Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc(-n2ccnc2)c2cccc(O)c2n1
Yield: 85.5 %

Procedure:
The solution of 4-chloro-8-hydroxy-2-methylquinoline (2.0 g), imidazole (3.52 g) in dioxane (20 ml) was refluxed for 18 hours. The cooled reaction mixture was added chloroform and aqueous sodium bicarbonate solution. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ether to give 8-hydroxy-4-(imidazol-1-yl)-2-methylquinoline (1.99 g) as colorless crystals.
Reaction SMILES: [Na].[N+]([C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[CH:6]=1)([O-])=O.[C:13](O)(=[O:15])C.C([O-])(O)=O.[Na+]>CO.O>[CH3:13][O:15][C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1
Temperature: 25 °C

Procedure:
With stirring, sodium pellets (3.95 g, 0.172 mol), maintained dry under hexane, were added to 540 ml dry methanol, under N2. Following dissolution, the mixture was diluted with 900 ml methanol, 4-nitro-2-methylpyridine N-oxide (26.0 g, 0.169 mol) was added, and the mixture heated at reflux for 1 hour, cooled to room temperature and acidified with 18 ml glacial acetic acid. After stirring 15 minutes, the reaction mixture was stripped of solvent, the orange residue taken up in 300 ml of H2O, neutralized with saturated NaHCO3, reconcentrated to dryness, and the residue triturated 5×50 ml of ethanol. The ethanol triturates were combined, stripped to dryness, and the residue restripped 3×50 ml toluene to yield solids (36.1 g) which were chromatographed on silica gel using 6:1 CH2Cl2 :CH3OH as eluant to yield purified title product, 21.14 g; MS 139 (M+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([C:12]([N:14]2[C:23]3[C:18](=[C:19]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:20]([N:24]4[CH:28]=[CH:27][CH:26]=[N:25]4)=[CH:21][CH:22]=3)[CH2:17][CH2:16][C@@H:15]2[CH3:36])=[O:13])[CH2:11][CH2:10]1>CN(C)C=O.O>[Br:1][C:27]1[CH:26]=[N:25][N:24]([C:20]2[C:19]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:14]([C:12]([CH:9]2[CH2:10][CH2:11]2)=[O:13])[C@@H:15]([CH3:36])[CH2:16][CH2:17]3)[CH:28]=1
Reactant: C[C@H]1CCc2c(ccc(-n3cccn3)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CCc2c(ccc(-n3cc(Br)cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
N-Bromosuccinimide (0.025 g, 0.15 mmol) was added to a solution of (S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1 (2H)-yl)methanone (0.050 g, 0.13 mmol) in N,N-dimethylformamide (2 mL), and the resulting solution stirred overnight at room temperature. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:10, ethyl acetate/petroleum ether) to afford (S)-(6-(4-bromo-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.055 g, 91%) as yellow oil. MS (ESI, pos. ion) m/z 452, 454 [M+H]+.
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>ClCCl>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:9][C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2])=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 76 %

