Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@@:7]2(O)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.[CH2:33]([SH:36])[CH:34]=[CH2:35]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:33]([S:36][C@:7]1([C:4]2[CH:5]=[CH:6][C:1]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:2][CH:3]=2)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]1)[CH:34]=[CH2:35]
Reactant: COC(=O)[C@@H]1C[C@@](O)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Reactant: C=CCS
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reaction time: 20 h
Yield: 22.1 %

Procedure:
To a clear solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (3236 mg, 7.5 mmol) and prop-2-ene-1-thiol (834 mg, 9.00 mmol) in Acetonitrile (40 mL) was added Scandium(III) trifluoromethanesulfonate (369 mg, 0.750 mmol) as solid by one portion at room temperature. The formed pink solution was stirred at this temperature for 20 h. Quenched with sat. ammonium chloride, extracted with EtOAc. Washed the organic layer with brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by Biotage column, eluted with 5%˜50% EtOAc-Hexane to afford a mixture of diastereomers (2.88 g, 79%) and recovered starting material (0.600 g, 18%). This mixture was purified by Biotage column again, eluted with 2%˜8% EtOAc-Toluene to afford the desired product (2S,4R)-1-benzyl 2-methyl 4-(allylthio)-4-(biphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (900 mg, 1.661 mmol, 22.15% yield) as an viscous oil and the undesired diastereomer plus some overlapped fraction (1.80 g) as an viscous oil. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.59-2.75 (m, 1 H), 2.77-2.93 (m, 3 H), 3.60 (s, 1.5 H), 3.77 (s, 1.5 H), 3.92 (d, J=11.60 Hz, 1 H), 4.20-4.30 (m, 1 H), 4.37-4.47 (m, 1 H), 4.92-5.34 (m, 4 H), 5.55-5.72 (m, 1 H), 7.20-7.65 (m, 14 H). LC-MS (retention time: 3.34 min, method B), MS m/z 488 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7]2.[C:22]1([S:28]([N:31]=C=O)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClCCl>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])[CH:5]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7]2
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(c1ccccc1)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-2-benzoyl-1,4-dihydroquinolin-4-one (0.57 g, 1.8 mmol) and benzenesulfonyl isocyanate (0.26 mL, 2.0 mmol) in acetonitrile (9 mL) and heat at reflux for 18 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a residue. Chromatograph the residue on a column of silica gel eluting with dichloromethane to obtain a solid. Recrystallize the solid from ethyl acetate/hexane to give the title compound; mp, 186°-187° C. Rf =0.37 TLC/silica gel/dichloromethane. Elem. Anal. Calcd. for C22H14Cl2 N2O3S: C, 57.77; H, 3.09; N, 6.13. Found: C, 57.76; H, 3.22; N, 5.91.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]([NH:17][C:18]3[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:24][C:19]2[C:18]([NH:17][C:15]([O:14][CH2:13][CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[O:16])=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1NC(=O)c1ccc(Br)cc1)OCC1CCN(c2ccncc2)CC1
Reaction time: 20 h
Yield: 42.7 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-yl-methoxycarbonyl)-1,2-benzenediamine (300 mg, 0.920 mmol) and pyridine (0.74 mL) in chloroform (5 mL) was treated with 4-bromobenzoyl chloride (405 mg, 1.84 mmol). After 20 h, the mixture was concentrated and the residue partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate and the combined organics were washed with 1 N aqueous sodium hydroxide, water, saturated sodium chloride solution. The solution was dried (potassium carbonate), filtered, and concentrated in vacuo. Recrystallization (methanol/chloroform and hexanes) yielded 200 mg (43%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[Cl:13][CH2:14][C:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:12])[NH:10]2)=[O:16]
Reactant: O=c1ccc2cccc(O)c2[nH]1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 70 °C
Reaction time: 20 h

