Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1.[Cu][C:18]#[N:19].CCOC(C)=O>CN1C(=O)CCC1>[C:18]([C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1)#[N:19]
Reactant: CCSc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCSc1c(C(N)=O)cnn2cc(C#N)cc12
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
A solution of 6-bromo-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (200 mg, 0.666 mmol) and copper(I) cyanide (119 mg, 1.333 mmol) in NMP (3 mL) was heated to 180° C. for 1.5 hrs, and then 200° C. for 1.5 hrs under microwave oven (CEM). To the reaction mixture was added 50 mL of EtOAc. The mixture was washed with 30 mL of 10% LiCl solution, 30 mL of saturated NH4Cl solution, and 30 mL of brine and dried over Na2SO4. Filtration and concentration yielded 6-cyano-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (140 mg, 77% yield). MS (ES+) m/z: 247.08 (M+H); HPLC retention time: 1.902 min (analytical HPLC Method F).
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=2)=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:17][NH:18][CH2:19][CH:20](N)N>ClCCl>[CH3:2][N:3]([CH2:4][CH2:5][NH:1][C:6]([NH:8][C:17]1[NH:18][C:19]([CH3:20])=[CH:12][C:13](=[O:15])[N:14]=1)=[O:7])[CH2:4][CH2:5][NH:1][C:6]([NH:8][C:9]1[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=1)=[O:7]
Reactant: Cc1cc(=O)nc(NC(=O)n2ccnc2)[nH]1
Reactant: CNCC(N)N
Solvent: ClCCl
Product: Cc1cc(=O)nc(NC(=O)NCCN(C)CCNC(=O)Nc2nc(=O)cc(C)[nH]2)[nH]1

Procedure:
3 g of 2-(1-imidazolylcarbonylamino)-6-methyl-4[1H]-pyrimidinone (136 mmol) prepared according to the procedure described by Meijer et al., J. Am. Chem. Soc. 2003, 125, p. 6860 are added to a solution of 0.81 g of N-methyldiaminoethylamine (6.8 mmol) in 150 ml of dichloromethane. The solution is stirred at reflux for 4.5 hours. The product is precipitated from acetone, filtered off and washed with acetone, and then dried under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].I.CS[C:33]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)=[NH:34]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:12]3[CH:21]=[CH:22][C:23]([NH:25][C:33]([C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)=[NH:34])=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2C2CCN(C)CC2)cc1
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CCOc1ccc(Cc2nc3cc(NC(=N)c4cccs4)ccc3n2C2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 55.6 %

Procedure:
2-(4-Ethoxy-benzyl)-1-(1-methyl-piperidin-4-yl)-5-nitro-1H-benzimidazole 54 (120 mg, 0.304 mmol) was dissolved in anhydrous ethanol (10 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (32.4 mg, 0.0304 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 22 hours, thin layer chromatography in a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) shows complete conversion to 55, 2-(4-Ethoxy-benzyl)-1-(1-methyl-piperidin-4-yl)-1H-benzoimidazol-5-ylamine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol 10 mL) and the ethanolic solution of the amine 55 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide 9a (173.4 mg, 0.608 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 30 hours. The solvent was removed and the residue partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude product. The product was purified using silica gel dry column chromatography eluting with a solvent system of 5% 2M NH3 in methanol/95% dichloromethane to afford a pale yellow-colorless residue 56 N-[2-(4-Ethoxy-benzyl)-1-(1-methyl-piperidin-4-yl)-1H-benzoimidazol-5-yl]-thiophene-2-carboxamidine Yield: 80 mg (55.5%). 1H NMR (DMSO) δ: 1.28 (t, 3H, J=6.9), 1.31-1.42 (m, 2H), 1.91 (br t, 2H, J=11.0), 2.19 (s, 3H), 2.19-2.35 (m, 2H), 2.81 (m, 2H), 3.96 (q, 2H, J=7.0), 4.16-4.32 (s, 2H, m, 1H), 6.36 (br s, 2H), 6.69 (dd, 1H, J=8.7, 1.6), 6.85 (d, 2H, J=8.7), 7.00 (d, 1H, J=1.5), 7.08-7.11 (m, 1H), 7.17 (d, 2H, J=8.5), 7.46 (d, 1H, J=8.5), 7.59 (d, 1H, J=5.3), 7.73-7.75 (m, 1H); MS (ESI): 474 (MH+, 80%), 377 (100%).
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].[F:6][C:7]([F:23])([C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][OH:9]>CCN(C(C)C)C(C)C>[OH:3][C@H:2]([CH2:1][O:9][CH2:8][C:7]([F:23])([F:6])[C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])[CH2:4][OH:5]
Reactant: OC[C@@H]1CO1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H](O)COCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 58.2 %