Procedure:
Tert-octylamine (51.7 g, 0.4 mol) and triethylamine (61.2 ml, 0.44 mol) in 260 ml of dichloromethane were introduced into a reactor. It was heated to 70° C. then 4-nitrobenzoyl chloride (77.9 g, 0.42 mol) was added in small portions over 50 minutes. It was heated under reflux for 4 hours. The reaction mixture was poured over ice water; it was extracted with dichloromethane, dried and the solvent was evaporated off. The beige precipitate obtained was recrystallized from a mixture of isopropyl ether and ethanol (ratio 10:1). After drying under vacuum, 84.6 g (yield: 76%) of 4-nitro-N-(tert-octyl)benzamide were obtained in the form of an off-white powder and used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:13]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:26]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:20]2[CH2:21][CH2:22][N:23]([CH2:4][CH:5]([OH:12])[CH2:6][O:12][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]4[C:6]=3[CH:7]=[CH:8][CH:9]=[N:10]4)[CH2:24][CH2:25]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Oc1ccc(Cl)c2ncccc12
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: OC(COc1ccc(Cl)c2ncccc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 0.64 g of 8-chloro-5-hydroxyquinoline and 1.48 g of 4-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine synthesized in Example 23-(b), in order to obtain 0.68 g of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-chloroquinoline.
Reaction SMILES: Br.BrCC(O[CH2:9][CH3:10])OCC.C(OCC)C.[Cl:16][C:17]1[N:22]=[N:21][C:20]([NH2:23])=[CH:19][CH:18]=1>O.C(O)CCC>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:9]=[CH:10][N:23]=2)[N:22]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCOC(CBr)OCC
Agent: Br
Solvent: CCOCC
Solvent: CCCCO
Solvent: O
Product: Clc1ccc2nccn2n1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
Hydrobromic acid (48% solution in water, 1.8 mL, 15.47 mmol) was added to a solution of 2-bromo-1,1-diethoxyethane (11.6 mL, 77.11 mmol) in water (18 mL) at ambient temperature and the resulting mixture was heated at 110° C. After 45 minutes, the reaction mixture was cooled and diethyl ether was added. The organic layer was separated, dried over magnesium sulphate and the solvent evaporated to obtain a colorless oil, which was added to a suspension at 0° C. of 6-chloropyridazin-3-amine (5.0 g, 38.60 mmol) in n-butanol (8 mL). The resulting mixture was heated at 130° C. overnight. The solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated. The aqueous layer was treated with solid sodium hydrogencarbonate until a basic pH was reached and extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting residue was treated with diisopropyl ether, filtered and dried in vacuo to yield the title compound (4.8 g, 85%) as a beige solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[O:16]([CH:8]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][N:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc(OC(Oc2ccccc2)c2ccccn2)cc1

Procedure:
To a solution of 10.42 grams (g) (0.032 mole (m)) of 6-chloro-2-(diphenoxy-methyl)pyridine, 8.02 g (0.079 m) of triethylamine in 200 milliliters (ml) of absolute ethanol in a Parr shaker bottle was added 0.5 g of 5 percent palladium on charcoal. Hydrogen was passed over the liquid surface using a Parr hydrogenator until ~3 pounds (0.3 m) had been consumed. The reaction mixture was filtered and the solvent removed by evaporation under reduced pressure. The residue was poured into a solution of 50 ml of water and 50 ml of 10 percent sodium hydroxide. This solution was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and the solvent stripped away under vacuum. The residue was heated at 0.02 millimeters of mercury to 110° C. to remove lower boiling impurities. The above named product was recovered as a pale yellow oil in a yield of 6.8 g and was ~99 percent pure. The Nuclear Magnetic Resonance spectrum (NMR) confirmed the product. The product has a refractive index of nd25 =1.5946 and upon analysis was found to have carbon, hydrogen and nitrogen contents of 77.78, 5.56 and 4.92 percent, respectively, as compared with the theoretical contents of 77.98, 5.24 and 5.05 percent, respectively, as calculated for the above named compound (Compound 1).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CCN(C(C)C)C(C)C.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42]([NH:4][CH2:3][CH2:1][OH:2])=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: NCCO
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NCCO)cn3)ccc2n1CC1CCOCC1
Reaction time: 0.33 h
Yield: 71 %

