Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[O:21]C)[CH2:9]1)(C)(C)C.ClC1[S:26][C:27]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=2[N:29]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[F:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:6]([NH:7][C@H:8]3[CH2:9][C@H:10]([N:12]4[C:16]5=[N:17][CH:18]=[CH:19][CH:20]=[C:15]5[NH:14][C:13]4=[O:21])[CH2:11]3)[S:26][C:27]=2[CH:33]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: COc1nc2cccnc2n1[C@H]1C[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2cccnc2n1[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Temperature: 90 °C

Procedure:
To a glass microwave reaction vessel was added 3-(trans-3-aminocyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (intermediate 43, 0.1288 g, 0.465 mmol), 2-chloro-6-fluorobenzo[d]thiazole (0.087 g, 0.465 mmol), and diisopropylethylamine (0.283 ml, 1.627 mmol) in dry dimethylsulfoxide (1.549 ml). The vial was sealed and heated at 90° C. for 14 hours. It was allowed to cool to room temperature and the crude product purified by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in acetonitrile/water, gradient 10% to 90% over 12 min) to give the desired 3-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (26.2 mg, 0.074 mmol, 15.86% yield). M+1: 355.99. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37-2.47 (m, 2 H) 3.25-3.34 (m, 1 H) 4.55 (d, J=5.28 Hz, 1 H) 5.20 (quin, J=8.41 Hz, 1 H) 6.99-7.12 (m, 2 H) 7.32 (dd, J=7.63, 1.17 Hz, 1 H) 7.41 (dd, J=8.80, 4.89 Hz, 1 H) 7.64 (dd, J=8.80, 2.74 Hz, 1 H) 8.00 (dd, J=5.18, 1.27 Hz, 1 H) 8.56 (d, J=6.06 Hz, 1 H) 11.15 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[O:18])=[CH:20][CH:21]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCSCC3)cc2)=C(C)C1=O
Yield: 50 %

Procedure:
4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (100 mg, 0.32 mmol) obtained in Example 21 and thiomorpholine (0.035 ml, 0.35 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (65 mg, 0.16 mmol, yield 51%).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[NH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(Cl)CCl>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)NCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Indomethacin (500 mg, 1.40 mmol) was taken up in 10 mL of CH2Cl2 along with tert-butyl 2-aminoethylcarbamate (223 mg, 1.40 mmol) and EDC (295 mg, 1.54 mmol). The resulting reaction mixture was stirred at room temperature for 18 and diluted with CH2Cl2 (10 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 550 mg of tert-butyl 2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethylcarbamate (79% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=O>CN(C1C=CN=CC=1)C.ClCCl>[C:22]([C:27]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:3][C:2]=2[N:1]=1)([CH3:26])([CH3:23])[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)Nc1ccc(NCC2CCCCC2)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl {3-amino-4-[(cyclohexylmethyl)amino]phenyl}carbamate (950 mg, 3.43 mmol) and DMAP (100 mg, 0.858 mmol) were dissolved in 25 mL of dichloromethane. Trimethylacetyl chloride (0.460 mL, 3.77 mmol) was added in dropwise and the solution was stirred at rt for 1 h. The solvent was concentrated. The residue was divided in two portions and each of them was dissolved in 3 mL of glacial AcOH in a sealed tube. The solutions were heated at 150° C. using a Personal Chemistry Smith Synthesizer microwave instrument for three intervals of 30 min (3×30 min). The contents of the two tubes were combined and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 3:1/dichloromethane:diethyl ether. Yield: 656 mg (56%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.08 (m, 2H), 1.18 (m, 3H), 1.54 (s, 9H), 1.65 (m, 1H), 1.69 (m, 2H), 1.73 (dd, J=5.96, 3.22 Hz, 2H), 2.02 (m, 1H), 3.78 (s, 3H), 4.10 (d, J=7.42 Hz, 2H), 6.64 (m, 1H), 7.25 (d, J=8.79 Hz, 1H), 7.39 (m, 1H), 7.59 (d, J=1.76 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=1)([CH3:4])[CH3:3].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:11][C:9]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:10]=1