Procedure:
(S)-2-hydroxy-3-(2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyloxy)-propanol was prepared by the following modification of a procedure described in U.S. Pat. No. 3,470,258 (Teroso et al.). (R)-glycidol (5.0 g, 67.5 mmol) was added dropwise to a 120° C. solution of 2,2,3,3,4,4,5,5,6,6,6-undecafluorohexanol (30 g, 101 mmol) and N,N'-diisopropylethylamine (0.47 ml, 2.7 mmol). The resulting mixture was then stirred for one hour. The resulting product was distilled (79°-81° C. at 0.4 mm Hg) from the mixture to give 14.7 g of (S)-2-hydroxy-3-(2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyloxy)-1-propanol as a clear liquid. (R)-2-fluoro-3-(2,2,3,3,4,4,5,5,6,6,6-undecafluorohexane-1-p-toluenesulfonate was then prepared using essentially the procedure described in Example 1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3]1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:24]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3]2)[O:1][CH2:22][CH2:23]1
Reactant: COC(=O)C1CC(=O)CCN1C(=O)OCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C1CC2(CCN1C(=O)OCc1ccccc1)OCCO2

Procedure:
A solution of the product of stage (ii) (5.06 g) and 1,2-ethanediol (1.06 ml) in benzene (100 ml) containing 4-toluenesulphonic acid (0.2 g) was stirred at reflux temperature under a Soxhlet cup filled with 4 Å molecular sieves for 4 h. The reaction mixture was allowed to cool to 22°, washed with 2N sodium carbonate (2×20 ml), water (20 ml) and dried. The benzene solution was evaporated in vacuo to give the title compound as an oil (5.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:23]=[C:24]([S:29]([OH:32])(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[NH2:28]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:21][C:22]3[C:27](=[CH:26][CH:25]=[C:24]([S:29]([OH:32])(=[O:30])=[O:31])[CH:23]=3)[N:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(S(=O)(=O)O)cc1N
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1

Procedure:
A solution of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (400 mg, 1.48 mmol, 1.00 equiv) and 3,4-diaminobenzenesulfonic acid (278 mg, 1.48 mmol, 1.00 equiv) in ethanol/water (1:1, 20 mL) was stirred overnight at reflux in an oil bath. The resulting mixture was concentrated in vacuo, resulting in 500 mg (80%) of 2,3-bis-(4-methoxyphenyl)quinoxaline-6-sulfonic acid as a brown solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][O:41][CH2:42][C@H:43]([O:45][CH2:46][CH3:47])[CH3:44])=[CH:36][CH:35]=2)[C@H:13]([CH2:48][NH2:49])[CH2:12]1)=O)C1C=CC=CC=1.CCN(CC)CC>C(Cl)Cl>[CH2:46]([O:45][C@H:43]([CH3:44])[CH2:42][O:41][CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C@@H:14]2[C@@H:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=4[CH:33]=3)[CH2:16][NH:11][CH2:12][C@H:13]2[CH2:48][NH2:49])=[CH:39][CH:38]=1)[CH3:47]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CN(C(=O)OCc3ccccc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reaction time: 1 h

