Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.CC(C)([O-])C.[K+].CN(C=O)C>C(OCC)(=O)C>[N:31]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)(=[O:23])=[O:24])=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3F)nccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3-n3ccnc3)nccc2c1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.090 g, 0.198 mmol), imidazole (0.054 g, 0.794 mmol), and potassium tert-butoxide (0.111 g, 0.992 mmol). DMF (0.992 ml) was added and the reaction was heated in a microwave reactor at 150° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, then acidified with concentrated HCl solution and extracted twice with ethyl acetate. The aqueous layer was passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The ammonia/methanol filtrate was combined with the previously isolated organic layers. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM) to afford 1-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.90 (br. s., 1H), 8.66 (d, J=5.7 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.13 (d, J=5.4 Hz, 1H), 8.08 (s, 1H), 8.03 (dd, J=1.2, 8.1 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.79-7.73 (m, 1H), 7.70-7.63 (m, 1H), 7.48 (t, J=1.0 Hz, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.89-6.81 (m, 2H), 6.62 (t, J=1.1 Hz, 1H). m/z (ESI) 502.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[O:29]([C:31]#[N:32])[K]>O.CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([C:31]([NH2:32])=[O:29])[CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: N#CO[K]
Reactant: O=C(NCc1cn(-c2ccc(N3CCNCC3=O)cc2)nn1)c1ccc(Cl)s1
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)N1CCN(c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)C(=O)C1
Temperature: 25 °C

Procedure:
5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (23 mg, 0.055 mmol, prepared as shown in Example 60) was dissolved in 2 mL water and 0.5 mL DMSO. To it was added KOCN (23 mg, 0.28 mmol). The mixture was stirred at RT over the weekend. The title compound was the major product in this reaction and was isolated using direct reverse phase prep HPLC. MS found for C19H18ClN7O3S (M+H)+ 460.1, 462.1 (Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1>C(O)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=Cc2cnc3nc(N)nc(N)c3c2)cc1
Solvent: O=CO
Product: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Yield: 79.1 %

Procedure:
A solution of 1.27 g of 2,4-diamino-6-[2-(4-tert-butoxycarbonylphenyl)ethenyl]pyrido[2,3-d]pyrimidine and 10 mL 88% formic acid was stirred at room temperature. A yellow solid started to form after about 12 hours and after 4 days of stirring, the reaction mixture was filtered. The collected solid was washed well successively with water, methanol, and acetone and was then dried under reduced pressure to give 0.85 g (79%) of the title compound, which can be alternatively named as 2,4-diamino-6-(4-carboxystyryl)-5-deazapteridine, mp >300° C.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[O:14]=[S:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]3=[O:37])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.CN1CCOCC1>ClCCl>[O:14]=[S:15]1(=[O:4])[CH:16]=[CH:17][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]3=[O:37])=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)CC3)cc2)C(=O)O1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic anhydride (2.98 mL, 21.1 mmol) is added dropwise at room temperature to a solution of N-[[(5S)-3-[4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2.46 g, 7.02 mmol; prepared as described in International Publication WO 97/09328) and N-methylmorpholine (3.86 mL, 35.1 mmol) in dichloromethane (60 mL). The reaction mixture is stirred overnight at room temperature and then evaporated to dryness. The resulting crude N-[[(5S)-3-[4-(3,4-dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2.77 g) is dissolved in tetrahydrofuran (100 mL) and peracetic acid (7.01 mL of a 32% solution in acetic acid) added dropwise at 0° C. The reaction mixture is allowed to warm to room temperature, stirred overnight, and then evaporated to dryness. The residue is purified by flash column chromatography (ethyl acetate) to give the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[Na].S(=O)(=O)=O>CC(N(C)C)=O.O>[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([C:17]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)=[CH:15][CH:14]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: NC(=O)c1ccccc1N