Reactant: CCOc1cccc(-c2ccc(CO)cc2C(C)(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOc1cccc(-c2ccc(CCl)cc2C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A dry, round bottom flask containing 41.2 (0.72 g, 2.53 mmol) and DCM (9.0 mL) was cooled to 0° C. After 15 minutes, thionyl chloride (1.0 mL, 13.7 mmol) was carefully added dropwise at 0° C. Upon complete addition of thionyl chloride, the mixture was allowed to warm to room temperature and stirred overnight. After 20 hours, the reaction was concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-15% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 41.3 as a colorless oil (0.57, 74%). 1H NMR (500 MHz, CDCl3) δ ppm 7.54 (1H, d, J=2.0 Hz), 7.25 (2H, m), 7.04 (1H, d, J=7.4 Hz), 6.90 (3H, m), 4.65 (2H, s), 4.05 (2H, m), 1.43 (3H, t, J=7.0 Hz), 1.24 (9H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[C:2]=1[OH:12].[N:13]([O-])=[O:14].[Na+].[OH-].[Na+].OS(O)(=O)=O>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[C:3](=[O:11])[C:2]1=[O:12]
Reactant: Oc1cc2ccccc2nc1O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccccc2C(=NO)C1=O
Temperature: 0 °C
Yield: 62.6 %

Procedure:
To a solution of 50.1 mg (0.311 mmol) of 11a and 52.0 mg (0.753 mmol) of NaNO2 in 1.5 mL of aqueous 0.2N NaOH in an ice-bath was added dropwise 1 mL of aqueous 2N H2SO4. A red precipitate was observed. The mixture was stirred in the ice-bath for 2 h and at 25° C. for 4 h, filtered and washed with water, and dried to leave 37 mg (62%) of 14a as a red solid, mp 241°-242° C. 1H CDCl3 +DMSO-d6), 6.83 (m, 2), 7.069 (t, 1 J=7.2), 8.544 (d, 1, J=8.1), 11.228 (m, 1). MS, 190 (100, M+), 162 (50), 145 (65), 117 (30). High resolution MS, Calcd for C9H6N2O3 190.0375, found 190.0377.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[N-:13]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>C(Cl)Cl>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([S:2]([CH3:1])(=[NH:13])=[O:3])=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
1.56 g (8.5 mmol) of 1-(methylsulfinyl)-4-nitrobenzene in 20 ml of DCM is mixed with 0.70 g (9.5 mmol) of sodium azide. The batch is slowly mixed at 0° C. with 2.3 ml of concentrated sulfuric acid and then heated to 45° C. After 16 hours, the batch is cooled to room temperature, mixed with water and extracted from DCM. The aqueous phase is set at pH 11 with 15% NaOH solution and extracted from DCM. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 1.08 g (5.4 mmol, corresponding to 63% of theory) of the product is obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=O)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[S:12]([NH2:16])([NH2:15])(=[O:14])=[O:13].[BH4-].[Na+]>C(O)C.O>[S:9]1[CH:8]=[C:7]([CH2:10][NH:15][S:12]([NH2:16])(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: NS(N)(=O)=O
Reactant: O=Cc1csc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)NCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thianaphthene-3-carboxaldehyde (1.62 g, 10.0 mmol) was dissolved in anhydrous ethanol (50 mL). Sulfamide (4.0 g, 42 mmol) was added and the mixture was heated to reflux for 16 hours. The mixture was cooled to room temperature. Sodium borohydride (0.416 g, 11.0 mmol) was added and the mixture was stirred at room temperature for three hours. The reaction was diluted with water (50 mL) and extracted with chloroform (3×75 mL). The extracts were concentrated and chromatographed (5% methanol in DCM) to yield the title compound as a white solid.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:16][C:17]1([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=O.C(N(CC)CC)C>O1CCCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[O:25][C:23](=[O:24])[C:17]2([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[N:16]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(c2ccco2)=NC12CCCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