Procedure:
1.4 mmol of 4-nitrophenylformiate are added to a solution of 1 mmol of (3R,4R,5R)-3-aminomethyl-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (example 6a) in 10 ml of CH2Cl2 under argon followed by the addition of 1 mmol of Et3N. After 60 min, the reaction mixture is evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
Reaction SMILES: Cl.CS([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[C:13]([C:31]3[CH:36]=[CH:35][C:34]([O:37]S(C)(=O)=O)=[CH:33][CH:32]=3)[S:12][C:11]=2[CH:42]=1)(=O)=O.O1CCCC1.[OH-].[Na+]>CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:30])[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:20][CH:21]=3)=[C:13]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:12][C:11]=2[CH:42]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A 23.8 g. portion of the product of Example 3 above was added to 600 ml. of tetrahydrofuran, 240 ml. of methanol and 40 ml. of 5 N sodium hydroxide. The mixture was stirred at ambient temperature for 60 hours, and then it was evaporated under vacuum. The residue was diluted to 400 ml. with water, and the solution was continuously extracted with diethyl ether for 8 hours. The aqueous phase was then filtered, cooled to below 10°, and acidified to pH 2 with methanesulfonic acid. It was then diluted to about 7 liters with water, and was extracted with diethyl ether. The aqueous layer was degassed under vacuum and made basic with sodium bicarbonate. The solids which precipitated were collected and vacuum dried, and purified by column chromatography on a 4.5×60 cm. column of silica gel, using as eluant a gradient composed of 2 liters of 1% methanol in chloroform phasing to 2 liters of 25% methanol in chloroform. Twenty ml. fractions were collected, and fractions 33 through 150 gave 13.5 g. of product, m.p. 146°-147° after crystallization from acetone. Its UV spectrum showed an absorption maximum at 290 nm. (32,500). The IR spectrum showed a maximum at 1607 cm.-1 attributable to the conjugated eneone system.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[N:12]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[C:13]=[O:14]>O1CCOCC1>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][NH:12][C:13]([N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[N:2]([CH3:1])[C:3]1=[O:11])=[O:14]
Reactant: Cc1ccccc1CN=C=O
Reactant: Cn1c(=O)[nH]c2ncccc21
Solvent: C1COCCO1
Product: Cc1ccccc1CNC(=O)n1c(=O)n(C)c2cccnc21

Procedure:
Analogously to Example 1, 75 mg (0.5 mmol) of 1-methyl-1,3-dihydroimidazo[4,5-b]pyridin-2-one were reacted with 74 mg (0.5 mmol) of 1-isocyanatomethyl-2-methylbenzene in dioxane at 80° C. Yield: 11 mg (7%), M+H+: 297.05.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.CO.C[O-].[Na+].[CH:19]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>O>[O:30]1[C:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[CH:19]=[N:20][CH:21]=[CH:22]3)=[CH:12][N:11]=[CH:10]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc2cnccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1cc2cc(-c3cnco3)ccc2cn1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To a 150 mL round-bottomed flask was added p-toluenesulfonylmethyl isocyanide (3.50 g, 18.0 mmol) and MeOH, followed by sodium methoxide (11.0 mL, 50.9 mmol) and a MeOH solution of isoquinoline-6-carbaldehyde (2.35 g, 15.0 mmol). The solution was stirred at reflux for about 1 hour and followed by LCMS. Water was added (50 mL) and the MeOH was removed in vacuo. The suspension was cooled to 0° C., and the resulting precipitate was filtered and dried in a vacuum oven overnight to give 6-(oxazol-5-yl)isoquinoline (2.50 g, 85% yield) as a tan powder. LCMS (API-ES) m/z (%): (100%, M++H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[N:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:19][CH2:18][C:16]1[CH:15]=[C:14]([C:20]([F:22])([F:23])[F:21])[N:13]=[C:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:17]=1
Reactant: OCc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(Oc2cc(CO)cc(C(F)(F)F)n2)CC1
Reaction time: 16 h

