Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@@H:20]([C:32](O)=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:35]1([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=2[Cl:47])[CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>CC(N(C)C)=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][C@H:20]([C:32](=[O:33])[N:38]([CH:35]4[CH2:36][CH2:37]4)[CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=4[Cl:47])[CH2:21][C@@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: Clc1cccc(CNC2CC2)c1Cl
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred, ice-cooled mixture of (3R*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (233 mg, 0.5 mmol), cyclopropyl-(2,3-dichloro-benzyl)-amine (112 mg, 0.52 mmol) and N-ethyldiisopropylamine (685 μL, 4 mmol) in dimethylacetamide (3 mL), propylphosphonic anhydride solution (˜50% in DMF, 0.48 mL, ˜0.75 mmol) is added. The mixture is stirred for 14 h at RT. After evaporation of the solvent in vacuo, the residue is diluted with ethyl acetate and washed with a 10% aqueous K2CO3 solution and brine. The organic layer is dried over Na2SO4, evaporated in vacuo and the residue purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with solid K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford (3R*,5R*)-3-tert-butoxycarbonylamino-5-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester as a colourless oil. tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, then 100% CH3CN+0.1% TFA for 2 min, flow 1.5 ml/min): 8.45 min. The product is dissolved in CH2Cl2/piperidine 4:1 (5 mL) and stirred for 1 h at RT. After evaporation in vacuo, the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 30 min, flow 20 mL/min). The combined pure fractions are treated with solid K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a colourless resin. MS: 442.3/444.2 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.58 min.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7]C(O)=O)(=O)[CH3:2].CC([O-])=O.[Na+].[OH-].[Na+]>C(OC(=O)C)(=O)C>[Br:15][C:13]1[CH:12]=[CH:11][C:5]2[O:6][CH:7]=[C:1]([CH3:2])[C:4]=2[CH:14]=1
Reactant: CC(=O)c1cc(Br)ccc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1coc2ccc(Br)cc12
Yield: 92.8 %

Procedure:
To a solution of 2-(2-acetyl-4-bromophenoxy)acetic acid (5.3 g, 19.41 mmol) in acetic anhydride (100 mL) was added NaOAc (3.19 g, 38.90 mmol). The resulting solution was heated to reflux overnight. The pH value of the resulting solution was adjusted to 7 with aqueous sodium hydroxide, extracted with ether (50 mL×3), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by silica gel chromatography (petroleum ether) to afford 5-bromo-3-methyl-1-benzofuran as a light yellow oil (3.8 g, 93%).
Reaction SMILES: [O:1]1C=CC=[CH:2]1.[CH3:6][O:7][C:8]1[O:12][CH2:11][CH2:10][C:9]=1OC>>[CH3:2][O:1][CH:11]1[CH2:10][CH2:9][CH:8]([O:7][CH3:6])[O:12]1
Reactant: COC1=C(OC)OCC1
Reactant: c1ccoc1
Product: COC1CCC(OC)O1
Yield: 1.4 %

Procedure:
After 1 F/mol of furan, the proportion of furan in GC-percent by area had dropped from 22.9% to 18.8%, while the proportion of dimethoxydihydrofuran had increased from 32.2% to 34.5%. At the same time, 1.4% of 2,5-dimethoxytetrahydrofuran were formed.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: c1c[nH]nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(OCC)n1ccnn1
Yield: 56.8 %

Procedure:
After the addition of 2.5 g of p-toluenesulphonic acid hydrate, 34.5 g (0.5 mol) of triazole in 222 g (1.5 mol) of triethyl orthoforrnate are heated until the internal temperature reaches 150° C., while ethanol is distilled off. 2 g of sodium carbonate are added and the mixture is distilled using high vacuum. 48.6 g (56.8% of theory) of N-diethoxymethyltriazole are obtained.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)([CH3:6])[CH3:5])=[C:2]=[O:3].O>ClCCCl>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:2](=[O:3])[NH:1][C:4]2([CH3:6])[CH3:5]
Reactant: COc1cccc(C(C)(C)N=C=O)c1
Solvent: O
Solvent: ClCCCl
Product: COc1ccc2c(c1)C(C)(C)NC2=O
Temperature: 0 °C

