Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=2[S:21](=[O:31])(=[O:30])[N:20]=1>C(O)C>[CH2:2]([O:9][NH:10][C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=2[S:21](=[O:30])(=[O:31])[N:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S1(=O)N=C(NOCc2ccccc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
To a solution of O-benzylhydroxylamine hydrochloride (500 mg) and triethylamine (200 mg) in ethanol (10 ml) was added 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (500 mg). The mixture was stirred for 3 h and concentrated in vacuo. The crude product was taken up in hot ethyl acetate (50 ml) and cooled to room temperature and the precipitate was collected by filtration to give the title compound (200 mg, 59%); m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 11.2 (br s, 1H, NH), 7.7-7.35 (m, 9H, arom. and NH), 4.49 (s, 2H, CH2). Analysis: C14H12ClN3O3S requires C, 49.78; H, 3.58; N, 12.44; (found C, 49.49; H, 3.80; N, 12.09).
Reaction SMILES: [CH3:1][C@@:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][N:3]2[CH2:4][CH2:5][CH2:6][C@@:2]2([CH3:1])[C:7]([OH:9])=[O:8])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: C[C@@]1(C(=O)O)CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CCN2CCC[C@@]2(C)C(=O)O)cc1
Yield: 73.6 %

Procedure:
A mixture of (S)-2-methylproline (1.47 g) (prepared by the method of D. Seebach et al., JACS, 105, 5390 (1983)), 4-methoxyphenethyl bromide (1.72 g) and sodium carbonate (2.12 g) in ethanol (30 ml) was heated under reflux for 48 hours, adjusted to pH8 with 2M hydrochloric acid, treated with glacial acetic acid to pH7, filtered and evaporated under reduced pressure. The residue was triturated with ethanol, filtered and evaporated under reduced pressure to give the title compound as a brown gum, (1.55 g), which was used directly in Preparation 10 without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.Br[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:13]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:14][CH2:15][CH3:16]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCCBr
Product: CCCCN1C(C)(C)CC(O)CC1(C)C
Temperature: -78 °C
Yield: 46.9 %

Procedure:
Into a 400-milliliter Hastalloy pressure tube are placed 62.8 grams of 2,2,6,6-tetramethyl-4-hydroxypiperidine and 35.6 grams of 1-bromobutane. The tube and contents are cooled to -78°C., evacuated and filled with nitrogen. The tube is sealed, shaken and warmed to 100°C. for 1 hour, 120°C. for 1 hour and 150°C. for 30 hours. The tube is cooled and the solid charge is removed and placed in a Soxlet extraction apparatus. The material is extracted for 8 hours with diethyl ether. The resulting ether solution is treated with activated charcoal, filtered and concentrated under vacuum. The residue is distilled at 120°-125°C. at 1 torr to give 26 grams of 1-(1-butyl)-2,2,6,6-tetramethyl-4-hydroxypiperidine, a white solid melting at 29°-33°C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)(O)=[O:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:16])[C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Product: NS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (30 mg) and 4-carboxybenzenesulfonamide to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminosulfonyl)-benzamide. MS (Q1) 388.0 (M)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:3])[CH3:2].[NH2:32][CH2:33][C:34]([NH2:36])=[O:35].CN1C(=O)CCC1>O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(OS(=O)(=O)C(F)(F)F)cc2OCC3)n(C(C)C)n1
Reactant: NCC(N)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2cnc(NCC(N)=O)cc2OCC3)n(C(C)C)n1
Temperature: 85 °C
Yield: 16.5 %

