Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][NH:11]3)=[C:5]([C:20](OCC)=[O:21])[N:4]([CH2:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[N:3]=1.CC1N(CC2ON=C(C)C=2)N=C(C(OCC)=O)C=1C1C=C(C(F)(F)F)C=C2C=1C=NN2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][NH:11]3)=[C:5]([CH2:20][OH:21])[N:4]([CH2:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[N:3]=1
Reactant: CCOC(=O)c1c(-c2cc(C(F)(F)F)cc3[nH]ncc23)c(C)nn1Cc1cc(C)no1
Agent: CCOC(=O)c1nn(Cc2cc(C)no2)c(C)c1-c1cc(C(F)(F)F)cc2[nH]ncc12
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(Cn2nc(C)c(-c3cc(C(F)(F)F)cc4[nH]ncc34)c2CO)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 40 ml, vial was charged with a mixture of ethyl 3-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazole-5-carboxylate and ethyl 5-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazole-3-carboxylate (0.210 g) in THF (6 mL). The mixture was cooled to 0° C. A 1M solution of lithium aluminum hydride (1.454 mL, 1.454 mmol) in ether was added and the reaction mixture was stirred for 30 minutes at room temperature. The reaction was quenched with 1N HCl (2 mL) at 0° C. The mixture was allowed to warm to room temperature and the product was extracted into EtOAc. The organic phase was washed with brine and dried over Na2SO4. The volatiles were evaporated and the crude residue was purified by LCMS, eluting with 35% ACN in H2O (containing 10 mM NH4HCO3) over a period of 10 minutes. The product-containing fractions were combined and the volatiles evaporated using a GeneVac™ to give the title compounds. The later-eluting peak was assigned to the regioisomer of EXAMPLE 411 (3.3 mg). 1H NMR (400 MHz, CD3OD) δ ppm 2.19 (s, 3H), 2.30 (s, 3H), 4.59 (s, 2H), 5.63 (s, 2H), 6.26 (s, 1H), 7.31 (d, J=1.26 Hz, 1H), 7.92 (s, 1H), 8.04 (d, J=0.76 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C18H16F3N5O2, 392.13. found 392.21. The earlier-eluting peak was assigned to the regioisomer of EXAMPLE 412 (2.8 mg). 1H NMR (400 MHz, CD3OD) δ ppm 2.30 (s, 3H), 2.31 (s, 3H), 4.50 (s, 2H), 5.55 (s, 2H), 6.28 (s, 1H), 7.34-7.43 (m, 1H), 7.90 (s, 1H), 7.96-8.05 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C18H16F3N5O2, 392.13. found 392.21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([O:33][CH3:34])[CH:27]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][C:28]=1[O:33][CH3:34])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(Cl)ccc1O
Reactant: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(COc2ccc(Cl)cc2OC)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate (718 mg, 2.0 mmol) in dry N,N-dimethylformamide (3.0 ml) at room temperature was added 4-chloro-2-methoxyphenol (0.301 ml, 2.2 mmol) followed by sodium hydride (88.0 mg of a 60% oil dispersion, 2.2 mol). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was diluted with ethyl acetate and poured into a separatory funnel. The organic phase was washed with saturated sodium bicarbonate and water (2×), then brine. The organic phase was separated, and the solvent removed under reduced pressure to provide a viscous oil. Upon sitting at room temperature overnight a solid formed, to which a mixture of 10% ethyl acetate/hexanes was added, and the resulting solid filtered off. The solid was washed with 20% ethyl acetate/hexanes and dried under reduced pressure to provide ethyl 6-chloro-2-((4-chloro-2-methoxyphenoxy)methyl)-4-phenylquinoline-3-carboxylate then provided PT-011 (558 mg, 58%) as a light yellow powder. TLC Rf=0.38 in 30% ethyl cetate:hexanes on a glass backed silica gel plate. 1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H, J=8.9 Hz); 7.69 (dd, 1H, J=8.9, 2.3 Hz); 7.58 (d, 1H, J=2.3 Hz); 7.48-7.52 (m, 3H); 7.36-7.30 (m, 2H); 6.95-6.92 (app d, 1H, J=8.6 Hz); 6.75 (s, 1H); 6.78-6.70 (m, 1H); 5.50 (s, 2H); 3.90 (q, 2H, J=7.0 Hz); 3.80 (s, 3H); 0.82 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 482.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].O1CCOCC1.Cl>CO>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(NCC3CCN(C(=O)OC(C)(C)C)CC3)nc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cccc2[nH]c(NCC3CCNCC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid methyl ester (2.28 g, 5.87 mmol) in methanol (3 ml), a 4N hydrogen chloride-1,4-dioxane solution (10 ml, 40 mmol) was added and the mixture was stirred at room temperature overnight. The precipitated crystals were filtered out, washed with ethyl acetate and then dried to obtain 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[N:7][NH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])(=O)[CH3:2]>[OH-].[Na+]>[CH3:2][C:1]1[N:15]=[C:13]([OH:14])[C:6]2[NH:7][N:8]=[C:9]([CH:10]([CH3:12])[CH3:11])[C:5]=2[N:4]=1