Procedure:
To an ice-cold slurry of FeCl3 (35.69 g, 220 mmol) in dry DCE (800 mL) is added a solution of isocyanate 56 (19.12 g, 100.0 mmol) in the same solvent (100 mL) over 45 min. After completion of the addition, GC analysis of an aliquot indicates complete reaction. Water (600 mL) is added and the resulting mixture is stirred vigorously. The layers are separated, and the organic phase is washed 2×1 L with 1 M tartaric acid solution and once with brine. The solution is dried (MgSO4), filtered and evaporated to a dark liquid. This is purified by FC (1:4 hexane/EtOAc, then EtOAc) to provide the 5-methoxy isoindolone 57 as a pale yellow solid, mp 146-147° C., 7.38 g (39%), and the regioisomeric 7-methoxy isoindolone 61 as a yellow solid, mp 155-158° C., 2.85 g (15%). For 57: 1H NMR (CDCl3) 7.74 (d, 1, J=8.5), 7.00-6.95 (m, 1), 6.85 (d, 1, J=2.2), 3.89 (s, 3), 1.54 (s, 6); 13C NMR (CDCl3) 169.57, 163.19, 155.44, 125.31, 123.14, 114.18, 105.92, 58.64, 55.61, 27.81; MS (MW=191.2, EI, eE=70 eV) m/z 191 (M+), 176 (base peak), 161, 133, 118, 88, 77, 63, 42.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([CH:14]([CH3:16])[CH3:15])=[C:8]([CH:13]=1)[O:9][CH2:10][C:11]#[N:12].[CH:19]([O:21][CH2:22]C)=O.IC>>[Br:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([CH:14]([CH3:16])[CH3:15])=[C:8]([CH:13]=1)[O:9][C:10](=[CH:19][O:21][CH3:22])[C:11]#[N:12]
Reactant: COc1cc(C(C)C)c(OCC#N)cc1Br
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC=C(C#N)Oc1cc(Br)c(OC)cc1C(C)C
Temperature: 80 °C
Yield: 48.2 %

Procedure:
Sodium hydride (0.122 g, 5.0 mmol, 60% w/w) was washed with dry hexanes and evaporated under a stream of nitrogen. 10 mL THF was added and the mixture was cooled to 0° C. (5-Bromo-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (0.577 g, 2.03 mmol) was added in portions. After 30 min ethyl formate (4.9 mL, 60.9 mmol) was added and the solution was warmed to 80° C. After 4.5 hours the mixture was cooled and 5.0 mL iodomethane was added in one portion. After 16 hours the solution was quenched with H2O, concentrated in vacuo, extracted with ethyl acetate, washed with H2O and then washed with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (9:1 hexane/ethyl acetate) afforded 2-(5-bromo-2-isopropyl-4-methoxy-phenoxy)-3-methoxy-acrylonitrile (0.319 g, 48%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10](OC)=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(O)(=[O:22])C>CN(C)C=O.O>[OH:22][C:8]1[C:9]2[CH:14]=[CH:15][CH:16]=[N:17][C:10]=2[S:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: COC(=S)c1cccnc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1c(-c2ccccc2)sc2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A suspension of 12.9 g (50 mmol) of methyl 2-phenylmethylthionicotinate and 2.6 g (110 mmol) of sodium hydride in 100 mL of dry N,N-dimethylformamide was stirred for 4 hours at room temperature. The solution was diluted with 200 mL water and acidified with glacial acetic acid. The precipitate was collected, washed with water, and dried to afford 10.6 g (93%) of a white crystalline solid to be used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:17](=[O:25])[C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])(=O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:17](=[O:25])[C:18]([CH3:23])([O:24][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])[C:19]([F:22])([F:21])[F:20])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC(O)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OC(C)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-amino-6-bromo-W-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-5-(trifluoromethyl)picolinohydrazide (step 1) (4 g, 9.11 mmol) in DCM (60 ml), triethylamine (1.270 ml, 9.11 mmol) was added to give a yellow solution. The solution was cooled to 0° C. (ice bath) and treated with triisopropylsilyl trifluoromethanesulfonate (4.94 ml, 18.22 mmol). The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to RT and stirred for 3 days. The reaction mixture was partitioned between DCM (100 ml) and water (100 ml), phases shaken and separated. The organic portion was washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo. The resulting oil was purified by chromatography on silica eluting with 0-30% DCM in iso-hexane to afford the title compound; LC-MS Rt=1.58 min [M+H]+ 595/597 Method 2minLC_v003.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>C1C=CC=CC=1>[CH3:23][N:24]([CH3:28])[C:25]([N:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1)=[O:26]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)CCNc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)CCN(C(=O)N(C)C)c1nc2ccccc2[nH]1

