Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([O:31][CH3:32])[CH:5](O)[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:8][CH:7]=1.CCC(CCCCC(NC(C(NC(C(NC(C(NC1C(=O)NC(CCN)C(=O)NC(CC2C=CC=CC=2)C(=O)NC(CC(C)C)C(=O)NC(CCN)C(=O)NC(CCN)C(=O)NC(C(O)C)C(=O)NCC1)=O)CCN)=O)C(O)C)=O)CCN)=O)C.OS(O)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:33])/[C:4](/[O:31][CH3:32])=[CH:5]/[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:8][CH:7]=1
Reactant: COC(=O)C(OC)C(O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Agent: CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(Cc2ccccc2)NC(=O)C(CCN)NC1=O)C(C)O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)OC
Temperature: 100 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
2.50 g of 3-hydroxy-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid methyl ester (5.25 mmol, syn/anti mixture of 1:4) was dissolved at room temperature in 25 ml of DMF. After the addition of 0.59 ml of conc. sufuric acid (10.5 mmol), the brown solution was stirred at 100° C. for 15 h. During cooling the reaction solution to r.t., the product crystallized. Under stirring, 15 ml of methanol were added at r.t. and the suspension stirred for 1 h at 0° C. The white crystals were filtered off, washed with 25 ml of cold (−15° C.) methanol in two portions and dried to constant weight (20° C./5 mbar/16 h) to afford 2.13 g (90%) of the title compound with a purity of 99.5% (GC area).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([C:18]([O:22]COCCOC)=[C:19]([F:21])[F:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.Cl[Si](C)(C)C.C(=O)(O)[O-].[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([C:18](=[O:22])[CH:19]([F:20])[F:21])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCCOCOC(=C(F)F)c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 3-chloro-7-{2,2-difluoro-1-[(2-methoxyethoxy)methoxy]vinyl}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (50 mg, 0.12 mmol) in a mixture of methanol (0.6 mL) and dichloromethane (0.6 mL) was added chlorotrimethylsilane (0.08 mL, 0.61 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was then poured into an aqueous sodium bicarbonate solution and extracted with ethyl acetate three times. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 0-60% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.84 (d 1H), 8.52 (d, 1H), 8.41 (s, 1H), 7.93 (dd, 1H), 7.76 (d, 1H), 7.42 (d, 1H), 7.33 (d, 1H), 5.79 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:24]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCCl.O>[Br:24][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8](=[O:11])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2ccc(Cl)cc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1C=C(Br)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 6-chloro-1-indanone (II) (100.0 g, 600.2 mmol) in 1,2-dichloroethane (1.00 L) was added 2,2′-azo-bis-isobutyronitrile (9.86 g, 60.0 mmol) followed by N-bromosuccinimide (224.3 g, 1.26 mol). The reaction mixture was quickly heated to reflux. After 30 min at reflux, more 2,2′-azo-bis-isobutyronitrile (9.86 g, 60.0 mmol) was added. The reaction mixture was kept for 4.5 h at reflux. Afterwards the mixture was stirred at room temperature overnight. The mixture was cooled to 0° C., and triethylamine (126 mL, 904 mmol) was added dropwise. The mixture was stirred for 1 h at 0° C., and then allowed to heat to room temperature. Water (1.0 L) was added. The mixture was vigorously stirred for 15 min. The stirring was stopped, and the aqueous layer was removed by suction. Fresh water (1.0 L) was added, and the mixture was stirred for 15 min. The aqueous layer was then separated by suction. The organic phase was further shaken with brine (500 mL) in a separating funnel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]2/[CH:17]=[CH:18]/[N+:19]([O-:21])=[O:20].C(O)C.[BH4-].[Na+].C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]2[CH2:17][CH2:18][N+:19]([O-:21])=[O:20]
