Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[OH-].[Na+].[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])([CH3:14])[CH3:13].C(Cl)Cl>C1(C)C=CC=CC=1.O>[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])([CH3:14])[CH3:13]
Reactant: COc1cc(C(=O)Cl)ccc1OC(C)C
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(=O)CC2)ccc1OC(C)C
Yield: 29.9 %

Procedure:
Piperidin-4-one hydrochloride hydrate (29.2 g, 190 mmol) was dissolved in an aqueous solution of sodium hydroxide (95 mL of 2.0 M, 190 mmol). The resulting clear solution was then stirred under nitrogen in an ice water bath. 4-isopropoxy-3-methoxy-benzoyl chloride (43.5 g, 190 mmol) was dissolved in toluene (90 mL) to provide a final volume of 100 mL. This solution was added dropwise in 2 mL portions followed by addition of 1 mL of an aqueous sodium hydroxide (48 mL of 4.0 M, 192 mmol) solution. This process was repeated until both reagents were completely added. When complete, the reaction mixture was allowed to stir at 0° C. for an additional 30 minutes. To the mixture was added CH2Cl2 (250 mL) followed by water (200 mL). The mixture was mixed well in a separatory funnel, and the aqueous layer was further extracted with CH2Cl2 (2×100 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a dark brown oil. Purification was performed by column chromatography to provide 1-(4-isopropoxy-3-methoxy-benzoyl)piperidin-4-one (16.56 g) as a clear light brown oil that crystallized to a slightly tan white solid upon standing. 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J=1.9 Hz, 1H), 7.02 (dd, J=8.2, 2.0 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 4.59 (dt, J=12.2, 6.1 Hz, 1H), 3.90-3.88 (br s, 4H), 3.88 (s, 3H), 2.51 (s, 4H), 1.40 (d, J=6.1 Hz, 6H). ESI-MS m/z calc. 291.15, found 292.0 (M+1)+; Retention time: 0.94 minutes (3 minute run).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1
Reactant: C1COCCN1
Reactant: CC1(C)OCC(c2ccc3c(n2)CCCC3=O)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)OCC(c2ccc3c(n2)CCC=C3N2CCOCC2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a mixture of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5(6H)-one (0.182 g, 0.736 mmol) and morpholine (0.321 mL, 3.68 mmol) in toluene (3 mL) at 0° C. was added titanium(IV) chloride (1.0 M in toluene) (0.405 mL, 0.405 mmol) dropwise. The ice-bath was removed, and the orange, heterogeneous reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of CELITE®, which was then rinsed with toluene (3×10 mL). The pale yellow filtrate was concentrated under reduced pressure to give 4-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5-yl)morpholine (0.194 g, 0.613 mmol, 83% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](I)=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.[BrH:13].O>C(O)(=O)C>[Br:13][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc(Br)c2nccn2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 5.0 (14.0 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c, 30 mL of hydrogen bromide solution in acetic acid (33%) was stirred at 120° C. for 1 hour under microwave irradiation. The mixture was poured into water and extracted with dichloromethane. The organic phase was washed with sodium thiosulfate and sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 3.0 g (78%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.C(ON)(C)(C)C>>[CH2:29]([O:36][NH:37][C:15](=[O:16])[C@H:14]([N:13]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:18]([CH3:20])[CH3:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Agent: CC(C)(C)ON
Agent: Cl
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOCc2ccccc2)C(C)C)cc1

Procedure:
The N-(benzyloxy) substituted prodrug derivative of the above compound is prepared as follows: 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride is reacted with O-benzylhydroxylamine hydrochloride under conditions described for reaction with O-t-butylhydroxylamine hydrochloride to yield N-(benzyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methyl-butanamide, m.p. 74.5°-76° C.