6.0 g (44 mmol) of isobutyl chloroformate was added dropwise to a solution of 10 g (42 mmol) of 1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylic acid obtained in Reference Example 14 and 6.1 ml (44 mmol) of triethylamine in tetrahydrofuran (80 ml), and the mixture was stirred at room temperature for 1 hour. The precipitated crystal was removed by filtration, and the filtrate was concentrated. The obtained crystal was washed with water to obtain 8.95 g (97%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[OH:13].CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.C(O)C>N1C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:38][C:37]1[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:42])[F:43])=[CH:41][CH:40]=1)=[C:5]2[OH:13]
Reactant: Oc1cc(O)c2cc(I)ccc2n1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: c1ccncc1
Solvent: CCO
Product: Oc1nc2ccc(I)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 105 °C
Reaction time: 6 h

Procedure:
To a suspension of 6-iodoquinoline-2,4-diol (498.2 g, 1.736 mol) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (439.6 g, 1.736 mol) in pyridine (3.5 L) was added 4-(trifluoromethyl)benzaldehyde (332.4 g, 1.909 mol). The resulting mixture was warmed with stirring to 105° C. for a period of 6 h. After cooling to room temperature, the heterogeneous mixture was treated with ethanol (4.6 L). White solids were isolated through filtration, washed with 57:43 ethanol:pyridine (800 mL), and dried in a vacuum oven at 65° C. The title compound was obtained in a 1:0.92 ratio with pyridine and used directly in the subsequent step.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[Cl:7][C:8]1[C:13]2[CH:14]=[CH:15][N:16]([CH3:17])[C:12]=2[C:11]([C:18]([OH:20])=O)=[CH:10][N:9]=1>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[C:13]2[CH:14]=[CH:15][N:16]([CH3:17])[C:12]=2[C:11]([C:18]([N:9]2[CH2:2][CH2:1][CH2:12][CH2:13][CH2:8]2)=[O:20])=[CH:10][N:9]=1
Reactant: Cn1ccc2c(Cl)ncc(C(=O)O)c21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccc2c(Cl)ncc(C(=O)N3CCCCC3)c21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of oxalylchloride (3.43 ml) in DCM (40 ml) was cooled to 0° C. and 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (3.75 g) was added portionwise followed by the addition of DMF (4 drops). The reaction mixture was stirred at 0° C. for 90 min, DCM (5 ml) was added and stirring continued for a further 30 min. The reaction mixture was evaporated and the residue dissolved in dichloromethane (20 ml) and dimethylformamide (10 ml). N-ethylmorpholine (9.09 ml) followed by piperidine (3.53 ml) were added and the mixture stirred at 0° C. for 45 min. The reaction mixture was evaporated and the residue dissolved in EtOAc (150 ml). The organic layer washed with water (100 ml), sodium bicarbonate (3×100 ml) and brine (30 ml) then dried (MgSO4) and evaporated to a yellow oil. The oil was triturated with diethyl ether, and the solid filtered and dried at 60° C. under vacuum, to afford the title compound (3.95 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([CH3:32])[S:14]([C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[NH2:11][C:9]1[N:10]=[C:3]2[C:2]([C:20]3[CH:19]=[CH:18][C:17]([S:14]([N:13]([CH3:32])[CH3:12])(=[O:15])=[O:16])=[CH:22][CH:21]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C)S(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N,N-dimethyl-benzenesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (150.0 mg, 0.7041 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (210.0 mg, 0.6748 mmol) in a manner analogous to Step 2c. The reaction product was isolated as a tan solid (0.074 g, 34%). MP=188-190° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.63 (d, J=6.4 Hz, 1H), 8.38 (d, J=8.2 Hz, 2H), 7.88-7.82 (m, 3H), 7.03 (t, J=6.8 Hz, 1H), 6.21 (br s, 2H), 2.66 (s, 6H). MS=318 (MH)+.
