Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]\[CH2:39]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39]/[CH:38]=[CH:37]\[C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:36][CH:35]=1)=[O:9]
Reactant: OC/C=C\c1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C\c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 215 mg (1 mM) of (Z)-3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylamino-pyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 528 mg (100%).
Reaction SMILES: C(Cl)(=O)C.C(O)(=O)C.[CH2:9]([NH:11][NH2:12])[CH3:10].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](=O)[C:23]([O:25]C)=O)=[CH:14]1>C(O)C>[CH2:9]([N:11]1[CH:14]=[C:15]2[C:22]([C:23](=[O:25])[NH:13][C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=32)=[N:12]1)[CH3:10]
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CCNN
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CCn1cc2c(n1)c(=O)[nH]c1ccccc12
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Acetyl chloride (0.7 mL, 9.8 mmol), acetic acid (1 mL), and ethylhydrazine (1.5 g, 9.8 mmol) were added sequentially to a suspension of methyl (1H-indol-3-yl)glyoxalate (1.0 g, 4.9 mmol) in ethanol (25 mL). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was combined with acetonitrile. A pink solid was isolated by filtration and then purified by automated flash chromatography (Biotage, eluted with a gradient of 0-30% CMA in chloroform) to provide a white solid. This material was recrystallized from acetonitrile to provide 360 mg of 2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as white crystals, mp>250° C. MS (APCI) m/z 214 (M+H)+; Anal. calcd for C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C, 67.52; H, 5.14; N, 19.90.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:43]#[N:44])[CH:41]=3)[NH:36][CH:35]=2)(=O)=O)=CC=1.C(N(CC)CC)C.CN(C)C=O>O>[C:43]([C:40]1[CH:41]=[C:42]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5]1)#[N:44]
Reactant: COC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2c[nH]c3ccc(C#N)cc23)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(N3CCN(CCCCc4c[nH]c5ccc(C#N)cc45)CC3)ccc2o1
Temperature: 79.5 °C
Reaction time: 0.75 h
Yield: 121.7 %

Procedure:
Methyl 5-(1-piperazinyl)benzofuran-2-carboxylate (5 g), 3-[4-(p-toluenesulfonyloxy)butyl]-1H-indole-5-carbonitrile (6.3 g) and triethylamine (7 ml) were added to dimethylformamide (6.3 ml) and the resulting mixture was heated to 77-82° C., followed by stirring for 45 minutes at the same temperature. Water (30 ml) was added to the reaction mass and then stirred for 5 minutes at 25-30° C. The separated aqueous layer was extracted two times with toluene (2×250 ml). The resulting organic layers were combined and then washed two times with water (2×250 ml) and then distilled off the solvent under vacuum to produce 9.5 g of the titled compound as a residue. Methanol (47.5 ml) was added to the residue at 25-30° C. and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed with chilled methanol (10 ml) and then dried the material at 70-75° C. to produce 6 g of Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate (Purity by HPLC: 99%; Yield: 76.9%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])[CH2:2][CH2:3][CH3:4].[CH2:12]([O:14][C:15]([C:17]#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])[CH3:13]>>[CH2:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:7]2[C:6]=1[C:19](=[O:20])[CH:18]=[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[NH:8]2)[CH2:2][CH2:3][CH3:4].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:9]([C:15](=[O:16])[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:8]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cccc(N)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Product: CCCCc1ccc2c(=O)cc(C(=O)OCC)[nH]c2c1
Product: CCCCc1cccc2[nH]c(C(=O)OCC)cc(=O)c12

Procedure:
Treatment of 3-butylaniline (7 g) with diethylacetylene dicarboxylate (7.5 ml), as described in Example 1b, gave ethyl 5-butyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.62 g) mp 132°-133° C., δ (360 MHz, DMSO-d6) 0.89 (3H, t, CH2CH2CH3), 1.36 (5H, m, CO2CH2CH3 and CH2CH2CH3), 1.47 (2H, m, CH2CH2CH2), 3.25 (2H, t, CH2CH2CH2CH3), 4.41 (2H, q, CO2CH2), 6.55 (1H, s, 3-H), 7.04 (1H, d, 8-H), 7.52 (1H, t, 7-H) 7.80 (1H, d, 6-H) and 11.75 (1H, bs, NH) and ethyl 7-butyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.78 g), mp 124°-126° C., δ (360 MHz, DMSO-d6) 0.91 (3H, t, CH2CH2CH3), 1.36 (5H, m, CO2CH2CH3 and CH2CH2CH3), 1.61 (2H, m, CH2CH2CH2), 2.70 (2H, t, CH2CH2CH2), 4.40 (2H, q, CO2CH2), 6.62 (1H, s, 3-H), 7.21 (1H, d, 6-H), 7.75 (1H, s, 8-H), 7.98 (1H, d, 5-H) and 11.87 (1H, bs, NH).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.[N:12]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.CN(C)C=O.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:20]3[CH2:21][CH2:22][CH:17]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[CH2:18][CH2:19]3)[S:8][C:4]=2[CH:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Clc1nc2ccc(Br)cc2s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc2nc(N3CCC(N4CCCC4)CC3)sc2c1
Temperature: 150 °C