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][C:5]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]1=[O:19])=O.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1.C1(C)C=CC=CC=1>[CH3:2][O:3][CH2:4][C:5](=[C:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]1=[O:19])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COCC(=O)C1CCN(C(=O)OC(C)(C)C)C1=O
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [K]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: O
Product: COCC(Nc1ccccc1)=C1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
Into a 200 mL four-mouthed flask were added tert-butyl 3-(2-methoxyacetyl)-2-oxopyrrolidine-1-carboxylate potassium salt (9.00 g) [mw. 295.37, 30.47 mmol], 1 mol/L aqueous hydrochloric acid solution (50 mL) and toluene (90 mL), and the mixture was stirred at room temperature for 10 min. After partitioning, the organic layer was washed with water (50 mL), and dried over magnesium sulfate. After filtration, aniline (2.84 g) [mw. 93.13, 30.50 mmol], p-toluenesulfonic acid monohydrate (0.58 g) [mw. 190.22, 3.05 mmol] and cyclohexane (50 mL) were added. Dean-Stark trap was set, and distillation by thermal dehydration was performed for 1 hr. After cooling to room temperature, 5 w/w % aqueous acetic acid solution (50 mL) was added to allow for partitioning. The organic layer was washed successively with 5 w/w % aqueous sodium bicarbonate solution (50 mL) and water (50 mL), further washed with water (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the concentrate were added methanol (78 mL) and activated carbon (0.78 g), and the mixture was stirred at room temperature for 1 hr. After filtration, the mother liquor was concentrated under reduced pressure, and the solvent was replaced with ethyl acetate. To the concentrate was added diisopropyl ether (22 mL) to allow for crystallization, and the crystals were aged for 1 hr. After filtration under reduced pressure, the crystals were washed with diisopropyl ether (8 mL), and dried at 40° C. under reduced pressure to give the object compound. Pale-yellow crystals, 3.47 g, yield 34.3%, 1H-NMR (500 MHz, DMSO-d6, TMS) δ 1.47 (s, 9H), 2.70 (t, J=7.7 Hz, 2H), 3.26 (s, 3H), 3.65 (t, J=8.1 Hz, 2H), 4.06 (s, 2H), 7.07-7.14 (m, 3H), 7.31-7.35 (m, 2H), 10.34 (s, 1H). 13C-NMR (125 MHz, DMSO-d6) δ 20.29, 27.74, 43.23, 57.83, 67.40, 89.97, 100.10, 121.40, 123.48, 129.20, 139.43, 148.97, 150.33, 169.16. MS (ESI) m/z 333.1776 [M+H]+, 355.1629 [M+Na]+, 331.1672 [M−H]−. Found: C, 65.04; H, 7.28; N, 8.43%. Calcd for C18H24N2O4: C, 64.97; H, 7.20; N, 8.37%.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.O[CH:29]([C:32]1[CH:48]=[C:47]2[N:35]([CH2:36][C:37]3[C:38]2=[N:39][C:40]2[C:45]([CH:46]=3)=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34](=[O:49])[C:33]=1[CH3:50])[CH2:30][CH3:31]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:50][C:33]1[C:34](=[O:49])[N:35]2[C:47](=[CH:48][C:32]=1[CH:29]([O:10][C:9](=[O:11])[CH2:8][NH:7][C:5]([O:4][C:2]([CH3:12])([CH3:1])[CH3:3])=[O:6])[CH2:30][CH3:31])[C:38]1=[N:39][C:40]3[C:45]([CH:46]=[C:37]1[CH2:36]2)=[CH:44][CH:43]=[CH:42][CH:41]=3
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(OC(=O)CNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-[(1,1-dimethylethoxy)carbonyl]glycine (1.15 g, 6.6 mmol) in CH2Cl2 (50 mL) under an argon atmosphere was added 1,3-dicyclohexylcarbodiimide (1.35 g, 6.5 mmol). After stirring at room temperature for 0.5 h, (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (1.0 g, 3.3 mmol) was added followed by a few mg of 4-dimethylaminopyridine. The resulting mixture was allowed to stir at room temperature overnight and then was filtered. The filtrate was washed successively with 2.5% aqueous NaHCO3 (100 mL), 0.1N HCl (100 mL) and H2O (100 mL), dried over sodium sulfate and concentrated in vacuo. The solid residue was purified by column chromatography on silica gel eluting with a solvent gradient of 0-2% MeOH/CH2Cl2 to provide the title compound. 