Reactant: CC(=O)Nc1c(C(N)=O)n[nH]c1C(C)C
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(O)c2[nH]nc(C(C)C)c2n1
Yield: 98 %

Procedure:
The solution of 4-acetamido-5-isopropylpyrazol-3-carboxamide XX (100 mg, 0.40 mmol) in 1 mL of 1 M sodium hydroxide was stirred at 80-90° C. for 3 hours. The product precipitated after cooling and acidifying with glacial acetic acid. Yield 98%; mp>250° C.; MS (ES+): 193.1 (100%, M+H+). 1H NMR (300 MHz; CD3OD): 1.38 d (6H, J=7.1 Hz); 2.41 s (3H); 3.02 sept (1H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][NH2:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][NH:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=1)(=[O:19])=[O:20])=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NNC(=O)c2ccccc2Cl)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 2-chlorobenzoyl chloride (22.3 g, 127.43 mmol) in toluene (200 mL). To the mixture was added 4-methylbenzenesulfonohydrazide (23.3 g, 125.27 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 75° C. in a bath of oil. A filtration was performed. The filter cake was dried in an oven under reduced pressure. This resulted in 37.7 g (91%) of 2-chloro-N′-tosylbenzohydrazide as a white solid.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=1.[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:29][C@@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH:28]=1)[C:25](O)=[O:26])(=[O:19])=[O:18]>>[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:29][C@@H:30]([CH3:35])[C:31]([F:32])([F:33])[F:34])=[C:24]([C:25]([N:9]2[CH2:8][CH2:7][C:6]3[N:5]=[C:4]([C:3]([F:2])([F:14])[F:15])[CH:13]=[CH:12][C:11]=3[CH2:10]2)=[O:26])[CH:28]=1)(=[O:19])=[O:18]
Reactant: FC(F)(F)c1ccc2c(n1)CCNC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2nc(C(F)(F)F)ccc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine hydrochloride (CA [741736-98-1]; WO2004069162) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[NH:8][C:6]1[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:2]([O:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=2)[N:7]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccc(C=O)cc3)n2)cc1Cl
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A mixture of compound 133 (1.8 g, 4.70 mmol), potassium carbonate (3.2 g, 23.45 mmol) in dimethylformamide (8 mL) was added 4-hydroxybenzaldehyde (0.69 g, 5.63 mmol). It is heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound as white solid (1.58 g, 72%). mp 218-220° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 265 nm, Rt 25.606 min, 98.06% purity; MS (CI): m/z 468 (M+H, 100).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.[CH2:13]1[CH2:18]CC(N=C=NC2CCCCC2)C[CH2:14]1>C(O)CC.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:9]([O:11][CH2:14][CH2:13][CH3:18])(=[O:10])/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[CH:2][CH:1]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CCCOC(=O)/C=C/c1ccc(O)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
Coumaric acid (0.030 mol) is dissolved in 1-propanol (0334 mol) in a 100 ml round bottom flask. DCC (0.033 mol) is added followed by DMAP (0.003 mol). The mixture is stirred at 50° C. for 24 hours, filtered and the propanol removed under reduced vacuum to leave an oily solid which is taken up in ethyl acetate, washed with saturated aqueous NaHCO3 and distilled water, the ethyl acetate layer dried over MgSO4 to leave after removal of the ethyl acetate the desired product as a pale yellow solid in 71% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4].[C:22]([O:26][C:27]([N:29]([CH2:47][CH:48]=O)[CH2:30][C@H:31]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:48][CH2:47][N:29]([CH2:30][C@@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[O:39][Si:40]([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:42])[CH3:41])[C:27]([O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:28])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]
Reactant: COC(=O)c1ccc(-c2cccc(N)c2)cc1C(=O)OC
Reactant: CC(C)(C)OC(=O)N(CC=O)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Product: COC(=O)c1ccc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)cc1C(=O)OC

Procedure:
Electrospray MS (positive ion): (M+H) 697.6; from 3′-amino-[1,1′-biphenyl]-3,4-dicarboxylic acid dimethyl ester (580 mg) and (R)-[(tert-butoxycarbonyl)-[2-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino]-acetaldehyde (1.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[CH3:32][O-:33].[Na+]>CO>[CH3:32][O:33][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1
Reactant: C[O-]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 76.4 %

Procedure:
A solution of 0.55 g (1.2 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) in 10 ml of MeOH was treated with 2.25 ml (12.2 mmol) of a sodium methoxide solution (5.4 molar in MeOH) and the reaction mixture was heated up to reflux. After 18 hours, it was poured into crashed ice and extracted three times with CH2Cl2/2-propanol 4:1; the organic phases were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.41 g (76%) of the title compound as light yellow oil. MS: 448.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11](Br)[CH3:12].[H-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCBr
Reactant: N#CCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(C#N)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A solution of 2-(3-chlorophenyl)acetonitrile (10.00 g, 66 mmol) and ethyl bromide (4.9 mL, 66 mmol) in DMSO (25 mL) was added dropwise to a stirred solution of NaH (60% dispersion in mineral oil (2.6 g, 66 mmol)) in DMSO (75 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at 0° C. and then brought to room temperature and stirred for 23 hours. The reaction mixture was carefully quenched with water, and was then diluted with EtOAc. The organic layer was separated, washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the crude product as an orange oil. The crude oil was purified by silica flash chromatography (0-5% EtOAc/hexane) to give the desired compound as a colorless oil (4.69 g).
Reaction SMILES: C(OC(N1CCN(C(C([NH:21][C:22]([C:24]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])CC2N=CNC=2)=O)CC1)=O)C.C(=O)([O-])[O-].[K+].[K+].[Na+].[I-]>CN(C=O)C>[NH2:21][C:22]([C:24]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1)=[O:23]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)nc2ccccc12
Temperature: 50 °C
Yield: 88.3 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline (69 mg, 0.14 mmol) in DMF (2 mL) was added t-butyl bromo acetate (0.026 mL, 1.2 eq.), potassium carbonate (30 mg, 1.5 eq), NaI (2.0 mg, 0.1 eq.). The reaction mixture was heated at 50° C. for 1 hour. Evaporation followed by flash column chromatography with 2%–3% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(1-(t-butoxycarbonyl)methyl)imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline (25 mg) which was treated with neat trifluoroacetic acid (0.5 mL) for 1.5 hours at ambient temperature. Repeated evaporation of the solvents and treatment with methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(1-(carboxymethyl)imidazol-4-yl)ethyl]-aminocarbonyl-4-methoxyquinoline (27 mg) as a trifluoroacetic acide salt: NMR (DMSO) 1.20 (t, 3), 3.2–3.6 (m, 11), 4.05 (q, 2), 4.1 (s, 3), 5.0 (s, 2), 5.3 (m, 1), 7.45 (s, 1), 7.5 (s, 1), 7.65 (t, 1), 7.8 (t, 1), 8.05 (d, 1), 8.16 (d, 1), 8.95 (s, 1) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][C:9]1[C:10](=[O:17])[NH:11][NH:12][C:13]=1[CH:14]([CH3:16])[CH3:15].[H-].[Na+].[CH3:29][C:30]([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41][C:42]([CH3:44])=[O:43])[C@@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@@H:35]1[O:49][C:50]([CH3:52])=[O:51])=[O:31].O>CN(C)C=O>[CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][C:9]1[C:10]([O:17][C@@H:38]2[O:39][C@H:34]([CH2:33][O:32][C:30](=[O:31])[CH3:29])[C@@H:35]([O:49][C:50](=[O:51])[CH3:52])[C@H:36]([O:45][C:46](=[O:47])[CH3:48])[C@H:37]2[O:41][C:42](=[O:43])[CH3:44])=[N:11][NH:12][C:13]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1ccc(C)c(COc2ccccc2Cc2c(C(C)C)[nH][nH]c2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccccc2OCc2cc(C)ccc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-1,2-dihydropyrazol-3-one (152 mg) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 18 mg), and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added a solution of acetobromo-α-D-glucose (214 mg) in N,N-dimethylformamide (1 mL), and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1-ethyl acetate) to give 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 0.400 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 2 mol/L hydrochloric acid and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol=10/1–5/1) to give the title compound (33 mg).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Si]([O:30][CH2:31][CH:32]([OH:58])[CH2:33][N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH:36]([NH:44][C:45]([C:47]2[NH:48][C:49]3[C:54]([CH:55]=2)=[CH:53][C:52]([Cl:56])=[CH:51][CH:50]=3)=[O:46])[C:35]1=[O:57])(C(C)(C)C)(C)C>C(Cl)Cl>[Cl:56][C:52]1[CH:53]=[C:54]2[C:49](=[CH:50][CH:51]=1)[NH:48][C:47]([C:45]([NH:44][CH:36]1[CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:34]([CH2:33][C:32](=[O:58])[CH2:31][OH:30])[C:35]1=[O:57])=[O:46])=[CH:55]2