Procedure:
One equivalent of 6-bromo-2-chlorobenzo[d]thiazole (248 mg, 1.0 mmol) and 1.1 equivalents of 4-(pyrrolidin-1-yl)piperidine (0.170 g, 1.1 mmol) were weighed into a 10 mL CEM microwave vial equipped with a magnetic stirbar. N,N-Dimethylformamide (1.0 mL) and three equivalents of N,N-diisopropylethylamine (0.524 ml, 3.00 mmol) were added via syringe. The reaction mixture was heated to 150° C. under microwave irradiation with the cooling power on for 15 minutes. The reaction mixture was transferred to a 250 mL round bottom flask (methanol rinse) and volatiles were removed under reduced pressure. The residue was partitioned between saturated aqueous sodium carbonate and CHCl3. The aqueous layer was extracted once more with CHCl3, then the combined organic extracts were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure to give a solid. This crude solid was purified by column chromatography on an Analogix IF-280 (Analogix SF15-12g, 100% dichloromethane to 97:3 dichloromethane/2 M ammonia in methanol). Fractions containing product were combined and concentrated under reduced pressure to give a solid that was dissolved in hot ethyl acetate, dried (MgSO4), and filtered. The filtrate was placed in a 0° C. freezer to promote crystallization. Crystals were collected by filtration and dried in a vacuum oven to give 6-bromo-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.51-1.66 (m, 2H), 1.78-1.88 (m, 4H), 2.04-2.14 (m, 2H), 2.34-2.46 (m, 1H), 2.63-2.72 (m, 4H), 3.16-3.27 (m, 2H), 4.06-4.15 (m, 2H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 366 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]2=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C.ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:6]2[NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C)c2c(c1O)C(=O)C(c1ccccc1)C2
Reactant: NCc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1O)C(NCc1ccccc1)=C(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.0 Grams of 4,6-dimethyl-7-hydroxy-2-phenyl-1-indanone was dissolved in 10 ml of diethyl ether and 10 ml of dichloromethane, then this solution was added dropwise gradually to a mixture of a solution of 2.55 ml of benzylamine in 10 ml of diethyl ether with 8 g of Molecular sieves 5A. The whole mixture was stirred at room temperature for 2 days and filtered by using Celite to obtain filtrate. The Celite used was washed with dichloromethane and ethanol, then these washing liquors were combihed with the above-mentioned filtrate and concentrated. Recrystallized from dichloromethane-ethanol to obtain 3.83 g of 4,6-dimethyl-7-hydroxy-1-benzylamino-2-phenyl-3H-indene. Orange needle-like crystals.
Reaction SMILES: [CH3:1][C:2]1([C:11]([OH:13])=O)[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1([CH3:10])[CH3:9].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:1][C:2]1([C:11]([Cl:16])=[O:13])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1([CH3:10])[CH3:9]
Reactant: CC1(C)C(C=C(Cl)Cl)C1(C)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC1(C)C(C=C(Cl)Cl)C1(C)C(=O)Cl