Procedure:
[2-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-6-(trifluoromethyl)pyridin-4-yl]methanol was dissolved in acetone (8 mL) and 10.0 M hydrogen chloride in water (1.5 mL, 15 mmol) was added. The reaction was stirred for 16 hours and LCMS analysis showed it was mostly complete. The reaction was neutralized with NaHCO3 and partitioned between EtOAc and water. The EtOAc extracts were washed with brine, dried and evaporated in vacuo. The crude product was used in the next reaction. MS (ES): 290 (M+1)
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:16]([CH3:17])[CH:15]=[CH:14][C:9]3=[N:10][C:11]=2[C:12]#[N:13])[CH2:3]1.[CH3:18][Mg]Br.CCOCC.[BH4-].[Na+]>C1COCC1>[NH2:13][CH:12]([C:11]1[N:10]=[C:9]2[CH:14]=[CH:15][N:16]([CH3:17])[C:8]2=[CH:7][C:6]=1[N:4]1[CH2:5][CH:2]([OH:1])[CH2:3]1)[CH3:18]
Reactant: Cn1ccc2nc(C#N)c(N3CC(O)C3)cc21
Reactant: C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(N)c1nc2ccn(C)c2cc1N1CC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(3-hydroxyazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (2.6 g, 11 mmol) in THF 100 mL at 0° C. was slowly added 3M methylmagnesium bromide in ether (15.2 mL, 45.6 mmol) to give a yellow solution. After 1 hour, the reaction mixture was warmed to RT and was stirred for an additional 2.5 hours. The reaction was then quenched with MeOH (5 mL). The mixture was stirred for 15 minutes. Sodium borohydride (0.862, 22.8 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction was subsequently quenched with 1M HCl (5 mL). The mixture was stirred for 15 minutes, diluted with EtOAc, and washed with saturated aqueous NH4Cl (3×). The aqueous layer was concentrated to give the title compound as a brown solid, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH3:15]>>[CH3:10][O:11][CH2:12][CH2:13][N:14]([CH3:15])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: CNCCOC
Product: COCCN(C)C(=O)c1cnn(C)c1

Procedure:
This compound was prepared in the same manner as described in example 97, step a starting from 1-methyl-1H-pyrazole-4-carboxylic acid (500 mg, 3.96 mmol) and 2-methoxy-N-methylethanamine (389 mg, 4.36 mmol). Yield: 580 mg (74%); colorless liquid; MS: m/z=198.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](=[C:15]2[S:19][CH:18]=[CH:17][S:16]2)[C:11](=[O:20])[C:10](C)([C:21](OCC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O>C(O)C>[CH2:1]([N:8]1[CH2:9][CH:10]([CH3:21])[C:11](=[O:20])[C:12](=[C:15]2[S:19][CH:18]=[CH:17][S:16]2)[C:13]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C)CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Ethyl 1-benzyl-5-(1,3-dithiol-2-ylidene)-3-methyl-4,6-dioxopiperidine-3-carboxylate (245 mg) is dissolved in ethanol (5 ml), and thereto is added a 10% sodium hydroxide solution (2.5 ml). The mixture is stirred at room temperature overnight. The mixture is acidified with 10% HCl, and poured into water. The aqueous solution is extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is dissolved in ethanol (20 ml) and the solution is refluxed for one hour. The mixture is distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, ethyl acetate:n-hexane=1:1), and is recrystallized from a mixture of ethyl acetate and n-hexane to give 1-benzyl-3-(1,3-dithiol-2-ylidene)-5-methyl-2,4-dioxopiperidine (138 mg, 69.1%) as pale yellow needles, m.p. 168°-170° C.
Reaction SMILES: [OH-].[Na+].CS(C)=O.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:16][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[OH:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A stirred solution of sodium hydroxide (16.8 g) in water (32 mL) at 20° C. is treated with dimethyl sulfoxide (560 mL). It is then treated with 3,4-dihydroxy-benzaldehyde (56.9 g), portionwise during 5 minutes, while keeping the temperature at 20° C. It is then treated with benzyl bromide (49.7 mL), portionwise, at 20° C. The solution is then heated at 80° C. for 6 hours and then allowed to stand at room temperature overnight. After dilution with ice-water (2240 mL) the solution is extracted with diethyl ether (1×1000 mL, 2×250 mL). The combined ether extracts are washed with water, dried over magnesium sulfate and concentrated, to give an oily solid, which is recrystallized from a mixture of ethyl acetate and isopropanol, to give 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g), in the form of pale yellow crystals, m.p. 118°-120° C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O[C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])C>C(O)(=O)C.C1C=CC=CC=1.[Zn]>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][N:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]3=[O:27])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCN
Reactant: O=CC1c2ccccc2CCc2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: O=C1CCCCN1CC1c2ccccc2CCc2ccccc21