Agent: O=S(=O)=O
Agent: [Na]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)c1ccc(-c2nc(O)c3ccccc3n2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-aminobenzamide (1.36 g, 9.99 mmol, 1.00 equiv) in dimethylacetamide (25 mL), 4-(dimethylamino)benzaldehyde (1.49 g, 9.99 mmol, 1.00 equiv) and sulfonylideneoxidane sodium (1.6 g, 15.53 mmol, 1.50 equiv). The resulting solution was stirred overnight at 150° C. in an oil bath. The reaction mixture was cooled to 25° C. The resulting solution was diluted with 100 mL of water. The solids were collected by filtration. The solid was washed with 2×20 mL of water and 1×20 mL of petroleum ether. This resulted in 2.1 g (79%) of 2-[4-(dimethylamino)phenyl]quinazolin-4-ol as a gray solid. MS (ESI) m/z 266 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)[CH2:3][CH3:4].I([O-])(=O)(=O)=[O:22].[Na+].CCOCC>CO.O>[CH3:1][CH:2]([S:5]([C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)=[O:22])[CH2:3][CH3:4]
Reactant: CCOC(=O)NCCOc1ccc(SC(C)CC)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)NCCOc1ccc(S(=O)C(C)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl N-[4-(1-methylpropylthio)phenoxyethyl]carbamate (cpd. 40, from Example 13) (2.13 g, 7.1 mmol) in 7 ml of methanol at 0° is added, dropwise over 5 min., sodium metaperiodate (1.67 g, 7.8 mmol) in 13 ml of water. The mixture is stirred for 3 hours while warming to RT. The reaction is worked up by addition of water and extraction of ether. The combined organic extracts are washed with saturated sodium thiosulfate, with water and with brine, dried and the solvent is removed to give ethyl N-{2-[4-(1-methylpropylsulfinyl)phenoxy]-ethyl}carbamate (compound 80, Table A).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[CH2:52][CH2:51]1>CN(C=O)C>[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[CH2:52][CH2:51]1
Reactant: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(c4)CCO5)c3)c(=O)oc12
Temperature: 25 °C
Yield: 95.4 %

Procedure:
DIEA (0.014 mL, 0.078 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.071 mmol) and HATU (0.030 g, 0.078 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzofuran-5-yl)-phenylamine (0.015 g, 0.071 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.028 g of product in 94% yield: LCMS (ESI) m/z 414 (MH+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[C:7]([F:13])[CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Br:12][C:8]1[C:9]([F:11])=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][C:7]=1[F:13]
Reactant: [N-]=[N+]=NCc1cc(F)c(Br)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(F)c(Br)c(F)c1
Temperature: 55 °C

Procedure:
To a mixture of the crude azide (70 mg, 0.28 mmol) in THF (4 mL) were added polymer-supported Ph3P (3.0 eq.) and water (1 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.37 min; [M+CH3CN+H]+=263.15.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.Cl>CO>[CH3:8][O:7][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[NH:12][C:13]1[CH:14]=[C:15]([CH:19]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
3,4-dimethoxy-3-cyclobutene-1,2-dione (428 mg) was added to a solution of N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]benzamide hydrochloride (555 mg) [prepared as described in step (d) above] in methanol (15 ml) at ambient temperature. After stirring for 10 minutes, a solution of triethylamine (153 mg) in methanol (10 ml) was added dropwise to the mixture. This mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then slightly acidified with hydrochloric acid (0.5N) and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford the title compound (505 mg) as a white foamy solid.
Reaction SMILES: BrC1C=CC2[C:6]3[C:11]([C:12]4[C:17]=2[C:16]=1[CH:15]=[CH:14][CH:13]=4)=[CH:10][C:9](Br)=[CH:8][CH:7]=3.[CH:19]1[C:33]2=[C:34]3[C:26]([C:27]4[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:24]=[CH:23][C:22]3=[CH:21][CH:20]=1.BrBr.[C:37]1([CH3:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[C:40]1([C:23]2[CH:24]=[CH:25][C:26]3[C:27]4[C:32]([C:33]5[C:34]=3[C:22]=2[CH:21]=[CH:20][CH:19]=5)=[CH:31][C:30]([C:15]2[CH:14]=[CH:13][C:12]([C:11]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:17][CH:16]=2)=[CH:29][CH:28]=4)[CH:41]=[CH:42][C:37]([C:43]2[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=2)=[CH:38][CH:39]=1