Procedure:
27 g of 8-hydroxycarbostyril (VII) and 37 ml of chloroacetyl chloride were dissolved in 250 ml of nitrobenzene, and to the resulting solution was added 85 g of aluminum chloride followed by stirring at 70° C. for 20 hours. 500 ml of 10% aqueous hydrochloric acid was added to the reaction mixture and the nitrobenzene was removed by steam distillation. After cooling the mixture, the precipitated crystals were collected by filtration which were then washed with 300 ml of hot water. Recrystallization from methanol gave 14.0 g of 5-chloroacetyl-8-hydroxycarbostyril (IV) having a melting point of 285°-287° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:26])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])[CH:10]=[CH:11][C:12]=1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=NN(C)C=1C1C=C(NC(=O)C2C=CC(OC)=CC=2F)C=CC=1O.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:91][C:92]([F:106])([F:105])[CH2:93][CH:94]([NH:97]C(=O)OC(C)(C)C)[CH2:95]O.[C:107]([OH:113])([C:109]([F:112])([F:111])[F:110])=[O:108]>C1COCC1>[F:110][C:109]([F:112])([F:111])[C:107]([OH:113])=[O:108].[NH2:97][CH:94]([CH2:93][C:92]([F:106])([F:105])[F:91])[CH2:95][O:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:26])[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc(C(=O)Nc2ccc(O)c(-c3c(Cl)cnn3C)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)NC(CO)CC(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(OCC(N)CC(F)(F)F)c(-c3c(Cl)cnn3C)c2)c(F)c1
Reaction time: 0.08 h
Yield: 24.4 %

Procedure:
N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide (20.0 mg, 53.2 μmol) was dissolved in anhydrous THF (0.3 mL). Triphenylphosphine (15.4 mg, 58.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide/THF solution. The reaction was stirred for 5 minutes and then DIAD (16.6 μl, 85.2 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the reaction. The mixture was stirred at r.t. for 5 more minutes and then tert-butyl 4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (16.2 mg, 66.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added. The reaction was then stirred for 4 hours and checked by LC/MS. While the reaction had not gone to completion, pushing the reaction by heating or extending the reaction time did not seem to improve the yield. Thus, the solvent was evaporated, the resulting oil re-suspended in CH2Cl2 (0.5 mL) and TFA (20.5 μl, 266 μmol) was added (to remove the Boc-protecting group from the amine). The reaction was stirred overnight at room temperature. The next day, the solvent was removed and the resulting oil was re-dissolved in DMSO (1 mL). The product was purified by Prep LC/MS (0-50% B, 30 min) to yield N-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide trifluoroacetate (8.1 mg, 13.0 μmol, 24.5%) as a colorless oil. LCMS m/z 501.3 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 2.48-2.86 (m, 2 H), 3.75 (d, J=2.78 Hz, 3 H), 3.87-3.97 (m, 1 H), 3.89 (s, 3 H), 4.10-4.43 (m, 2 H), 6.85 (dd, J=12.88, 2.27 Hz, t H), 6.91 (dd, J=8.72, 2.40 Hz, 1 H), 7.30 (dd, J=9.09, 2.27 Hz, 1 H), 7.61 (d, J=2.53 Hz, 1 H), 7.65-7.69 (m, 1 H), 7.76 (t, J=8.59 Hz, 1 H), 7.90 (dd, J=8.97, 2.65 Hz, 1 H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]1[O:24][C:23]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[O:14]1.Cl.[CH3:26][NH:27][O:28][CH3:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C(N(CC)CC)C>[CH3:29][O:28][N:27]([CH3:26])[C:18]([C:17]1[CH:21]=[CH:22][C:23]2[O:24][CH2:13][O:14][C:15]=2[CH:16]=1)=[O:20]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CNOC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
1,1'-Carbonyl-diimidazole (48.8 g) was added portionwise within 30 minutes under argon and while stirring to a suspension of 50.0 g of 3,4-methylenedioxy-benzoic acid in 500 ml of methylene chloride. The resulting clear solution was stirred at room temperature for 2 hours and added dropwise within 30 minutes to 42 ml of triethylamine. Thereafter, 29.4 g of N,O-dimethylhydroxylamine hydrochloride were added and the mixture was stirred at room temperature overnight. After the addition of 800 ml of 30% citric acid solution the mixture was extracted twice with 300 ml of methylene chloride each time. The organic phases were washed in succession with 300 ml of 30% citric acid solution, 500 ml of saturated sodium hydrogen carbonate solution and 300 ml of saturated sodium hydrogen carbonate solution. The organic phases were combined, dried with MgSO4 and freed from solvent. 60.9 g (97%) of N-methoxy-N-methyl-1,3-benzodioxol-5-carboxamide were isolated as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(OCC)(=O)C>Cl.O>[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: Nc1ccc(I)cc1F
Reactant: Cn1cc(C(=O)O)c(Cl)cc1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Yield: 41.4 %

