Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5](=O)[NH:4][CH:3]=1.C(Br)(=O)C([Br:23])=O>CN(C=O)C.ClCCCl>[Br:23][C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: O=C(Br)C(=O)Br
Reactant: Cc1c[nH]c(=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cnc(Br)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
6-Methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione (0.52 g, 1.92 mmol) and 1,2-dichloroethane (10 ml) were placed in a vial (20 ml). To the resulting suspension was added carefully oxalyl bromide (0.53 ml, 1.24 g, 5.75 mmol). A foam was formed during the addition, and as the foam was settling down the stirring was started. DMF (3 drops) was added and the vial was sealed and the mixture was stirred overnight. Another portion of oxalyl bromide (0.2 ml, 0.46 g, 2.23 mmol) and DMF (3 drops) was added and the reaction was run for another 24 h. The mixture was partitioned between DCM (20 ml) and water (20 ml) and the organic phase was dried. Filtration and evaporation gave a crude product, which was purified on silica, affording 0.59 g (93%) of 3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-one.
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:8](=O)[CH3:9])\[C:6]#N)C.C(O)C.CC(O)C.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:9][C:8]1[C:5]([C:4]#[N:2])=[CH:6][N:31]=[C:29]([NH:28][CH2:27][CH2:26][CH2:25][CH:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[N:30]=1
Reactant: CC(=O)/C(C#N)=C/N(C)C
Reactant: CN1CCC(CCCNC(=N)N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)O
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Temperature: 72.5 °C
Reaction time: 1 h

Procedure:
In a 100 L glass-lined reactor, a solution of (E)-2-[(dimethylamino)methylene]-3-oxobutanenitrile in ethanol/2-propanol (4.48 kg, 32.43 mol in 8.81 kg of ethanol/2-propanol) was added at 20-25° C. to a stirring solution of N-[3-(N-methyl-4-piperidinyl)-1-propyl]guanidine in ethanol/2-propanol (5.41 kg, 27.28 mol in 28.35 kg of ethanol/2-propanol). The resultant mixture was heated for 1.5 h at reflux, followed by an additional charge of (E)-2-[(dimethylamino)methylene]-3-oxobutanenitrile in ethanol/2-propanol (2.02 kg, 14.57 mol in 3.96 kg of ethanol/2-propanol). The resultant mixture was stirred and cooled to 70-75° C. and then potassium carbonate (7.50 kg, 54.26 mol) was added. The resultant mixture was heated to reflux until the reaction was deemed complete by HPLC. When the reaction was deemed complete, about 35-40 L of solvent was removed via atmospheric distillation. The heating was discontinued and purified water (80.00 kg) was added to the resultant suspension, which was then cooled to 20-25° C. and stirred for about 1 h. The resultant suspension was then further cooled to 0-5° C. and aged for 30 min. The solid was filtered, washed with purified water (40.00 kg) and dried at 75-80° C. under vacuum to yield the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].OS([O-])(=O)=O.[K+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COC(=O)CCc1cccc(CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(CCC(=O)O)c2)CC1

Procedure:
A solution of 11-6 (290 mg, 0.80 mmoles), 1N NaOH (3 mL), and CH3OH (4 mL) was stirred at ambient temperature for 1.0 hour. The reaction was then acidified with 10% KHSO4 and extracted with EtOAc. The EtOAc portion was then washed with brine, dried (MgSO4), and concentrated to give 11-7 as a yellow oil. Rf 0.58 (silica, 10.5:0.5 CH2Cl2 /CH3OH/HOAc).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[CH:13](=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>CO>[CH:13](=[N:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]
Reactant: O=Cc1ccccc1O
Reactant: NC1=NN(c2ccccn2)CC1
Solvent: CO
Product: Oc1ccccc1C=NC1=NN(c2ccccn2)CC1

Procedure:
3-Amino-1-(2-pyridyl)-2-pyrazoline (1.6 g) and salicylaldehyde (1.2 g) were dissolved together with methanol (16 ml). The resulting solution was heated to reflux and after about 15 minutes a crystalline solid separated. After another 15 minutes at reflux the suspension was cooled and the separated 3-salicylideneamino-1-(2-pyridyl)-2-pyrazoline was re-crystallized from methanol m.p. 242°-243° (yield 500 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]([CH3:19])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][CH:6]([CH3:19])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CCCCCCCN(CCCC)C(C)CCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCN(CCCC)C(C)CCCc1ccc(N)cc1
Yield: 90.6 %