Reactant: Brc1ccc2c(c1)-c1cccc3c(Br)ccc-2c13
Reactant: c1ccc2c(c1)-c1cccc3cccc-2c13
Reactant: Cc1ccccc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2ccc(-c3ccc4c(c3)-c3cccc5c(-c6ccc(-c7ccccc7)cc6)ccc-4c35)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
1 g of 3,8-dibromofluoranthene, prepared by dibromination of fluoranthene in chloroform with elemental bromine, was dissolved under protective gas in 100 ml of dried toluene and degassed repeatedly. 19.4 g of potassium carbonate dissolved in 47 ml of ethanol/water (1:1 parts by volume) and 1 g of 4-biphenylboronic acid were added and degassed again. Subsequently, 0.32 g of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) was added under protective gas and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was filtered and dried. Yield: 14% as a yellowish solid. λmax,em (toluene)=479 nm, quantum yield (toluene): 74%.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[S:12]([NH2:22])(=[O:21])([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:13].O.[NH2:24][NH2:25]>CCO>[NH2:2][C:1]1[NH:25][N:24]=[C:7]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([S:12](=[O:21])(=[O:13])[NH2:22])=[CH:19][CH:18]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: NN
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CCO
Solvent: O
Product: NC(=O)c1c(Nc2ccc(S(N)(=O)=O)cc2)n[nH]c1N
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added Sulfanilamide (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-sulfamoylphenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])O.C1[CH:10]2[O:11]C([CH:8]3[C:15](=O)[O:14]C(=O)[CH:9]32)C=1.C([OH:19])C>>[OH:14][CH2:15][CH2:8][C:9]1[C:10]([NH:4][C:3](=[O:19])[CH:1]=1)=[O:11]
Reactant: NCCO
Reactant: O=C1OC(=O)C2C3C=CC(O3)C12
Reactant: CCO
Product: O=C1C=C(CCO)C(=O)N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethanolamine (80.96 g, 1.32 mol) was added to 500 mL of ethanol and cooled to 0° C. using an ice bath. 3,6-Endoxo-1,2,3,6-tetrahydrophthalic anhydride (220.21 g, 1.32 mol) was added to the solution and allowed to stir overnight. The yellow tinted crystals were used without purification. The solution was refluxed for four hours with azeotropic removal of water. The solution was cooled to 0° C. and the resulting crystals filtered (151.74 g, 54.95%). Removal of furan was facilitated by refluxing the crystals in xylenes for 4 hours with quantitative yield of hydroxy ethylmaleimide after purification by sublimation to yield white crystals, —CH2O—), 134.2 (2C, —CH═CH—), 171.2 (2C, —NC═O m.p. 68° C. 1H-NMR (CDCl3, δ, ppm): 2.62 (1H, —OH, s), 3.82-3.77 (4H, —NCH2CH2O—, overlapping), 6.76 (2H, —CH═CH—, s). 13C-NMR (CDCl3, δ, ppm): 40.5 (1C, —NCH2—), 60.5 (1C,).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O.[C:23](=O)([O-])[OH:24].[Na+]>CN(C=O)C.O>[N:12]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([C:3]([CH:23]=[O:24])=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C([O-])O
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
A solution of (1H-indol-6-yl)(morpholino)methanone (200 mg, 0.869 mmol, 1.0 eq) in DMF (3.0 ml) was added dropwise at 0° C. to phosphorus oxychloride (0.34 mL, 2.60 mmol, 3.0 eq) in DMF (5.0 mL) under stirring. The mixture was stirred at room temperature for 3 h, then neutralized with saturated sodium hydrogen carbonate solution, diluted with water (20 mL), and extracted with ethyl acetate (2×10 mL). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography [100-200 mesh; methanol/dichloromethane=1:9]. White solid. Yield: 100 mg (45% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].C(N(CC)CC)C.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][CH2:59][NH2:60])[CH2:53][CH2:52]2)[CH:48]=[CH:49][CH:50]=1>CN(C=O)C>[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][CH2:59][NH:60][C:24]([NH:1][C:2]3[CH:3]=[C:4]([N:8]4[C:9]([C:20]([O:22][CH3:23])=[O:21])=[C:10]([CH3:19])[NH:11][C:12]([CH3:18])=[C:13]4[C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][CH:7]=3)=[O:25])[CH2:53][CH2:52]2)[CH:48]=[CH:49][CH:50]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N)c1
Reactant: COc1cccc(C2CCN(CCCN)CC2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(NC(=O)NCCCN2CCC(c3cccc(OC)c3)CC2)c1