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1/C=C/[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2ccc(OC)cc2c1CC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a mixture of ethyl 5-methoxy-3-[(E)-2-nitrovinyl]-1H-indole-2-carboxylate (4.92 g) and ethanol (100 mL) was added sodium borohydride (1.92 g), followed by stirring at room temperature for 2 hours. To the mixture were added acetic acid and then water under ice-cooling, and the precipitated solid was collected by filtration and dried to obtain ethyl 5-methoxy-3-(2-nitroethyl)-1H-indole-2-carboxylate (4.01 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:35])([F:34])[C@H:26]([OH:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CC1C=CN=C(N)C=1C.C(N(CC)CC)C>C(Cl)Cl>[F:24][C:25]([F:34])([F:35])[C@H:26]([O:33][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)=[O:22])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Reactant: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: Cc1ccnc(N)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC[C@@H](OC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1)C(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of 4-benzyloxybiphenyl-4'-carboxylic acid chloride (1.23 g) in methylene chloride (10 ml) was added by little and little under ice-cooling a solution of (R)-(+)-1,1,1-trifluoro-2-octanol (0.96 g) ([α]D22.5 =+20.1, optical purity 96.3%ee), dimethyl-aminopyridine (0.55 g) and triethylamine (0.48 g) in methylene chloride (20 ml). The mixture was left to stand over-night at room temperature in order to complete the reaction before the mixture obtained was poured in ice-water.
Reaction SMILES: C1(N([C@H]2CC[C@H](COC)CC2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)CCCCC1.[CH:30]1([NH:37][C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH2:40][CH2:39]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([O:52][C:53](=[O:63])C(SC1SC(N)=NC=1)C)C>>[CH:30]1([N:37]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH2:40][CH2:39]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][CH2:17][C:53]([OH:63])=[O:52])=[CH:13][N:14]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Reactant: C1CCCC(N[C@H]2CC[C@H](COCC3CC3)CC2)CC1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCCC2)[C@H]2CC[C@H](COCC3CC3)CC2)s1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cycloheptyl-(trans-4-cyclopropylmethoxymethyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[S:8])[NH2:7])#[N:2].[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22]([CH3:24])=O)[CH3:18]>C(O)(C)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:26])=[C:22]([CH3:24])[N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])#[N:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)COc1ccc(C(N)=S)cc1C#N
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
3-Cyano-4-isobutoxybenzothioamide (100.0 g), ethyl-2-chloroacetoacetate (91.29 g), and isopropyl alcohol (700 mL) were placed into a round bottom flask and stirred for about 30 minutes. The mixture was heated to reflux and maintained at that temperature until reaction completion. After the reaction was complete, the mass was cooled to about 55° C. and maintained for about 30 minutes. The mass was filtered at the same temperature and the solid was washed with hot isopropyl alcohol (400 mL). The wet solid was dried at about 60° C. to a constant weight to yield 156.4 g of the title compound. Purity by HPLC: 98.8%.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([NH:19][C:3](=[O:4])[CH2:2][Cl:1])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC(Cc1ccccc1)c1cccs1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NC(Cc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of chloroacetyl chloride (4 mL, 0.05 mol) in chloroform (40 mL) was added dropwise to a solution of α-(2-thienyl)benzeneethanamine (10 g, 0.049 mol) and triethylamine (14 mL, 0.098 mol) in chloroform (180 mL) at 0° C. The mixture was stirred to room temperature for 1 hour. Dilute HCl (300 mL of 0.75N) was added and the reaction mixture was partitioned. The chloroform layer was separated, dried (MgSO4) and concentrated to give the amide as a light brown solid (11 g).