Procedure:
A solution of 16.2 g (0.045 mol) of N-butyl-N-heptyl-α-methyl-4-nitrobenzenebutanamine in 182 ml of ethanol was hydrogenated at room temperature overnight in the presence of 1.6 g of 5% palladium-on-carbon. Hydrogen uptake observed was 74% of theoretical. The reaction mixture was filtered through Celite and the filtrate was evaporated under reduced pressure. The resulting material indicated the presence of one spot by thin-layer chromatography and afforded 13.56 g of 4-amino-N-butyl-N-heptyl-α-methylbenzenebutanamine as an oil.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]([F:15])([F:14])[C:11]([OH:13])=[O:12].O>C(Cl)Cl>[N:7]([C:1]1([O:13][C:11](=[O:12])[C:10]([F:15])([F:14])[F:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(O)C(F)(F)F
Reactant: ON=C1CCCCC1
Solvent: O
Solvent: ClCCl
Product: O=NC1(OC(=O)C(F)(F)F)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of cyclohexanone oxime (4.88 g, 43.16 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (19.14 g, 43.16 mmol) and trifluoroacetic acid (49.22 g, 431.6 mmol) in methylene chloride (200 ml) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was purified by column chromatography to give 1-Nitroso-1-trifluoroacetoxycyclohexane as a bright blue liquid (30% yield): Rf 0.57 (pentane); 1H NMR (300 MHz, Benzene-d6) δ 1.1-1.9 (m, 10H); 13C NMR (300 MHz, Benzene-d6) δ 19.9 (2CH2), 22.9 (CH2), 27.4 (2CH2), 113.8 (q, J=286.2 Hz), 127.2 (O—C—N), 153.7 (q, J=42.5 Hz); 19F NMR (300 MHz, Benzene-d6) δ −75.7 (CF3).
Reaction SMILES: [OH-].[Na+].C([O:10][C:11](=[O:30])[C@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1.Cl>O1CCOCC1>[C:17]([O:16][C:14]([NH:13][C@H:12]([C:11]([OH:30])=[O:10])[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccnc(C#N)c1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccnc(C#N)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.4 %

Procedure:
1M Aqueous sodium hydroxide solution (10.8 ml, 10.8 mmol) was added dropwise over 5 minutes to a stirred, ice-cooled solution of N-t-butoxycarbonyl-3-(2-cyano-4-pyridyl)-(S)-alanine benzyl ester (Preparation 12; 2.73 g, 7.1 mmol) in 1,4-dioxan and the resulting solution allowed to warm to room temperature. After 1.5 hours, the pH of the solution was adjusted to 9 using 2M hydrochloric acid and the bulk of the organic solvent removed under reduced pressure. The residual aqueous solution was washed with ethyl acetate, acidified with solid citric acid and extracted with ethyl acetate, then the latter extracts dried (MgSO4) and evaporated under reduced pressure to furnish the title compound (1.6 g) as a white solid. Rf 0.67 (SS 13). Found: C,57.86; E,5.99; N,13.52. C14H17N3O4 requires C,57.72; E,5.88; N,14.42%.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:21])[CH:5]=[C:6]1[CH2:11][CH2:10][C:9]([N:18]([CH3:20])[CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>CO.[Pd]>[ClH:1].[CH3:2][O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:7][CH2:8][C:9]([N:18]([CH3:19])[CH3:20])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)C=C1CCC(c2ccccc2)(N(C)C)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Reaction time: 5 h

Procedure:
Palladium-on-charcoal (5%, 90 mg) was added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid methyl ester hydrochloride (1.79 g, 5.77 mmol) in methanol. The reaction mixture was hydrogenated at RT under a pressure of 3 bar for 5 h. The catalyst was separated off over Celite and the filtrate was concentrated. The product was thereby isolated as a colourless, oily compound in a quantitative yield (1.79 g).
Reaction SMILES: [O:1]=[CH:2][CH:3]([CH2:5][SH:6])[OH:4].N(CCO)(CCO)[CH2:8][CH2:9][OH:10].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>>[O:10]=[CH:9][CH2:8][C@@H:2]([C@@H:3]([CH2:5][SH:6])[OH:4])[OH:1]
Reactant: O=CC(O)CS
Reactant: OCCN(CCO)CCO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Product: O=CC[C@H](O)[C@H](O)CS
Temperature: 0 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
The acceptor aldehyde, 3-thioglyceraldehyde (Compound 3), was prepared by the method of Effenberger. [Effenberger Tetrahedron Lett., 33:5157 (1992)]. DERA (400U) was added to a 10 mL solution containing the acceptor aldehyde (100 mM Compound 3) and donor aldehyde (300 mM acetaldehyde), triethanolamine buffer (100 mM, pH 7.3) and EDTA (1 mM). This reaction is shown in Scheme 1. The resulting solution was stirred in the dark for 2 days under a N2 atmosphere. The reaction was quenched by addition of 2 volumes of acetone and cooling to 0° C. for 20 minutes. The precipitated protein was removed by centrifugation. After removal of the solvent under reduced pressure, a 33 percent yield of Compound 4 was obtained (characterized as 2-deoxy-5-thio-1,3,4-tri-O-acetyl-D-erythro-pentose). Compound 4 was purified from the residue by preparative TLC on silica (methanol/chloroform/hexane, 1:90:10).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: OC1CC=CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C1=CCC(OCc2ccccc2)C1

