Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[CH2:41][OH:42])[CH:12]=[CH2:13].CCN(CC)CC>C(Cl)Cl>[CH2:11]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[CH:41]=[O:42])[CH:12]=[CH2:13]
Reactant: C=CCn1c(-c2ccc(OC)cc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCn1c(-c2ccc(OC)cc2C=O)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
DMSO (5 eq.) was dissolved in DCM and the solution was cooled to −78° C. To the stirred solution oxalylchloride (2.5 eq.) was added and the mixture was left stirring for 30 min. A solution of methyl 1-allyl-3-cyclohexyl-2-[2-(hydroxymethyl)-4-methoxyphenyl]-1H-indole-6-carboxylate (1 eq.) in DCM (0.25M solution) was added and the mixture was left stirring for 30 min at −78° C. Et3N (8 eq.) was added and the mixture was allowed to warm to 0° C. At this temperature stirring was continued for 2 h, and then stirring was continued at RT overnight. The mixture was diluted with DCM, and then washed with water, 1N HCl, saturated aq. NaHCO3 solution and with brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The residual material was purified by flash chromatography (PE:EtOAc, 9:1). After evaporation of the solvents the product was obtained as a yellow foam (88%). MS (ES+): 432.1 (M+H+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]=[CH:13][C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.[F:19][C:20]([F:32])([F:31])[CH2:21][CH2:22][S:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:15][C:14]([F:17])([F:16])[CH:13]=[CH:12][CH2:11][CH:26]([S:23]([CH2:22][CH2:21][C:20]([F:19])([F:31])[F:32])(=[O:24])=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OCC=CC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CC=CC(F)(F)F)S(=O)(=O)CCC(F)(F)F
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a solution of 2.4 g of 4,4,4-trifluoro-2-butenyl p-toluenesulfonate and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide, 1.2 g of potassium carbonate was added at room temperature and stirred at the same temperature for 16 hours. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.40 g of methyl 6,6,6-trifluoro-2-(3,3,3-trifluoropropylsulfonyl)-4-hexenoate (hereinafter referred to as the present compound (17)).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=O)#[N:2].[CH3:20][NH2:21]>>[C:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)[N:6]=[CH:5][C:4]=1[C:15]([NH:21][CH3:20])=[O:17])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N
Reactant: CN
Product: CNC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N

Procedure:
A solution of 3.2 g of 5-cyano-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 40 ml of 3 A alcohol and 10 ml of 40% aqueous monomethylamine was refluxed for approximately 2 hours. Ten additional milliliters of 40% aqueous monomethylamine was added to the reaction mixture which was then refluxed for an additional 3 hours. The mixture was cooled and the precipitated solid was collected by filtration to provide 1 g of 5-cyano-1-(4-bromophenyl)-N-methyl-1H-pyrazole-4-carboxamide. MP=240°-241° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[CH2:3][CH2:2]1.[N:23]([CH3:26])=[C:24]=[O:25]>ClCCCl>[CH3:26][NH:23][C:24]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[CH2:5][CH2:6]1)=[O:25]
Reactant: O=c1[nH]c2nccc(NC3CCNCC3)c2c2ccccc12
Reactant: CN=C=O
Solvent: ClCCCl
Product: CNC(=O)N1CCC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
358 (50 mg, 0.17 mmol) and isocyanatomethane (15 mg, 0.25 mmol) were suspended in DCE (2 mL), and stirred overnight at room temperature. The crude material was purified directly via HPLC to provide 359 (26 mg, 44% yield) as a solid. LC-MS (M+H=351, obsd.=351).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[I:15]I>CO.FC(F)(F)C([O-])=O.[Ag+]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[I:15]
Reactant: COC(=O)C(C)(C)c1ccc(N)nc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: COC(=O)C(C)(C)c1cnc(N)c(I)c1
