Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1cccc(O)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccc(O)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 79 °C
Yield: 33.9 %

Procedure:
A mixture of 1-(3-hydroxyphenyl)-2-phenylethanone (Intermediate 64) (154 mg, 0.726 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (153.3 mg, 0.726 mmol), urea (130.7 mg, 2.178 mmol), concentrated hydrochloric acid (0.5 mL) in ethanol (2 mL) was refluxed at 79° C. for 50 h. Removed solvent and purified by preparative HPLC to give Compound 129 (110 mg, yield 33.9%). HNMR (DMSO-d6 400 MHz): δ 10.29 (s, 1H), 9.41 (s, 1H), 8.62 (d, J=1.6 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 7.05-6.97 (m, 4H), 6.83-6.80 (m, 2H), 6.65-6.58 (m, 3H), 5.12 (d, J=2.8 Hz, 1H), 4.05-4.02 (m, 2H), 1.34-1.30 (m, 3H); MS (ESI): m/z 448.0 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[C:22]([Cl:23])=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([O:24][CH3:25])[CH:15]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:18]([C:17]2[CH:21]=[C:22]([Cl:23])[C:14]([NH2:13])=[CH:15][C:16]=2[O:24][CH3:25])=[O:20])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
1,1′-Carbonyldiimidazole (1.61 g, 9.91 mmol) was added to a solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.0 g, 9.91 mmol) in dimethylformamide (5 ml). After stirring for 5 min. at room temperature, solution of N-tert-butyloxycarbonyl-4-(aminomethyl)piperidine (1.77 g, 8.26 mmol) in dimethylformamide (5 ml) was added and the reaction mixture was heated at 55° C. After 23 h, the product was extracted into ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Flash chromatography of the crude product with 2:1, ethyl acetate/hexanes as the eluant gave N-tert-butyloxycarbonyl-4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine (2.63 g) as a foam.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccc3)no2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2cc(C3CCNCC3)on2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
tert-Butyl 4-(3-phenylisoxazol-5-yl)piperidine-1-carboxylate (225 mg, 0.78 mmol) was diluted in dichloromethane (3 mL). Trifluoroacetic acid (3 mL) was added to the mixture. Reaction stirred at room temperature for 1 hour. Mixture was diluted with dichloromethane and then concentrated in vacuo. Residue was treated with aqueous sodium bicarbonate. Mixture was extracted 2× ethyl acetate. Combined extracts were washed 1× water, 1× brine. Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 76% yield. MS m/e (M+H)+=229.1.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21]CC=C[C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CC[O:34]CC1.[O-]S([O-])=O.[Na+].[Na+].[CH3:44][C:45]([CH3:47])=[O:46].C1COCC1.O>O.O=[Os](=O)(=O)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:47][CH:45]([OH:46])[CH:44]([OH:34])[C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC=Cc1ccccc1-3
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(O)C(O)c1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution (0.11 M) of methyl 14-cyclohexyl-7,8-dihydroindolo[2,1-a][2]benzazocine-11-carboxylate (prepared as in Example 41, Step 3) in acetone/THF/H2O (1/1/1) was treated with N-methylmorpholine-N-oxide (1.2 eq), followed by OsO4 (4% wt in H2O, 0.1 eq) and left stirring at RT overnight. The clear solution was then treated with 10% wt Na2SO3 and left stirring for 30 min, then diluted with H2O and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated i. vac. to give the clean title compound as a creamy solid; MS (ES+) m/z 420 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:33])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]>C(Cl)Cl.CCOCC>[BrH:2].[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:33])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(OCCN2CCOCC2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Br
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1ccc(OCCN2CCOCC2)cc1
Yield: 61 %

Procedure:
1 M PBr3 in DCM (1.82 mL, 1.82 mmol) was added to 3-(1-hydroxyethyl)-4-(4-(2-morpholinoethoxy)phenyl)-1H-isochromen-1-one (Intermediate B15, 180 mg, 0.455 mmol) in DCM (2 ml) at RT. The reaction mixture was then was diluted with Et2O and filtered. The residue was further washed with Et2O and finally dried to give the title compound (150 mg, 61%) as a pink-red solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([CH3:25])[C:21](=[O:26])[CH:20]=1>CN(C)C=O.O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([CH3:25])[C:21](=[O:26])[CH:20]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: Cn1ccc(CN)cc1=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1=O
Yield: 86.2 %