Procedure:
Following the procedure of Example 1C, using 9.4 g. (0.046 moles) of N,N-dimethyl-N'-(2-benzimidazolyl)-1,2-ethane diamine, 6.0 g. (0.06 moles) of triethylamine, 5.7 g. (0.053 moles) of N,N-dimethylcarbamoyl chloride and 150 ml. of benzene, there is obtained N,N-dimethyl-N'-(2-dimethylaminoethyl)-N'-(2-benzimidazolyl)urea, which, after chromatographic separation on 375 g. of silica gel, and elution with a mixture of 500 ml. of chloroform, 100 ml. of isopropanol, 100 ml. of toluene and 10 ml. of triethylamine, affords 9.4 g. of oil. This is treated with hydrogen bromide and recrystallized from ethanol to give 8.2 g. of dihydrobromide salt, m.p. 193°-195° C.
Reaction SMILES: O[CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[O:8]=[C:6]1[NH:7][C@H:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CC[C@@H](CN2C(=O)c3ccccc3C2=O)N1
Temperature: -30 °C
Reaction time: 16 h

Procedure:
To (S)-5-(hydroxymethyl)pyrrolidin-2-one (2.00 g, 17.39 mmol) dissolve in 25 mL THF was added phthalimide (2.81 g, 19.13 mmol), triphenylphosphine (5.01 g, 19.13 mmol) and diisopropylazodi-carboxylate (3.33 g, 19.13 mmol). This mixture was stirred for about 16 hr, and then diluted with 200 mL of hexanes and 2 mL of DCM, and then cool at −30° C. The product precipitated and was filtered and dried (4.11 g, 96%, white solid).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:27]=[C:16]2[C:17]3[C:22]([CH2:23][CH2:24][N:15]2[C:14](=[O:28])[N:13]=1)=[CH:21][C:20]([O:25][CH3:26])=[CH:19][CH:18]=3>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][O:8][C:12]1[CH:27]=[C:16]2[C:17]3[C:22]([CH2:23][CH2:24][N:15]2[C:14](=[O:28])[N:13]=1)=[CH:21][C:20]([O:25][CH3:26])=[CH:19][CH:18]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: OCC1COCCO1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCn1c-2cc(OCC2COCCO2)nc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[1,4]Dioxan-2-yl-methanol (42 mg, 0.36 mmol, 2 eq.) was dissolved in DCM (3 mL) with NaH (14 mg, 0.36 mmol, 2 eq., 60% in mineral oil). After 30 min, intermediate 38 (50 mg, 0.18 mmol, 1 eq.) was added to the mixture and the reaction was stirred at RT for 16 h. The reaction mixture was evaporated to dryness and the crude product was purified by preparative HPLC-MS to provide compound 162.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[NH2:15][OH:16]>CCO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Solvent: CCO
Product: COC(=O)c1ccc(OC)c(C(N)=NO)c1
Yield: 98.7 %