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A solution of methyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate (10.0 g, 51.5 mmol) in MeOH (50 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a vigorously stirred suspension of iodine (17.0 g, 67.0 mmol) and silver trifluoroacetate (14.8 g, 67.0 mmol) in MeOH (200 mL) at room temperature. After 3 h, the reaction was quenched sequentially with 1M Na2S2O3 followed by saturated aqueous NaHCO. The resulting mixture was filtered through celiteo washing copiously with ethyl acetate, the filtrate concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was re-extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution; 35-40% ethyl acetate/hexanes as eluent) to give the title compound as an off-white solid (10.3 g, 62%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:14][C:15]1[C:20]([OH:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].N1C=CC=CC=1>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:21][C:20]2[C:19]([F:22])=[C:18]([F:23])[C:17]([F:24])=[C:16]([F:25])[C:15]=2[F:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 10.8 g of 4-acetoxybenzoyl chloride in dry acetonitrile was treated with 10 g of pentafluorophenol, and stirred at 0° C. whilst 4.4 ml of pyridine was added dropwise. The solution was permitted to warm to room temperature then heated to reflux temperature until the reaction was complete. Solvent was evaporated in vacuo and the residue obtained partitioned between ethyl acetate and water. The organic solution was washed with further portions of water and brine and dried over magnesium sulphate. Evaporation afforded 18 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13])=[O:4].CCN(C(C)C)C(C)C>C(#N)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][O:13][C:7]=2[CH:8]=1
Reactant: O=C(CCl)Nc1ccc(F)cc1O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1COc2cc(F)ccc2N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide (5.5 g, 27 mmol) in acetonitrile (40 mL) was added DIPEA (7 g, 54 mmol) and the reaction solution was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 3.5 g (78%) of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one as a brown solid. 1H NMR (400 MHz, CDCl3) δ 8.35 (br. s, 1H) 6.67-6.77 (m, 3H) 4.62 (s, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH2:4][C@H:3]1[CH2:13][C:14]#[N:15].C(N(C(C)C)CC)(C)C.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C.CO>[C:14]([CH2:13][C@@H:3]1[CH2:4][C@H:5]([N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH2:6][CH2:7][C@@H:2]1[NH:1][C:34](=[O:35])[CH2:33][NH:32][C:30](=[O:31])[C:29]1[CH:37]=[CH:38][CH:39]=[C:27]([C:26]([F:25])([F:41])[F:40])[CH:28]=1)#[N:15]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CC#N)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC#N
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CC#N)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-((1S,2S,5R)-2-amino-5-(isopropyl(methyl)amino)cyclohexyl)acetonitrile (100 mg, 0.27 mmoles) in 2 ml of anhydrous acetonitrile were added diisopropylethylamine (0.24 ml, 1.35 mmoles), 2-(3-(trifluoromethyl)benzamido)acetic acid (66.6 mg, 0.27 mmoles) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (95.2 mg, 0.3 mmoles, Bachem), and the mixture was stirred for 18 hours at room temperature. Then several drops of methanol was added, and it was stirred for additional two hours. The solvent was evaporated off and the residue was purified by chromatography (silica gel, 0.7:6.3:93 cNH4H-MeOH—CH2Cl2) to give N-(2-((1S,2S,4R)-2-(cyanomethyl)-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide. MS found: (M+H)+=439.3.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:23])[CH2:9][CH2:10][N:11]([CH2:15][C:16]1[S:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=1)[C:12]([NH2:14])=[S:13])([CH3:6])([CH3:5])[CH3:4].CCO[C:27]([CH3:29])=O>>[C:3]([O:7][C:8](=[O:23])[CH2:9][CH2:10][N:11]([C:12]1[S:13][CH:15]=[C:16]([CH:20]2[CH2:19][CH:18]3[CH2:29][CH:27]2[CH2:22][CH2:21]3)[N:14]=1)[CH2:15][C:16]1[S:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=1)([CH3:5])([CH3:6])[CH3:4]
Reactant: CCOC(C)=O
Reactant: CCc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Solvent: CO
Product: CCc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc(C3CC4CCC3C4)cs2)s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Following a method analogous to General Procedure C, a portion of the above crude alpha-bromoketone (81 mg, 0.37 mmol) was added to a methanol (about 10 mL) solution of 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (122 mg, 0.371 mmol) and the reaction was heated at 60° C. and stirred overnight. The solvent was evaporated and ethyl acetate and saturated aq sodium bicarbonate solution were added to the residue. Extraction of the aq layer was performed two times with ethyl acetate. The combined organic portion was dried over sodium sulfate, and the dried solvent was decanted from the drying agent. The solvent was removed under reduced pressure to give the crude material. This was purified using silica gel chromatography (eluent: hexanes→19:1 hexanes:EtOAc→9:1 hexanes:EtOAc to give the purified 3-[(4-bicyclo[2.2.1]hept-2-yl-thiazol-2-yl)-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester (139 mg, 0.311 mmol, 84%) after evaporation of the eluent under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+]>C(#N)C>[F:16][CH:12]([F:17])[O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:16][CH:12]([F:17])[N:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]1=[O:1]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC(F)F)nc1