Procedure:
(4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (130 mg, 0.40 mmol), 4-aminomethyl-1-methyl-1H-pyridin-2-one (55 mg, 0.40 mol) were coupled in N,N-dimethylformamide (2 mL) at room temperature. The reaction mixture is diluted with water and the precipitate is collected by Büchner filtration and then dried under house vacuum to give (4Z)-6-iodo-4-({[(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as an orange solid (0.15 g, 88%).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(Cl)(=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[CH3:26][C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:5])[CH2:9][CH2:10]2)[O:19][C:18]2=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]2[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(CN2CCN(C(=O)c3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
A mixture of 2-(4-tert-butoxycarbonylpiperazin-1-yl)methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 306 (142 mg, 0.39 mmol), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (2 ml). To the mixture, triethylamine (2 ml, 14.35 mmol) was added. To the solution, benzoyl chloride (54 μl, 0.46 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with a saturated sodium hydrogencarbonate solution, water and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether to afford [4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]phenylmethanone (72 mg, yield 50%) as a yellow powder.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]2[CH:15]=[C:16]([CH3:18])[N:17]=[C:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][NH:21][CH3:22].C=O.[CH2:25](O)[CH3:26]>>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([CH2:26][CH2:25][N:21]([CH3:22])[CH3:20])=[C:16]([CH3:18])[N:17]=[C:10]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: CCO
Reactant: Cc1cn2c(n1)C(OCc1ccccc1)CCC2
Agent: C=O
Agent: Cl
Product: Cc1nc2n(c1CCN(C)C)CCCC2OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture consisting of the product of Example 20 (1.52 g), dimethylamine hydrochloride (565 mg), paraformaldehyde (238 mg) and ethanol (10 ml) was refluxed for four hrs. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, the solution washed four times with 5% aqueous potassium carbonate, dried over Na2SO4 and then the solvent was evaporated on a rotary evaporator. The residue was chromatographed on silica gel, eluting with acetone, to obtain the title compound (m.p. 68°-70° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1S(=O)(=O)N.NC1CCN(CC2C=CC(OC)=CC=2)CC1>>[CH2:6]([OH:7])[CH2:5][CH2:4][CH2:3][CH3:2].[O:7]=[C:6]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:12][CH:11]=2)[C:9](=[O:10])[NH:8]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Agent: COc1ccc(CN2CCC(N)CC2)cc1
Product: CCCCCO
Product: O=C1NC(=O)c2ccccc21

Procedure:
Reaction of 4-chloro-5-sulfamoylphthalimide (5.21 g., 0.02 mole) and 4-amino-1-(4-methoxybenzyl)piperidine (4.5 g., 0.02 mole) in 80 ml. of n-pentanol according to the procedure of Example 1(a) afforded the crude 1,3-dioxoisoindole product purified by chromatography (silica gel, ethyl acetate-n-hexane) to yield 2.88 g. (31%) of 6-chloro-2,3-dihydro-2-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-1,3-dioxo-1H-isoindole-5-sulfonamide. The NMR spectral data was consistent for the compound used without further purification below.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O>[C:19]([Si:16]([CH3:18])([CH3:17])[O:15][CH2:14][CH2:13][O:5][CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][CH2:7][OH:8])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(CCO)CCO
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CCO)CCOCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.4 %