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13]([NH:18][CH3:19])=[CH:14][N+:15]([O-:17])=[O:16])[N:7]=1.[CH2:20]([N:22](CC)[CH2:23]C)C.C1(S(Cl)(=O)=O)C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][NH:18]/[C:13](/[NH:12][CH2:11][CH2:10][S:9][CH2:8][C:6]1[N:7]=[C:3]([CH2:2][N:22]([CH3:23])[CH3:20])[S:4][CH:5]=1)=[CH:14]\[N+:15]([O-:17])=[O:16]
Reactant: CNC(=C[N+](=O)[O-])NCCSCc1csc(CO)n1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: CN/C(=C\[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Temperature: -20 °C
Yield: 50.5 %

Procedure:
In a 100 ml three-necked round bottomed flask, filled with a nitrogen atmosphere, equipped with a thermometer, stir bar and dropping funnel and installed in a temperature controlled cooling bath was placed 2.0 g of N-[2-[[[2-(hydroxymethyl)-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, prepared according to the process described in U.S. Pat. No. 5,541,335. Into the same flask was added 120 ml of methylene chloride, 2.0 g of triethylamine, and 0.04 g of 4-dimethylaminopyridine. The contents were cooled to -20° C. internal. To this mixture was added dropwise from the pressure-equalized dropping funnel 1.3 g of benzenesulfonyl chloride in 18.0 ml of methylene chloride so as to maintain the internal temperature of the reaction mixture at or below -20° C. When the starting material was almost entirely consumed (2-3.5 hours), as determined by thin layer chromatography on silica gel eluting with 8/2 v/v EtOAc/MeOH, approximately 7.0 ml of dimethylamine was condensed into the reaction mixture. The temperature was held at or near -20° C. When the intermediate had disappeared, as indicated by TLC, the volatile components of the mixture were removed under vacuum and the residue dissolved in 15 ml methylene chloride and 8.0 ml water. The pH of the aqueous phase was adjusted to pH 4.5 by addition of 3N HCl. This acidification aids dissolution. The lower organic layer was separated and the aqueous phase was washed twice with 8.0 ml portions of methylene chloride. The aqueous phase containing the product was retained and adjusted to pH 10.5 using saturated potassium carbonate solution. The separated crude product was extracted with three 15 ml portions of methylene chloride, which were combined and evaporated. To remove trace amounts of methylene chloride, the product was twice evaporated to dryness from a slurry in isopropanol. The residue was then dissolved hot in 20.0 ml of isopropanol and allowed to crystallize. The solid was cooled to 0-5° C. for 16 hours and then filtered and washed with cold isopropanol. The solid was dried at 40° C. under vacuum, to give 1.1 g (50.3%) of nizatidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[OH-].[Na+]>CC(C)=O>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:14]
Reactant: C1CNCCN1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccco1)N1CCNCC1

Procedure:
To a solution of 21.5 g. (0.25 mol) of piperazine in a mixture of 960 ml. of acidified water (pH = 4.5) and 1200 ml. of acetone, 32.5 g. (0.25 mol) of furoyl chloride are added dropwise while the pH is maintained at 4.5 by dropwise addition of a sodium hydroxide solution. The mixture is made alkaline, and extracted several times with chloroform. The chloroform is distilled off and the concentrated extract is distilled in vacuo. 18.3 g. of the N-(2-furoyl)piperazine thus obtained in 50 ml. of diethyl ether are added to an equivalent amount of cyanogen bromide in a mixture of 60 ml. of water and 60 ml. of diethyl ether. The mixture is stirred overnight at room temperature and then subjected to continuous extraction with benzene. The extract is dried over sodium sulphate and the solvent is distilled off. According to the NMR and IR spectra the residue consists of 1-cyano-4-(2-furoyl)piperazine, m.p. 63°-65°C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[N+:8]([O-:11])(O)=[O:9].[CH:12]1[CH2:18][CH2:17]CC=[CH:14][CH:13]=1>>[C:5]([O:4][CH:1]1[CH2:17][CH2:18][CH2:12][CH:13]([N+:8]([O-:11])=[O:9])[CH:14]=[CH:2]1)(=[O:7])[CH3:6]
Reactant: C1=CCCCC=C1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Product: CC(=O)OC1C=CC([N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 0.6 Mol of acetic anhydride were added at 25° C. 0.16 Mol 90% HNO3 over 30 minutes. The mixture was stirred for an additional 15 minutes before 0.1 Mol of 1,3-cyclo-heptadiene was added over a 45 minute period, maintaining the temperature at 25° C. The reaction mixture was stirred for an additional 45 minutes before it was poured onto ice water and extracted with methylene chloride. An oily residue (100.5% weight yield) was obtained, which was purified by column chromatography, using silica gel and benzene/ethylacetate 4:1 as eluent. The product has the appearance of a yellow oil.