Product: O=c1ccc([N+](=O)[O-])cn1C(F)F
Yield: 1.5 %
Yield: 15 %

Procedure:
2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro-acetate (11.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) afforded 2-difluoromethoxy-5-nitro-pyridine (1 g, 15%) and 1-difluoromethyl-5-nitro-1H-pyridin-2-one (90 mg, 1.5%). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MH+); 1H NMR (400 MHz, CDCl3) 7.05 (d, 1H), 7.51 (t, 1H), 8.53 (dd, 1H), 9.09 (d, 1H). 1-Difluoromethyl-5-nitro-1H-pyridin-2-one: MS (ES+) 191 (MH+); 6.65 (d, 1H), 7.63 (t, 1H), 8.14 (dd, 1H), 8.73 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=1>CN(C=O)C>[CH3:17][N:14]1[C:15]([CH3:16])=[C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=3)=[CH:3][CH:4]=2)=[O:10])[C:12](=[O:24])[N:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
To a solution of N-(4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.80 g, 5.57 mmol) in DMF (35 mL) was added potassium tert-butoxide (1.87 g, 16.7 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (1.046 g, 6.68 mmol). The reaction was heated at 120° C. for 3 hours, then concentrated to 2 mL in vacuo, and diluted with water (60 mL). The precipitate was obtained by filtration, washed with water (5 mL) and dried. The crude product was washed with DCM (20 mL) to give the title compound as a brown solid (1.8 g, 73%).
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.[C:19]([O-])(=O)[CH3:20].[Na+].Cl.[Br:25][C:26]1[CH:27]=[CH:28]C=[C:30]([NH:32][NH2:33])[CH:31]=1>>[Br:25][C:26]1[CH:27]=[CH:28][C:19]([CH3:20])=[C:30]([N:32]2[C:2]3[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=3)[C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:33]2)[CH:31]=1
Reactant: CC(=O)[O-]
Reactant: NNc1cccc(Br)c1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(Br)cc1-n1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Yield: 10 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.5 g, 2 mmol), sodium acetate (0.25 g, 3 mmol) and 5-bromophenylhydrazine hydrochloride (0.440 g, 2.4 mmol) to give 0.082 g of product as an off-white solid
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=O.[CH3:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2>C(O)(=O)C>[CH3:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[C:18]([C:19]=1[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: C1CCNCC1
Reactant: C=O
Reactant: Cc1cc2ccccc2c(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c2ccccc2c1CN1CCCCC1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Piperidine (0.747 mL) and paraformaldehyde (271 mg) were dissolved in acetic acid (3 mL), and the mixture was stirred at 70° C. for 5 min. 3-Methyl-2H-isoquinolin-1-one (302 mg) was added to the reaction mixture, and the mixture was heated under reflux for 2.5 hrs. After the completion of the reaction, the reaction mixture was concentrated, aqueous potassium carbonate solution was added. The mixture was extracted with chloroform, and the organic layer was dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 3-methyl-4-(piperidin-1-yl)methyl-2H-isoquinolin-1-one (99.3 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][CH:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:14]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Using a modified procedure by R. M. Kellogg et al. (J. Org. Chem., 33: 2902-290 (1968)), to a 0° C. solution of 6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (Eras, J.; Galvez, C.; Garcia, F., J. Heterocycl. Chem., 21: 215-217 (1984); 1.45 g, 7.44 mmol) in acetic acid (15 mL) and CHCl3 (15 mL) was added N-chlorosuccinimide (1.04 g, 7.81 mmol) over 2 h. The reaction mixture was slowly allowed to warm to room temperature over several hours, stirred overnight, concentrated to remove the chloroform, diluted with water, basified with 5 N NaOH, and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated. The product was purified by chromatron chromatography (radial) using 90:10 hexanes/diethyl ether and then then then the product obtained was recrystallized using hexanes/diethyl ether (90:10). Last, the product of the recrystallization was further purified by flash column chromatography using 90:10 petroleum ether/isopropyl ether. The resulting product was obtained as a white solid (824 mg, 48%).