Reaction SMILES: [CH3:1][Si:2]([C:5]1[C:6]([Si](C)(C)C)=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>C(OC(=O)C)(=O)C>[N+:19]([C:9]1[CH:10]=[C:5]([Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:6]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)([O-:21])=[O:20]
Reactant: C[Si](C)(C)c1cccc([Si](C)(C)C)c1[Si](C)(C)C
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: C[Si](C)(C)c1cc([N+](=O)[O-])cc([Si](C)(C)C)c1
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 1.18 g (4.00 mmol) of sym-tris(trimethylsilyl)benzene in 1.7 ml of acetic anhydride was added a solution of 0.4 ml (9.1 mmol) of 94% nitric acid in 1.7 ml of acetic anhydride at -10° C. The mixture was stirred at 10° to -5° C. for 2 hours and then at room temperature for 22 hours. The reaction mixture was poured into sodium hydroxide solution and the aqueous solution was extracted with methylene chloride. The extract was evaporated. The residue was purified by column chromatography on silica gel [eluent: petroleum ether] to give 636 mg of pale yellow crystals, m.p. 86°-87° C. (yield 59%). 1H-NMR spectrum δ(CDCl3)ppm: 0.33 (18H,s), 7.90 (1H,t,J=1.1 Hz), 8.29 (2H,d,J=1.1 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:66])[C@H:10]([CH2:62][CH:63]([CH3:65])[CH3:64])[NH:11][C:12](=[O:61])[C@H:13]([C:57]([CH3:60])([CH3:59])[CH3:58])[NH:14][C:15](=[O:56])[C@H:16]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:55])[NH:17][C:18](=[O:47])[C@H:19]([CH2:38][CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:20]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:66])[C@H:10]([CH2:62][CH:63]([CH3:64])[CH3:65])[NH:11][C:12](=[O:61])[C@H:13]([C:57]([CH3:59])([CH3:58])[CH3:60])[NH:14][C:15](=[O:56])[C@H:16]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:55])[NH:17][C:18](=[O:47])[C@H:19]([CH2:38][CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccccc1C[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C

Procedure:
A solution of 10.89 g (12.07 mmol) of N-[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml of piperidine and 120 ml of dichloromethane was stirred for 30 minutes at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly 20% ethyl acetate in hexane and then 10% methanol in dichloromethane for the elution. Evaporation gave N-[N-[N-[O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in the form of an oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:34][CH3:35])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNCc2ccc(Cl)c(Cl)c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)c(Cl)c1

Procedure:
4-Amino-5-chloro-N-((1-(3-(3,4-dichlorobenzylamino)propyl)-piperidin-4-yl)methyl)-2-methoxybenzamide (2.0 g) as starting compound, acetaldehyde (0.27 ml) and sodium cyanoborohydride (0.3 g) were reacted and treated in the same manner as in Example 136 to give 0.7 g of 4-amino-5-chloro-N-((1-(3-(N-(3,4-dichlorobenzyl)-N-ethylamino)propyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [N:1]([C:4]1[CH:19]=[CH:18][C:7]([S:8]/[C:9](=[C:13](\O)/[C:14]([OH:16])=[O:15])/[C:10](O)=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[N:1]([C:4]1[CH:19]=[CH:18][C:7]([S:8][C:9]2[C:10]([O:15][C:14](=[O:16])[CH:13]=2)=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3]