1H NMR (CDCl3) d 8.34 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.91, (d, J=8.3 Hz, 1H), 7.81, (m, 1H), 7.63, (m 1H), 7.32 (s, 1H), 5.96 (apparent br t, J=7.0 Hz, 1H), 5.25 (s, 2H), 5.03 (br s, 1H), 4.15-3.94 (m, 2H), 2.36 (s, 3H), 2.04-184 (m, 2H), 1.44 (s, 9H), 0.99 (t, J=7.4 Hz, 3H). Anal. Calcd for C26H29N3O5.1/8 H2O: C, 67.04; H, 6.33; N, 9.02. Found: C, 66.95; H, 6.54; N, 8.83.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].ClC(OCC)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]1[O:35][CH3:36]>ClC(Cl)Cl>[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:23][C@H:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][C@H:25]2[O:35][CH3:36])=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)O)c2O1
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)c3c2OC(C)(C)C3)[C@H](OC)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 8.1 parts of 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid in 218 parts of trichloromethane and 3.43 parts of N,N-diethylethanmine were added dropwise 3.63 parts of ethyl chloroformate, keeping the temperature below 10° C. After stirring for 1/2 hour at 10° C., the whole was added to a solution of 6.26 parts of ethyl 4-amino-3-methoxy-1-piperidinecarboxylate in 145 parts of trichloromethane at 10° C. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was washed with water, NaOH 5% and water and was then dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 12.3 parts (93.2%) of ethyl cis-4-[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonylamino]-3-methoxy-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=O.[CH3:11][NH:12][NH2:13]>CS(C)=O.O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:13][N:12]2[CH3:11]
Reactant: O=Cc1c(F)cccc1Br
Reactant: CNN
Solvent: CS(C)=O
Solvent: O
Product: Cn1ncc2c(Br)cccc21
Temperature: 85 °C

Procedure:
The product of Example 2B (2.0 g) was dissolved in DMSO (2 g) and the solution was added to methylhydrazine (98%, 3.2 g, 7 eq.). The mixture was heated for 24 hours at 85° C., cooled to ambient temperature and diluted with water (50 mL). The solution was extracted with CH2Cl2 (2×50 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:18])[CH:6]=[C:7]([CH:15]([CH3:17])[CH3:16])[C:8](=[O:14])[C:9]=1[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH3:3].C[SiH](C)O[SiH](C)C.II>C(Cl)Cl>[CH2:1]([C:4]1[C:9]([C:10]([CH3:12])([CH3:11])[CH3:13])=[C:8]([OH:14])[C:7]([CH:15]([CH3:17])[CH3:16])=[CH:6][C:5]=1[OH:18])[CH2:2][CH3:3]
Reactant: CCCC1=C(C(C)(C)C)C(=O)C(C(C)C)=CC1=O
Agent: C[SiH](C)O[SiH](C)C
Agent: II
Solvent: ClCCl
Product: CCCc1c(O)cc(C(C)C)c(O)c1C(C)(C)C

Procedure:
Dissolve 2-propyl-3-t-butyl-5-isopropylbenzoquinone (10mmol), 1,1,3,3-tetramethyldisiloxane (1.79mL, 10mmol) and iodine (0.05g) in methylene chloride (30mL). Stir at reflux for 30 minutes and extract with 1N sodium hydroxide (30mL). Acidify the aqueous phase with concentrated hydrochloric acid and extract into ethyl acetate (4×10mL), dry (NazSO4) and evaporate the solvent in vacuo to give 2-propyl-3-t-butyl-4-hydroxy-5-isopropylphenol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C-:28]#[N:29].[K+]>O>[C:28]([CH:6]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2])#[N:29]
Reactant: N#Cc1cccc(C=O)c1
Reactant: [C-]#N
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: O
