Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([OH:13])(=[O:12])[CH:10]=O.[CH2:14]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]=[CH2:28])[CH3:15]>>[CH2:14]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:8]=2)[NH:6][CH:10]([C:9]([OH:13])=[O:12])[CH2:28]1)[CH3:15]
Reactant: C=Cc1c(OCC)ccc2ccccc12
Reactant: Nc1ccc(I)cc1
Reactant: O=CC(=O)O
Product: CCOc1ccc2ccccc2c1C1CC(C(=O)O)Nc2ccc(I)cc21

Procedure:
Compound 73 was prepared from 4-iodoaniline, glyoxylic acid and 2-ethoxy-1-vinylnaphthalene by the automated process.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:37]([NH:41][C:42]([C@@H:44]1[C:48]([CH3:50])([CH3:49])[S:47][CH2:46][N:45]1[C:51](=[O:69])[C@@H:52]([OH:68])[C@@H:53]([NH:61][C:62](=[O:67])[C@@H:63]([NH2:66])[CH2:64][CH3:65])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C.C(OCC)(=O)C>[C:37]([NH:41][C:42]([C@@H:44]1[C:48]([CH3:50])([CH3:49])[S:47][CH2:46][N:45]1[C:51](=[O:69])[C@@H:52]([OH:68])[C@@H:53]([NH:61][C:62](=[O:67])[C@@H:63]([NH:66][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([N:2]([CH3:1])[CH3:14])[CH:4]=1)[CH2:64][CH3:65])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:43])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC[C@H](N)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NC(C)(C)C
Reactant: CN(C)c1cccc(OCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)COc1cccc(N(C)C)c1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 73 %

Procedure:
3-dimethylaminophenoxyacetic acid (51 mg), HOBt (35mg), and EDC.HCl (53 mg) were added to a solution of H-Abu-Apns-Dmt-NHtBu (120 mg) obtained in the step 1 in DMF and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography to obtain the title compound (120 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Br:11][C:12]1[C:13]([OH:21])=[C:14]([CH:17]=[C:18]([Br:20])[CH:19]=1)[CH:15]=O.[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>>[Br:11][C:12]1[C:13]([OH:21])=[C:14]([CH:15]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:22][C:23]3=[CH:27][CH:26]=[N:25][N:24]23)[CH:17]=[C:18]([Br:20])[CH:19]=1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: Nc1cc[nH]n1
Product: CC1(C)CCC2=C(C1=O)C(c1cc(Br)cc(Br)c1O)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3,5-dibromo-2-hydroxybenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17](C)C(Cl)=O.C[Si](C)(C)C#N.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:16]#[N:17])[CH:11]=[CH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccc[n+]([O-])c1-c1cccc(F)c1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C#N)nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A solution (40 mL) of 2-(3-fluorophenyl)-3-methylpyridine 1-oxide (4.26 g, 21.0 mmol), dimethylcarbamic acid chloride (2.94 g, 27.3 mmol) and trimethylsilanecarbonitrile (2.71 g, 27.3 mmol) in tetrahydrofuran was heated under reflux, and the mixture was stirred for 2 hr. After cooling to room temperature, the reaction solution was divided into two layers with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution and subjected to extraction (3 times) with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound (4.42 g, 99%).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[CH2:4]([O:3][C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=CC1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=C[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-carbobenzyloxypyrrolidine-2-carboxaldehyde (1.17 g, 5.00 mmol) in anhydrous tetrahydrofuran at −78° C. was added (carboethoxymethylene)triphenylphosphorane (2.09 g, 6.00 mmol, 1.2 eq) as a solid portionwise. The resulting reaction mixture was stirred at room temperature under nitrogen for 2 hours, and then heated at reflux under nitrogen for 1 hours. The reaction mixture was evaporated under reduced pressure and the residue was column chromatographed using silica