Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])([O-:3])=[O:2].[CH2:13]=[O:14]>CN(C)C=O>[OH:14][CH2:13][NH:11][C:9](=[O:10])[C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6][CH:7]=1
Reactant: C=O
Reactant: NC(=O)c1cncc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=C(NCO)c1cncc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A solution of 1.0 g of 5-nitronicotinamide and 2ml of 37% formalin in 3 ml of dimethylformamide was stirred at 100° C. for 2 hours. After cooling, ice-water was added and the mixture was extracted with ethyl acetate. The extract was chromatographed over silica gel and recrystallized from ethanol to give 0.6 g of the desired product. mp 145° - 146° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl.C(N(CC)CC)C>[C:24]([NH:2][CH:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:26])[CH3:25]
Reactant: CCCCCCCCc1ccc(CCC(N)C(=O)OC)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)C(=O)OC)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 2-amino-4-(4-octylphenyl)butyrate hydrochloride (16 g) in methylene chloride (300 ml), triethylamine (16 ml) and acetyl chloride (3.8 ml) were added and the mixture was stirred at room temperature for an hour. Then, methylene chloride (500 ml) was further added to the mixture, the whole mixture was washed with a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine in order and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel chromatography (eluent; hexane-ethyl acetate=1:2) to give the subject compound (11 g). MS: 348(M++1).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][O:9][N:10]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([F:21])[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24].C(N)CCC.[ClH:30].Cl.NO>C(O)C>[ClH:30].[F:1][C:2]1[C:7]([CH2:8][O:9][NH2:10])=[C:6]([F:21])[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24]
Reactant: O=C1c2ccccc2C(=O)N1OCc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: NO
Solvent: CCCCN
Solvent: CCO
Product: NOCc1c(F)c(F)c(F)c(F)c1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N-(Pentafluorobenzyloxy)phthalimide 15.9 g, 46 mmol), n-butylamine (3.7 g, 50 mmol) and absolute ethanol (90 ml) were placed in a dry flask under a nitrogen atmosphere. This reaction mixture was stirred at 60° C. for 1 hour, cooled and adjusted to pH 3 using dry hydrogen chloride gas. The resulting white precipitate was filtered and the crystals washed with ice-cold ethanol/ether (1:1). The filtrate was concentrated to give a second crop of crystals. The combined yield of the hydroxylamine hydrochloride was 11.15 g, 99%, m.p. (sublimed) 150°. Analysis: (Found: C, 33.7; H. 2.2; Cl, 13.9; F, 37.8; N, 5.7, C7H5ClF5NO requires C, 33.7; H, 2.0; Cl, 14.2; F, 38.1; N, 5.6%).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]1([C@@H:30]([NH2:33])[CH2:31][CH3:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:34]([O:38][C:39]([NH:41][C@@H:42]([CH2:48][CH2:49][CH2:50][CH3:51])[C@H:43]([OH:47])[C:44](O)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]>ClCCl>[C:34]([O:38][C:39]([NH:41][C@@H:42]([CH2:48][CH2:49][CH2:50][CH3:51])[C@H:43]([OH:47])[C:44]([NH:33][C@H:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:31][CH3:32])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC[C@H](N)c1ccccc1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)N[C@@H](CC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
229 mg of 1-hydroxybenzotriazole monohydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 148 mg of (S)-(−)-1-phenylpropylamine were added in sequence to a solution of 260 mg of 3(S)-(tert-butoxyformamido)-2(S)-hydroxyheptanoic acid in 10 ml of dichloromethane. The mixture was stirred at room temperature for 3 hours, then diluted with dichloromethane and washed in sequence with 5% citric acid solution, saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated to give 285 mg of 3(S)-(tert-butoxyformamido)-2(S)-hydroxy-N-(1(S)-phenylpropyl)heptanamide, MS: m/e 379.1 [M+H]+.