Procedure:
Step A To the solution of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) prepared in Example 116a Step A. in anhydrous dimethylformamide (15 mL) was added NaH (60%, 0.68 g, 17 mmol). The mixture was stirred at room temperature for 15 min, then (2-bromoethoxy)-tert-butyldimethylsilane (3.3 g, 14 mmol) was added. The mixture was stirred at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3) to give 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentan-1-ol as a yellow oil (0.3 g, 9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.O.O.[Sn](Cl)Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(O)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1ccc2c(Cc3ccc(N)cc3)ccnc2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol (0.187 g, 0.603 mmol) and tin(II) chloride dihydrate (0.823 g, 3.62 mmol) in MeOH (10 mL) was heated to 60° C. After 1 hr an additional 5 eq of tin(II) chloride dihydrate was added. After 3 hrs, the mixture was concentrated in vacuo and diluted with EtOAc and water. Saturated NaHCO3 was added until the aqueous layer was basic. The resulting suspension was filtered and the solids washed with EtOAc. The organic fraction was washed with water, brine, and dried with Na2SO4. After concentrating in vacuo, the crude, yellow solid, 4-((7-methoxyquinolin-4-yl)methyl)benzenamine was advanced without further purification. MS found: M+H+=265.1.
Reaction SMILES: [C:1](=[O:4])(O)[O-:2].[Na+].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C)[CH:16]=[O:17]>>[OH:17][C@@H:16]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]([O:2][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Reactant: O=C([O-])O
Agent: [Na+]
Product: O=C(OCc1ccccc1)[C@@H](O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To mixture of the title A compound (9.97 g, 60 mmols) and sodium bicarbonate (10 g, 120 mmols) in dimethyformamide (50 mL) was added a solution of benzyl bromide (7.13 mL, 60 mmols) in dimethylformamide (10 mL). The mixture was stirred at 25° C. under argon for 48 hours, after which it was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, saturated sodium bicarbonate solution, and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue (12.7 g) was chromatographed on silica gel (eluting with 4:1 hexane:ethyl acetate) to give 12 g of the title B compound.
Reaction SMILES: [C:1]([N:5]1[CH:9]([NH2:10])[CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:7](=[O:18])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].I[CH:20]([CH2:22][CH3:23])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:5]1[CH:9]([NH2:10])[CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:7](=[O:18])[N:6]1[CH:20]([CH2:22][CH3:23])[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)I
Reactant: Cc1ccccc1C1C(=O)NN(C(C)(C)C)C1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(C)N1C(=O)C(c2ccccc2C)C(N)N1C(C)(C)C
Yield: 16 %

Procedure:
A mixture of 1.23 g of 1-tert-butyl-4-(2-methylphenyl)-5-amino-pyrazolin-3-one, 1.84 g of 2-iodobutane, 2.1 g of potassium carbonate and 20 ml of ethanol was heated under reflux for 10 hours. The solvent was distilled off under reduced pressure, then, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate anhydride, then, the solvent was distilled off under reduced pressure. The residue was analyzed by 1H-NMR on the ratio of N-alkyl compound to O-alkyl compound being 16 to 84 was applied to column chromatography to obtain 250 ml (yield: 16%) of 1-tert-butyl-2-sec-butyl-4-(2-methylphenyl)-5-aminopyrazolin-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](C3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:10]=1.[NH2:35][C:36]1[CH:46]=[CH:45][C:44](Br)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[NH2:35][C:36]1[CH:46]=[CH:45][C:44]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:33])[CH3:32])[C:12]3=[N:13][CH:14]=2)=[CH:43][C:37]=1[C:38](=[O:39])[N:40]([CH3:41])[CH3:42]
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Reactant: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(C3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (6.5 g, 14 mmol), 2-amino-5-bromo-N,N-dimethyl-benzamide (3.4 g, 14 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloromethane adduct (511 mg, 0.7 mmol) in THF/Acetonitrile/saturated NaHCO3 (25 ml/25 ml/30 ml) was stirred at 100° C. for 4 hours. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2,2-dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(2-methoxy-phenyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (3.7 g, 52% yield).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([O:17][CH2:18][C:19]3[N:23]=[CH:22][N:21]([CH3:24])[N:20]=3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:5]2=[N:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)CCC>CN(C=O)C>[CH3:24][N:21]1[CH:22]=[N:23][C:19]([CH2:18][O:17][C:8]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:5]3[N:6]([C:2]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[N:3][N:4]=3)[N:7]=2)=[N:20]1
Reactant: Cn1cnc(COc2nn3c(Br)nnc3cc2N2CCOCC2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Solvent: CN(C)C=O
Product: Cn1cnc(COc2nn3c(-c4cccs4)nnc3cc2N2CCOCC2)n1
Temperature: 100 °C
Yield: 60.2 %