Reaction SMILES: [H-].[Na+].[H][H].[I-].[CH3:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:26]([O:29][C:30]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]2[C:31]=1[CH2:32][CH2:33][CH2:34][C:35]2=O)([CH3:28])[CH3:27]>CS(C)=O>[CH:26]([O:29][C:30]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]2[C:31]=1[CH2:32][CH2:33][CH2:34][C:35]2=[CH2:6])([CH3:28])[CH3:27]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Reactant: COc1ccc2c(c1OC(C)C)CCCC2=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=C1CCCc2c1ccc(OC)c2OC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 8.7 %

Procedure:
To a dry 250 mL 3-necked round bottom flask equipped with a reflux condenser and magnetic stir bar was added sodium hydride (1.09 g, 47.4 mmol) under nitrogen. 20 mL of anhydrous dimethylsulfoxide was added and the reaction mixture was heated to 70-75° C. for 30 min, until the evolution of hydrogen ceased. The reaction mixture turned green in color at this point, and then, the reaction mixture was cooled to room temperature and additional 15 mL of DMSO was added. Methyltriphenylphosphonium iodide (12.76 g, 31.57 mmol) was added in portions over a period of 30 min. 15 mL of additional DMSO was added and the reaction mixture was stirred for 20 minutes at room temperature. 35 (3.73 g, 15.8 mmol) dissolved in 5 mL of anhydrous DMSO was added to reaction mixture and the temperature was raised to 60-65° C., and stirred at that temperature for 8 h. The reaction mixture was poured into a 250 mL Erlenmeyer flask containing 75 mL ice and 75 mL of hexanes. The resulting mixture was stirred vigorously for 15 min, and then extracted with hexanes. The combined organic layers were washed DMSO:Water (1:1) and then dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Purification by flash column chromatography (silica gel 5:95, EtOAc:Hexanes) yielded 320 mg of 36 (10%). Rf −0.632, (30% ethylacetate in hexanes).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][N:3]1[CH2:13][C:14]([O:16]C)=O.[CH:18]([N:21]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:23][CH2:24][NH2:25])([CH3:20])[CH3:19]>>[CH3:20][CH:18]([N:21]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:23][CH2:24][NH:25][C:14](=[O:16])[CH2:13][N:3]1[CH2:4][CH:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][C:2]1=[O:1])[CH3:19]
Reactant: CC(C)N(CCCN)C(C)C
Reactant: COC(=O)CN1CC(c2ccccc2)CC1=O
Product: CC(C)N(CCCNC(=O)CN1CC(c2ccccc2)CC1=O)C(C)C

Procedure:
From 6.2 g. of methyl 2-oxo-4-phenylpyrrolidineacetate and 8.0 g. of 3-(diisopropylamino)propylamine [J.A.C.S. 65, 2012 (1943)], following the procedure of Example 1, there is obtained N-[3-[bis(1-methylethyl)amino]propyl]-2-oxo-4-phenyl-1-pyrrolidineacetamide in pure form as an oil, without need for distillation.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20](=[O:34])[C:21]([CH3:33])([CH3:32])[O:22][C:23]=4[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:15][CH:14]=3)[N:10]=2)[N:7]=1.C(NCC)C.[H][H]>CO.[OH-].[Pd+2].[OH-]>[N:10]1[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20](=[O:34])[C:21]([CH3:32])([CH3:33])[O:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:7]2
Reactant: [H][H]
Reactant: COc1ccc(C2=C(c3ccc(OCc4cn5nc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCNCC
Solvent: CO