Procedure:
Ethanolamine (29 mg, 0.47 mmol) and DIPEA (122 uL, 90 mg, 0.70 mmol) were added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (4.0 mL, 0.23 mmol) (see following step B for preparation). Stirring for 20 min, HATU (117 mg, 0.47 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with H2O (100 mL), and extracted with EtOAc (3×50 mL). The combined organic phases were washed with NaCl saturated aqueous solution (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc/MeOH (20:1-9:1) on silica gel to give 80 mg (71%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.57 (m, 4 H), 1.60 (s, 9 H), 2.25-2.36 (m, 1 H), 3.24-3.34 (m, 2 H), 3.40 (t, J=5.66 Hz, 2 H), 3.63 (t, J=5.76 Hz, 2 H), 3.86-3.94 (m, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 7.95 (d, J=8.8 Hz, 1 H), 8.02 (dd, J=8.8, 1.8 Hz, 1H), 8.06 (d, J=0.78 Hz, 1 H), 8.35 (d, J=1.17 Hz, 1 H), 8.78 (s, 1 H); MS (ESI) (M+H)+=490.3.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([OH:22])=O)=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:23])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]3[O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:20](=[O:22])[C:9]=3[CH:10]=2)[CH2:5][C:4]1=[O:23])[CH3:2]
Reactant: CCN1C(=O)Cc2cc(OCc3ccccc3C(=O)O)ccc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCN1C(=O)Cc2cc3c(cc21)C(=O)c1ccccc1CO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a suspension of 5.0 g. (16.1 mmoles) of 1-ethyl-5-(2-carboxybenzyloxy)oxindole in 100 ml. of methylene chloride was added 3.34 g. (16.1 mmoles) of phosphorous pentachloride and the reaction mixture allowed to stir 30 minutes at 25° C. The reaction mixture was cooled to --15° C. and 8.56 g. (64.4 mmoles) of aluminum chloride was added. The resulting mixture was allowed to stir at room temperature for 30 minutes and was then added to ice. The organic phase was separated, dried over magnesium sulfate and concentrated to give the desired product which was recrystallized from ethyl acetate-hexane, 2.3 g (69% yield), m.p. 186.5°-188.5° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:24])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Methanesulfonyl chloride (2.74 mL, 35.41 mmol) was added dropwise to (S)-tert-butyl 1-(4-chlorophenyl)-3-hydroxypropylcarbamate (Intermediate 58) (9.2 g, 32.19 mmol) and triethylamine (5.38 mL, 38.63 mmol) in DCM (161 mL) at 25° C. over a period of 15 minutes under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was evaporated to dryness and the residue was purified by flash silica chromatography, elution gradient 40 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (S)-3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (10.03 g, 86%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]2[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:5]2=[N:6][CH:7]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:3]1[C:2]([NH:1][C:29]([NH:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[F:20])=[O:30])=[CH:7][N:6]=[C:5]2[S:8][C:9]([CH2:11][CH3:12])=[CH:10][C:4]=12
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCc1cc2c(-c3ccccc3Cl)c(N)cnc2s1
Solvent: C1CCOC1
Product: CCc1cc2c(-c3ccccc3Cl)c(NC(=O)Nc3ccc(F)cc3F)cnc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a solution of 5-amino-4-(2-chlorophenyl)-2-ethylthieno[2,3-b]pyridine (288 mg) in tetrahydrofuran (3 ml) was added 2,4-difluorophenyl isocyanate (0.13 ml) and the mixture was stirred at room temperature for 18 hours, and then the solvent was distilled off. To the residue was added isopropyl ether to obtain N-[4-(2-chlorophenyl)-2-ethylthieno[2,3-b]pyridin-5-yl]-N'-(2,4-difluorophenyl)urea as crystals (416 mg, 93.9 %). Colorless prisms were obtained by recrystallization from acetone-hexane, mp: 217°-218° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[NH:21][N:20]=2)=[CH:13][CH:12]=1>>[N:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:3]4/[C:2](=[O:10])[NH:1][C:5]5[C:4]/4=[CH:9][CH:8]=[CH:7][N:6]=5)=[CH:25][CH:26]=3)[NH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc2c(C=Cc3ccncc3)n[nH]c2c1
Reactant: O=C1Cc2cccnc2N1
Product: O=C1Nc2ncccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Yield: 87.6 %