Product: N#Cc1cccc(C(C#N)N2CCOCC2)c1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To 3-cyanobenzaldehyde (8.0 g, 61.0 mmol) was added morpholine (10.63 g, 122.0 mmol), p-toluenesulfonic acid (12.18 g, 64.05 mmol), and then a solution of potassium cyanide (3.97 g, 61.0 mmol) in 12mL water. The mixture was refluxed for 75 minutes then cooled to room temperature and partitioned between satd. sodium bicarbonate and methylene chloride. The aqueous portion was extracted with methylene chloride (1×), and the resulting organic portion washed with satd. sodium bisulfite (1×). The organic portion was dried over sodium sulfate and concentrated in vacuo. Crystallization from hot ethanol gave 3-[cyano(morpholin-4-yl)methyl]benzonitrile (11.83 g, 85%). LRMS m/z (M+H) Calcd: 228.3, found: 228.1.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:42])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:39][CH3:40])[CH2:25][N:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[C:5]1=[O:41])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:42])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:39][CH3:40])[CH2:25][N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[C:5]1=[O:41])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)piperazine-1-carboxylate (Example 95, Step A) (187 mg, 0.304 mmol in DCM (2.4 mL) was added TFA (600 μL, 7.79 mmol). The reaction mixture was stirred at room temperature for 16 hours before concentrating under reduced pressure. The residue was taken up in DCM (15 mL) and washed with sat. sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford the title compound as a white foam.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][C:7]1=[O:12].[N:13]1([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][N:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[OH2:11].[O:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]([N:13]2[CH2:14][CH2:15][N:16]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH2:9][S:8][C:7]3=[O:12])[CH2:17][CH2:18]2)=[N:20]1
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Reactant: O=C1CSC(=O)N1CCCCBr
Product: O
Product: O=C1CSC(=O)N1CCCCN1CCN(c2noc3ccccc23)CC1
Yield: 44 %

Procedure:
Reaction of 3-(4-bromobutyl)-2,4-thiazolidinedione with 3-(1-piperazinyl)-1,2-benzisoxazole according to the procedure of Example 3 affords a 44% yield of 3-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]butyl]-2,4-thiazolidinedione hydrate, m.p. 104.5°-106.6° C., from methanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]1[CH:16]=[N:15][C:14]([NH2:17])=[N:13][C:12]1=[O:18])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CC#N>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]1[CH:16]=[N:15][C:14]([N:17]=[CH:21][N:22]([CH3:24])[CH3:23])=[N:13][C:12]1=[O:18])[CH3:2]
Reactant: CCc1cccc(CC)c1-n1cnc(N)nc1=O
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CCc1cccc(CC)c1-n1cnc(N=CN(C)C)nc1=O
Reaction time: 8 h

Procedure:
1-(2', 6'-diethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one (5.9 g, 20 mmo) is combined with 30 ml of CH3CN, none of the solid dissolves. To this is added 1.19 g (10 mmol) of N,N-dimethylformamide dimethylacetal. The solid dissolves within seconds. The reaction solution was stirred overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].O.[C:25]([OH:29])(=[O:28])[CH:26]=O>C(#N)C.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:26]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)[C:25]([OH:29])=[O:28])[CH:10]=[CH:9][CH:8]=1)(=[O:6])[NH2:7]
Reactant: O=CC(=O)O
Reactant: NC(=O)c1cccc(N)c1
Reactant: COc1ccc(B(O)O)cc1OC