Procedure:
A mixture of trifluoro-methanesulphonic acid 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl ester (174 mg, 0.38 mmol), 2-amino-acetamide (281 mg, 3.8 mmol) and NMP (2 mL) was heated at 85° C. for 18 hours. The reaction mixture was treated with water and stirred, the precipitate formed collected by filtration. The aqueous filtrate was passed down an Isolute SCX-2 cartridge washing with methanol and eluting with 2M ammonia in methanol. Appropriate fractions were combined and concentrated in vacuo, the resultant residue subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 458 (24 mg, 17%). LCMS: RT=2.18 min, [M+H]+=383. 1H NMR 400 MHz (DMSO-d6) δ: 9.00 (1 H, s), 7.78 (1 H, s), 7.31 (1 H, br, s), 7.00 (1 H, br, s), 6.94 (1 H, br, t), 6.10 (1 H, s), 5.85 (1 H, m), 4.47 (4 H, m), 3.83 (2 H, d, J=5.85 Hz), 2.25 (3 H, s), 1.45 (6 H, d, J=6.61 Hz)
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1COc2cc(F)ccc2N1
Agent: O=S(=O)(O)O
Product: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
To a solution of 7-fluoro-4H-benzo[1,4]oxazin-3-one (3.00 g, 17.95 mmol) in concentrated H2SO4 (12 mL) at −10° C. was added a mixture of fuming nitric acid (1.131 g, 17.95 mmol, 0.75 mL) and concentrated H2SO4 (0.75 mL) dropwise, keeping the internal temperature below 0° C. After addition, the reaction mixture was stirred at −10° C. for 10 min. The reaction mixture was poured onto crushed ice (200 g) with care. The precipitate was collected by filtration, washed with water (50 mL) and dried in vacuo to give 7-fluoro-6-nitro-4H-benzo[1,4]oxazin-3-one as a light yellow solid (3.5 g, 92%). 1H NMR (DMSO-d6, 400 MHz): δ 11.02 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.23 (d, J=12.0 Hz, 1H), 4.77 (s, 2H).
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].Cl.N[N:19]1[CH:23]=[C:22]([CH2:24][CH3:25])[N:21]=[C:20]1[NH2:26]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:19]1[CH:23]=[C:22]([CH2:24][CH3:25])[N:21]=[C:20]1[NH2:26])=[NH:5]
Reactant: CCc1cn(N)c(N)n1
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: Cl
Solvent: CC(C)O
Product: CCc1cn(N=C2CCc3c(C(=N)NO)cccc32)c(N)n1
Temperature: 80 °C
Reaction time: 90 h

Procedure:
3.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) are added, with stirring, to a mixture of 3.28 g (0.016 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 2.6 g (0.016 mol) of 1,2-diamino-4-ethyl-imidazole hydrochloride and 150 ml of isopropanol, and the reaction mixture is stirred at 80° C. for 90 hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and dried. In that manner there is obtained the title compound, m.p. 245°-246° C., 1H-NMR (DMSO/D2O): δ=8.22 (d, 1H); 7.73 (d, 1H); 7.59 (t, 1H); 7.19 (s, 1H); 3.2 (m, 4H); 2.47 (m, 2H); 1.17 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([O:14]C2C=CC=CC=2)=O)[CH:6]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCCC1>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:14])[CH:6]=2)=[C:2]([Cl:1])[CH:24]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ccn1)Oc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A crude product of 4-(2-chloro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (634.8 mg) was dissolved in tetrahydrofuran (6.5 ml), and then morpholine (0.942 ml) was added thereto at room temperature, followed by stirring overnight and evaporating the solvent under a reduced pressure. The resultant residue was dissolved in ethanol (20 ml)-water (5 ml), and then electrolytic iron powder (500 mg) and ammonium chloride (1 g) were added thereto, followed by heating under reflux for 1 hr. The reaction mixture was cooled down to room temperature, and filtered through celite to remove an insoluble portion, which was washed with ethyl acetate-tetrahydrofuran (1:1) and water. The organic layer of the filtrate was separated, washed with water and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (283.3 mg) as pale yellow powder.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1C=CC=CC=1N>>[Cl:23][C:24]1[CH:2]=[CH:3][CH:4]=[CH:5][C:1]=1[NH:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Nc1ccccc1Cl
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccccc2Cl)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2-chlorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.13 (s, 3H), 2.38 (s, 3H), 4.75 (d, J=2.8 Hz, 2H), 6.05 (bs, 1H), 6.94 (t, J=6.4 Hz, 1H), 7.06-7.20 (m, 3H), 7.36 (d, J=6.8 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 8.40 (d, J=5.8 Hz, 1H), 8.60 (d, J=3.4 Hz, 1H); MS (ESI) m/z 340.6 (M+1)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1O.N1C=CC=CC=1.P(Br)(Br)[Br:18]>C(Cl)(Cl)Cl>[Br:18][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: OC1Cc2ccccc2C1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: BrC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 80 gms of 2-indanol in 200 ml of chloroform was added 12 ml of pyridine. The solution was cooled to 0° C. with an ice bath, and 64 ml of phosphorous tribromide slowly added over 30 minutes. The ice bath was removed, and the solution was refluxed for 1 hour, and let stand overnight.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CCCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)C1