Procedure:
To a solution of cyclopent-3-en-1-ol [cf. J. Org. Chem., 32, 4138 (1967)] (7.00 g) and benzyl bromide (10.5 ml) in dimethylformamide (35 ml) is added gradually 60% sodium hydride (in oil) (3.68 g) with stirring under ice-cooling, and the mixture is stirred at room temperature for 1.5 hour. The reaction mixture is diluted with ethyl acetate and washed with water six times. The ethyl acetate solution thus obtained is dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure, and then purified by medium pressure liquid column chromatography (eluent; n-hexane, n-hexane:ethyl acetate--50:1, v/v) to give 4-benzyloxycyclopent-1-ene (11.22 g) as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][C:17]([CH2:18][NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: COCCN
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 52.9 %

Procedure:
To a solution of 25 (2.864 g, 7.24 mmol) in DCM (30 mL) was added 2-methoxyethylamine (8) (0.756 mL, 8.69 mmol). After 45 min, sodium triacetoxyborohydride (2.149 g, 10.14 mmol) was added and the reaction mixture was stirred at r.t. for 18 h. More sodium triacetoxyborohydride (2.149 g, 10.14 mmol) was added and the mixture was stirred for an additional 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and the phases were separated. Organic phase was collected and the aqueous layer was extracted with DCM (3×100 mL). The combined organic solutions were concentrated and the residue was purified by flash column chromatography (eluent DCM/MeOH) to afford, intermediate 26 (1.742 g, 53% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.62 (d, J=5.6 Hz, 1H), 8.55 (d, J=1.2 Hz, 1H), 8.48 (dd, J=10.2, 2.6 Hz, 1H), 8.37 (s, 1H), 8.26-8.23 (m, 1H). 8.21 (ddd, J=8.8, 2.8, 1.2 Hz, 1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H), 7.71 (dd, J=9.0, 8.2 Hz, 1H), 6.97 (dd, J=5.6, 0.4 Hz, 1H), 3.78 (s, 2H), 3.40 (t, J=5.6 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J=5.6 Hz, 2H). MS (m/z): 455.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[NH:13][CH3:14])[C:6]([O:8]C)=[O:7].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[NH:13][CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CNc1c(OC)cc(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1c(OC)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h
Yield: 86 %

Procedure:
To a solution of methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate (13.69 g, 57.0 mmol) in tetrahydrofuran (THF) (100 mL) and water (50.0 mL) was added a single portion of lithium hydroxide (4.09 g, 171 mmol). The resulting suspension was stirred for 19 hr at room temperature. The reaction was acidified with aq. 2N HCl (˜50 mL), until pH reached ˜4. The resultant suspension was filtered and the orange solid dried on the high vacuum line overnight to give the title compound as an orange solid (11.09 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:25]1([C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH2:27][CH2:26]1.Cl>O1CCCC1.CCCCCC.O.CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[C:17][C:28]([CH:30]3[CH2:32][CH2:31]3)([CH:25]3[CH2:27][CH2:26]3)[OH:29])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reactant: O=C(C1CC1)C1CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1Cc2c(C#CC(O)(C3CC3)C3CC3)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 1.5 h

Procedure:
4.07 g (15 mmol) of 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was suspended in 30 ml of tetrahydrofuran and treated dropwise within 35 minutes at a maximum of -5° with 20 ml (30 mmol) of 1.6M butyllithium in hexane. After stirring in an ice-bath for 1.5 hours the mixture was cooled to -74° and there are added thereto 5 ml of hexamethylphosphoric acid triamide and, after 10 minutes, 3.30 g (30 mmol) of dicyclopropyl ketone. The mixture was left to come to room temperature during 6 hours and was stirred over the weekend. The reaction mixture was then poured into 200 ml of water, acidified to pH 7 with 4N hydrochloric acid and extracted four times with ethyl acetate. The combined organic extracts were washed twice with water, dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel while eluting with methylene chloride/methanol (19:1) and subsequent recrystallization from ethyl acetate there was obtained 7-chloro-3-(3,3-dicyclopropyl-3-hydroxy-1-propynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 179°-181°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:19]([OH:21])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>>[NH:36]1[C:35]([NH:34][C:19]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[CH:12][CH:13]=3)[N:5]=2)=[O:21])=[N:39][N:38]=[N:37]1
Reactant: Nc1nnn[nH]1
Reactant: CCN(CC)c1ccc(-c2cc(C)cc(C(=O)O)n2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCN(CC)c1ccc(-c2cc(C)cc(C(=O)Nc3nnn[nH]3)n2)cc1
Yield: 65.5 %