Reactant: O=C(O)/C(O)=C(/Sc1ccc(N=C=S)cc1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1C=C(Sc2ccc(N=C=S)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The 2-[4'-(Isothio-cyanato)thiophenoxy]-3-hydroxymaleic acid (4.510 g, 15.07 mmol) was slurried in 140 mL of CHCl3 under nitrogen, treated with trifluoroacetic anhydride (5.30 mL, 7.88 g, 37.5 mmol), and heated to reflux. After 6.5 hours, the homogeneous reaction mixture was allowed to cool to room temperature, concentrated, taken up in hot CCl4 (80 mL), filtered hot, concentrated to one third volume, and diluted with 10 mL of hexane. Crystallization occurred upon standing at room temperature over 30 minutes. After storing at 0° C. an additional 2 hours, the light orange crystals of 2-[4'-(isothiocyanato)thiophenoxy] maleic anhydride (the titled compound) were collected by filtration, washed twice with 30 mL portions of hexane and dried overnight under vacuum (0.05 mm Hg).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1([CH2:31][CH2:32]OS(C2C(C)=CC=CC=2)(=O)=O)[CH:30]=[CH:29][N:28]=[CH:27]1>O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: Clc1ccc(N2CCN=C2Cc2ccccc2)c(Cl)c1
Reactant: Cc1ccccc1S(=O)(=O)OCCn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccc(N2CCN=C2C(CCn2ccnc2)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
1-(2,4-Dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole To a stirred solution of 2-(imidazol-1-yl)ethanol (1.9 g, 0.0156 mol), triethylamine (2.8 ml, 0.0187 mol), and 4-N,N-dimethylaminopyridine (20 mg) in dichloromethane (20 ml) at a temperature of -78° C. under nitrogen atmosphere, was added p-toluenesulphonyl chloride (3.6 g, 0.0187 mol) in dichloromethane (10 ml). The reaction mixture was allowed to warm to -10° C. and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. The organic phase was separated and the aqueous phase extracted with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield colorless crystals of 2-(imidazol-1-yl)-1-toluenesulphonyloxyethane (4.23 g). n-Butyllithium (3.9 ml, 0.0059 mol, 1.5M in hexane) was added to a stirred solution of 1-(2,4-dichlorophenyl)-4,5-dihydro-2-phenylmethylimidazole (1.5 g, 0.0049 mol) in dry tetrahydrofuran (10 ml) at -78° C. under a nitrogen atmosphere. Copper(I)bromide-dimethyl sulphide complex (50 mg, 0.0024 mol) was added to the reaction mixture. After a period of one hour, a solution of 2-(imidazol-1-yl)-1-toluenesulphonyloxyethane (2 g, 0.0072 mol) in tetrahydrofuran (7 ml) was added to the reaction mixture. The resulting mixture was allowed to warm to room temperature and allowed to react for 15 hours before being quenched with saturated aqueous ammonium chloride. The phases were separated and the aqueous phase extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield an oil which was chromatographed on silica gel with ammonia/methanol/ethyl acetate (1:4:45) to yield 1-(2,4-dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole (1 g) which upon treatment with ethereal hydrogen chloride yielded the hydrochloride salt of 1-(2,4-dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole. (Found C, 49.00; H, 5.03; N, 10.76. C21H22N4Cl4.9/4H2O requires C, 49.19; H, 5.21; N, 10.93) having the formula ##STR43##
Reaction SMILES: [C:1]([C:4]([C:16](=[O:18])[CH3:17])=[CH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH2:14][CH3:15])(=O)[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1>C(O)(C)C>[C:16]([C:4]1[CH:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=2[CH2:14][CH3:15])[C:21]2[C:22](=[O:26])[NH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:1]=1[CH3:2])(=[O:18])[CH3:17]
Reactant: CCc1cc(C#N)ccc1C=C(C(C)=O)C(C)=O
Reactant: Nc1cc[nH]c(=O)c1
Solvent: CC(C)O
Product: CCc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cc[nH]c(=O)c21
Reaction time: 96 h

Procedure:
1 g (4.14 mmol) of 4-(2-acetyl-3-oxobut-1-en-1-yl)-3-ethylbenzonitrile and 0.45 g (4.14 mmol) of 4-aminopyridin-2(1H)-one [Scats, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] are dissolved in 20 ml of isopropanol and stirred at the reflux temperature under argon for 4 days. The mixture is then concentrated and the residue is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 10:1). 277 mg (20% of theory) of the title compound are obtained as a pale yellow solid.