Reaction SMILES: C1COCC1.Br[C:7]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24](B(O)O)=[C:25]2[CH2:30][CH2:29][CH2:28][N:26]2[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C.C1COCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([C:7]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:25]2[CH2:30][CH2:29][CH2:28][N:26]2[N:27]=1
Reactant: Brc1ccnc2ncccc12
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(-c2nn3c(c2-c2ccnc4ncccc24)CCC3)nc1
Yield: 35.2 %

Procedure:
Add THF (1 mL) to 4-bromo-[1,8]naphthyridine (Barlin, G. B. and Tan, W-L. Australian J. Chem. 1984, 37, 1065-1073; 66 mg, 0.31 mmol) and purge the solution with nitrogen for 10 min. Add tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol) and bis(1,2-bis(diphenylphosphino)ethane) palladium(0) (24 mg, 0.026 mmol), purge the reaction mixture with nitrogen for 2 min, and stir the reaction at room temperature for 20 min. Add 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5, 60 mg, 0.26 mmol) in 1:1 DMF/THF (1 mL) and stir for 10 min. Add 2.0 M aqueous potassium carbonate (0.32 mL, 0.63 mmol) and heat the reaction to 40° C. Add additional tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol) after 1 h and 3.5 h. Stir the reaction at 40 DC for 24 h and concentrate in vacuo. Load the crude reaction mixture onto SCX resin with methanol, wash the resin with methanol (100 mL), and elute with methanolic ammonia solution (2M, 100 mL). Concentrate the ammonia fraction in vacuo, purify by flash column chromatography and triturate with hexanes to provide the title compound (28.7 mg, 35%) as a tan solid. MS ESI+ m/e 314 (M+1). 1H NMR (CDCl3) δ 9.11 (m, 1H), 9.07 (m, 1H), 8.25 (m, 1H), 8.10 (m, 1H), 7.35-7.50 (m, 3H), 7.04 (m, 2H), 4.38 (m, 2H), 2.88 (m, 2H), 2.70 (m, 2H). HPLC: 94.8%, Rt=6.75 min. TLC (SiO2): Rf0.3 (1:1 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:10]([O-])([OH:12])=[O:11].Cl>C(OC(=O)C)(=O)C>[CH3:9][C:7]1[CH:8]=[C:2]([CH3:1])[C:3]([NH2:4])=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=1
Reactant: Cc1ccc(N)c(C)c1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
2,4-Dimethylaniline (8.0 g, 66.0 mmol) was dissolved in acetic anhydride (50 mL), and nitric acid (5 mL) was slowly added in drops thereto at 0° C. After stirring for 30 min, the mixture was diluted with ice water (200 mL). Conc. hydrochloric acid (10 mL) was added in drops thereto, and the resulting mixture was stirred under reflux for 4 h. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The residue was diluted with aqueous ammonium hydroxide solution. The resulting orange solid was filtered and dried to give the title compound (10.6 g, Yield 97%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)=[C:18]([CH:33]=[CH2:34])[CH:17]=1)=[N:5][CH:6]=[N:7]2>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][N:24]=3)=[C:18]([CH2:33][CH3:34])[CH:17]=1)=[N:5][CH:6]=[N:7]2
Reactant: C=Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Reaction time: 8 h
Yield: 30.7 %

Procedure:
(5,8-Difluoroquinazolin-4-yl)-{2-[4-(4-trifluoromethyl-pyridin-2-yloxy)-3-vinylphenyl]-ethyl}-amine (250 mg), 10% Pd—C (100 mg) and ethyl acetate (10 mL) were added to a 230 mL Corning shaker bottle filled with nitrogen gas. The bottle was evacuated, then charged with hydrogen (55 psi starting pressure) and shaken overnight. The reaction mixture was filtered through Celite, and concentrated in vacuo. The residue was purified by reverse phase chromatography (C-18 solid phase with acetonitrile/water eluent, 0.5% H3PO4) to provide (5,8-difluoroquinazolin-4-yl)-{2-[3-ethyl-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as a white powder (77 mg), M.P. 121-122°. 1H NMR (CDCl3): δ 8.69 (s, 1H), 8.31 (d, 1H), 7.36 (m, 1H), 7.22 (m, 1H), 7.17 (m, 2H), 7.13 (s, 1H), 7.00 (m, 2H), 6.76 (bm, 1H), 3.95 (m, 2H), 3.04 (t, 2H), 2.55 (q, 2H), 1.16 (t, 3H). MS: m/z 474.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](O)=[O:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:54]([O:56][C:57](=[O:65])[C:58]1[CH:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=1)[CH3:55]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:19])[NH:64][C:61]3[CH:62]=[CH:63][C:58]([C:57]([O:56][CH2:54][CH3:55])=[O:65])=[CH:59][CH:60]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-tert-butyl ester (1.0 g, 3.61 mmol) in dimethylformamide (20 ml) was treated with diisopropyl ethyl amine (0.51 g, 3.97 mmol, 1.1 equiv.), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (1.27 g, 3.97 mmol, 1.1 equiv.) and 4-amino-benzoic acid ethyl ester (0.65 g, 3.97 mmol, 1.1 equiv.). The mixture was stirred at room temperature overnight, then the solvent was evaporated and the residue purified by flash chromatography (heptane/ethyl acetate gradient) to afford 7-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a white solid, 1.1 g (70%). MS (ISP): m/e=423.1 (M−H).