Reactant: CC(C)(C)[Si](C)(C)OCC(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CO)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 2 h
Yield: 31.2 %

Procedure:
Dess-Martin Periodinane (120 mg, 0.28 mmol) was added to a stirring solution of N-[1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-5-chloro-1H-indole-2-carboxamide (Method 6, 74 mg, 0.14 mmol) in DCM and the reaction was stirred for 2 hours. The reaction was quenched by addition of sat. aqueous NaHCO3 (20 mL) and EtOAc (40 mL) and the organic layer was separated and further washed with acidified (pH 0) sodium metabisulfite (10 mL) and the organic layer was dried (MgSO4), filtered and evaporated. Purification by column chromatography (1:19 MeOH:DCM) afforded the title compound (18 mg, 31%) as a white solid.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:6]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][NH:1][CH2:2][CH2:3][C:4]=2[CH:5]=1)([O-:14])=[O:13]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reaction time: 1 h

Procedure:
1,2,4,5-Tetrahydro-3H-benzazepine (1 g) (See P. Ruggli et al., Helv. Chim. Acta, 18, 1388, [1935]) was added slowly dropwise to stirred fuming nitric acid (25 ml) at −10° C. Stirring was continued at −10° C. for 1 hour and the reaction mixture was then poured onto ice, the precipitate collected by filtration and dried to give the title compound as the nitrate salt, 1.4 g. This was suspended in water, cooled to 5° C. and neutralised with 5M sodium hydroxide. The precipitate was collected by filtration, recrystallised from water and dried, affording the title compound D1a as a white solid (0.6 g)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH:18]=1
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C#N)cn1

Procedure:
A suspension of 831 mg (5 mmol) of 3-cyano-4-fluoronitrobenzene, of 0.82 g (10 mmol) 4-methylimidazol and of 1.38 g (10 mmol) potassium carbonate in acetonitrile (10 mL) was stirred for 60 h at 20° C. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, and the solvent was evaporated under reduced pressure. The crude product was crystallized from ethanol/water yielding the title compound (0.65 g, 57%) as an off-white solid. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=8.95 (s, 1H), 8.62 (d, 1H), 8.16 (s, 1H), 7.93 (d, 1H), 7.49 (s, 1H), 2.21 (s, 3H).
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:41]/[O:42][CH3:43])/[C:12]([NH:14][C@@H:15]2[C:25](=[O:26])[N:24]3[C@@H:16]2[S:17][CH2:18][C@H:19]2[C@:23]3([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])[O:22][C:21](=[O:40])[CH2:20]2)=[O:13])[N:10]=1)=O.CNC(=S)[S-].[Na+].C(OCC)(=O)C>CN(C)C=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:41]/[O:42][CH3:43])/[C:12]([NH:14][C@@H:15]2[C:25](=[O:26])[N:24]3[C@@H:16]2[S:17][CH2:18][C@H:19]2[C@:23]3([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=3)=[O:28])[O:22][C:21](=[O:40])[CH2:20]2)=[O:13])[N:10]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@H]1CC(=O)O[C@@]12C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(NC(=O)CCl)n1
Agent: CNC(=S)[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@H]1CC(=O)O[C@@]12C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
In 5 ml of anhydrous N,N-dimethylformamide was dissolved 0.334 g of the compound obtained in Example 16, to which was added 0.132 g of sodium N-methyldithiocarbamate, folowed by stirring at room temperature for 1.5 hour. To the reaction mixture was added 30 ml of ethyl acetate, which was washed with water and then dried (MgSO4). The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography, followed by elution with ethyl acetate-chloroform-methanol (15:15:1). Fractions containing the end product were combined and concentrated under reduced pressure to give 0.206 g of the subject compound as powders.