Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH2:32][CH3:33])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:24]2)[O:12]1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:68]([C:72]1[CH:73]=[C:74]([NH2:79])[C:75]([NH2:78])=[CH:76][CH:77]=1)([CH3:71])([CH3:70])[CH3:69]>C(Cl)Cl.O>[NH2:79][C:74]1[CH:73]=[C:72]([C:68]([CH3:71])([CH3:69])[CH3:70])[CH:77]=[CH:76][C:75]=1[NH:78][C:29](=[O:30])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH2:32][CH3:33])[CH2:24]1
Reactant: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2ccc(C(C)(C)C)cc2N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(ethyl)amino)cyclobutyl)propanoic acid (2 g, 4.35 mmol), HOAT (768 mg, 5.65 mmol), HATU (2.2 g, 5.65 mmol) and TEA (3 mL, 21.3 mmol) in DCM (40 mL) was added 4-tert-butylbenzene-1,2-diamine (785 mg, 4.79 mmol) and the mixture was stirred at rt for 2 h. Water (15 mL) was added and the mixture was extracted with DCM (30 mL×2). The combined organic phase was washed with H2O (20 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude was purified by SGC (DCM: MeOH=70:1-20:1) to obtain the target (1.6 g, yield: 61%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.28-8.27 (m, 1H), 8.24-8.23 (m, 1H), 7.10-6.92 (m, 2H), 6.81-6.76 (m, 1H), 6.22 (s, 1H), 5.54-5.52 (m, 1H), 5.03 (s, 1H), 4.36 (s, 1H), 3.03-2.50 (m, 5H), 2.32-2.26 (m, 2H), 2.16-1.80 (m, 4H), 1.73-1.69 (m, 2H), 1.59 (s, 3H), 1.39 (s, 3H), 1.28-1.24 (m, 9H), 0.94-0.85 (m, 3H) ppm; ESI-MS (m/z): 607.3 [M+1]+.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:17][CH:18]=[C:19]([S:21][CH3:22])[CH:20]=3)[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.Cl>C(OCC)C>[F:38][C:35]([F:36])([F:37])[C:27]1[CH:26]=[C:25]([CH2:24][O:23][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:15][C@H:14]3[C:16]2[NH:17][CH:18]=[C:19]([S:21][CH3:22])[CH:20]=2)[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=1
Reactant: CSc1c[nH]c([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Product: CSc1c[nH]c([C@@H]2C[C@]3(c4ccccc4)N[C@H]2CC[C@H]3OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
A solution of (1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]-methoxy}-6-[4-methylthioazol-2-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Example 78; 50 mg, 0.081 mmol) in diethyl ether (2 ml) was treated 1M etheral HCl (0.3 ml). The mixture was concentrated in vacuo. The residue was treated with 10% palladium on charcoal (180 mg) ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 30 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified by preparative TLC (dichloromethane:methanol) to give the title compound (15 mg, 35%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH3:9])[CH3:8])[C:3]=1[C:10]#[N:11].[CH3:12][N:13]=[C:14]=[O:15].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:12][NH:13][C:14]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH3:8])[CH3:9])[C:3]=1[C:10]#[N:11])=[O:15]
Reactant: CN(C)c1nsc(N)c1C#N
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CNC(=O)Nc1snc(N(C)C)c1C#N
Reaction time: 1.5 h