Reaction time: 1 h
Yield: 71.9 %

Procedure:
4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyrazinedicarboxylic acid, dimethyl ester (150 mg, 0.47 mmol) was slowly added into a mixture of 1,1′-carbonyidiimidazole (117 mg, 0.72 mmol) and triethylamine (145 mg, 1.44 mmol) in 5 mL of DMF and the reaction mixture was stirred for 60 min. 4-(3-Methoxyphenyl)piperidine-1-propanamine (176 mg, 0.69 mmol) was added to the reaction mixture, and the reaction was stirred at room temperature for 30 min. DMF was removed in vacuo and the residue was purified by chromatography (on silica gel, 10% (v/v) methanol in methylene chloride then followed by 2M ammonia in methanol) to give the title compound as an orange foam (200 mg, 72%); 1H-NMR (CDCl3) δ 7.55 (br, 1H), 7.35 (br, 1H), 7.20 (t, 1H, J=7.6 Hz), 6.92 (t, 1H, J=8.1 Hz), 6.60-6.80 (m, 4H), 6.54 (d, 1H, J=7.6 Hz), 6.32 (dd, 1H, J=8.2, 2.0 Hz), 5.99 (br, 1H), 3.77 (s, 3H), 3.71 (s, 6H), 3.16 (m, 2H), 3.03 (m, 2H), 2.46 (m, 3H), 2.29 (s, 6H), 1.95-2.20 (m, 2H), 1.60-1.90 (m, 6H); 13C-NMR (CDCl3) δ 166.6, 159.7, 156.8, 151.9, 149.7, 147.4, 139.4, 129.5, 129.2, 119.3, 112.9, 111.4, 108.9, 108.5, 106.1, 56.0, 55.2, 54.1, 51.7, 42.2, 38.6, 32.8, 26.8, and 17.6.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](O)(=[O:20])[CH:18]=[CH2:19]>CN(C)C=O>[C:17]([NH:9][C:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)=[O:8])(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)O
Reactant: NC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)NC(=O)C1CCNCC1

Procedure:
Into a liquid reaction mixture of 4-piperidinecarboxamide (5.0 mg) and triethylamine (5.3 ml) in dimethylformamide (70 ml), a solution of acrylic acid (3.2 ml) dissolved in dimethylformamide (20 ml) was dropped under ice-cooling over 3 hours. After the completion of the addition, the resultant mixture was stirred at room temperature for 1 hour and then filtered. From the filtrate thus obtained, the solvent was eliminated by using a rotary evaporator. After adding an acetone solution to the residue, the mixture was treated with a silica gel column to give N-acryloyl-4-piperidinecarboxamide (1.4 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:28][CH2:27][CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCOc1ccccc1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCOc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 96.8 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.700 mmol), TEA (0.106 g, 1.050 mmol) and 2-phenoxyethylamine (0.144 g, 1.050 mmol) in MeCN (3 mL) was heated at in a microwave reactor 120° C. for 5 mins. The residue was purified by silica gel column chromatography (Horizons Biotage) using a 65:35 mixture of heptane and EtOAc as eluant to give the title compound (0.262 g, 97%); 1H NMR (500 MHz, CDCl3): δ 7.57-7.54 (m, 2H), 7.49-7.45 (m, 3H), 7.32-7.27 (m, 2H), 7.02-6.97 (m, 1H), 6.86-6.83 (m, 2H), 5.71-5.66 (br m, 1H), 4.46-4.39 (m, 1H), 3.89 (t 2H), 3.27 (q 2H), 1.60 (d 6H); 13C NMR (125 MHz, CDCl3): δ 158.5, 158.2, 135.6, 131.7, 130.0, 129.8, 129.1, 125.1, 121.8, 114.7, 108.0, 65.8, 47.8, 43.6, 20.4; Mass Spectrum: M−H+ 387.
Reaction SMILES: [CH:1]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][Cl:20].O>C1COCC1.C1COCC1.CCCCCC>[Cl:20][CH2:19][C:1]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCBr
Reactant: N#CC1CCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(CCl)CCCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
A solution of cycloheptanecarbonitrile (12.3 g), 100 mmol) in THF (50 ml) was added dropwise to a well stirred solution of lithium diisopropylamide (105 mmol) in THF/hexane (75 ml/60 ml) under nitrogen, keeping the temperature at -65°. After 1 h, the solution was allowed to warm to ambient temperature and added dropwise to a well stirred solution of bromochloromethane (32.5 ml; 500 mmol) in THF (50 ml) under nitrogen keeping the temperature between -50° and -60°. After 10 min, the solution was allowed to warm to ambient temperature, poured into water (250 ml) and the aqueous mixture extracted with chloroform (3×150 ml). The extracts were washed with 2N-HCl (2×50 ml), saturated aq. NaHCO3 (100 ml), and water (100 ml), then dried (MgSO4) and evaporated under reduced pressure to give a brown oil (18.0 g). Distillation gave the title compound (12.65 g), b.p. 78°-80° at 0.25 mmHg.