILES: O[CH2:2][C:3]1([C:6]2[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][CH:9]=[C:8]([CH3:16])[C:7]=2[OH:17])[CH2:5][CH2:4]1.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH3:15][O:14][CH2:13][O:12][C:11]1[C:6]2[C:3]3([CH2:2][O:17][C:7]=2[C:8]([CH3:16])=[CH:9][CH:10]=1)[CH2:4][CH2:5]3
Reactant: COCOc1ccc(C)c(O)c1C1(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1ccc(C)c2c1C1(CC1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a solution of 2-[1-(hydroxymethyl)cyclopropyl]-3-(methoxymethoxy)-6-methyl-phenol (Intermediate 154, 65 mg, 0.27 mmol) in dry tetrahydrofuran (5 ml) triphenylphosphine (84 mg, 0.32 mmol) was added and the reaction mixture was stirred until complete dissolution of PPh3. DIAD (0.056 ml, 0.285 mmol) was then added dropwise and the reaction mixture was stirred for 30 minutes at room temperature. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound (40 mg) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7](Cl)[C:3]=1[C:4]([OH:6])=[O:5].OO.C1CCCCCCC=1.[C:22]([O-])([OH:24])=[O:23].[Na+]>CC(=O)CC.CCOCC.O>[C:22]([OH:24])(=[O:23])[CH2:2][CH2:10][CH2:9][CH2:8][CH2:7][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=C([O-])O
Agent: C1=CCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: O
Product: O=C(O)CCCCCCC(=O)O
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a mixture of [Mn2O3(Me3-TACN)2] (PF6)2.H2O (16.2 mg, 20 μmol, 0.2 mol %) and 2,6-dichlorobenzoic acid (57.3 mg, 0.30 mmol, 3.0 mol %) in 2-butanone (7 ml) was added H2O2 (30 μl of a 50% aq. solution, 0.53 mmol) at room temperature and the resulting mixture was stirred for 20 min. Subsequently cyclooctene (1.149 g, 9.90 mmol) was added together with 2-butanone (2 ml) and water (1 ml). H2O2 (5.67 ml of a 50% aq. solution, 100 mmol, 10.0 equiv.) was then added at 40° C. using a syringe pump (0.7 ml/h). New batches of [Mn2O3(Me3-TACN)2] (PF6)2.H2O (16.2 mg, 20 μmol, 0.2 mol % per batch) were added to the reaction mixture 1.5, 3, 4.5, 6 and 7.5 hours after the addition of H2O2 had commenced. When the addition of H2O2 was completed, the mixture was stirred for additional 15 hours. Water (10 ml) and Et2O (10 ml) were added and the pH of the aqueous layer was set to pH >9 by adding some saturated NaHCO3 (aq.). The organic layer was separated and the aqueous layer was washed with Et2O (3×15 ml). The pH of the aqueous layer was subsequently set to pH <2 with some 10% HCl (aq.) and was extracted with Et2O (3×20 ml). The combined organic extracts were dried over anhydrous Na2SO4. The solvents were removed in vacuo yielding 926 mg of a solid with a purity of circa 74% (determined by 1H NMR), 40% yield of suberic acid. N.B. NMR showed other compounds as well, including 2,6-dichlorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[Li+].[OH-]>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Part C: Ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (0.810 gram, 2.06 mmol) and LiOH (0.173 g, 7.20 mmol) are dissolved in a H2O/THF (20 mL/20 mL) mixture and stirred at 50° C. for 16 hours. The mixture is concentrated in vacuo to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid. Thionyl chloride (60 mL) is added and the mixture is heated at reflux temperature for 1 hour and concentrated in vacuo to give crude 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carbonyl chloride.
Reaction SMILES: ClS(N=C=O)(=O)=O.C(O)=O.[Si]([O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:34]([CH2:35][CH2:36][C@:20]12[CH3:21])[C:33]1[CH:32]=[C:31]([CH:37]=[O:38])[C:30]([OH:39])=[CH:29][C:28]=1[CH2:27][CH2:26]3)(C(C)(C)C)(C)C.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[OH:39][C:30]1[C:31]([CH:37]=[O:38])=[CH:32][C:33]2[C@@H:34]3[C@H:25]([C@H:22]4[C@@:20]([CH2:36][CH2:35]3)([CH3:21])[C@@H:19]([OH:18])[CH2:24][CH2:23]4)[CH2:26][CH2:27][C:28]=2[CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(C=O)cc4[C@H]3CC[C@]12C
Agent: O=C=NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
To a solution of chlorosulfonyl isocyanate (0.13 mL, 1.5 mmol) in CH2Cl2 (1.0 mL) was added formic acid (0.31 mL of a CH2Cl2 solution, 5.0M, 1.6 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. To a solution of 17β-tert-butyldimethylsilyloxy-3-hydroxyestra-1,3,5(10)-triene-2-carbox aldehyde (9, 0.129 g, 0.31 mmol) in DMF (3.0 mL) was added sodium hydride (0.044 g of a mineral oil dispersion, 60%, 1.1 mmol) at 0° C. The reaction mixture was stirred for 1 h, the pre-prepared reagent was added, and stirring continued for 4 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl at 0° C. and extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (MgSO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:acetone (2:1→1:1, v/v) to afford 0.017 g of 2a (18% yield) and 0.030 g of 10 (27% yield), m.p. 170°-172° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-])=O)[CH:10]=2)[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=2)[NH2:19])[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a solution of 1-methyl-4-[3-nitro-5-(trifluoromethyl)benzyl]piperazine (0.35 g, 1.15 mmol) in EtOAc (15 mL) was added Pd (10% on C, 0.035 g). The reaction mixture was allowed to stir at rt under an atmosphere of hydrogen over night. The reaction mixture was filtered through Celite, washed with EtOAc, and concentrated to give 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)aniline (0.285 g, 90%) as a white solid which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 0 °C

