Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:22]C(=O)OC(C)(C)C)([CH3:21])[CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[N:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:6]1.FC(F)(F)C([O-])=O>>[CH3:21][C:2]([NH2:22])([CH3:1])[CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[N:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:6]1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)nn1CCC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])C(F)(F)F
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)nn1CCC(C)(C)N

Procedure:
Prepared according to the method described for intermediate product 1d) from tert-butyl {1,1-dimethyl-3-[5-methyl-3-(4-trifluoromethyl-phenyl)-[1,2,4]triazol-1-yl]-propyl}-carbamate. White solid. Yield: 4.72 g (trifluoroacetate); mass spectroscopy [M+H]+=313.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](/[C:21](=[N:23]/[OH:24])/[CH3:22])[CH:16]=2)([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].[H-].[Na+].Cl.Cl[CH2:32][CH2:33][NH2:34]>CN(C=O)C>[NH2:34][CH2:33][CH2:32][O:24]/[N:23]=[C:21](/[C:17]1[CH:16]=[C:15]([C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:25]([O-:27])=[O:26])[CH:4]=2)=[O:10])([CH3:14])[CH3:13])[CH:20]=[CH:19][CH:18]=1)\[CH3:22]
Reactant: NCCCl
Reactant: C/C(=N\O)c1cccc(C(C)(C)NC(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C(=N\OCCN)c1cccc(C(C)(C)NC(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
(E)-1-(4-Chloro-3-nitrophenyl)-3-(2-(3-(1-(hydroxyimino)ethyl)phenyl)propan-2-yl)urea (7b, 100 mg, 0.25 mmol) in 3 mL dry DMF was added drop wise at 0° C. to sodium hydride dispersion in mineral oil (15.3 mg, 0.50 mmol). The resulting mixture was stirred at 0° C. for 30 min. 2-Chloroethylamine hydrochloride (29.6 mg, 0.25 mmol) in 2 mL DMF was added and the reaction mixture was stirred at room temperature for 2 h and then the volatiles were removed under reduced pressure. The residue was dissolved in a minimal amount of methanol and purified by column chromatography using methanol/chloroform to obtained 9 (49 mg, 46%) 1H NMR (DMSO-d6, 400 MHz) δ 1.61 (s, 6H), 2.19 (s, 3H), 2.79 (t, J=5.6 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 6.95 (s, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.42-7.47 (m, 3H), 7.56 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 8.20 (d, J=2 Hz, 1H), 9 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 13.3, 30.1, 41.6, 55.4, 76.6, 113.8, 116.2, 122.7, 122.9, 124.5, 126.3, 128.8, 132.2, 136.5, 141.1, 148.1, 148.8, 154.2, 154.9; ESI-HRMS for C20H24Cl N5O4 (M+H)+ calcd. 434.1595. found. 434.1595.
Reaction SMILES: [C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([O:18]C(C)C)=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC(=O)C1CCn2c(C(=O)c3cccs3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1cccs1)c1ccc2n1CCC2C(=O)O

Procedure:
A solution of 336 mg. of isopropyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 10 ml. of methanol is treated with a solution of 690 mg. of potassium carbonate in 5 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 2 hours, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and 50 ml. of water and the resultant mixture extracted with ethyl acetate (2 × 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate affords 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, identical to the product obtained in Example 10 A.
Reaction SMILES: [OH:1][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH2:23][OH:24])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].[H-].[Na+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Br.Cl>CN(C)C=O.C(OCC)(=O)C>[OH:10][C:4]1[CH:5]2[CH2:9][CH:8]([CH2:7][CH2:6]2)[C:2](=[O:1])[C:3]=1[C:11]([C:13]1[C:14]([CH2:23][O:24][CH2:27][CH:29]2[CH2:30][O:31]2)=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1)=[O:12]
Reactant: O=C(C1=C(O)C2CCC(C2)C1=O)c1ccc(C(F)(F)F)nc1CO
Reactant: BrCC1CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C1=C(O)C2CCC(C2)C1=O)c1ccc(C(F)(F)F)nc1COCC1CO1
Reaction time: 18 h