Reaction SMILES: CS[S:3][CH3:4].C(P(CCCC)CCCC)CCC.[C:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH2:38]O)=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1.C(OCC)(=O)C>[C:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH2:38][S:3][CH3:4])=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)Oc1ccc(CCCCn2ccnc2CO)cc1
Reactant: CSSC
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CSCc1nccn1CCCCc1ccc(OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dimethyl disulfide (8.94 ml) and tributylphosphine (24.7 ml) were added to a solution of [1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazol-2-yl]methanol (10.0 g) in pyridine (13.4 ml) at room temperature, and the mixture was stirred at room temperature for 17 hr. The reaction mixture was diluted with ethyl acetate, successively washed with 1N aqueous sodium hydroxide solution (3 times) and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 1-[4-(4-tert-butoxyphenyl)butyl]-2-[(methylthio)methyl]-1H-imidazole. 4N Hydrochloric acid (33 ml) was added to the product, and the mixture was stirred at 50° C. for 2 hr. After cooling, the reaction mixture was combined with water and ethyl acetate and separated. The water layer was adjusted to pH 6 by adding 30% aqueous sodium hydroxide solution to salt out and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with diisopropyl ether to give the titled compound (7.31 g) as a colorless crystal powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13](=O)[CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.[C:27]([NH:30][NH2:31])([NH2:29])=[NH:28].[ClH:32]>Cl.C(O)C>[ClH:32].[C:27]([NH:30][N:31]=[C:13]([CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH:12]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[NH:28])[NH2:29]
Reactant: N=C(N)NN
Reactant: O=C(C=Cc1ccc2ccccc2c1)C=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=C(C=Cc1ccc2ccccc2c1)C=Cc1ccc2ccccc2c1

Procedure:
Utilizing the general procedure of Example 1, 6.9 grams of 1,5-bis(2-naphthyl)-1,4-pentadien-3-one, 2.5 grams of aminoguanidine hydrochloride, 5 drops of concentrated hydrochloric acid, and 250 ml. of ethanol, and employing a 16 hour reflux period, 6.4 g. of the above compound is obtained, melting at 232°-234° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])C#N)C.C[O:11][CH:12]([C:15]([CH:17](OC)[O:18]C)=O)OC>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:17]([OH:18])[CH2:15][CH2:12][OH:11].[O:3]1[CH2:1][CH2:9][CH2:8][O:7][CH2:4]1
Reactant: CCOC(C#N)OCC
Reactant: COC(OC)C(=O)C(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C1COCOC1
Product: OCCCO

Procedure:
The new route to Michael acceptors enabled expansion of the structural diversity of these intermediates. Diethoxymethyl Michael acceptor 1b was prepared from commercially available diethoxyacetonitrile in analogy with the synthesis of 1a. Transacetalization of diethoxyacetal 1b with 1,3-propanediol in benzene/TsOH afforded 1,3-dioxane 1c in 64% yield. On the other hand, attempted transacetalization of 1b with ethylene glycol gave an inseparable mixture consisting of 1,3-dioxolane 1d and a by-product assumed to be bis(1,3-dioxolane) C (Scheme 6). Transacetalization of diethoxyacetonitrile with ethylene glycol in the presence of TsOH also did not proceed. Therefore, we considered an alternative approach to 1d.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:33](N1C=CC=CC1=O)(N1C=CC=CC1=O)=S.[NH2:49][CH2:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:52]([C:51]1[O:56][C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[CH:10][C:11]([C:14]45[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25][CH2:26][C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)=[O:24])([CH2:18][CH2:19]4)[O:16][CH2:15]5)=[CH:12][CH:13]=3)=[N:6][CH:7]=2)=[N:49][CH:50]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)C(=O)CN
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1ccc(-c2ccc(C34CCC(CC(=O)OCc5ccccc5)(CC3)OC4)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)OCc6ccccc6)(CC4)OC5)cc3)nc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of benzyl 2-(4-(4-(5-aminopyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (150 mg, 0.350 mmol) in DCM (6 ml) at room temperature was added 1,1′-thiocarbonyldi-2(1H)-pyridone (85 mg, 0.368 mmol) and the reaction was stirred at room temperature for 0.5 hr. To the mixture was added 1-amino-3,3-dimethylbutan-2-one (80 mg, 0.525 mmol) and DIPEA (0.110 ml, 0.630 mmol) and the mixture was stirred at 40° C. or until the reaction was completed. To the mixture was added EDC.HCl (268 mg, 1.400 mmol) and the reaction was stirred at 40° C. overnight. The reaction mixture was concentrated and purified by flash chromatography (10 to 50% EtOAc/Heptane) to give the title compound (100 mg, 51.8% yield). LC/MS, ESI-MS(+) m/z 552.1, RT: 1.73 (Condition R).