Procedure:
Ten drops of dibutyltin diacetate were added to a solution of 3.0 g of 5-amino-4-cyano-3-(dimethylamino)-isothiazole and 1.9 g of methyl isocyanate in 25 ml of tetrahydrofuran. The solution was heated under reflux for two hours, at which time thin-layer chromatographic analysis indicated the reaction to be 40% complete. After the addition of 5 ml more of dibutyltin diacetate and 2 ml more of methyl isocyanate, heating was continued for 90 minutes. Thin-layer chromatographic analysis indicated the reaction to be 60% complete. An additional 15 ml of tetrahydrofuran to dissolve the precipitate which had formed, 10 drops of dibutyltin diacetate, and 3 ml of methyl isocyanate were added and heating was continued for three hours. Thin-layer chromatographic analysis indicated approximately 90% conversion to the desired product. The reaction mixture was stirred at ambient temperature overnight, 2 ml more of methyl isocyanate were added, and the solution was heated under reflux for 1 hour. Thin-layer chromatographic analysis indicated 95% completion. The reaction mixture was cooled to -10°, the solid was collected by filtration and washed with water. Purification was accomplished by recrystallization from 300 ml of methanol to give a solid, m.p. 240°-241°. A second crop of solid, m.p. 240°-241°, was also collected to give a total yield of 6.2 g of 1-methyl-3-(4-cyano-3-(dimethylamino)-5-isothiazolyl)urea. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(CC)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f51) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][C@H:20]1[NH:21][C@@H:22]([CH3:26])[CH2:23][N:24]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=2)[CH2:25]1
Reactant: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)C[C@H](C)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2-nitro-1-[(phenylmethyl)oxy]benzene (7.0 g, 22.7 mmol) in dioxane (120 ml) was added cis-2,6-dimethylpiperazine (7.8 g, 67.4 mmol) followed by cesium carbonate (11.0 g, 33.8 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (2.1 g, 3.4 mmol) and palladium acetate (516 mg, 2.3 mmol). The resulting mixture was heated at 100° C. under an atmosphere of argon overnight. The mixture was allowed to cool, charcoal was added and the mixture stirred at room temperature for 30 minutes. The solids were then removed by filtration through celite and the residue washed with ethyl acetate. The filtrate was then reduced in vacuo and the residue dissolved in 2M aqueous hydrochloric acid and ethyl acetate added. A yellow solid formed that was immiscible in both phases so the mixture was filtered and the solid washed with ethyl acetate. The biphasic filtrate was then separated and the aqueous layer washed with more ethyl acetate. The aqueous was then basified with 0.880 ammonia and the yellow solid collected by filtration added. The resulting basified aqueous solution was then extracted with dichloromethane (×2) and the combined dichloromethane layers dried over anhydrous magnesium sulfate, filtered and reduced in vacuo. The residue was then purified by chromatography on silica gel (gradient 0 to 15% methanol in dichloromethane) to afford the title product. MS (ES+) m/e 342 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:22]=[CH:21][C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][C:7]=2[CH:6]=1)(=[S:3])[CH3:2].[OH-].[Na+]>CO.O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:2][C:1]1[S:3][C:22]2[C:5]([N:4]=1)=[CH:6][C:7]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9][C:8]=1[CH:21]=2
Reactant: CC(=S)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc2cc3c(cc2s1)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 60 °C

Procedure:
1,1-dimethylethyl 7-(ethanethioylamino)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (411 mg), was dissolved in MeOH (12 ml), and 1N NaOH (6.1 ml) and added to potassium ferricyanide [K3Fe(CN)6] (2.1 g), in H2O (12 ml). This mixture was warmed up to 60° C. for 1.5 h, cooled at rt. concentrated and the material thus obtained was purified by flash chromatography over silica gel, eluting with 20% ethyl acetate in hexane, affording a 2:1 mixture of title compound and its regioisomer (167 mg) that was further used as such.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([N+:24]([O-])=O)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:27])[C:3](=[O:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1COCC1>C(O)C>[NH2:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH2:13][CH2:12][N:2]([CH3:1])[C:3](=[O:11])[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:15](=[O:27])[CH2:16][CH2:17]2
Reactant: CN(CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCN1C(=O)CCc2cc(N)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Phenyl methyl(2-(6-nitro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl)carbamate (1.29 g, 3.49 mmol) was dissolved by stirring in ethanol (40 mL) and THF (30 mL) in a round bottom flask. The solution was stirred under an atmosphere of hydrogen for 6 h at room temperature. When TLC confirmed the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated. The resulting residue was chromatographed on silica gel eluting with ethyl acetate, giving a white/pink foam. Yield: 990 mg, 84%. 1H NMR (DMSO-d6) δ 7.36 (m, 2H), 7.20 (m, 1H), 7.01 (m, 2H); 6.91 (d, 1H, J=8.4 Hz), 6.43 (m, 2H), 4.87 (s, 2H), 4.11 and 4.03 (2m, 2H), 3.56 and 3.44 (2t, 2H, J=6.0 Hz), 2.99 and 2.87 (2s, 3H), 2.66 (m, 2H), 2.43 (m, 2H); ESI-MS (m/z, %): 362 (MNa+, 35), 340 (MH+, 100), 202 (44).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].C([O:11][C:12](=O)[CH2:13][C:14]([CH3:16])=O)C>>[CH3:16][C:14]1[CH2:13][C:12](=[O:11])[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccccn1
Product: CC1=NN(c2ccccn2)C(=O)C1