Procedure:
A mixture of 3-bromo-6-(1-methyl-1 H-1,2,4-triazol-3-ylmethoxy)-7-(morpholin-4-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.25 mmol) and 2-(tributylstannyl)thiophene (240 mL 0.75 mmol) in dry DMF (3 ml) was deoxygenated by bubbling through nitrogen gas for 15 minutes. Dichlorobis(triphenylphosphine)palladium (II) (20 mg) was then added. The whole apparatus was further deoxygenated by three ‘evacuate/fill N2’ cycles. The mixture was then stirred and heated at 100° C. for 16 hours under nitrogen. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated. Residual DMF was removed under high vacuum. The residue was purified by chromatography on silica gel, eluting with 5% methanol/dichloromethane to give the title compound (60 mg, 60%). Data for the title compound: 1H NMR (360 MHz, CDCl3) δ3.26-3.29 (4 H, m), 3.85-3.89 (4 H, m), 3.94 (3 H,-s), 5.64 (2 H, s), 7.19-7.23 (2 H, m), 7.47-7.59 (1 H, m), 8.05 (1 H, s), 8.18-8.20 (1 H, m); MS (ES+) m/e 399 [MH+]. Anal. Found C, 50.84; H, 4.39; N, 27.35. C17H18N8O2S. 0.3(H2O) requires C, 50.56; H, 4.64; N, 27.75%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc([N+](=O)[O-])cc4)c3C2=O)C(=O)N1
Yield: 74 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (2.2 g, 8.0 mmol) and 4-nitrobenzoyl chloride (3.0 g, 16.0 mmol) in THF (80 mL) was heated to reflux for 15 h. To the mixture was added methanol (20 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-nitro-benzamide as a white solid (2.5 g, 73% yield): mp, 298-300° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 5.18 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.73 (d, J=7.2 Hz, 1H, Ar), 7.93 (t, J=8.0 Hz, 1H, Ar), 8.19-8.22 (m, 2H, Ar), 8.42-8.47 (m, 3H, Ar), 10.65 (s, 1H, NH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.99, 119.30, 119.56, 124.06, 127.49, 129.01, 131.58, 135.77, 136.23, 138.96, 149.69, 163.65, 166.57, 167.48, 169.68, 172.72; Anal Calcd for C20H14N4O7: C, 56.88; H, 3.34; N, 13.27. Found: C, 57.15; H, 3.02; N, 13.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[O:12][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)=[CH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:7][CH:8]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:16])=[CH:7][CH:8]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(C=C(C2=NC(C)(C)CO2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C=O)cc1

Procedure:
2-[1,2-Bis(4-methoxyphenyl)ethenyl]-4,4-dimethyl-2-oxazoline (P-1728) was prepared by reacting 4-methoxyphenyl acetic acid with 2-amino-2-methyl-1-propanol and condensing the product thereby obtained with p-methoxybenzaldehyde. The boiling point was about 223 at 0.38 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[S:30][C:29]([CH:31]([CH:35]([CH3:37])[CH3:36])[C:32](O)=[O:33])=[CH:28][C:27]=2[CH:38]=1>CCOCC>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[S:30][C:29]([CH:31]([CH:35]([CH3:36])[CH3:37])[C:32]([O:14][CH2:13][C:9]3[NH:10][CH:11]=[CH:12][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:33])=[CH:28][C:27]=2[CH:38]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1[nH]ccc1Cc1ccccc1)c1cc2cc(Cl)ccc2s1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-benzylpyrrolylmethyl alcohol (0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about15 ml), under nitrogen, is added a solution of the acid chloride of 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (1.5 mmol) in either. The mixture is stirred for about 60 minutes and then quenched with saturated aqueous NaHCO3. The ether phase is washed with aqueous NaHCO3, water and brine, dried over sodium sulfate and solvent evaporated to give 3-benzylpyrrolylmethyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.