Procedure:
4-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (133 mg, 0.709 mmol) and 2-fluoro-4-iodoaniline (172 mg, 0.726 mmol) were combined in a round bottom flask equipped with magenetic stir bar. The flask was immersed in an ice bath and lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 5.0 mL, 5.0 mmol) was added slowly (5 min) with vigorous stirring under an atmosphere of nitrogen. The reaction mixture was further stirred for 1 h at 0° C. and 1 h at ambient temperature. The reaction mixture was diluted with 1 M hydrochloric acid and water and was extracted with ethyl acetate (3×). The extracts were dried over magnesium sulfate and concentrated in vacuo. Upon concentrateion, 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (114 mg, 41% yield) was isolated directly from the ethyl acetate by filtration and drying in vacuo: 1H NMR (DMSO-d6, 400 MHz) δ 13.30 (v br s, 1H), 9.66 (s, 1H), 8.52 (s, 1H), 7.76 (dd, J=10.1, 1.9 Hz, 1H), 7.59 (br d, J=8.5 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.49 (s, 1H), 3.41 (s, 3H); MS (APCI+) 388.9.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([C:21]([OH:23])=[O:22])[CH:12]([C:18]([OH:20])=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH2:14].OS(O)(=O)=O>O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH:12]([C:18]([OH:20])=[O:19])[CH2:11][C:21]([OH:23])=[O:22]
Reactant: C=C(C(=O)O)C(CC(=O)O)C(=O)O
Reactant: Sc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC(C(=O)O)C(CSc1nc2ccccc2s1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.45 g of 2-mercaptobenzothiazole and 5 g of but-3-ene-1,2,3-tricarboxylic acid are ground together in a mortar. The powdered mixture is introduced in portions into 60 ml of 70% H2SO4 at 48°-50° in the course of 1 hour, with stirring. After a further 3 hours at 48°-50°, the reaction mixture is cooled to room temperature and diluted with 250 ml of water at 25°-30°, with stirring. The aqueous solution is decanted from a little glutinous sediment and diluted with a further 200 ml of water. After stirring for 1 hour, the precipitate is filtered off and dried. The 4-(benzothiazol-2-ylthio)-butane-1,2,3-tricarboxylic acid obtained has a melting point of 188°-190°, after recrystallisation from methanol/water.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH:20]([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])[CH:13]=3)=[CH:10][C:9]([NH2:29])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:30]=[C:31]1[NH:35][CH2:34][C@@H:33]([C:36](O)=[O:37])[CH2:32]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH:20]([C:21]([F:22])([F:23])[F:24])[C:25]([F:28])([F:26])[F:27])[CH:13]=3)=[CH:10][C:9]([NH:29][C:36]([C@H:33]3[CH2:32][C:31](=[O:30])[NH:35][CH2:34]3)=[O:37])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(-c2cccc(COC(C(F)(F)F)C(F)(F)F)c2)n(-c2ccccc2)n1
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1C[C@H](C(=O)Nc2cc(-c3cccc(COC(C(F)(F)F)C(F)(F)F)c3)n(-c3ccccc3)n2)CN1
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of 1-phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (78 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (29 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (44 mg) at room temperature, and the mixture was stirred overnight. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. The resulting solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (54 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:24]=1)=[O:21]>>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:33]3[CH2:34][CH2:35][CH:30]([C:25]4[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:36])[CH3:18])[CH:28]=[CH:27][C:26]=4[CH3:29])[CH2:31][CH2:32]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cc(NC(=O)C(C)C)ccc4C)CC3)ccc21

Procedure:
Prepared by Procedure AA and Scheme AJ using 9-ethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 468.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][C:3]=1C(OCC)=O)=[CH:13][CH:12]=[CH:11][CH:10]=3>C(O)C.O.Cl>[CH:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[C:7]1[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][N:6]12
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1CCCn2c1cc1ccccc12
Yield: 99.8 %