gel (approximately 100 g) and elution with 20% diethyl ether in hexane to afford the title compound as a clear, colorless oil (1.11 g, 3.65 mmol, 73%): 1H NMR (CDCl3-d6) δ 7.34-7.25 (m, 5H), 6.89-6.76 (m, 1H), 5.88-5.74 (m, 1H), 5.18-5.05 (m, 2H), 4.60-4.43 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.55-3.40 (m, 2H), 2.11-2.00 (m, 1H), 1.90-1.75 (m, 3H), 1.28 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) [Note: due to slow nitrogen inversion two conformers of the products are seen by NMR spectroscopy] δ 166.3, 154.7, 147.9, 147.4, 136.6, 128.4, 127.9, 120.9, 66.9, 65.8, 60.4, 58.1, 57.7, 46.8, 46.4, 31.6, 30.9, 23.6, 22.8, 22.6, 15.3, 14.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:23](OC1C=CC([N+]([O-])=O)=CC=1)=[O:24].[Cl:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[C:41]([N:46]1[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][NH2:54])[CH2:48][CH2:47]1)[CH:40]=[CH:39]2>ClCCl.ClCCCl>[Cl:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[C:41]([N:46]1[CH2:47][CH2:48][CH:49]([CH2:52][CH2:53][NH:54][C:23]([O:1][CH2:2][C:3]3[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=3)=[O:24])[CH2:50][CH2:51]1)[CH:40]=[CH:39]2
Reactant: CCOC(=O)c1cc(CO)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(COC(=O)NCCC2CCN(c3ccc4cc(Cl)ccc4n3)CC2)on1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 3.54 g (20.70 mmol) of ethyl 5-hydroxymethylisoxazole-3-carboxylate (commercial), 7.88 mL (41.41 mmol) of N,N-diisopropylethylamine and 1.26 g (10.35 mmol) of N,N-dimethylaminopyridine in 120 mL of dichloromethane, cooled to 0° C., are added portionwise 4.17 g (20.70 mmol) of p-nitrophenyl chloroformate. The mixture is stirred at 10° C. for 2 hours and then evaporated to dryness. The residue obtained is taken up in 120 mL of 1,2-dichloroethane, followed by addition of 6.00 g (20.70 mmol) of 2-[1-(6-chloroquinolin-2-yl)piperidin-4-yl]ethylamine, obtained in step 11.2. and 5 mL (26.27 mmol) of N,N-diisopropylethylamine. The mixture is heated at 70° C. for 12 hours.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](S(C)(=O)=O)[CH:7]=[C:8]([C:10](=[N:20][NH2:21])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[CH:9]=1)=[O:4].Br[C:27]#[N:28]>CO>[NH2:28][C:27]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[C:10]([C:8]2[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[NH:6][CH:7]=2)=[N:20][N:21]=1
Reactant: COC(=O)c1cc(C(=NN)Nc2cccc(Cl)c2Cl)cn1S(C)(=O)=O
Reactant: N#CBr
Solvent: CO
Product: Nc1nnc(-c2c[nH]c(C(=O)O)c2)n1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[N-(2,3-dichloro-phenyl)-N′-amino-carbamimidoyl]-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (Prepared by the same method described above for the preparation of the corresponding difluoro compound) (150 mg, 0.37 mmol) in MeOH (2 mL) was added BrCN (60 mg, 0.57 mmol) at RT. The mixture was stirred at RT for 12 h. The solvent was removed by evaporation, the residue was dissolved in MeOH (4 mL), and the resulting solution was treated with 6N NaOH (1 mL) at 50° C. for 4 h. After cooling to RT, the solution was acidified with 6N HCl. The organic solvent was evaporated, the remaining aqueous solution was diluted with CH3CN, and the inorganic salt was removed by filtration. The filtrate was concentrated under vacuum to give a crude product, which was purified by HPLC for next reaction. MS (ES+): m/e=338.0 (M+H); LC: 2.44 min.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=CC=C[C:4]=2N[CH:2]=1.[CH2:10]1[CH2:14]OC[CH2:11]1.[CH3:15]N(C=O)C>C(Cl)Cl>[CH3:15][CH2:2][N:1]([CH:10]([CH3:14])[CH3:11])[CH:5]([CH3:6])[CH3:4]
Reactant: c1ccc2[nH]cnc2c1
Reactant: C1CCOC1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C

Procedure:
The benzimidazole is formed by coupling the diamino compound with the appropriate carboxylic acid, preactivated carboxylic acid, mixed anhydride or anhydride in solvents such as THF, DMF or DCM and in the presence of a base such as TEA or DIPEA to form the corresponding amide. The amide is than treated with an acid at 40-80° C. for 2-24 hours.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].[CH3:19][Mg]Br>O1CCCC1.C(OCC)C>[CH2:14]([C:9]1[NH:10][C:11]2[C:6]([C:7](=[O:18])[N:8]=1)=[CH:5][C:4]([C:1]([OH:3])([CH3:19])[CH3:2])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH3:17]
Reactant: C[Mg]Br
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(C)(C)O)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.00 g 6-acetyl-2-butyl-4(1H)-quinazolinone in 250 ml of dry tetrahydrofuran, cooled to 0° C., is added dropwise 16.4 ml of 3.0M methylmagnesium bromide in diethyl ether. The reaction is stirred at 0° C. for 0.5 hours and then allowed to warm to room temperature followed by quenching with 100 ml of saturated ammonium chloride solution. The mixture is diluted with 50 ml of water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 100:0.25 chloroform-methanol to give 2.75 g of the desired product as a white solid. CI MASS SPEC 261(MH+).
Reaction SMILES: C1([C:7]2[C:8]([C:14]([C:16]3[N:17]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[N:19][CH:20]=3)=[O:15])=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)C=CC=CC=1.[C:40]1(C)[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[Mg]Br.Cl[CH2:50]Cl>>[C:40]1([C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH3:50])([C:16]2[N:17]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:18]=[N:19][CH:20]=2)[OH:15])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[CH3:13][C:9]1[C:10]([CH3:50])=[CH:11][CH:12]=[CH:7][C:8]=1[C:14]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:16]1[N:17]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[N:19][CH:20]=1)[OH:15]
Reactant: ClCCl
Reactant: Cc1ccccc1[Mg]Br
Reactant: Cc1cccc(-c2ccccc2)c1C(=O)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1cccc(C(O)(c2ccccc2)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Product: Cc1ccccc1C(O)(c1ccccc1)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of phenyl-o-tolyl-(3-trityl-3H-imidazol-4-yl)-methanone (500 mg, 1.2 mmol) in dichloromethane (25 mL) at rt was treated with o-tolyl magnesium bromide (1.2 mL, 2.4 mmol, 2M in ether) and the reaction mixture was then stirred at rt for 16 h. The mixture was quenched with water (50 mL) and a sat. solution of ammonium chloride (20 mL). The residue was isolated in a typical aqueous to give phenyl-o-tolyl-(3-trityl-3H-imidazol-4-yl)-methanol, (Intermediate 4) (620 mg, crude).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH2:8][CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:39])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([Br:39])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Yield: 94.1 %

Procedure:
To a stirred mixture of 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (5 g, 14.70 mmol) in CCl4 (100 mL) was added AIBN (0.24 g, 1.46 mmol) and NBS (2.88 g, 16.18 mmol). The mixture was heated to reflux overnight. Then the mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography to afford 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (5.8 g, 94%) as a light yellow solid; LC-MS: 422.3 (M+3). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J=2.4 Hz, 1H), 7.53 (dd, J1=8.6 Hz, J2=2.44 Hz, 1H), 7.10 (d, J=8.64 Hz, 1H), 6.34 (d, J=1.8 Hz, 1H), 4.57 (m, 2H), 3.93 (s, 3H)
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.N.C(OC(C1C(C2[N+:27]([O-:28])=[C:26]([CH3:29])[CH:25]=CC=2)C(C(OCC)=O)=C(C)NC=1C)=O)C>C(O)C>[CH3:29][C:26]1[CH:25]=[CH:5][CH:3]=[C:2]([CH:1]=[O:7])[N+:27]=1[O-:28]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc(C)[n+]1[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: N
Solvent: CCO
Product: Cc1cccc(C=O)[n+]1[O-]

Procedure:
Analogously to the process described in Example 1 there is obtained from 24.1 g of 2-methylpyridine-6-carboxaldehyde-1-oxide, 40 ml of ethanol, 50.4 ml of ethyl acetoacetate and 20 ml of 25% aqueous ammonia, 2,6-dimethyl-4-(2-methyl-1-oxido-6-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester which, after recrystallisation from ethanol, melts at 224°-225° (with decomposition).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.CN(C)[CH:25]=[O:26]>O1CCCC1>[F:9][C:10]([F:21])([F:22])[C:11]1[CH:12]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:15][C:16]=1[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of 100 ml (0.21 mol) of lithium diisopropylamide in tetrahydrofuran is cooled under argon to -70° and at this temperature there are added dropwise thereto while stirring 31 ml (0.2 mol) of 1,3-bis(trifluoromethyl)benzene. The resulting dark red, viscous suspension is stirred at -70° for a further 30 minutes and then 31 ml (0.4 mol) of N,N-dimethylformamide are allowed to flow in rapidly. The internal temperature rises to -20° as a consequence of the exothermic reaction in spite of continuous cooling. The violet solution obtained is then processed further as described in Example 3a). 2,4-Bis(trifluoromethyl)-benzaldehyde is obtained.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N:23]1([C:29]([N:31]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:34][CH:33]([C:47]([NH2:49])=O)[CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[N:23]1([C:29]([N:31]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:34][CH:33]([C:47](=[S:10])[NH2:49])[CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
45 mg (0.11 mmol) of Lawesson reagent (2,4-bis[4-methoxyphenyl] 1,3-dithia-2,4-diphosphetane 2,4-disulphide) were added to a solution of 10 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxamide (Example 52A) in 1 ml of dioxane, and the reaction mixture was stirred at 60° C. for 30 minutes and then at room temperature for 3 h. After addition of saturated aqueous sodium bicarbonate solution and removal of the dioxane, the residue was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. This gave 43 mg (100% of theory) of crude product, which was reacted without any further purification steps.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:53]2[C:52]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N:46]=[C:45]([NH2:54])[C:44]=2[N:43]=[C:42]1[CH2:55][CH2:56][O:57][CH3:58]>ClCCl.N1C=CC=CC=1>[NH2:54][C:45]1[C:44]2[N:43]=[C:42]([CH2:55][CH2:56][O:57][CH3:58])[N:41]([CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[C:53]=2[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[N:46]=1
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cc2ccccc2cn1
Temperature: 0 °C
Yield: 29.6 %

Procedure:
Under a nitrogen atmosphere isoquinoline-3-carboxylic acid (1.32 g, 7.63 mmol), 1-hydroxybenzotriazole (1.12 g, 8.27 mmol), and dichloromethane (60 mL) were combined, allowed to stir for several minutes and then cooled to 0° C. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added. Pyridine (1.8 mL) was added and the resulting mixture was allowed to stir for at least 60 minutes. A solution of 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.37 mmol) in dichloromethane (250 mL) was added dropwise. The reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was washed with sodium bicarbonate, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The crude material was purified by column chromatography (40 g silica gel eluting with dichloromethane/methanol 9/1) followed by recrystallization from methanol to provide 882 mg of N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}isoquinoline-3-carboxamide as a yellow crystalline solid, m.p. 199-200° C. Analysis: Calculated for C27H28N6O2: % C, 69.21; % H, 6.02; % N, 17.94. Found: % C, 69.03; % H, 5.99; % N, 18.11.
