Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][N:38]([CH3:53])[CH2:39][CH2:40][N:41]([CH3:52])[C:42]1[S:43][C:44]2[CH:50]=[C:49]([NH2:51])[CH:48]=[CH:47][C:45]=2[N:46]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:37][N:38]([CH3:53])[CH2:39][CH2:40][N:41]([CH3:52])[C:42]1[S:43][C:44]2[CH:50]=[C:49]([NH:51][C:8](=[O:10])[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[CH:48]=[CH:47][C:45]=2[N:46]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)C=Cc3ccc(F)cc3)cc2s1
Yield: 11.3 %

Procedure:
Prepare according to Method A, using 4-fluorocinnamic acid (100 mg, 0.602 mmol), HATU (228 mg, 0.600 mmol), N2-(2-dimethylamino-ethyl)-N2-methyl-benzothiazole-2,6-diamine (100 mg, 0.400 mmol), DIEA (260 μL, 1.49 mmol), and a chromatography gradient of MeOH in CH2Cl2 (8-20%) to yield the title compound (18 mg, 11%). mass spectrum (m/e): 399.0 [M+H]. 1H NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 8.30 (d, 1H, J=1.8 Hz), 7.72-7.66 (m, 2H), 7.57 (d, 1H, J=15.8 Hz), 7.50 (dd, 1H, J=8.8, 2.2 Hz), 7.43 (d, 1H, J=8.8 Hz), 7.32-7.25 (m, 2H), 6.84 (d, 1H, J=15.8 Hz), 3.95 (dd, 2H, J=6.4, 6.4 Hz), 3.39-3.33 (m, 2H), 3.13 (s, 3H), 2.83 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH2:20][CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([NH2:34])=[CH:32][C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[N:25]1([C:28]2[C:33]([NH:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[C:3]=3[CH2:20][CH3:21])=[CH:32][C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:30][N:29]=2)[CH2:24][CH2:23][O:22][CH2:27][CH2:26]1
Reactant: CCc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-3-ethyl-5,7-difluoro-2-(pyridin-2-yl)quinoline (40.0 mg, 0.131 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-3-ethyl-5,7-difluoro-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.70 (1H, td, J=2.4, 1.0 Hz), 7.79-8.00 (2H, m), 7.53-7.66 (2H, m), 7.45 (1H, d, J=6.3 Hz), 7.40 (1H, ddd, J=7.3, 4.8, 1.6 Hz), 6.98 (1H, ddd, J=12.8, 8.7, 2.6 Hz), 6.43 (1H, d, J=2.3 Hz), 3.87-4.07 (4H, m), 3.73-3.82 (4H, m), 3.15-3.35 (4H, m), 2.93-3.03 (4H, m), 2.70 (2H, br. s.), 0.98 (3H, t, J=7.5 Hz). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: CO[C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[N:8]([CH2:18][CH2:19][CH2:20][CH3:21])[C:7](=[O:22])[CH2:6]1)=[O:4].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>C1(C)C=CC=CC=1>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11](=[O:12])[CH:5]([C:3](=[O:4])[NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH2:6][C:7](=[O:22])[N:8]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]=2[CH:16]=1
Reactant: Nc1nccs1
Reactant: CCCCN1C(=O)CC(C(=O)OC)C(=O)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)CC(C(=O)Nc2nccs2)C(=O)c2ccc(Cl)cc21

Procedure:
The mixture of 3.8 g of 8-chloro-1-n-butyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester, 1.17 g of 2-aminothiazole and 70 ml of toluene is distilled for 20 hours so that after collecting 25 ml of toluene each, this amount is returned to the reaction mixture. It is finally concentrated to a small volume, the resulting suspension cooled with ice, filtered and the residue recrystallized from chloroform-acetonitrile, to yield the 8-chloro-1-n-butyl-4-(2-thiazolylcarbamoyl)-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione melting at 238° to 240°.
Reaction SMILES: C1OC1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](=[O:15])([OH:14])[OH:13].C=CCCCCCCCC>>[CH2:10]1[CH:9]([C:8]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:14][C:12](=[O:13])[O:15]1
Reactant: O=C(O)O
Reactant: CCCCCCCCC1CO1
Agent: C=CCCCCCCCC
Product: O=C1OCC(c2ccccc2)O1