Procedure:
A solution of 1.03 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate in 20 ml of ethanol, 10 ml of water and 10 ml of concentrated hydrochloric acid was heated at 80° C. for 3 hours. The solvents were evaporated to give 740 mg of 7,8-dihydropyrido[1,2-a]indol-9(6H)-one of melting point 138°-140° C.
Reaction SMILES: [ClH:1].[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl.C([O:16][CH2:17][CH3:18])C.[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2)=[NH:23])[CH3:20]>C(O)C>[ClH:1].[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2)=[NH:23])[CH3:20].[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:21][C:22]4[CH:18]=[C:17]([OH:16])[CH:31]=[CH:32][C:24]=4[N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: CCOCC
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: CCOC(=N)c1ccc2[nH]ncc2c1
Agent: Cl
Solvent: CCO
Product: Oc1ccc2nc(-c3ccc4[nH]ncc4c3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1H-Indazole-5-carbonitrile hydrochloride (1.5 g) was suspended in ethanol (15 mL) at 0° C. The mixture was saturated with hydrogen chloride while the temperature was raised to room temperature. The reaction was then left overnight. Diethylether was added and the resulting precipitate, 1H-indazole-5-carboximidic acid ethyl ester.2HCl (1.39 g), was collected and dried in under high vacuum. According to synthetic method B except that pyridine (540 ?L) was added, from 4-amino-benzene-1,3-diol hydrochloride (0.36 mg) and 1H-indazole-5-carboximidic acid ethyl ester hydrochloride (0.71 g) was obtained the title compound (0.34 mg) as an off-white solid. The work-up of the reaction was modified as follows: After completion of the reaction, the mixture was diluted with ether and water, and filtered. The solids were washed with water and ether, and dried under high vacuum. MS: 252.4 (MH+); HPLC tR: 1.80 min.
Reaction SMILES: Br[C:2]([C:5](=[O:11])[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:4])[CH3:3].[N-:12]=[N+:13]=[N-:14].[Na+].O>CS(C)=O>[N:12]([C:2]([C:5](=[O:11])[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:4])[CH3:3])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(Br)C(=O)c1ccsc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(N=[N+]=[N-])C(=O)c1ccsc1

Procedure:
0.87 of 2-bromo-2-(3-thenoyl)propane was dissolved in 5 ml of dimethyl sulfoxide, then 0.44 g of sodium azide was added thereto and reacted at 70° C. for 1 hour. After completion of the reaction, the reaction mixture was allowed to cool and put into 200 ml of water, and then extracted with ethyl ether. The organic layer was washed with water, then dried over magnesium sulfate, followed by concentration to obtain 0.70 g of 2-azido-2-(3-thenoyl)propane. The NMR spectrum data of this product were as follows.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5]1.C(N(CC)CC)C.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH2:38]([O:37][C:35]([CH2:34][NH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: NCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 3-[2-(2-aminoethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (1.5 g), triethylamine (1.5 ml), and N,N-dimethylformamide (15 ml) was added ethyl 2-bromoacetate (0.60 ml), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, and the residue was partitioned between chloroform and water. The organic layer was separated, washed with sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated. Purification of the residue by column chromatography on silica gel (gradient elution, using 50:1 and 25:1 mixture of chloroform and methanol) gave 3-[2-{2-(ethoxycarbonylmethylamino)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.90 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.[B-](F)(F)(F)[O+](C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([O:14][CH3:15])[CH:3]=1)[S:8][CH2:9][CH2:10][C:11]2=[O:13]
Reactant: COc1cc(Cl)ccc1SCCC(=O)O
Agent: C[O+](C)[B-](F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)cc2c1SCCC2=O

Procedure:
To a solution/suspension of 3-(4-chloro-2-methoxyphenylthio)propanoic acid (1.46 g, 5.92 mmol; see step (ii) above) in dichloromethane (50 mL) under N2(g) was added boron trifluoride dimethyl etherate (1.4 mL, 15 mmol) and trifluoroacetic anhydride (2.1 mL, 15 mmol). After 2.5 h at rt the reaction was quenched with water (2 mL), then washed with more water. The deep green colour disappeared when it was further washed with sat. aq. sodium hydrogencarbonate. Drying (MgSO4) and removal of the solvent in vacuo afforded the sub-title compound as a yellow solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:48][CH2:47][CH2:46][CH2:45][CH2:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCCCCc1ccccc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCCCc4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 61 %

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-phenylbutylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound (61% yield) as a yellow powder, m.p. 154-159° C. MS [(+)ESI, m/z]: 584 [M+H]+