Reaction SMILES: Cl.[NH2:2]O.[C:4]([O-])(=O)[CH3:5].[Na+].[F:9][C:10]([F:48])([F:47])[C:11]1[CH:12]=[C:13]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:14][N:15]([C:34](=[O:39])[CH2:35]C(=O)C)[CH:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:18]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:17]1=2>CO>[F:47][C:10]([F:9])([F:48])[C:11]1[CH:12]=[C:13]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:14][N:15]([C:34]1([CH3:35])[O:39][NH:2][CH:4]=[CH:5]1)[CH:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:18]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:17]1=2
Reactant: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Reactant: CC(=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2(C)C=CNO2)c2ccc(Cl)cc21
Yield: 797.7 %

Procedure:
Add hydroxylamine hydrochloride (39 mg, 0.55 mmol) and sodium acetate (1.5 mg, 0.018 mmol). to a solution of compound (+/−)-5-[(3,5-bistrifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester (Example 51, Step 1) (218 mg, 0.37 mmol) in methanol (1.8 mL) at 0° C., Heat the reaction mixture under reflux overnight. Cool and remove the solvents under reduce pressure. Dilute the residue with ethyl acetate and brine. Separate the layers and dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate to afford the title compound (85 mg, 39%). MS (ES+): 590 (M+H).
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[O:13])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[NH2:8][C:9]1([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[O:13])[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(NC(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 4′-{[({1-[(tert-butoxycarbonyl)amino]cyclopropyl}carbonyl)-amino]methyl}-1,1′-biphenyl-2-carboxylate (0.84 g, 2.0 mmol) dissolved in a mixture of DCM (3 mL) and MeOH (45 mL) was cooled to 0° C. This homogenous solution was saturated with anhydrous hydrogen chloride and allowed to sit for 30 minutes. Dry nitrogen was then bubbled through the solution for about 30 min. Solvent was then removed under reduced pressure to yield an oily residue. The oil was then dissolved in DCM and the solvent removed. This process being repeated until a solid amine hydrochloride was obtained. Alternatively, the residue could be dissolved in chloroform followed by saturation with ammonia gas, filtration and solvent removal to obtain solid methyl 4′-({[(1-aminocyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate as the free-base.
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[C:10]=1[O:18][CH3:19])[CH3:7])[CH3:2].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)C>[OH:3][CH:4]1[C:14]2[C:9](=[C:10]([O:18][CH3:19])[C:11]3[O:17][CH2:16][O:15][C:12]=3[CH:13]=2)[CH2:8][N:6]([CH3:7])[CH2:5]1.[CH2:1]([O:3][CH:4]1[C:14]2[C:9](=[C:10]([O:18][CH3:19])[C:11]3[O:17][CH2:16][O:15][C:12]=3[CH:13]=2)[CH2:8][N:6]([CH3:7])[CH2:5]1)[CH3:2]
Reactant: CCOC(CN(C)Cc1ccc2c(c1OC)OCO2)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC1CN(C)Cc2c1cc1c(c2OC)OCO1
Product: COc1c2c(cc3c1OCO3)C(O)CN(C)C2
Yield: 61 %
Yield: 17 %

Procedure:
780 mg (2.5 mmol) of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde diethylacetal (3) was dissolved in 1.6 ml of ethanol. The solution was added with 5 ml of 6N sulfuric acid and refluxed under heating for 2 hours and 45 minutes. After cooling, this solution was made basic by adding a 25% aqueous solution of sodium hydroxide and extracted with 5 ml and then with 2 ml of methylene chloride successively. The extracts were joined, washed with 2 ml of water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was separated by silica gel column chromatography to obtain 360 mg of 4-hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (6) (yield: 61%) and 110 mg of 4-ethoxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (8) (yield: 17%).