Product: COc1ccc(C2=C(c3ccc(OCc4cn5ncccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Palladium hydroxide (36 mg) was added to a solution of 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 0.37 mmol) and diethyl amine (28 mg, 0.37) in methanol (25 ml) at RT under an atmosphere of nitrogen. The nitrogen atmosphere was exchanged for hydrogen and was stirred at RT for 2 h (the reaction was monitored by TLC). The compound was filtered through a bed of Celite® bed washing with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (160 mg, 96.7%) as a white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.4 (s, 1H) 8.15 (d, 1H), 7.55 (d, 2H), 7.25 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H), 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=442.3. HPLC: (97.4%, Condition-A).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCl.[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15]Br>ClCCCl>[Br:15][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH:7]=[O:14]
Reactant: BrBr
Reactant: O=Cc1ccccc1
Agent: ClCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=Cc1cccc(Br)c1
Reaction time: 2 h
Yield: 149.2 %

Procedure:
Into a mixture of 1,2-dichloroethane (1,2-dichloroethane: 173.7 g, 1-bromo-2-chloroethane: 63.5 g, 1,2-dibromoethane: 2.2 g) and recovered from Example 1 with 98% aluminum chloride (0.365 mol, 88.6 g) was blown chlorine (0.25 mol, 17.8 g) at 25° C., and 97% benzaldehyde (0.50 mol, 54.6 g) was added over 1 hour at 40° C. After bromine (0.30 mol, 48.0 g) was added dropwise to this mixture over 2 hours at 40° C., the resulting mixture were stirred for 2 hours at that temperature. The post-treatment was carried out by the similar procedure to that in Example 1. As a result, 82.8 g of 3-bromobenzaldehyde were obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[OH-:21].[Na+]>O1CCCC1.O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:9](=[O:19])[C:10]2[CH:18]=[CH:17][C:13]([C:14]([O:21][C:5]3[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][CH:4]=3)=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Oc1ccc(O)cc1)c1ccc(C(=O)Oc2ccc(O)cc2)cc1
Yield: 43.3 %

Procedure:
bis(4-Hydroxyphenyl)terephthalate (Structure IV) is synthesized by the reaction of hydroquinone with terephthaloyl chloride through the addition of NAOH. The hydroquinone (162.7 grams, 1.48 moles) and terephthaloyl chloride (150.0 grams, 0.74 moles) are first dissolved in 750 ml of tetrahydrofuran in a two liter round bottom flask which is stirred. The NaOH (59.1 grams, 1.48 moles) in 300 ml of deionized water is next added dropwise using an addition funnel over a one hour period and the mixture is then allowed to stir an additional two hours at ambient temperature (pH=6). The precipitate obtained is collected by vacuum filtration and then added to 500 ml of deionized water and 1000 ml of methanol. This solution is stirred for one hour at 40°-55° C. and then filtered. The solids collected here are added to 1100 ml of anhydrous methanol and stirred at 40°-55° C. for one hour followed by a third filtration. The resultant solids are then dried in a 80° C. vacuum oven. This final product (111.9 grams, yield=43.3%) exhibited a sharp melting endotherm by DSC at 415° C. ##STR12##
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O>[CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC(OCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CC(OCc2ccccc2)C1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
(3-Benzyloxy-cyclobutyl)-methanol (1.46 g) in N,N-dimethylformamide was treated at 0° C. with imidazole (1.55 g) and tert-butyldimethylsilyl chloride (1.37 g) and allowed to warm to room temperature over 16 hours. The reaction mixture was extracted with ethyl acetate, the organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 1:9 by volume) to give the title compound (2.24 g).