Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cc(OC)cc(OC)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (3.9 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (50 mL), 3,5-dimethoxyphenylboronic acid (10.0 g), copper acetate (10.0 g) and pyridine (8.9 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.0 g, 40%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][NH:6][CH:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.[CH3:26][O:27][C:28]1[C:29](=O)[C:30](=[O:34])[C:31]=1[O:32]C>>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][NH:6][CH:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[C:10]([NH:14][C:29]2[C:30](=[O:34])[C:31](=[O:32])[C:28]=2[O:27][CH3:26])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(C(NCc2cccc(F)c2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Product: COc1ccc(C(NCc2cccc(F)c2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 90.3 %

Procedure:
In a similar manner to that described in Example (1c), 3-[(3-fluorobenzyl amino)-(4-methoxyphenyl)methyl]phenylamine (409 mg) [prepared as described in step (b) above] and 3,4-dimethoxy-3-cyclobutene-1,2-dione (173 mg) were reacted, to afford the title compound (490 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1)#[CH:2].Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])=[CH:29][CH:28]=2)[N:17]=1>CN(C=O)C.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.[Cu]I>[C:12]([C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[C:2][C:20]2[C:21]([C:22]([F:23])([F:25])[F:24])=[CH:16][N:17]=[C:18]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])=[CH:31][CH:32]=3)[N:19]=2)[CH2:11][CH2:10]1)(=[O:13])[NH2:14]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cc1
Temperature: 120 °C

Procedure:
A solution of 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (0.15 g, 0.81 mmol) in DMF (3 mL) was added to a reaction vessel containing tert-butyl 1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate A80 (0.34 g, 0.81 mmol), PdCl2(PPh3)2 (0.028 g, 0.040 mmol) tri-tert-butylphosphonium tetrafluoroborate (0.023 g, 0.081 mmol) and copper(I)iodide (0.015 g, 0.081 mmol). The mixture was bubbled with nitrogen for 10 minutes before Et3N (1.5 mL) was added. The mixture was heated at 120° C. under microwave irradiation for 15 minutes. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-100% EtOAc in cyclohexane) to give the title compound A81 as a yellow oil (0.26 g, 56%). LCMS-C: rt 5.80 min; m/z 566 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C@H:12]([NH2:14])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[C:6]1([C@H:12]([NH:14][S:2]([CH:1]=[CH:13][C:12]2[C:6]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[N:14]([CH2:12][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:14]=2)(=[O:4])=[O:3])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClCCl
Product: C[C@@H](NS(=O)(=O)C=Cc1nn(Cc2ccccc2)c2c1CCCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride Compound 11f1 (2.0 g, 17 mMol) and TEA (2.43 mL, 17.46 mMol) were added to a solution of (1R)-1-phenyl-ethylamine Compound 11f2 (1.75 g, 17.5 mMol) in CH2Cl2 (50 mL) at 0° C. under a N2 atmosphere. The mixture was stirred for 3 hrs while warming to r.t., then the reaction was quenched with water (5 mL). The organic layer was diluted with CH2Cl2 (100 mL) and then washed with water and brine. The organic layer was separated, dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to afford the corresponding N-(1-phenyl-ethyl)-methanesulfonamide Compound 11f3 as an oil.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
450 mg of the 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine prepared above was dissolved in 20 ml of dichloromethane to obtain a solution. 760 mg of thionyl chloride was dropwise added to this solution at 0° C. The obtained mixture was stirred at a room temperature for 2 hours. After the completion of the reaction, the reaction mixture was distilled to remove the dichloromethane and the thionyl chloride. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue. The obtained mixture was extracted with chloroform. The obtained chloroform layer was concentrated to obtain 470 mg of 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine as a brown crystal.
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([Cl:20])[C:11]=1[O:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:28]1([NH:31][C:5]([N:24]2[C:25]([CH3:27])=[CH:26][C:22]([O:21][C:11]3[C:10]([Cl:9])=[CH:15][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:13][C:12]=3[Cl:20])=[N:23]2)=[O:4])[CH2:30][CH2:29]1
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: NC1CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.8 %