Procedure:
0.60 Part of the above carboxylic acid was agitated with 0.38 part of thionyl chloride at 80° C. for 30 minutes in benzene as a solvent to obtain 1,2,2-trimethyl-3-(2',2',-dichlorovinyl)-cyclopropane-carboxylic acid chloride. The acid chloride was agitated with 0.53 part of 3-phenoxybenzyl alcohol in the presence of pyridine at room temperature in benzene as a solvent to obtain 1.02 parts of 3-phenoxybenzyl-1',2',2'-trimethyl-3'-(2",2"-dichlorovinyl)-cyclopropane-carboxylate. The results of the NMR spectrum (60 MHz ) analysis of the so obtained product were as follows:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.O>[CH2:12]([NH:19][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: ClCCCOc1cccnc1
Solvent: O
Solvent: CO
Product: c1ccc(CNCCCOc2cccnc2)cc1
Temperature: 120 °C
Yield: 2.2 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (0.65 g, 3.78 mmol) was dissolved in methanol (20 mL) and added to a mixture of benzylamine (13.5 mL) in water (20 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 120° C. (oil bath temperature) for 3 h. After cooling, the mixture was concentrated by rotary evaporation, and saturated NaCl solution (25 mL) was added to the residue. The mixture was acidified to pH 1 with 10% HCl solution and extracted with CHCl3 (2×35 mL) to remove impurities. The aqueous phase was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give a brown oil. The oil was concentrated by vacuum distillation to remove excess benzylamine (bp 85° C. at 15 mm Hg). The remaining residue (0.483 g) was purified by column chromatography on silica gel (25 g) eluting with CH3OH—NH4OH (50:1, v/v). Fractions containing the product (Rf 0.39) were combined and concentrated on a rotary evaporator. The residue was re-chromatographed on silica gel (10 g). Fractions containing the product were combined and concentrated on a rotary evaporator. The residue was dissolved in CHCl3 and the CHCl3 solution was dried (MgSO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 20 mg (2.2%) of a light-brown oil. The compound exhibits a Ki of 3000 nM. The compound exhibits neurotransmitter release of 29 percent.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=2[CH:27](O)[CH3:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P([N:44]=[N+:45]=[N-:46])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:44]([CH:27]([C:19]1[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:18]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:28])=[N+:45]=[N-:46]
Reactant: CC(O)c1oc2ccccc2c1-c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(N=[N+]=[N-])c1oc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
DBU (155 μL, 1.04 mmol) was added dropwise to a solution of 1-(3-phenylbenzofuran-2-yl)ethanol (206 mg, 0.86 mmol) and diphenyl phosphoryl azide (255 μL, 1.04 mmol) in anhydrous THF (7 mL) at 0° C. under a nitrogen atmosphere. After 30 min 0° C., the mixture was slowly warmed to RT and stirring was continued for 1.5 h. Additional diphenyl phosphoryl azide (255 μL, 1.04 mmol) and DBU (155 μL, 1.04 mmol) were added and stirring continued for 18 h. The volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) affording the title compound as an oil (186 mg, 82%). LCMS (Method C): RT 4.48 min [M+H-N2]+ 236.1
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH2:12][C:11](=[O:14])[C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.O[O:23][S:24]([O-:26])=O.[K+].Cl[CH2:29]Cl>CO.O>[CH3:29][S:24]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:13][CH2:12][C:11](=[O:14])[C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)(=[O:26])=[O:23]
Reactant: ClCCl
Reactant: CSc1ccc(C2=C(Oc3ccccc3)C(=O)CC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=C(Oc3ccccc3)C(=O)CC2)cc1
Reaction time: 1 h

Procedure:
To the compound obtained in Step 2 (60 mg) in dichloromethane (4.5 mL) and methanol (2.4 mL) was added Oxone® (450 mg) in water (1 mL) and the reaction mixture was stirred for 1 h.Water was added to the mixture which was then extracted with dichloromethane, the organic layers were combined and dried over MgSO4, filtered and the solvent evaporated under vacuum. Purification by silica gel chromatograohy afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 52.9 %

Procedure:
1-Cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 3 g of 1-methylpiperazine in 10 cm3 of pyridine. After recrystallizing from 10 cm3 of dimethylformamide, 0.63 g of 1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 250° C.
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(C)C>[C:10](/[N:9]=[C:8](\[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)/[NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][CH2:25][CH2:24][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:28][CH:29]=1)#[N:11]
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: N#C/N=C(/Nc1ccc(OCCN2CCCC2)cc1)Oc1ccccc1