Procedure:
The title compound (64 mg, 64%) was synthesized as orange red solid according to the method described for Example A11B from 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H, NH), 11.28 (s, 1H, NH), 8.57 (d, J=5.6 Hz, 2H), 8.39 (d, J=8.4 Hz, 1H), 8.12 (d, J=4.8 Hz, 1H), 7.95 (s, 2H), 7.90 (d, J=6.4 Hz, 1H, partially overlapping with the peak at 7.87 ppm), 7.87 (d, J=16.4 Hz, 1H, partially overlapping with the peak at 7.90 ppm), 7.71 (d, J=5.6 Hz, 2H), 7.57 (d, J=8.0 Hz, 1H, partially overlapping with the peak at 7.56 ppm), 7.56 (d, J=16.4 Hz, 1H, partially overlapping with the peak at 7.57 ppm), 6.91 (dd, J=7.6 Hz, 5.2 Hz, 1H); MS ESI 366.1 [M+H]+, calcd for [C22H15N5O+H]+ 366.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9].[ClH:35].C(O)C.C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:35].[ClH:35].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26](=[NH:43])[NH2:27])=[CH:24][CH:25]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CCc3ccc(C#N)cc3)nc2c1)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CN(C(=O)c1ccc2sc(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccn1
Yield: 95 %

Procedure:
Prepared analogously to Example 9 from 2-[2-(4-cyanophenyl)ethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 95% of theory, C26H25N5O3S (487.58); Rf value: 0.20 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid); EKA mass spectrum: (M+H)+=488.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:27]([C:30](OC(C)(C)C)=O)[NH:28]C)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:27]([CH3:30])[NH2:28])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(N)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-benzyl 3-(4-(benzyloxy)phenyl)-2-(N-(tert-butoxycarbonyl)-N′-methylhydrazinyl)propanoate (Compound XXVII-1) 491 mg (1.00 mmol) in dichloromethane 1 ml, trifluoroacetic acid 743 μl (10.0 mmol) was added and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate solution 50 ml. The organic phase was washed with water 50 ml and brine 50 ml. The organic phase was dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:92][CH2:91][CH2:90][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:89][CH2:88][CH2:87][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH:69][C@H:70]([C:83]([O:85][CH3:86])=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][NH:75]C(OC(C)(C)C)=O)=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].C(OC(C)C)(C)C.[F:107][C:108]([F:113])([F:112])[C:109]([OH:111])=[O:110]>>[NH:1]1[CH2:92][CH2:91][CH2:90][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:89][CH2:88][CH2:87][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH:69][C@H:70]([C:83]([O:85][CH3:86])=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][NH2:75])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].[C:109]([OH:111])([C:108]([F:113])([F:112])[F:107])=[O:110]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)OC
Reaction time: 0.5 h

Procedure:
Stage 2.7 330 mg of Boc-Pro-His-Pro-Phe-His-Sta-Ile-His-Lys(Boc)-OMe are dissolved in 1.7 ml of 95% strength trifluoroacetic acid and left to stand for 30 minutes at 25°. Then, 14 ml of diisopropyl ether are added, the whole is stirred for 30 minutes at 0°, filtered and dried in a high vacuum over KOH, yielding H-Pro-His-Pro-Phe-His-Sta-Ile-His-Lys-OMe×5 TFA; Rf (D)=0.17; Rf (K)=0.20.
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[C:3]([Cl:7])=[C:4](Cl)[Cl:5].[CH3:10][NH:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:10][N:11]1[C:2]([Cl:1])=[C:3]([Cl:7])[C:4]([Cl:5])=[N:12]1
Reactant: ClC(Cl)=C(Cl)C(Cl)(Cl)Cl
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1nc(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 250 g (1 mole) of hexachloropropene in 250 ml toluene, there was added 94.4 g (2.05 moles) of methyl hydrazine dropwise.The temperature of the reaction mixture was maintained in the range of about 50° to about 60° C. by the use of external cooling. When the addition of methyl hydrazine was complete, the reaction mixture was cooled to room temperature and 276 g (2 moles) of potassium carbonate was added. The resulting mixture was carefully heated first to about 60° C., then gradually to about 85° to 90° C. Heatingwas carefully monitored to control occasional exotherm and degassing. Afterabout three hours, the heat source was removed and the reaction mixture wasallowed to cool to room temperature. The reaction mixture was diluted with about 500 ml ice water and extracted with methylene chloride. The organic layer (containing the product) was washed twice with water, dried over magnesium sulfate and concentrated on a rotovac to give a red oil (about 275 ml). The red oil was dissolved in hexane and filtered through a short silica column twice to give 133 g of a yellow oil which solidified. Spectra of the solid were identical to those of the product of Example 1.