Procedure:
To a mixture of 6-bromo-2-naphthol (1.99 g, 8.9 mmol) and benzyl bromide (1.2 ml, 1.1 equiv.) in DMF (18 ml) at 0° C. was added a suspension of NaH 80% in oil (324 mg, 1.2 equiv.) and the mixture was stirred at 0° C. for an hour and at r.t. for another hour. After addition of half saturated NH4Cl, the product was extracted in i-PrOAc, washed with 1N HCl, dried over Na2SO4 and concentrated to yield 2.84 g of an oil.
Reaction SMILES: C[O-].[Na+].[N+:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[C-:5].[CH3:11][CH:12]([CH3:16])[C:13](Cl)=[O:14]>CN(C=O)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:11][CH:12]([C:13]1[O:14][CH:5]=[N:4][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH3:16]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC(C)C(=O)Cl
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ncoc1C(C)C
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium methoxide (1.86 g) in DMF (30 ml) was added methyl isocyanoacetate (2.38 ml) dropwise at −50° C. and the mixture stirred for 30 min at −50° C. 2-Methylpropanoyl chloride (3.36 ml) was added gradually to the mixture at −50° C. and the mixture stirred for 2 h at −50° C. The mixture was diluted with DCM (50 ml) and saturated sodium bicarbonate solution (50 ml) was added and the organic layer collected using a hydrophobic frit. The aqueous layer was washed with DCM (2×50 ml) and separated by hydrophobic frit. The combined organic phases were concentrated in vacuo. This was purified by chromatography on silica gel, eluting with a gradient of 0-100% ethyl acetate in cyclohexane, followed by 0-20% methanol. The residue was distilled using a Kugelrohr to give the title compound (553 mg) as yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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]>[CH:15]1[CH:16]=[CH:17][C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Yield: 93.4 %

Procedure:
According to the general procedure B, 4-chloronitrobenzene (80 mg, 0.51 mmol) reacted with aniline (57 mg, 0.60 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and K3PO4 (254 mg, 1.21 mmol) in DME at 100° C. to give the title compound (102 mg, 95%) as a yellow solid: 1H-NMR (400 MHz, CDCl3): δ 8.12 (d, 2H, J=7.2 Hz), 7.40 (t, 2H, J=7.2 and 8.8 Hz), 6.96 (d, 2H, J=7.2 Hz), 7.24-7.18 (m, 3H), 6.48 (bs, 1H). 13C{1H}-NMR (125 MHz, CDCl3): δ 150.26, 139.51, 139.44, 129.64, 126.18, 124.54, 121.83, 113.59. GC/MS(EI): m/z 214 (M+). Anal. Calcd for C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found: C, 67.45; H, 4.75; N, 13.02.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22](Cl)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.O>[CH:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1C
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 96 °C
Yield: 129.4 %