Procedure:
From the reaction of 2-pyridylhydrazine and ethylacetoacetate, 2,4-dihydro-5-methyl-2-(2-pyridyl)-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 4-(2-ethylanilinomethylene)-2,4-dihydro-5-methyl-2-(2-pyridyl)-3H-pyrazol-3-one, Mp 182.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[OH:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])=[O:6]
Reactant: O=C(CO)c1ccccc1
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)OCC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
2-Methoxybenzoyl chloride (about 51 g) from Example 1a was added dropwise to a mixture of 2-hydroxyacetophenone (27.2 g, 24.1 ml, 0.20 mol) and pyridine (40 ml). The reaction mixture was warmed to about 60° C. exothermically. After stirring for 15 minutes, the reaction mixture was poured onto a mixture of ice (800 g) and 36% hydrochloric acid (120 ml). The solid was filtered off, washed with water, and dried. The crude product was crystallized from methanol to yield 48.4 g (89.6%) of the compound (m.p.: 78-79° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][NH:33][CH3:34])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:33]([CH2:32][CH:28]4[CH2:29][CH2:30][CH2:31][N:27]4[CH2:25][CH3:26])[CH3:34])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CCN1CCCC1CNC
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCCC1CN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(1-ethylpyrrolidin-2-yl)-N-methylmethanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.36 (m, 3H) 1.60-1.96 (m, 2H) 2.11 (br. s., 1H) 2.43 (s, 3H) 2.60-2.95 (m, 2H) 3.06 (br. s., 3H) 3.12-3.58 (m, 5H) 3.58-3.84 (m, 1H) 7.54 (d, J=8.08 Hz, 1H) 7.59 (s, 1H) 7.93 (s, 1H) 7.98 (dd, J=8.72, 2.15 Hz, 1H) 8.07 (br. s., 1H) 8.48 (d, J=8.08 Hz, 1H) 8.50-8.54 (m, 1H); ESI-MS m/z [M+H]+ 445.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[Cl:28][C:29]1[CH:30]=C([CH:34]=[CH:35][CH:36]=1)CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:34]=[CH:35][CH:36]=[C:29]([Cl:28])[CH:30]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCc1cccc(Cl)c1
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1cccc(Cl)c1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 48 h

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg of powdered potassium cyanide and 14.2 g of 3-chlorobenzyl alcohol is stirred at 130° for 48 hours, the mixture is diluted with about 20 ml of methylene chloride and chromatographed on about 300 g of silica gel while eluting with ethyl acetate. By crystallization from ethyl acetate and hexane there is obtained m-chlorobenzyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 114°-116°.
Reaction SMILES: [CH2:1]([C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[C:10](=[O:37])[CH2:11][CH2:12][NH:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=2[Cl:23])[N:16](C(OC(C)(C)C)=O)[C:15]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[C:10](=[O:37])[CH2:11][CH2:12][NH:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=2[Cl:23])[NH:16][C:15]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2Cc2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1Cc1ccccc1
Yield: 91.8 %

Procedure:
Dissolve 3-[(2-benzylphenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (320 mg, 0.55 mmol) in methylene chloride (5 mL). Add trifluoroacetic acid (1 mL) and stir at room temperature for 3 hours. Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give the title compound (250 mg, 95%); mp 208°-209° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH3:9][C:10]1[S:14][C:13]([N:15]=[C:16]=[O:17])=[CH:12][CH:11]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:9][C:10]1[S:14][C:13]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])=[CH:12][CH:11]=1
Reactant: CN1CC(=O)N=C1N
Reactant: Cc1ccc(N=C=O)s1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)N=C2NC(=O)CN2C)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 74.7 %