Procedure:
Decene oxide (8.98 mins), decene carbonate (13.40 mins)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:16][OH:17])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][O:5][N:6]=1.C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[C:23](=[O:24])[O:17][N:16]=2)=[N:4][O:5][N:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nonc1C(=NO)Nc1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Yield: 95.4 %

Procedure:
A solution of 4-amino-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (540 mg, 2.1 mmol) and N,N-carbonyldiimidazole (380 mg, 2.3 mmol) in tetrahydrofuran (10 mL) was heated at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with 0.1 N HCl (3×75 mL) and brine (75 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated to give the desired product (560 mg, 94%) as a white solid which was used without further purification. LCMS for C10H7ClN5O3 (M+H)+: m/z=279.9.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.C1C=C[NH+]=CC=1.[Br:43][Br-]Br.C(OCC)(=O)C.O>C1COCC1>[Br:43][C:2]1[N:1]=[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6]3[N:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:26][CH2:27][CH2:28]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3cnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
tert-Butyl {1-[4-(9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (9.8 g, 20.4 mmol) was dissolved in THF (350 mL). A solution of pyridinium bromide perbromide (6.5 g, 20.4 mmol) in THF (50 mL) was added to the mixture at −78° C. After three hours stirring at r.t., pyridinium bromide perbromide (2.6 g, 8.2 mmol) in THF was added to the mixture and the mixture was stirred at rt overnight. The mixture was poured into ethyl acetate (1.5 L) and mixed with water and separated. The combined organic phase was washed with saturated sodium bicarbonate solution in water, then dried with anhydrous sodium sulfate and evaporated. The residue was purified with silica gel column chromatography (dichloromethane/ethyl acetate, 20:1) to give the titled compound as a white solid (6.8 g, 59%). 1HNMR (CDCl3) 400 MHz δ: 8.04 (d, J=8.0 Hz, 2H), 7.40 (d, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 1H), 7.23 (d, J=6.9 Hz, 2H), 7.12 (t, J=7.7 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.88-6.80 (m, 1H), 6.66-6.62 (m, 1H), 6.29 (s, 1H), 5.10 (s, 1H), 2.58-2.37 (m, 4H), 2.18-2.08 (m, 1H), 1.94-1.84 (m, 1H), 1.39 (br s, 9H); LC/MS [M+H]: 558
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([N:19]2[C:23](=[O:24])[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][NH:20]2)[CH:14]=1.C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>C(O)C.O>[CH:1]1([CH2:7][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([N:19]3[C:23](=[O:24])[C:22]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][NH:20]3)[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=CC1CCCCC1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(CNCC2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.2 mg (100 μmol) of cyclohexanecarbaldehyde are initially charged, 34.0 mg (100 mol) of the compound from Example 4A, dissolved in 0.6 ml of ethanol, and 25.8 mg (200 μmol) of diisopropylethylamine are added and the mixture is stirred at RT overnight. 5.7 mg (150 μmol) of sodium borohydride are then added, and the mixture is shaken at RT for 3 h. 100 μl of water are then added, and the mixture is concentrated. The residue is taken up in DMSO, the precipitate is filtered off and the filtrate is purified by preparative HPLC (Method 4).
Reaction SMILES: [OH:1][CH:2]([C:4]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7][C:6]([O:11][CH3:12])([O:9][CH3:10])[CH2:5]1)[CH3:3].C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:27]([O:1][CH:2]([C:4]1([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8][CH2:7][C:6]([O:11][CH3:12])([O:9][CH3:10])[CH2:5]1)[CH3:3])(=[O:29])[CH3:28]
Reactant: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)O)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)OC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 1-(1-hydroxyethyl)-3,3-dimethoxycyclopentanecarboxylate (8.64 g, 31.5 mmol) in 100 mL of DCM was treated with triethylamine (8.78 mL, 63.0 mmol) followed by acetic anhydride (5.94 mL, 63.0 mmol). Then DMAP (˜200 mg) was added and the resulting mixture was stirred at rt overnight. The reaction mixture was diluted with DCM, washed twice with 1N HCl solution, once with saturated NaHCO3 solution, and once with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by flash chromatography (silica, 20% ethyl acetate/hexanes) provided tert-butyl 1-[1-(acetyloxy)ethyl]-3,3-dimethoxycyclopentanecarboxylate.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]1[S:41][C:40]([CH:42]=[O:43])=[N:39][CH:38]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH:42]([C:40]2[S:41][C:37]([CH3:36])=[CH:38][N:39]=2)[OH:43])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: Cc1cnc(C=O)s1
Product: Cc1cnc(C(O)c2nc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(Cl)c2F)s1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 5-methylthiazole-2-carbaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([C:21](O)=[O:22])[C:12]3[CH:13]=[N:14][N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=3[CH:17]=2)[CH2:5][CH2:4]1.[NH2:25][CH2:26][C:27]1[C:28](=[O:37])[NH:29][C:30]([CH3:36])=[CH:31][C:32]=1[CH2:33][CH2:34][CH3:35].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:24][N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([C:21]([NH:25][CH2:26][C:27]3[C:28](=[O:37])[NH:29][C:30]([CH3:36])=[CH:31][C:32]=3[CH2:33][CH2:34][CH3:35])=[O:22])[C:12]3[CH:13]=[N:14][N:15]([CH:18]([CH3:19])[CH3:20])[C:16]=3[CH:17]=2)[CH2:7][CH2:8]1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(C)n1ncc2c(C(=O)O)cc(N3CCC(N(C)C)CC3)cc21
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(N2CCC(N(C)C)CC2)cc2c1cnn2C(C)C
Reaction time: 48 h
Yield: 67 %