Procedure:
Trichloromethyl chloroformate (0.59 g, 3.0 mmol) was added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.83 g, 3.0 mmol) in chloroform (10 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, it was further stirred at room temperature for 3 hours. Cyclopropylamine (0.17 g, 3.0 mmol) and potassium carbonate (0.50 g, 3.6 mmol) were added to the reaction mixture, and the reaction mixture was refluxed under heating for 5 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with chloroform (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a colorless viscous substance of N-cyclopropyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.27 g, yield: 22.8%). 1H-NMR (CDCl3, TMS, ppm): δ 0.55-0.65 (m, 2H), 0.75-0.85 (m, 2H), 2.59 (d, J=0.4 Hz, 3H), 2.60-2.75 (m, 1H), 5.71 (m, 1H), 6.75-6.90 (m, 1H), 7.67 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>C(#N)C>[CH2:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:9][CH2:10]1)=[O:6])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCNc1cc(C(=O)NC2CC2)ccc1C
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a solution of 3-amino-N-cyclopropyl-4-methylbenzamide (2 g) in acetonitrile (10 ml) was added with potassium carbonate (2.6 g). The mixture was heated to 80° C. and a solution of allyl bromide (1.1 ml) in acetonitrile (6 ml) was added dropwise and heating was continued for 17 hours. The insoluble material was removed by filtration. The filtrate was concentrated and the residue was recrystallised from 50% ethyl acetate/hexane. The mother liquors was concentrated and by column chromatography on a silica column eluting using a gradient of iso-hexane to 50% ethyl acetate/iso-hexane to yield 3-(allylamino)-N-cyclopropyl-4-methylbenzamide as a colourless oil which solidified to a white solid (688 mg); NMR Spectrum: (DMSOd6) 0.53 m, 2H), 0.78 (m, 2H), 2.10 (s, 3H), 2.81 (m, 1H), 3.67 (s, 1H), 3.81 (d, 2H), 5.13 (d, 1H), 5.23 (d, 1H), 5.93 (m, 1H), 6.11 (s, 1H), 6.83 (d, 1H), 6.98 (m, 2H); Mass Spectrum: M+H+ 231.
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C@:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([O:17][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: BrCCCCCBr
Reactant: COC(=O)[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@]1(C)CCc2c(C)c(OCCCCCBr)c(C)c(C)c2O1
Yield: 88.5 %