Procedure:
186 g of aniline, 60 ml of xylene, 4.5 g of 1,10-phenanthroline, 157.5 g of 4-nitrochlorobenzene, 2 g of CuO and 76.3 g of potassium carbonate are heated to 195° C. for 7 hours in a water separator. The reaction mixture is cooled to 96° C. After the precipitated salts have been separated off by filtration, the filter cake is thoroughly washed with 200 ml of hot xylene. The filtrate and the washing liquid are combined, and after the solution has been cooled to 0° C., 127 g of 4-nitrodiphenylamine of melting point 128°-130° C. crystallize out and are separated off by filtration. 93 g of aniline, 157.5 g of p-nitrochlorobenzene and 76.3 g of potassium carbonate are added to the mother liquor produced in this procedure, and the mixture is freed from excess xylene by distillation, and heated at 195° C. for 11 hours in a water separator. After the salts have again been filtered off, the filtrate is worked up by steam distillation, as described in Example 7. 277 g of 4-nitrodiphenylamine of melting point 107°-111° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.CCCCCC>C(OCC)(=O)C>[NH2:5][C:4]1[CH:3]=[C:2]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Nc2cccc(N)c2)cc1
Yield: 42.9 %

Procedure:
Following the general procedure, 3-bromoaniline (56 μL, 0.5 mmol) was coupled with ethyl 4-aminobenzoate (125 mg, 0.75 mmol) with the reaction temperature of 80° C. and the reaction time of 17 h. Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 55 mg (43%) of the title compound as a pale brown solid.
Reaction SMILES: C1C=CC=CC=1.II.[C:9]1([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22][CH2:21]3)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH:30](C)[C:31]([O:33][CH2:34]C)=[O:32]>O.[Zn]>[CH3:34][O:33][C:31](=[O:32])[CH2:30][C:24]1([OH:28])[C:25]2[C:20](=[CH:19][C:18]([S:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)(=[O:17])=[O:16])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CC1(O)CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution/suspension of anhydrous benzene (25 mL), powdered Zinc metal (0.505 g, 7.72 mmol), I2 (0.01 g) and 6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one was stirred for 10 minutes at room temperature. Ethyl bromopropionate (0.784 mL, 1.18 g, 7.07 mmol) was added and the reaction mixture was heated to reflux for 2.5 hours. The reaction mixture was allowed to cool, diluted with 300 mL of water and extracted twice with 250 mL of EtOAc. The combined organic layers were washed with water and saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield (6-benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid methyl ester. MS: 375 (M+H)+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40].[OH-].[NH4+:43]>C(Cl)(Cl)Cl.ClCCl>[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[C:19]([NH2:43])[C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1nc2cnc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Reaction time: 0.5 h

Procedure:
Part B of the general methods described for Examples 35-40 was followed using 2.00 g of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol to provide 2.33 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline as a yellow solid. Parts C and D of the general methods described for Examples 35-40 were replaced by the following procedure. mCPBA (0.853 g, 2.97 mmol) was added in one portion to a solution of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline (1.00 g, 2.47 mmol) in chloroform (17 mL), and the reaction was stirred for 30 minutes. Ammonium hydroxide (17 mL) was then added, followed by/7-toluenesulfonyl chloride (0.710 g, 3.70 mmol). The reaction was stirred for 16 hours and then diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic solutions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown solid. The solid was recrystallized from acetonitrile to provide 0.680 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a reddish-brown, crystalline solid, mp 209-211° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH3:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(N(CC)CC)C.O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: COC1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 88.7 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-methoxycyclopropyl)-benzene (Intermediate 59, 300.0 mg, 1.32 mmol) in triethylamine (4 mL) and anhydrous tetrahydrofuran (4 mL) was treated with copper(I)iodide (93.0 mg, 0.13 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.39 g, 14.2 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (93.0 mg, 0.13 mmol). The resulting reaction mixture was heated to 70° C. for 60 h. The title compound (286.0 mg, 90%) was isolated by chromatography (0-3% EtOAc—hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:23])=[CH:20][CH:19]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)cc3)c2)CC1
Yield: 78.4 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 4-fluorobenzoyl chloride (81 μl, 0.687 mmol), 61.1 mg (78%) of the title compound were recovered.