Procedure:
Intermediate 51 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 481.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24](N(OC)C)=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH3:30][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[C:24]([C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:7][C:2]=1[NH2:1])(=[O:25])[CH3:30]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Reaction time: 5 h

Procedure:
Under ice-bath cooling, to a suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-N-methoxy-N-methyl-5-phenyl-2-pyrazinecarboxamide (200 mg) in THF (4.0 ml) was added 3.0M solution of methylmagnesium chloride in THF (0.85 ml) dropwise. The mixture was stirred at the same temperature for 5 hours. The mixture was poured into sat. aq ammonium chloride (20 ml) and an organic layer was extracted with EtOAc (50 ml), washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography (CH2Cl2:MeOH=50:1-15:1). The desired fraction was recrystallized from MeOH and dried in vacuo to give 5-(6-acetyl-5-amino-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (111 mg).
Reaction SMILES: Cl[O-].[F:3][C:4]([F:16])([F:15])[CH2:5][N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][C:9](=[O:14])[CH2:10]2.Cl.C(OCC)C.[C-:23]#[N:24].[K+]>O>[C:23]([C:9]1([OH:14])[CH2:8][CH:7]2[N:6]([CH2:5][C:4]([F:3])([F:15])[F:16])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1)#[N:24]
Reactant: O=C1CC2CCC(C1)N2CC(F)(F)F
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOCC
Product: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A 500 ml 3-necked round bottom flask was equipped with an overhead paddle stirrer, thermometer and hypochorite scrubber. 8-(2,2,2-Trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (10.82 g, 50 mmol) was charged to the reaction flask followed by hydrochloric acid (5M, 100 ml) and the mixture was cooled to 0° C. Diethyl ether (70.8 g, 955 mmol) was added and the mixture stirred for 5 minutes. Potassium cyanide (36.9 g, 550 mmol) was added to the stirred reaction mixture portionwise over 0.5 hour. After complete addition the resultant pink mixture was stirred for 3 hour at about 3° C. The pH of the mixture was adjusted to 5.8 using hydrochloric acid (5M), water (50 ml) was added and the pH re-adjusted from 7 to 5.8. The organic layer was separated off and the aqueous phase was extracted with diethyl ether (2×100 ml). The ether extracts were combined, washed with highly dilute (pH 5.6) hydrochloric acid to leave a solution of 3-cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane in diethyl ether (303 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[ClH:11].[O:12]([NH2:14])[CH3:13]>C(O)C>[ClH:11].[CH3:13][O:12][N:14]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH3:9]
Reactant: CON
Reactant: CC(=O)c1ccccc1N
Agent: Cl
Solvent: CCO
Product: CON=C(C)c1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.4 %

Procedure:
To a 250-mL rotted bottom flask were added 2′-aminoacetophenone (3.0 g, 22.2 mmol), methoxylamine hydrochloride (2.0 g, 24.4 mmol, 1.1 eq) and ethanol (30 mL). The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 3 h. The oil bath was removed and the reaction mixture was allowed to cool at room temperature. The reaction mixture was filtered and the filtered solid was washed with ethanol followed by diethyl ether to give 0.64 g of 1-(2-aminophenyl)-1-ethanone O-methyloxime hydrochloride as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]([CH2:37][C:38]([O:40]C)=O)[C:11](=[O:36])[N:12]([CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][C:18]5[CH2:35][C@:25]6([C:33]7[C:28](=[N:29][CH:30]=[CH:31][CH:32]=7)[NH:27][C:26]6=[O:34])[CH2:24][C:19]=5[CH:20]=4)[N:15]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>CC(O)=O.[Fe]>[O:34]=[C:26]1[NH:27][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:33]2[C@:25]21[CH2:24][C:19]1[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=1[CH2:35]2)[N:15]=[C:14]([CH2:13][N:12]1[C:8]2[C:9]4[N:10]([CH2:37][C:38](=[O:40])[NH:1][C:4]=4[CH:5]=[CH:6][CH:7]=2)[C:11]1=[O:36])[CH:23]=[CH:22]3
Reactant: COC(=O)Cn1c(=O)n(Cc2ccc3cc4c(cc3n2)C[C@]2(C4)C(=O)Nc3ncccc32)c2cccc([N+](=O)[O-])c21
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Cn2c(=O)n(Cc3ccc4cc5c(cc4n3)C[C@]3(C5)C(=O)Nc4ncccc43)c3cccc(c32)N1
Temperature: 80 °C