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:35]=[CH:34][C:17]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:19])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:12]([C:14]1[CH:35]=[CH:34][C:17]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:19])=[CH:16][CH:15]=1)(=[NH:11])[NH2:13]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(C(=O)N2CCC[C@H]2CC(=O)NCCC(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(C(=O)N2CCC[C@H]2CC(=O)NCCC(=O)O)cc1
Yield: 55.5 %

Procedure:
115 mg of N-[[(S)-1-[p-[N-[(benzyloxy)carbonyl]-amidino]benzoyl]-2-pyrrolidinyl]acetyl]-β-alanine and 50 mg of Pd/C were stirred under hydrogen for 4 hours in 2.5 ml of acetic acid. The catalyst was filtered off and the solution was evaporated. The residue was dissolved in water, evaporated again and chromatographed on silica gel using methanol. 46 mg of N-[[(S)-1-(p-amidino-benzoyl)-2-pyrrolidinyl]acetyl]-β-alanine, m.p.>250° C., are obtained.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)(=[O:3])[CH3:2]
Reactant: Nc1cccc2cccnc12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a stirred solution of 100 mg (0.348 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (pal Piaz, V et al., J. Med. Chem. 1997, 40, 1417) in 5 ml of ethanol, 75 mg (0.522 mmol) of 8-aminoquinoline was added. The resulting mixture was stirred at room temperature for two hours and the final product was collected by filtration and washed with diethylether to yield the title compound (100 mg, 74.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([F:10])=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:6]([F:10])=[CH:7][C:8]=1[Cl:9]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1cc(Cl)c(Cl)cc1F
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
3,4-Dichloro-6-fluoroaniline (1 equivalent) was reacted with 4-chloro-6-nitroquinazoline (3.5 equivalents), in iso-propylalcohol. After filtration, 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline (compound 1) was obtained in 78% yield.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9](=[O:15])[C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C.CCOCC>[CH:1]1([CH2:7][C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@@H:9]([OH:15])[C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)c1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)c1nccs1
Reaction time: 1 h

Procedure:
The product from part (c) (2.73 g., 8.07 mmole) is dissolved in absolute ethanol (50 ml.) and cooled to 5°. Sodium borohydride (0.6 g., 16.14 mmole) is added portionwise and the reaction mixture is stirred for one hour, diluted with ether (200 ml.), and quenched with 1N HCl to pH 1. The organic layer is separated, washed twice with water and brine, dried (MgSO4), and concentrated in vacuo. The two isomers are separated by flash chromatography on silica gel (Merck, 300 g.) eluting with ethyl acetate:hexane (3:8). The slower moving isomer is identified as the S,S configuration and the faster moving isomer is identified as (1S,2R)-[1-(cyclohexylmethyl)-2-hydroxy-2-(2-thiazolyl)ethyl]carbamic acid, 1,1-dimethylethyl ester; [α]D =-30.72° (c=0.55, methanol). TLC (silica gel; ethyl acetate:hexane; 1:1) Rf =0.70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([NH2:34])[C:28]=2[CH:27]=[CH:26][N:25]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:34][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:28]=3[CH:27]=[CH:26][N:25]=[CH:24]4)=[S:16])[N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: Nc1cccc2cnccc12
Reactant: CN1C(=O)C(N=C=S)N=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: ClCCl
Product: CN1C(=O)C(NC(=S)Nc2cccc3cnccc23)N=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