Procedure:
To a solution of 6-[4-(dimethylamino)-1-piperidinyl]-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (34 mg, 0.103 mmol) in DMSO (1 mL) were added 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (29.0 mg, 0.134 mmol), N-methylmorpholine (0.045 mL, 0.412 mmol), 1-hydroxy-7-azabenzotriazole (28.0 mg, 0.206 mmol) and EDC (39.5 mg, 0.206 mmol), and the mixture was stirred for 48 h. The mixture was purified using reverse-phase HPLC to afford the title compound as a pale yellow solid (34 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.96 (m, 3H), 1.43 (d, J=6.57 Hz, 6H), 1.46-1.66 (m, 4H), 1.89 (m, 2H), 2.13 (s, 3H), 2.31 (s, 6H), 2.33 (m, 2H), 2.55 (s, 3H), 2.65-2.84 (m, 2H), 3.86 (m, 2H), 4.38 (m, 2H), 4.85-5.04 (m, 1H), 5.91 (s, 1H), 7.07 (s, 1H), 7.32 (m, 1H), 8.15 (m, 1H), 8.25 (br. s., 1H), 8.44 (t, J=4.93 Hz, 1H); LCMS: (M+H)+=493.2
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1>ClCCl>[Cl:7][C:8]1[N:9]=[CH:10][C:11]([CH:14]=[N:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: Nc1nccs1
Solvent: ClCCl
Product: Clc1ccc(C=Nc2nccs2)cn1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
2-Aminothiazole (0.75 g, 7.5 mmol) was added to 2-chloropyridine-5-carboxaldehyde (1.0 g, 7.1 mmol) in dichloromethane (25 mL) at room temperature. The suspension was stirred an additional 10 min and then concentrated to dryness under vacuum. The resulting residue was heated to 90 ° C. on a rotory evaporator with a non-returning bump trap to facilitate water removal. After 30 min the resultant yellow solid was checked by NMR to verify reaction completion (by disappearence of the characteristic aldehyde peak at 10.10 ppm (s, 1H)). The title compound was obtained as a yellow solid (1.55 g) and used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13](F)[C:12]=1[F:21]>C1COCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]=1[F:21]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Sodium hydride (60% oil dispersion) (2.125 g, 53.1 mmol) was added in portions to a solution of phenol (5.00 g, 53.1 mmol) in THF (100 mL) while cooling in an ice bath. After 30 min, 1,2,3-trifluoro-4-nitrobenzene (6.11 mL, 53.1 mmol) was added. The mixture was stirred at RT overnight. The reaction mixture was poured on to ice/10% aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. Chromatography of the residue (ethyl acetate:hexane) gave the crude product (10.78 g, 43%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:33][CH2:34][CH3:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].OO.O.C(=O)([O-])[O-:40].[K+].[K+]>CS(C)=O>[C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH2:33][CH2:34][CH3:35])[CH:9]3[CH2:10][C:11]4[CH:12]=[C:3]([C:1]([NH2:2])=[O:40])[CH:4]=[CH:5][C:6]=4[CH2:7][CH2:8]3)=[O:32])=[CH:21][CH:22]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCN(CCCCNC(=O)c1ccc(-c2ccccc2)cc1)C1CCc2ccc(C#N)cc2C1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCCCNC(=O)c1ccc(-c2ccccc2)cc1)C1CCc2ccc(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
To a solution of 7-cyano-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetrahydronaphthalene (0.983 g, 2.11 mmol) in dimethyl sulfoxide (4 ml) at 15° C. was added a solution of hydrogen peroxide in water (27.5% w/v; 0.26 ml; 2.12 mmol) followed by anhydrous potassium carbonate (0.42 g, 3.06 mmol). The mixture was stirred for 6 h at room temperature, then poured into water (100 ml) and the resulting solid filtered off to give the title compound (0.84 g, 82%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]C)=O.[CH3:10][C:11]([CH3:13])=[O:12].CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH2:10][C:11](=[O:12])[CH3:13]
Reactant: COC(=O)c1ccco1
Reactant: CC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)c1ccco1
Reaction time: 8 h