Procedure:
To 1.44 g (12.8 mM) of creatinine in 25 ml of anhydrous DMF was added with stirring 1.78 g (12.8 mM) of 5-methyl-2-thienyl isocyanate in 12 ml of toluene. After 6 hrs. at 60° C., the mixture was cooled, poured into 100 ml of water and filtered. The collected solid was recrystallized twice from ethyl acetate to give 2.4 g of the above urea as a yellow-orange solid, m.p. 207°-209° C.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1>CN(C=O)C>[C:1]1([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[O:15][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([O:23][CH3:22])=[O:33])=[CH:26][CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cccc(CNc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cccc(CNc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 19.1 %

Procedure:
To a suspension of 3-((phenylamino)methyl)phenol (398 mg, 2 mmol) and cesium carbonate (651 mg, 2 mmol) in anhydrous DMF (8 mL) was added methyl-4-(bromomethyl)benzoate (481 mg, 2.1 mmol). The resulting mixture was stirred for 22 hours at room temperature, after which time the solvent was removed in vacuo. The residue was partitioned between dichloromethane (30 mL) and water (10 mL). The mixture was passed through a phase separator, washed with dichloromethane and solvent was removed in vacuo to afford a brown oil. The crude material was purified by silica gel chromatography eluting with 25% ethyl acetate in iso-hexane to afford the title compound as a yellow oil (133 mg, 19%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[C:25]([C:35]#[N:36])=[N:26][C:27]([CH3:34])=[C:28]([O:31][CH2:32][CH3:33])[C:29]=1[CH3:30])=[N+]=[N-].O1CCCC1>O>[CH2:32]([O:31][C:28]1[C:29]([CH3:30])=[C:24]2[CH2:23][N:20]=[C:35]([NH2:36])[C:25]2=[N:26][C:27]=1[CH3:34])[CH3:33]
Reactant: CCOc1c(C)nc(C#N)c(CN=[N+]=[N-])c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(C)nc2c(c1C)CN=C2N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.7 %

Procedure:
Triphenylphosphine (170 mg, 0.648 mmol) was added to a solution of the 3-(azidomethyl)-5-ethoxy-4,6-dimethyl-2-pyridinecarbonitrile (113 mg, 0.489 mmol) in a tetrahydrofuran (3 ml) —H2O (0.15 ml) mixed solvent while cooling on ice, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: ethyl acetate-methanol-29% NH3(aq)) to yield the title compound (69 mg, 69%) as a yellow solid.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)=[CH:3][CH:2]=1.[O:21]=[C:22]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:23](O)=[O:24]>>[OH:21][C@@H:22]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:23]([N:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=1)[CH2:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1)=[O:24]
Reactant: O=C(O)C(=O)c1cccnc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2cccnc2)cc1
Yield: 26.2 %

Procedure:
In analogy to example 13, p-tolyl-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (95 mg, 0.34 mmol, prepared as in example 14, step1) was coupled to oxo-pyridin-3-yl-acetic acid (54 mg, 0.36 mmol) and reduced to give the title compound as a colorless oil (37 mg, 25%) MS m/e: 416.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:18][C@@H:17]1[CH2:31][C:32]([O:34]C)=[O:33].[OH-].[Na+].[ClH:38].O>O1CCOCC1>[ClH:38].[ClH:38].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:18][C@@H:17]1[CH2:31][C:32]([OH:34])=[O:33]
Reactant: COC(=O)C[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCSC4CCCCC4)C[C@@H]3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of 0.3 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-acetate in 8 cm3 of dioxane in the presence of 0.5 cm3 of 5N aqueous sodium hydroxide solution was heated with stirring at a temperature in the region of 60° C. for 20 hours. After cooling to a temperature in the region of 20° C., the reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. A foam with a yellow color was obtained, which product was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 1.6 cm; silica volume 40 cm3), elution was carried out with a chloroform/methanol/28% aqueous ammonia (12/3/0.5 by volume) mixture, and first a fraction of 125 cm3 and then approximately 10-cm3 fractions were collected. Fractions 3 to 7 were combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.27 g of a lacquer was obtained, which product was taken up in 5 cm3 of dioxane, 11 cm3 of 0.1N aqueous hydrochloric acid and 14 cm3 of distilled water. The dioxane was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then the residual solution was lyophilized. 0.29 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)-ethyl]piperidine-3-acetic acid dihydrochloride was obtained in the form of a lyophilizate with a white color.