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Temperature: 55 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A mixture of 3-aminobenzamide (204 mg, 1.5 mmol), 3,4-dimethoxyphenylboronic acid (273 mg, 1.5 mmol) and glyoxylic acid monohydrate (138 mg, 1.5 mmol) in acetonitrile (8.0 mL) and DMF (0.8 mL) was heated at 55° C. for 4.0 h and then stirred at rt for 18 h. The precipitate formed was collected by filtration and washed with ethyl acetate to give 1A (390 mg, 78% yield) after drying. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.03-7.19 (m, 5H) 6.91 (d, J=9.0 Hz, 1H) 6.81 (d, J=8.00 Hz, 1H) 5.05 (s, 1H) 3.83 (s, 3H) 3.72 (s, 3H). LC-MS 331 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:16])[CH:8]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][C:27](=[O:29])[CH3:28])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(O)c2)c(OC)c(OC)c1OC
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(OC(C)=O)c2)c(OC)c(OC)c1OC
Yield: 60 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoic acid (97 mg, 0.2679 mmol) was dissolved in acetic anhydride (20 ml) and the resulting solution was refluxed under heating for 2 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to obtain the titled compound (65 mg, 0.1608 mmol, 60%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[Cl:13][C:14]([Cl:38])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:27]=1.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:38][C:14]([Cl:13])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=2)=[O:34])[CH:27]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
(4-Trifluoromethyl-phenyl)-methanol (58 mg, 0.332 mmol) was added to a stirred mixture of 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (120 mg, 0.277 mmol), EDC×HCl (80 mg, 0.415 mmol), DMAP (3.4 mg, 0.028 mmol) and DCM (4 mL). The reaction mixture was stirred at rt overnight. More DCM was added and the mixture was washed with 0.25M HCl, the organic phase was dried through a phase separator and concentrated. The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as the eluent to yield the titled compound (105 mg, 64%) as a colourless oil; 1H NMR (400 MHz, CDCl3): δ 3.62 (s, 2H), 4.54 (s, 2H), 4.96 (s, 2H), 5.18 (s, 2H), 7.09-7.15 (m, 1H), 7.18-7.24 (m, 4H), 7.30-7.43 (m, 4H), 7.60 (d, 2H), 8.08 (d, 1H); Mass spectrum: M−H+ 590.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][C:15]3[N:16]([CH3:23])[C:17](=[O:22])[NH:18][C:19](=[O:21])[C:20]=3[N:12]2[CH:11]=[C:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]([O-])([O-])=[O:31].[Na+].[Na+]>C(O)(=O)C.C=O.CO>[OH:31][CH2:30][C:11]1[N:12]2[C:13](=[N:14][C:15]3[N:16]([CH3:23])[C:17](=[O:22])[NH:18][C:19](=[O:21])[C:20]=32)[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccccc1-n1c(-c2ccccc2)cn2c3c(=O)[nH]c(=O)n(C)c3nc12
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1-n1c(-c2ccccc2)c(CO)n2c3c(=O)[nH]c(=O)n(C)c3nc12
Yield: 5 %

Procedure:
A mixture of commercially available 8-(2-methoxyphenyl)-1-methyl-7-phenyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (5, 100 mg, 0.258 mmol) in acetic acid (0.387 mL) and formalin (36%, 1.1 mL) was refluxed for 15 h. The solution was then was cooled to room temperature and neutralized with sat. Na2CO3, and the resulting precipitate was filtered off. Cristallization in methanol afforded the desired product as a white solid (6 mg, 5% yield). 1H NMR (500 MHz, DMSO-d6): δ=11.27 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.32-7.37 (m, 3H), 7.23-7.24 (m, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 5.90-5.93 (m, 1H), 4.69-4.72 (m, 2H), 3.55 (s, 3H), 3.32 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ=154.7, 154.5, 153.6, 150.6, 147.1, 131.1, 129.7, 129.4, 129.2, 128.7, 128.2, 127.0, 122.1, 120.7, 119.4, 112.7, 99.4, 55.5, 52.9, 28.9; IR (film): ν=3134, 2995, 2806, 1668, 1496, 1024, 749, 596 cm−1; HRMS (ESI): m/z: calcd for C22H19N5O4Na+: 440, 1335, found: 440, 1336.