Procedure:
A mixture of methyl 2-furoate (23 g, 0.18 mole) and acetone (10.6 g, 0.18 mole) was slowly added to a stirred suspension of potassium tert-butoxide (41 g, 0.36 mole) in anhydrous toluene (300 ml) at 0° C. Upon standing overnight at room temperature, glacial acetic acid (22 ml, 0.36 mole) and then water (100 ml) were added. The organic layer was separated, combined with an ether extract of the aqueous phase, washed with water, dried, and distilled to give 1-(2-furyl)-1,3-dioxobutane: b.p. 66°-70° C./0.1 mm (18.5 g).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]N1C(CCC(O)=O)C(O)=O>>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:1]1[CH:2]1[CH2:3][CH2:4][C:5](=[O:7])[NH:6][C:8]1=[O:10]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(O)CCC(C(=O)O)N1Cc2ccccc2C1=O
Product: O=C1CCC(N2Cc3ccccc3C2=O)C(=O)N1

Procedure:
In a further method, a dialdehyde is allowed to react with glutamine and the resulting 2-(1-oxoisoindolin-2-yl)glutaric acid then cyclized to yield a 1-oxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline of Formula I:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH2:9][C:10]([OH:12])=O)#[N:8].[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:27])[CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C=O)C>[C:7]([CH2:9][C:10]([NH:27][CH:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][O:14][CH3:13])=[CH:22][CH:21]=1)[CH2:24][CH2:25][CH3:26])=[O:12])#[N:8]
Reactant: N#CCC(=O)O
Reactant: CCCC(N)c1ccc(OCOC)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCC(NC(=O)CC#N)c1ccc(OCOC)cc1
Temperature: 25 °C
Yield: 102.4 %