Procedure:
Using the procedure and molar proportions of example 71, (S)-(-)-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester was alkylated with 1,5-dibromopentane giving (S)-(-)-6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester, [α]D25 -34.60° (c2, CHCl3), in 88.5% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([CH:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:43][O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]([CH:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:48][CH2:47][CH2:46][C:45]([O:44][CH3:43])=[O:49])=[O:24])=[CH:26][CH:27]=2)[CH2:16][CH2:17][CH3:18])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])=[CH:9][CH:10]=1
Reactant: COC(=O)CCN
Reactant: CCCC(c1ccc(C(=O)O)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the product from Step A (6.2 g, 15.3 mmol), EDC (4.4 g, 23.0 mmol), and HOBt (3.1 g, 23.0 mmol) in anhydrous DCM (200 mL) was stirred for 30 min at RT, then β-alanine methyl ester (2.1 g, 15.3 mmol) and DIEA (8.0 mL, 45.9 mmol) were added. After being stirred for 12 hours at RT, the mixture was diluted with DCM then washed with 100 mL of 0.5 M HCl (aq) then 100 mL of saturated NaCl (aq). The organic layer was dried over Na2SO4, filtered, then concentrated. The major diastereomer of the title compound was obtained by trituration with hexane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH3:32][NH:33][C@H:34]([C:36]([OH:38])=[O:37])[CH3:35].Cl>C1COCC1.O>[CH3:32][N:33]([C:14](=[O:16])[CH2:13][CH2:12][S:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C@H:34]([C:36]([OH:38])=[O:37])[CH3:35]
Reactant: CN[C@@H](C)C(=O)O
Reactant: O=C(O)CCSSc1ccc([N+](=O)[O-])cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)O)N(C)C(=O)CCSSc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a stirred solution of 3-(4-nitrophenyldithio)-propanoic acid (5b) (0.100 g, 0.386 mmol) in dry THF (10 mL) at −40° C. under argon was added isobutyl chloroformate (0.053 g, 0.386 mmol) and triethylamine (0.039 g, 0.38 mmol) and the reaction stirred at 0° C. for one hour. An aqueous solution (5 mL) of N-methyl-L-alanine (0.040 g, 0.386 mmol) and triethylamine (0.039 g, 0.386 mmol) was then added and the mixture stirred at 0° C. for five hours. The mixture was diluted with water (50 mL), acidified (aqueous HCl), and extracted with ethyl ether (3×25 mL). The combined organic layers were dried (Na2SO4), and the solvent evaporated under reduced pressure. The residue was chromatographed over silica gel eluting with methylene chloride/ethyl acetate to yield 0.048 g (36%) yellow crystals: mp 74-77° C. 1H NMR (CDCl3) δ1.4 (3H, d), 2.6-3.4 (4H, m), 2.9 (3H, s), 5.1 (1H, q), 7.6-8.3 (4H, 2d).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28].CN(C)C=O>O>[ClH:1].[ClH:1].[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:32]2[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]2)=[N:3][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CCN1CCNCC1
Reactant: COc1ccc(-c2nc(Cl)c3ccccc3c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)c(Cl)c3ccccc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the resulting 1,4-dichloro-3-(4-methoxyphenyl)isoquinoline (0.30 g) were added potassium carbonate (0.14 g), N-ethylpiperazine (126 ml) and N,N-dimethylformamide (10 ml). The resulting mixture was stirred at room temperature overnight. To the mixture was then added N-ethylpiperazine (126 ml), and the mixture was stirred at room temperature for 4 hr. Still additionally, N-ethylpiperazine (378 ml) was added thereto, and the mixture was stirred at 50° C. for 1.5 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water (four times) and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/acetone system), to give 0.10 g of the free compound of the title compound as a colorless viscous oil.
Reaction SMILES: [C:1]([C:5]([Br:8])(Br)[Br:6])([F:4])([F:3])[F:2].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].O>CN(C=O)C.[Zn]>[Br:6][C:5]([Br:8])([C:1]([F:4])([F:3])[F:2])[CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[Cl:9])[OH:13]
Reactant: FC(F)(F)C(Br)(Br)Br
Reactant: O=Cc1ccccc1Cl
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: OC(c1ccccc1Cl)C(Br)(Br)C(F)(F)F
Reaction time: 6 h

Procedure:
83.5 g of CF3CBr3 in anhydrous DMF and 28 g of 2-chlorobenzaldehyde were reacted under a nitrogen atmosphere. The mixture was brought to 5° C. and zinc in powder (g.16.0) was added to it slowly. Then the mixture was let reach the room temperature and kept under stirring for 6 hours. The mixture was poured into water and extracted three times with ethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C=O)CC1
Temperature: 150 °C
Yield: 44 %