Procedure:
A solution of methyl 3-cyano-4-methoxybenzoate (518 mg, 2.71 mmol), hydroxylamine (810 μL, 50% in water, 13.55 mmol) in EtOH (20 mL) was heated for 18 h at 60° C. after which time solvents were removed under vacuum, solid residue was triturated with water filtered and dried under vacuum overnight to give the title compound as an off-white solid (600 mg, quant). 1H NMR (DMSO-d6, 300 MHz) δ 9.48 (s, 1H), 7.97-7.95 (m, 2H), 7.20-7.17 (m, 1H), 5.70 (bs, 2H), 3.87 (s, 3H), 3.82 (s, 3H). LC/MS (Method B): 225.1 (M+H)+.
Reaction SMILES: [NH2:1][OH:2].[C:3]12([CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]1)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2>>[OH:2][N:1]=[C:11]([OH:12])[CH2:10][C:3]1([CH2:15][C:14]([OH:13])=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1CC2(CCCCCC2)CC(=O)O1
Reactant: NO
Product: O=C(O)CC1(CC(O)=NO)CCCCCC1

Procedure:
In a manner analogous to that described in Example 1, by the reaction of hydroxylamine with 1,1-cycloheptane-diacetic anhydride, there was obtained 1,1-cycloheptane-diacetic acid N-hydroxylimide (m.p. 90°-100° C.) which, by acylation with benzene-sulphonyl chloride, was converted into benzene-sulphonyloxy-1,1-cycloheptane, diacetic acid imide (m.p. 130°-133° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17]2[C:9](=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[N:8]([CH3:18])[C:7]=1[C:19]([O:21]C(C)(C)C)=[O:20])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:17]2[C:9](=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[N:8]([CH3:18])[C:7]=1[C:19]([OH:21])=[O:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OC(C)(C)C)n(C)c2c1ccc1[nH]ncc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(C(=O)O)n(C)c2c1ccc1[nH]ncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methyl-1,6-dihydro-1,6,7-triaza-as-indacene-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester C3 (0.68 mmol in DCM (10 mL), trifluoroacetic acid (1 mL) was added. The solution was stirred at rt for 2 h then the reaction mixture was evaporated to dryness affording the title compound in quantitative yield. ESI (+) MS: m/z 288 (MH+); MS (ES−) 286. 1H NMR: 1.35 (t, J=7.07, 3H), 4.18 (s, 3H), 4.33 (q, J=7.07, 2H), 7.47 (d, J=9.02, 1H), 7.91 (d, J=9.02, 1H), 8.51 (s, 1H), 13.46 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]([C:13]3[CH:23]=[CH:22][C:16]4[O:17][CH2:18][C:19](=[O:21])[NH:20][C:15]=4[CH:14]=3)=[O:12])[CH:9]([CH2:24][C:25]([OH:27])=O)[CH2:8][O:7][C:6]=2[CH:28]=1.[CH3:29][NH2:30].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]([C:13]3[CH:23]=[CH:22][C:16]4[O:17][CH2:18][C:19](=[O:21])[NH:20][C:15]=4[CH:14]=3)=[O:12])[CH:9]([CH2:24][C:25]([NH:30][CH3:29])=[O:27])[CH2:8][O:7][C:6]=2[CH:28]=1
Reactant: O=C(O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CNC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.1 %