Procedure:
Oxalyl chloride (1.03 g, 8.15 mmol) was added drop-wise at ice bath temperature under nitrogen to a stirred solution of cyanoacetic acid (0.67 g, 7.9 mmol) in tetrahydrofuran (15 mL) to which 1-2 drops of DMF had been added. The mixture was stirred for an hour, then added slowly in one portion to a stirred solution of 1-(4-(methoxymethoxy)phenyl)butan-1-amine (1.1 g, 5.3 mmol) in THF (15 mL) at ice bath temperature under nitrogen. The mixture was allowed to warm gradually to room temperature and after 20 hours was stirred into 50 mL of saturated aq sodium bicarbonate and extracted 3× with dichloromethane. The combined extracts were washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo, leaving 1.5 g of dark violet syrup. The product was flash chromatographed on a column (50×70 mm) of silica gel (43-60 μm) eluting with Hxa/EtOAc 1:1 to afford 1.0 g (69%) of clear, dark oil; homogeneous by TLC.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5]2[CH:10]=[CH:11][N:12]=[CH:13][C:4]=2[S:3]1(=[O:15])=[O:14].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOCC>O1CCOCC1>[CH2:16]([NH:23][C:7]1[N:2]([CH3:1])[S:3](=[O:15])(=[O:14])[C:4]2[CH:13]=[N:12][CH:11]=[CH:10][C:5]=2[N:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CSC1=Nc2ccncc2S(=O)(=O)N1C
Reactant: NCc1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN1C(NCc2ccccc2)=Nc2ccncc2S1(=O)=O

Procedure:
A solution of 2-methyl-3-methylsulfanyl-2H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g) and benzylamine (0.5 mL) in dioxane (2.5 mL) was refluxed until completion of the reaction (t.l.c.). After cooling, the addition of ether gave rise to the precipitation of the title compound. The precipitate was collected by filtration, washed with ether and recrystallized from methanol-ether (yield: 0.4 g); m.p. 142°-146° C. (Compound 20).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:26]=[C:25]2[C:18]([NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.C(Cl)CCl.C(OCC)(=O)C>CCCCCC>[OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([NH:24][CH2:23][CH2:22][C:21]2[C:25]3[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:26]=3)[NH:19][CH:20]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: COc1ccc2[nH]cc(CCNC(=O)/C=C/c3ccc(O)cc3)c2c1

Procedure:
(E)-3-(4-hydroxyphenyl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl) acrylamide (2h) was synthesized by the condensation of 4-hydroxy cinnamic acid (150 mg, 0.914 mmol) and 5-methoxy tryptamine (207 mg, 1.09 mmol) using standard EDC coupling method. 2h was isolated as yellowish solid (181 mg, 59%) by elution with 25% ethyl acetate in hexane.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCON=C(C(=O)O)c1csc(N)n1
Reaction time: 5 h
Yield: 69.6 %

Procedure:
A solution of ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer, 10 g.) in a mixture of tetrahydrofuran (39 ml.), methanol (39 ml.) and 1N sodium hydroxide (75.8 ml.) was stirred at 35° to 40° C. for 5 hours. After the resultant solution was concentrated under reduced pressure, the aqueous residue was adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by filtration and dried to give 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetic acid (synisomer, 6.2 g.), mp 161° C. (dec.)
Reaction SMILES: [F:1]C1C=C(C(OC)=O)C2C3C(=O)CNCC=3NC=2C=1.C1(C(Cl)=O)CC1.[CH:26]1([C:29]([N:31]2[CH2:43][C:42]3[NH:41][C:40]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:44](=[O:47])[NH:45][N:46]=[C:33]([C:34]=3[C:35]=45)[CH2:32]2)=[O:30])[CH2:28][CH2:27]1>>[CH:26]1([C:29]([N:31]2[CH2:43][C:42]3[NH:41][C:40]4[CH:39]=[C:38]([F:1])[CH:37]=[C:36]5[C:44](=[O:47])[NH:45][N:46]=[C:33]([C:34]=3[C:35]=45)[CH2:32]2)=[O:30])[CH2:27][CH2:28]1
Reactant: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cccc1c4c32
Reactant: COC(=O)c1cc(F)cc2[nH]c3c(c12)C(=O)CNC3
Agent: O=C(Cl)C1CC1
Product: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cc(F)cc1c4c32

Procedure:
Compound 49 was prepared from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and cyclopropanecarbonyl chloride according to the procedures similar to those for Compound 47. 1H NMR (DMSO-d6) δ 9.64 (s, 1H), 6.80-7.08 (m, 2H), 4.95 (s, 1H), 4.74 (s, 1H), 4.40 (s, 1H), 4.20 (s, 1H), 2.03-2.07 (m, 1H), and 0.75 (s, 4H). MS (ESI) m/e [M+1]+ 313.