Procedure:
A mixture of 5-chloro-2-fluoro-benzaldehyde (10 g, 63 mmol), Piperazine-1-carboxylic acid tert-butyl ester (12 g, 63 mmol), K2CO3 (17 g, 123 mmol) in DMF (60 mL) was heated at 150° C. for 2 h. After cooled to room temperature, the mixture was poured into water (300 mL) and partitioned between diethyl ether and water. The combined organic phases were washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a yellow solid (9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[CH:7]=[C:8]([O:13][CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[N-:24]=[N+]=[N-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[CH:7]=[C:8]([O:13][CH3:14])[C:9](=[O:12])[NH:24][C:10]=2[CH:11]=1
Reactant: COC1=CC(=O)c2ccc(Cl)cc2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
7-Chloro-2-methoxy-1,4-naphthoquinone (14.74 g) was added to trifluoromethanesulfonic acid (153 mL) chilled in an ice bath, and sodium azide (4.74 g) was added. The reaction mixture was maintained in an ice bath for 0.33 hour then allowed to warm to room temperature and maintained thus for 90 hours. The reaction mixture was recooled in an ice bath, and an additional portion of sodium azide (2.15 g) was added. After 0.08 hour the mixture was allowed to warm to room temperature for 19 hours. The reaction mixture was then poured into ice cold aqueous sodium bicarbonate (2.3 L). The resulting precipitate was filtered, washed (water) and dried under vacuum (25° C., 15 Pa) to give a tan solid (13.83 g). The solid was recrystallized from hot dimethylformamide (300 mL) and dried under vacuum (25° C., 15 Pa) to give the benz[b]azepine as a light tan solid (8.12 g); mp 340°-342° C. (dec). Analysis for C11H8ClNO3 : Calculated: C, 55.60; H, 3.39; N, 5.89; Found: C, 55.35; H, 3.38; N, 6.07.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1CCOC.[F:24][C:25]1[CH:30]=[C:29]([CH:31]([CH3:35])[C:32](Cl)=[O:33])[CH:28]=[CH:27][C:26]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[CH:31]([C:29]3[CH:28]=[CH:27][C:26]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[C:25]([F:24])[CH:30]=3)[CH3:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CC(C(=O)Cl)c1ccc(-c2ccccc2)c(F)c1
Product: CC(C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21)c1ccc(-c2ccccc2)c(F)c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-(2-fluoro-4-biphenylyl)propionyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(2-fluoro-4-biphenylyl)propanamide as a white powder, m.p. 76.1-79.9° C. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.03 (m, 2H), 7.62 (d, J=8.3 Hz, 1H), 7.49-7.14 (m, 10H), 6.59 (broad s, 2H), 4.58 (t, J=6.9 Hz, 2H), 3.59 (q, J=7.0 Hz, 1H), 3.09 (pentet, J=6.7 Hz, 2H), 1.82 (m, 2H), 1.45 (m, 2H), 1.30 (d, J=7.0 Hz, 3H); MS (EI) m/e 481.2268 (481.2278 calcd for C29H28FN5O).
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[N:4][N:3]=[N:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].O>O1CCCC1>[NH:1]1[C:5]([NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[N:4][N:3]=[N:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nnn[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nnn[nH]1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 1H-tetrazole-5-amine (1.00 g, 11.8 mmol) and pyridine (1.15 ml, 14.1 mmol) in tetrahydrofuran (39 ml) was added 2,2,2-trichloroethyl chloroformate (1.95 ml, 14.1 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the residue was added hexane and a solid was collected by filtration to obtain the desired product (1.29 g, 42.1%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:21][C:20]1[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cccnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2Cl)CC1
Yield: 20 %

Procedure:
tert-butyl piperazine-1-carboxylate (1.0 g, 5.37 mmol) and 2,3-dichloropyridine (795 mg, 5.37 mmol) charged to a microwave vial was added with diisopropylethylamine (2.34 mL, 13.42 mmol) and DMF (1.0 mL). The reaction mixture was subject to microwave irradiation at 165° C. for 30 minutes. The reaction was repeated six times in order to scale up. Combined reaction mixture was partitioned between EtOAc and water, organic layer washed with brine and dried over MgSO4. The crude product obtained by solvent evaporation was purified via flash column chromatography. tert-butyl 4-(3-chloropyridin-2-yl)piperazine-1-carboxylate was obtained in 20% yield (1.9 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][CH2:21][CH3:22])[NH2:18]>>[CH3:14][O:15][C:16](=[O:23])[CH:17]([NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Reactant: CCCC[C@H](N)C(=O)OC
Agent: Cl
Product: CCCCC(NC(=O)Cc1cc(Cl)cc(Cl)c1)C(=O)OC

Procedure:
Following General Procedure BF above, an using 3,5-dichlorophenylacetic acid (from Example BC above) and L-norleucine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid having a melting point of 77°-78° C. The reaction was monitored by tlc on silica gel (Rf=0.70 in 40% EtOAC/hexanes) and purification was by flash chromatography on silica gel using 40% EtOAc/hexanes as the eluant.