Procedure:
1.5 g of 4-hydroxy-3-(2-hydroxymethyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one are dissolved in 15 ml of dimethylformamide and, at room temperature, treated with 0.4 g of sodium hydride (80% suspension in oil, 0.013 mol), a little at a time. After 15 minutes at a temperature of 22° C., 3 ml (0.036 mol) of epibromohydrin are added dropwise, and the reaction mixture is stirred at this temperature for another 18 hours. Ethyl acetate is then added, and the mixture is acidified to pH 3 using 10% hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the crude product is purified chromatographically (mobile phase: toluene/ethyl alcohol/dioxane/triethylamine/water 100:40:20:20:5 parts by volume). This gives the title compound (triethylamine salt) in the form of a yellowish resin, which is released similarly to example H4. Trituration with hexane gives 600 mg of pure 4-hydroxy-3-(2-oxiranylmethoxy-methyl-6-trifluoromethylpyridin-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one of melting point 54-56° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][OH:27])[CH3:23]>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([O:27][CH2:26][CH2:25][N:24]([CH2:28][CH3:29])[CH2:22][CH3:23])=[O:15]
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F
Reactant: CCN(CC)CCO
Solvent: CCOCC
Product: CCN(CC)CCOC(=O)C(C)(OCc1ccc2ccccc2c1)C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (3.0 g.) in ether (20 ml.) is added dropwise at ambient temperature to a stirred solution of 2-diethylaminoethanol (3.0 ml.) in ether (100 ml.). The mixture is stored for 18 hours, filtered, and the solid is washed with ether. The filtrate and washings are evaporated to an oil (3.5 g.), which is dissolved in ether and run through a column of silica gel made up in ether. The column is eluted with 200 ml. of ether, and the eluate evaporated to give 2.4 g. of an oil which is similarly passed through a column of alumina (Neutral, Grade I, 30 g.). Elution with ether yields (±)-2-diethylaminoethyl 2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (1.05 g.) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][C:8]([CH3:25])([CH:23]=[CH2:24])[C:7]=2[N:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:10]2[CH2:9][C:8]([CH3:25])([CH:23]=[CH2:24])[C:7]3[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]=3[NH:11]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: C=CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)OC)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
To a solution of 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (300 mg, 0.8 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at room temperature for 16 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL×3), and the combined organics were dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by preparative HPLC to afford 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (180 mg, 62.7%) as a yellow oil. MS (ESI+) [(M+H)+] 347.2.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][NH2:23].[BH4-].[Na+]>CO>[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][NH:23][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)cc1
Reaction time: 8 h
Yield: 31.2 %

Procedure:
Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (0.150 g, 0.617 mmol), 3-methylbutylamine (0.0537 g, 0.617 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.1 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 2.0 M NH3 in methanol, ethyl acetate and hexanes to give the title compound (0.0606 g, 31.2%): MS ES+ 315.1 (M+H)+, base peak 228.0 (M−C5H12N)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=8.5 min., 96.4% purity.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15](=[O:39])[NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([N:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:33])[C:27]=3[C:26]3=[N:34][O:35][C:36]([CH3:37])=[C:25]3[C:24]2=[O:38])[CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.Cl>C(O)(=O)C>[NH2:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([N:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:33])[C:27]=3[C:26]3=[N:34][O:35][C:36]([CH3:37])=[C:25]3[C:24]2=[O:38])[CH2:18]1)=[O:39]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)C1)c1cccc(Cl)c21
Agent: Cl
Solvent: CC(=O)O
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(N)c3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}-carbamic acid tert-butyl ester (1.24 g; 2.2 mmol) was dissolved in excess, neat acetic acid saturated with HCl(g) (20 mL). After stirring 30 min at room temperature, the solution was concentrated to dryness by rotary evaporation. Acetic acid was removed from the resulting solid by consecutive dissolution in, and drying from, acetonitrile (thrice) and then diethyl ether (once). The solid was dissolved in 25% (v/v) isopropyl alcohol in chloroform, washed with saturated NaHCO3(aq), and dried by rotary evaporation to yield the desired product in 97% isolated yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:27]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22]C)=[O:21])[CH:8]=2)[N:3]=1.[OH-].[Na+].[ClH:36]>CO>[ClH:36].[NH2:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:27]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([OH:22])=[O:21])[CH:8]=2)[N:3]=1
Reactant: COC(=O)c1cccc(CCC(C)(C)C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CCc1cccc(C(=O)O)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C