Procedure:
In the same manner as described in Example 1-(1), 4-methyl-6-(4-diethylaminophenyl)-2-pyridinecarboxylic acid (1.0 g), carbonyldiimidazole (1.0 g) and 5-aminotetrazole (0.32 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(4-diethylaminophenyl)-2-pyridinecarboxamide (0.81 g). M.P. 254°-256° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([N+:17]([O-])=O)[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].C(O)(=O)C>[Fe].O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])c2nc(NC(C)=O)ccc2c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)c2nc(NC(C)=O)ccc2c1
Reaction time: 18 h
Yield: 78.9 %

Procedure:
A mixture of 10.5 g (0.04 mole) of crude 2-acetamido-6-methoxy-8-nitroquinoline, 14 g of iron filings, 2 ml of glacial acetic acid, and 120 ml of water was stirred on the steam bath for 18 hr. The mixture was filtered and the solid residue was washed thoroughly with acetone. The acetone washings were concentrated and the residue was eluted through a short silica gel column with methylene chloride to give 7.3 g (78%) of 2-acetamido-8-amino-6-methoxyquinoline. A sample recrystallized from 95% ethanol melted at 192°-194°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Mg]Cl)(C)C.[O:15]=[CH:16][C@@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][CH3:19].[Cl-].[NH4+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:16]([OH:15])[C@@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH3:19]
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: c1ccc2ocnc2c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, benzo[d]oxazole (5 g, 42.0 mmol, Eq: 1.00) was combined with THF (100 ml) to give a light yellow solution. At −5° C. isopropylmagnesium chloride 2M in THF (21.0 ml, 42.0 mmol, Eq: 1.00) was added dropwise. The reaction was stirred for 1.5 h at −5° C. Then (S)-tert-butyl 1-oxobutan-2-ylcarbamate (4.72 g, 25.2 mmol, Eq: 0.6) diluted in 20 ml THF was added. The reaction was stirred overnight at RT. Satd. ammoniumchloride solution (6 ml) was added to the reaction. The THF was evaporated under vacuum. The reaction mixture was poured into 50 ml H2O and extracted with ethyl acetate (2×100 ml). The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in heptane). The title compound was obtained as a brown gum (5.08 g, 39.5%, MS (m/e)=307.2 [M+H+]).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:11][C:10]=2[CH3:33])=[CH:4][CH:3]=1.Cl.[CH3:35][P:36]1(=O)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[O:30][C:29]([CH2:31][N:39]6[CH2:40][CH2:41][P:36]([CH3:35])[CH2:37][CH2:38]6)=[CH:28][CH:27]=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:11][C:10]=2[CH3:33])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(-c5ccc(C=O)o5)cc34)cc2C)cn1
Reactant: CP1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(-c5ccc(CN6CCP(C)CC6)o5)cc34)cc2C)cn1
Temperature: 25 °C

Procedure:
5-(4-(4-(6-methylpyridin-3-yloxy)-3-methylphenylamino)quinazolin-6-yl)furan-2-carbaldehyde, 4-methyl-1,4-azaphosphinane 4-oxide hydrogen chloride salt and DIPEA were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (2 equiv.) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid. LCMS ESI(+) m/z: 554 (M+1). 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.47 (s, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 7.77 (d, 1H), 7.69 (m, 1H), 7.60 (d, 1H), 7.28 (m, 2H), 6.99 (m, 2H), 6.51 (d, 1H), 3.83 (s, 2H), 3.73 (m, 2H), 3.24 (m, 2H), 2.95 (m, 2H), 2.51 (s, 3H), 2.27 (s, 3H), 2.04 (m, 2H), 1.58 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[ClH:20]>CN(C)C=O>[Cl:20][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: Cl
Reactant: O=C(Cc1ccc(O)cc1Br)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1Cl)OCc1ccccc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl (2-bromo-4-hydroxyphenyl)acetate (500 mg) in N,N-dimethylformamide (12.5 mL) was added cuprous chloride (1.62 g), followed by stirring at 140° C. overnight. The reaction mixture was left to be cooled, and then ice water and 1 M hydrochloric acid was added thereto, followed by stirring. After extraction with ethyl acetate, the organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-chloro-4-hydroxyphenyl)acetate (381 mg).