Procedure:
By subjecting a mixture of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carboxaldehyde (2.2 g), described in Example 168, and 5-aminovaleric acid ethyl ester (1.45 g) and zinc dust (3.0 g) in 3.0 ml of acetic acid and 100 ml of benzene, to a 2 hour reflux, followed by removal of the excess zinc by filtration, addition of dilute sodium hydroxide solution to render the mixture alkaline and extraction with benzene affords the cyclic amide, N-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]2-piperidone, γmaxCHCl3 1650 cm-1, as an oil. Further treatment of this oil according to the conditions of the Bischler-Napieralski reaction described in Example 2, yields a product identical with the quaternary salt, 1,3,4,5,6,10,11,15b-octahydrobenzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolinium chloride obtained in Example 2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[Na].[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10])[CH3:13]
Reactant: CCO
Reactant: COc1c(Cl)ccnc1C
Agent: [Na]
Product: CCOc1ccnc(C)c1OC

Procedure:
4-Chloro-3-methoxy-2-methylpyridine (3.14 g) was added to a solution of sodium (2.0 g) in ethanol (30 ml), and the solution was refluxed by heating for 10 hours. The solvent was evaporated and the residue was added to ice water, which was extracted with chloroform, washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel, to give 4-ethoxy-3-methoxy-2-methyl-pyridine (2.6 g) as a light brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][C@H:12]3[C@:14]4([CH2:18][N:17]([CH2:19][C:20]([F:23])([F:22])[F:21])[S:16](=[O:25])(=[O:24])[NH:15]4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:26]=1)#[CH:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[N+:35]=[N-:36])=[CH:30][CH:29]=1>CC1C=CC(C)=CC=1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:2]=[C:1]([C:3]3[CH:4]=[CH:5][C:6]4[CH2:13][C@H:12]5[C@:14]6([CH2:18][N:17]([CH2:19][C:20]([F:21])([F:22])[F:23])[S:16](=[O:25])(=[O:24])[NH:15]6)[C@H:9]([CH2:10][CH2:11]5)[CH2:8][C:7]=4[CH:26]=3)[N:36]=[N:35]2)=[CH:30][CH:29]=1
Reactant: [N-]=[N+]=Nc1ccc(F)cc1
Reactant: C#Cc1ccc2c(c1)C[C@H]1CC[C@@H](C2)[C@]12CN(CC(F)(F)F)S(=O)(=O)N2
Solvent: Cc1ccc(C)cc1
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4ccc(F)cc4)nn3)cc2C1

Procedure:
A solution of the alkyne from Step 2 (0.075 g, 0.195 mmol) and 4-fluorophenylazide (0.035 g, 0.25 mmol) in p-xylene (5 mL) was refluxed under nitrogen for 21 hr. The solution was evaporated to dryness. Preparative HPLC on a normal phase column, eluting with an ethyl acetate-isohexane gradient gave the major cycloadduct (0.022 g). Further purification by reverse phase HPLC, eluting with an acetonitrile-pH3 buffer gradient, gave the triazole as yellow solid, which was rinsed with diethyl ether and dried to give a pale yellow powder (0.010 g, 10%).