Procedure:
Diphenylcyanocarbonimidate (1.1 equiv) and 4-(2-(pyrrolidin-1-yl)ethoxy)aniline (1 equiv) were stirred in iso-propyl alcohol at ambient temperature overnight. The resulting white precipitate was filtered and washed with iso-propyl alcohol and dried to yield (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate. 3-Hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (82 mg, 0.36 mMol) and (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate (128 mg, 0.36 mMol) were suspended in isopropanol (3 mL) and subjected to microwave irradiation (150° C., 20 min). The precipitate which formed in the microwave vial was re-dissolved in hot isopropanol. The mixture was cooled to ambient temperature and then filtered to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #1, as a yellow solid, 23 mg. 1H NMR (CDCl3, 300 MHz) 7.90 (s, 1H), 7.83 (t, 1H), 7.43 (m, 3H), 7.29 (t, 1H), 6.93 (d, 1H), 6.83 (br s, 2H), 6.39 (s, 1H), 4.17 (m, 2H), 2.98 (m, 2H), 2.60-2.80 (m, 8H), 2.32 (m, 2H), 1.87 (m, 4H) ppm; MS (ES) 483.16 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:33][CH:34]=3)[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(OCc4ccccc4)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (17.75 g, 58.0 mmole) in dry DMF (150 mL) at was added 4-benzyloxybenzylchloride (14.85 g, 63.8 mmole). After 10 min, 60% NaH (2.78 g. 69.6 mmole),was added and the reaction slurry was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (200 mL) and extracted with EtOAc (2×200 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure gave a waxy solid. Purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (27.13 g, 93%) as a white solid: MS (ES) m/e 503 (M+H)+.
Reaction SMILES: [CH2:1]([CH:5]1[C:11](OC)=[N:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH2:1]([CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1=[NH:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCCCN=C1OC
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Product: CCCCC1CCCCNC1=N
Product: Cl

Procedure:
The product of EXAMPLE 185 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1O.C(N(CC)CC)C.FC(F)(F)[S:22](OS(C(F)(F)F)(=O)=O)(=O)=O.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[SH:22]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
2-methoxy-4-nitrophenol (19.2 g) was dissolved in methylene chloride (192 ml), triethylamine (20.5 ml) was added to the mixture, trifluoromethanesulfonic acid anhydride (23.0 ml) was added dropwise to the solution at 0° C., and the mixture was stirred for 1 hour at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was dissolved in ethanol (274 ml) under heat reflux, and an aqueous solution (342 ml) of sodium sulfate nanohydrate (21.1 g) and sulfur (2.8 g) in ethanol was added dropwise thereto for 20 minutes. Aqueous solution of sodium hydroxide (7.02 g, 28.1 ml) was added dropwise to the solution for 20 minutes, and then, the mixture was cooled to room temperature, ice-water was added thereto. The precipitates were filtered, and the pH of the filtrate was adjusted to about pH 5 with 6N hydrochloric acid, and the precipitates were collected by filtration, and washed with water to give 2-methoxy-4-nitrobenzenethiol (15.8 g, 75%).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(F)(F)C([O-])=O.[Na+]>COCCOCCOC>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Agent: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: COCCOCCOC
Product: CC(=O)c1ccccc1
Reaction time: 0.08 h

Procedure:
Specifically, (1-phenylvinyloxy)-trimethylsilane (Compound 1g; 61.3 mg, 0.1 mmol) and diglyme (0.5 mL) were put into a two-neck evacuation flask under nitrogen atmosphere, and a diglyme (1.0 mL) solution of sodium chlorodifluoroacetate (18.3 mg, 0.12 mmol) was added dropwise to the mixture at 150° C. for 10 minutes, and then the mixture was stirred for 5 minutes. The reaction mixture was washed with water, and then dried with sodium sulfate. The solvent was distilled away under reduced pressure, and then the residue was subjected to GC/MS measurement. As a result, Compound 2g, Compound 3 and acetophenone (Compound 5) were obtained with yields of 4%, 4% and 19%, respectively.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)=[O:9])=[N:4][CH:3]=1.Br[CH2:21][CH2:22][O:23][CH3:24].[H-].[Na+]>O1CCCC1.CN(C)C=O.O>[Br:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8]([C:10]23[CH2:11][CH:12]4[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]4)[CH2:19]2)[CH2:17]3)=[O:9])/[N:4]([CH2:21][CH2:22][O:23][CH3:24])[CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)C12CC3CC(CC(C3)C1)C2
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCn1cc(Br)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
A solution of Example 131A (2.55 g, 7.43 mmol), 1-bromo-2-methoxyethane (0.77 mL, 8.15 mmol) and sodium hydride (60%) (386 mg, 9.66 mmol) in tetrahydrofuran/N,N-dimethylformamide (2:1) (60 mL) was heated at 75° C. for 12 hours. The mixture was cooled to ambient temperature, diluted with water, and extracted with dichloromethane. The organic extract was dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel, 100% dichloromethane) afforded the title compound. MS (ESI) m/z 399 (M+H)+.