Procedure:
A solution of methyl 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbutyl)benzoate (520 mg, 1.162 mmol) in MeOH (20 mL) and 5N NaOH (0.929 mL, 4.65 mmol) was heated to 80° C. for 7 h. The solution was cooled to RT and acidified with 5N HCl to pH of ˜4. The solution was concentrated under reduced pressure. The residue was dissolved in MeOH and filtered. The filtrate was concentrated under reduced pressure to yield 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbutyl)benzoic acid hydrochloride as a brown solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:22]([OH:34])[C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.[OH-].[K+].C(N)CC(C)C>CCO>[CH3:1][C:2]1[C:3]([CH:22]([OH:34])[C:23]2[NH:24][C:25]3[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Agent: CC(C)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)c2[nH]ccc2c1C(O)c1nc2ccc(C#N)cc2[nH]1
Temperature: 100 °C

Procedure:
A mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile, KOH (84 mg, 1.50 mmol) and isoamylamine (0.35 mL, 3 mmol) in EtOH (1.5 mL) was heated at 100° C. for 1 h under the microwave irradiation. The reaction mixture was concentrated. The residue was diluted with CH2Cl2 and brine. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over NaSO3, filtered and evaporated. The resulting residue was purified by flash column chromatography on NH-modified silica gel (CH2Cl2:MeOH=100:0 to 10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.90 (br.s, 1H) 10.84 (s, 1H) 7.87-7.91 (m, 1H) 7.56-7.61 (m, 1H) 7.45-7.50 (m, 1H) 7.14 (t, J=2.65 Hz, 1H) 6.71 (s, 1H) 6.44-6.45 (m, 1H) 6.35-6.36 (m, 1H) 2.43 (s, 3H) 2.39 (s, 3H). HRMS calcd. for C22H20N5O (M+H)+ 317.1397. found 317.1404.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][NH:10][C:9]=2[CH:13]=1)=[O:4].[OH-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH2:20][CH2:19][CH2:18][CH2:17][Cl:16])[C:9]=2[CH:13]=1)=[O:4]
Reactant: ClCCCCBr
Reactant: COC(=O)c1ccc2nn[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2nnn(CCCCCl)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
6-methoxycarbonyl-benzotriazole (17.7 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3, and eluted with dichlormethane to produce 19.5 g of 6-methoxycarbonyl-1-(4-chlorobutyl)-1H-benzotriazole, with a yield of 73.0%.
Reaction SMILES: C(=O)(OCC(CCCCCC)C=CC=CC=CC)N.NC1C=CC=CC=1.[C:27](=[O:55])([O:29][CH2:30][CH:31]1[C:43]2([OH:45])[O:44][N:38]([CH2:39][CH:40]3[CH:42]2[NH:41]3)[C:37]2[C:32]1=[C:33]([OH:54])[CH:34]=[C:35]([CH:46]=[N:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:36]=2)[NH2:28]>CO.[Pd]>[C:27](=[O:55])([O:29][CH2:30][CH:31]1[C:43]2([OH:45])[O:44][N:38]([CH2:39][CH:40]3[CH:42]2[NH:41]3)[C:37]2[C:32]1=[C:33]([OH:54])[CH:34]=[C:35]([CH2:46][NH:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH:36]=2)[NH2:28]
Reactant: NC(=O)OCC1c2c(O)cc(C=Nc3ccccc3)cc2N2CC3NC3C1(O)O2
Agent: [Pd]
Agent: CC=CC=CC=CC(CCCCCC)COC(N)=O
Solvent: Nc1ccccc1
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(CNc3ccccc3)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 [tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) was dissolved in methanol (5 ml). Aniline (0.50 ml) was added to this solution and the mixture was allowed to stand at room temperature for 3 hours to give a solution containing 6,9-dihydroxy-4-phenyliminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate. 10% Palladium on carbon (100 mg) was added to the solution, and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere (4.5 atm). The mixture was filtered through cellulose powder and the filter cake was washed with methanol (20 ml). The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform, methanol and water (65:25:4, v/v/v) to afford 4-anilinomethyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (25 mg).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]1[N:19]2[C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][C:21]=3[N:30]=[C:18]2[CH2:17][NH:16][C:15](=[O:31])[CH2:14]1.[OH-].[NH4+:33].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:33][C:22]1[C:21]2[N:30]=[C:18]3[CH2:17][NH:16][C:15](=[O:31])[CH2:14][CH:13]([CH3:12])[N:19]3[C:20]=2[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: CC1CC(=O)NCc2nc3cnc4ccccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1CC(=O)NCc2nc3c(N)nc4ccccc4c3n21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