As illustrated in the scheme above, to a solution of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 7) (0.035 g, 0.1 mmol) in dichloromethane (5 ml) was added 5-isoquinolinamine (0.015 g, 0.1 mmol). The reaction mixture was heated at reflux for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (20 mg, 40%). 1H-NMR (CDCl3): δ 9.33 and 9.19 (2×s, 1H), 8.63 and 8.49 (2×d, J=5.6 Hz and J=6.0 Hz, 1H), 8.34 (br s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.92 (t, J=11.6 Hz, 2H), 7.58-7.32 (m, 10H), 6.03 (d, J=7.6 Hz, 1H) and 3.3 (s, 3H). MS (ESI) (M+H)+=486
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[Na].[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+]=[N-])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[NH:15][C:4]2[CH:3]=[C:2]([Cl:1])[O:6][C:5]=2[CH:7]=1)=[O:18])[CH3:11]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(Cl)o1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc2oc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-furan-2-carbaldehyde (Snyder, H. R., Jr.; Seehausen, P. H., J. Heterocycl. Chem., 10: 385-6 (1973)) was annulated according to Procedure H (8 equiv sodium; aldehyde and azido-acetic acid ethyl ester added as ethanol solution (0.9 M of ester); condensation reaction mixture allowed to warm to room temperature, stirred for 1 h, quenched at −40° C., diluted with water, and extracted with ether; acrylate not purified; crude furanopyrrole filtered before concentration).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[N:29][C:30]#[N:31])[C:8]=2[CH:32]=1)([O-:3])=[O:2].[C:33]([O-])([O-])=O.[K+].[K+].CI.C([O-])(O)=O.[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]([CH3:33])[C:21]3=[N:29][C:30]#[N:31])[C:8]=2[CH:32]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=NC#N)n(C)c3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
400 mg (0.91 mmol) of the compound obtained in example 1 was dissolved in 5 ml of DMF, then 250 mg (1.82 mmol) of K2CO3 and 170 mg (1.18 mmol) of CH3I were added thereto. The reaction was stirred at room temperature for 12 hours, 30 ml of saturated NaHCO3 solution was added, and aqueous layer was extracted with 50 ml of ethyl acetate. Organic layer was washed with brine and dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 390 mg (yield: 95%) of the target compound.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[CH3:17][C:18]1[C:26]([CH3:27])=[C:25]([CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([CH3:28])=[C:26]([CH3:27])[C:18]=2[CH3:17])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1C
Agent: Cl
Product: Cc1ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2O)c(C)c1C

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 2,3,4-trimethylbenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(2,3,4-trimethylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(2,3,4-trimethylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][NH:28][C:29](=[O:33])[CH:30](Cl)[CH3:31])[CH2:10]1)(C(C)(C)C)(C)C.[O-:34][C:35]#[N:36].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([CH2:27][N:28]2[C:29](=[O:33])[CH:30]([CH3:31])[NH:36][C:35]2=[O:34])[CH2:10]1
Reactant: CC(Cl)C(=O)NC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: N#C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1NC(=O)N(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A solution of (2S,4R)-4-(t-butyldimethylsilyloxy)-2-(2-chloropropionyl)aminomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (18.4 g), potassium cyanate (14.9 g) and tetrabutylammonium iodide (13.6 g) in N,N-dimethylformamide (180 ml) was stirred at 100°-110° C. for 3 hours. The reaction mixture was poured into water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was dissolved in a mixture of methanol (150 ml) and conc. hydrochloric acid (6.1 ml). The solution was stirred at ambient temperature for 2 hours and evaporated in vacuo. The resulting residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-hydroxy-2-(4-methyl-2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8.16 g).