Procedure:
A mixture of 2-(7-chloro-4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)acetic acid (Intermediate 22, 38 mg, 0.09 mmol), methanamine (0.236 mL, 0.47 mmol) (2 M solution in THF), and TEA (0.039 mL, 0.28 mmol) in EtOAc (2 mL) was treated with T3P (50 wt. % in EtOAc, 0.112 mL, 0.19 mmol) at rt. The reaction mixture was stirred at rt over night and concentrated. The crude product was purified by preparative HPLC (Kromasil C8 column (10 μm 250×20 ID mm), using a gradient of 20-60% ACN in H2O/ACN/FA 95/5/0.2 buffer, over 20 min with a flow of 19 mL/min, UV detection at 240 nm). Freeze-drying gave the title compound (24 mg, 61%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[C:29]([O-])(=O)C.[Na+].C(O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:29][NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)[O-]
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1cc(CC(C)C)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of the compound of Example 46 (135 mg, 0.34 mmol), sodium acetate (28 mg, 0.34 mmol) and acetic acid (41 mg, 0.68 mmol) in methanol (3.4 mL), formaldehyde (37% in water, 0.033 mL, 0.41 mmol) and sodium cyanoborohydride (21 mg, 0.34 mmol) were added. The mixture was stirred for 1 hour, concentrated, diluted with ethyl acetate and washed with water and brine, dred and concentrated. The residue was subjected to preparative HPLC on a 30×500 mm ODS S10 column using 56% methanol, 44% water and 0.1% trifluoroacetic acid to provide 23 mg of the title compound (16%) as a white solid, m.p. 125-128° C., as well as 30 mg of the title compound of Example 50 (20%) as a light yellow solid, m.p. 127-129° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O>C(#N)C>[CH:5]1[C:6]([C:10]#[N:11])=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]1[C:2]([NH:1]2)=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]#[N:11])=[CH:5][C:4]=3[C:3]2=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]#[N:11])=[CH:5][C:4]=3[C:3]=12
Reactant: N#Cc1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2[nH]c3c4[nH]c5ccc(C#N)cc5c4c4c5cc(C#N)ccc5[nH]c4c3c2c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 87.2 %

Procedure:
10 ml of acetonitrile was poured into a 200 ml three-neck flask, and 1.42 g of indole-5-carbonitrile was dissolved therein. On the other hand, an oxidant solution was prepared by dissolving 16.2 g of ferric chloride anhydrate and 5.4 g of water in 40 ml of acetonitrile and agitating the resultant mixture for 10 minutes. Then the prepared oxidant solution was dripped into the indole-5-carbonitrile solution for 30 minutes, which was then agitated for 10 hours at the temperature of 60° C. Color of the reaction solution changed from yellow to green with slight heat generation, and the pH was less than 1. After the end of the reaction, the reaction solution was suction-filtered with a perforated funnel, and the filtrate was washed with acetonitrile and then methanol, and then dried to obtain 1.22 g of 6,11-dihydro-5H-diindolo[2,3-a:2′,3′-c] carbazole-2,9,14-tricarbonitrile (indole-5-carbonitrile trimer) with a green color (yield: 86%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and found to be 0.50 S/cm. The result of elemental analysis was: <C9.00H4.03N1.97Cl0.10>3. Further the result of X-ray diffraction crystal analysis indicated that the interlaminar spacing was 0.44 nm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34][CH2:35][C:36](Br)=[O:37].C(=O)([O-])O.[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:36](=[O:37])[CH2:35][Br:34])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1)OCc1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CBr)c3ccccc32)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a solution of (3aR*,10aS*)-9-[4-(benzyloxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (610 mg, 1.4 mmol) in dichloromethane (7 mL) was added bromoacetyl bromide (0.15 mL, 1.7 mmol) dropwise and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was diluted with water (5 mL) with vigorous stirring and neutralized with sodium hydrogen carbonate. The aqueous layer was separated and the organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethyl acetate to provide 519 mg (yield 66%) of the title compound. m.p. 222°-223° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[C:20]([N:21]2[CH2:26][CH2:25][NH:24][CH:23]([CH3:27])[CH2:22]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH2:28]=O.[OH-].[K+]>C(O)=O>[CH3:27][CH:23]1[N:24]([CH3:28])[CH2:25][CH2:26][N:21]([C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:22]1
Reactant: C=O
Reactant: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CCN1
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CCN1C

Procedure:
A solution of 1.15 g of 7-fluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 1.35 cm3 of 98% formic acid and 3.25 cm3 of a 30% aqueous solution of formaldehyde is heated at a temperature close to 100° C. for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. and 5 cm3 of water are then added, the solution obtained is brought to pH 7 by adding 0.5 cm3 of 2N aqueous potassium hydroxide solution and heated at a temperature close to 100° C. for 2 minutes. The product, which crystallizes, is drained at 20° C. and washed with twice 10 cm3 of water. The crude product obtained is recrystallized twice from 10 cm3 of dimethylformamide each time. 0.55 g of 8-(3,4-dimethyl-1-piperazinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 306°-308° C.