MCPBA (2.73 g of 77% purity, 16 mmol) was added to a solution of 12-methyl-8,9,11,12-tetrahydro-10H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-10-one (1.3 g, 4.9 mmol) in chloroform (20 mL), and the reaction mixture was stirred for 15 minutes at room temperature. Concentrated ammonium hydroxide (30 mL) and p-toluenesulfonyl chloride (1.12 g, 5.86 mmol) were sequentially added, and the resulting mixture was stirred at room temperature for two hours. An analysis by LC/MS indicated the presence of the 5N-oxide, and additional p-toluenesulfonyl chloride (1 equivalent) was added. The mixture was stirred at room temperature overnight. The organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 0% to 15% 2 N methanolic ammonia in chloroform over a period of 42 minutes) followed by recrystallization from acetonitrile to provide 389 mg of 6-amino-12-methyl-8,9,11,12-tetrahydro-10H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-10-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[NH:19]([C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[C:20]([NH2:22])=[NH:21].[OH-].[Na+]>CO.O>[N:27]1[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][C:23]=1[N:19]=[C:20]1[NH:22][C:8]2([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:22][C:20](=[N:19][C:23]3[NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[NH:21][C:10]2([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[NH:21]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Brc1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccc(Br)cc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 4,4'-dibromobenzil (4.42 g, 12 mmol) and 2-guanidinobenzimidazole (1.75 g, 10 mmol) in methanol (100 mL) was treated with a solution of sodium hydroxide (400 mg, 10 mmol) in 10 mL of water. The title compound was isolated as pale yellow crystals (800 mg, 24% yield). mp: 274-278 ° C. (dec); MS (ESI) m/z 683 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[NH:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(Cc2ccc(Cl)cc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc(CC2CCCN2)cc1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
Heat 1.05 g of 5-(4-chlorobenzyl)pyrrolidin-2-one and 0.2 g of lithium aluminum hydride under reflux for 20 hours in 20 ml of tetrahydrofuran. Effect decomposition of the reaction product by admixing it with ice water. Then add 5 ml of 6 N sodium hydroxide solution to the resulting admixture and extract the thus-prepared base with diethyl ether. After drying the ether extract over sodium sulfate, concentrate it to obtain 0.7 g of the title compound as an oil. Convert the oil into the corresponding hydrochloride with methanol/ethereal hydrochloric acid; yield: 580 mg; m.p. of the hydrochloride 189° to 192°.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][C:5]1([O:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16].[CH:23]1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CO>[CH3:23][O:20][C:19](=[O:21])[CH2:18][O:17][C:5]1([CH2:4][CH2:3][CH:2]([CH3:22])[CH3:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16]
Reactant: CC(C)CCC1(OCC(=O)O)C(=O)CC(=O)c2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)COC1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Yield: 90.4 %

Procedure:
A solution of Example 40B (20 mg, 0.066 mmol), 1,3-dicyclohexylcarbodiimide (20 mg, 0.1 mmol) in tetrahydrofuran (2 mL) and methanol (0.5 mL) was stirred at 25° C. for 16 hours. The solution was and concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound (19 mg, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.37-0.47 (m, 1H), 0.68 (dd, J=13.24, 6.62 Hz, 6H), 0.76-0.91 (m, 1H), 1.15-1.34 (m, 1H), 1.81-1.98 (m, 1H), 2.05-2.22 (m, 1H), 3.40 (d, J=15.08 Hz, 1H), 3.57 (s, 3H), 3.76 (d, J=15.07 Hz, 1H), 5.75 (s, 1H), 7.43-7.57 (m, 1H), 7.55-7.70 (m, 2H), 7.89 (d, J=7.72 Hz, 1H), 11.94 (br. s, 1H); MS (ESI) m/z 319.0 (M+H)+.