Procedure:
A mixture of methyl (7-nitro-2-oxo-3-{[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2-yl]methyl}-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step A (55 mg, 0.100 mmol) and iron powder (15 mg, 0.269 mmol) was heated to 80° C. in AcOH (1 mL) for 2 h. Iron powder (15 mg, 0.269 mmol) was added and the mixture was heated to 80° C. for 1 h, then more iron powder (15 mg, 0.269 mmol) was added and the mixture was heated to 100° C. for 1 h. The cooled mixture was filtered then partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=489 (M+1). HS: m/z=489.1662; calculated m/z=489.1670 for C28H21N6O3.
Reaction SMILES: [C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[N:26](CC4C=CC(OC)=CC=4)[N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:41][CH2:42][CH3:43])[C:5]=1[OH:44])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:41][CH2:42][CH3:43])[C:5]=1[OH:44])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2cccc(NC(=O)c3nnnn3Cc3ccc(OC)cc3)c2C#N)ccc(C(C)=O)c1O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(OCC(O)COc2cccc(NC(=O)c3nnn[nH]3)c2C#N)ccc(C(C)=O)c1O

Procedure:
A solution of 7.1 g (11.8 mmol) of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropoxy]-2-cyanophenyl}-1-(4-methoxybenzyl)tetrazole-5-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole is heated at reflux temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, about 200 ml of ether and 300 ml of petroleum ether are added to the residue, and the crystals are filtered off. The N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropoxy]-2-cyanophenyl}-1H-tetrazole-5-carboxamide of melting point 210°-213° thus obtained is dissolved in 50 ml of hot acetone, and one equivalent of triethanolamine in 20 ml of acetone is added. Crystallisation sets in after ether has been addded. This gives the triethanolammonium salt of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropoxy]-2-cyanophenyl}-1H-tetrazole-5-carboxamide of melting point 80°-82°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7].[NH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>>[CH3:29][O:28][C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:25]=1[O:26][CH3:27])[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:21])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7]
Reactant: COC(=O)CCCN
Reactant: COc1cc(C(=O)N(CCCC(=O)O)c2c(C)cccc2C)cc(OC)c1OC
Product: COC(=O)CCCNC(=O)CCCN(C(=O)c1cc(OC)c(OC)c(OC)c1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(3,4,5-trimethoxybenzoyl)-4-(2,6- dimethylanilino)butyric acid and methyl 4-aminobutyrate and suitable processing produces methyl N-[N-(3,4,5-trimethoxybenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-aminobutyrate (M.P. 97° to 99°), saponification of which and processing of the reaction product yields N-[N-(3,4,5-trimethoxybenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-aminobutyric acid (M.P. 100° to 101°).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[NH:10].[CH2:22]([O:29][C:30](=[O:45])[C@H:31]([CH2:40][CH2:41][C:42](O)=[O:43])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C1C=CN=CC=1)C>[C:36]([O:35][C:33]([NH:32][CH:31]([CH2:40][CH2:41][C:42]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[NH:10])=[O:43])[C:30]([O:29][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:45])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCOC(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 119.8 %

Procedure:
2.48 g (7.9 mmol, 1 eq.) of N—(N-(6-hydroxyhexyl)carbamimidoyl)-4-methylbenzenesulfonamide and 2.67 g (7.9 mmol, 1 eq.) of Boc-L-glutamic acid 1-benzyl ester were dissolved under nitrogen in dry dichloromethane. 198.9 mg (1.58 mmol, 0.2 eq.) of DMAP and 1.810 g (8.7 mmol, 1.1 eq.) of DCC were added at room temperature. The reaction was stirred overnight and a white precipitate appeared. The precipitate was removed by filtration and the solvent evaporated to afford 5.99 g of a mixed yellow oil/solid compound. This compound was purified by flash chromatography over silica (eluant pure AcOEt; Rf=0.71) to afford 4.83 g of a slightly yellow oil (yield=97%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH:15]=[CH:16][N:17](C)C)=[C:10]([Cl:21])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.NO>O1CCOCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:20][N:17]=[CH:16][CH:15]=2)=[C:10]([Cl:21])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccno2)c(Cl)c1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butyl ester (270 mg) in dioxane (3 ml) is treated with hydroxylamine hydrochloride (122 mg) and the mixture is stirred at room temperature for 10 days. The mixture is diluted with ethyl acetate, washed successively with water, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (33% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless solid.