Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=[O:17].[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13](=[O:15])[CH2:29][C:30]([O:31][CH2:32][CH3:28])=[O:17])[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: C1CCOC1
Product: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 100.0 ml portion of ethanol were added 5.0 g (0.21 mmol) of magnesium and 15.0 ml of carbon tetrachloride in that order, followed by 1 hour of stirring at room temperature. Thereto was added dropwise ethyl hydrogen malonate. After 1 hour of stirring at room temperature, the solvent was evaporated to yield magnesium malonate as a colorless foamy substance. Separately, 55.29 g (0.26 mmol) of 1-tert-butoxycarbonylaminocyclobutanecarboxylic acid was dissolved in 450.0 ml of THF, mixed with 45.81 g (0.28 mmol) of 1,1'-carbonyldiimidazole and then stirred at room temperature for 1.5 hours. To this was added dropwise 450.0 ml of THF solution of the above magnesium salt in 30 minutes, followed by 2 days of stirring at room temperature. After evaporation of the solvent, the resulting residue was distributed between 10% citric acid aqueous solution and ethyl acetate. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent, the title compound was obtained quantitatively.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][NH:6][C:7](=[O:40])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.Cl>C1COCC1.[OH-].[Na+].C(OCC)C.O>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:41])=[O:2])=[O:40])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][CH:24]=2)=[CH:31][CH:32]=1)([CH3:37])([CH3:38])[CH3:39]
Reactant: CCCCCCC(Oc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(Oc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The 3-(4-{1-[4-(4-tert-Butyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-propionic acid methyl ester is dissolved in the THF (1.0 mL) and 5N NaOH (1.0 mL) is added. The mixture is heated to reflux under nitrogen and monitored by HPLC. Upon complete conversion, the reaction is neutralized with 5N HCl (1.0 mL), diluted with diethyl ether and water. The two phases are separated and the organic layer is washed, dried, and concentrated to provide the title compound (80 mg, 0.15 mmol). MS (ES): 544.2 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:27]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH2:41])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:30]([O:29][C:27](=[O:28])[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:7]([C:6]1[CH:5]=[N:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1)=[O:9])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C#N)nc1
Temperature: 5 °C
Yield: 78.3 %

Procedure:
To a solution of 444 mg (3.0 mmol) 6-cyano-nicotinic acid and 354 mg (3.5 mmol) N-methylmorpholine in 7 ml DMF at −20° C. was added 450 mg (3.3 mmol) isobutyl chloroformate. The reaction mixture was warmed to 5° C., and 625 mg (3.0 mmol) mono-boc-ortho-phenylenediamine was added. The reaction mixture was warmed to rt overnight and then poured into 50 ml 5% aqueous citric acid. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with bicarbonate and brine and dried over Na2SO4. The solvent was evaporated and the residue was subjected to silica gel chromatography (petrol ether/ethyl acetate 2:1) to yield 795 mg (2.35 mmol) {2-[(6-Cyano-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester; mp.183–184° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH2:19][CH2:20][CH3:21])=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[C:6]([CH2:19][CH2:20][CH3:21])[CH:7]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(O)cc1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)COc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product from Step 8 (0.50 g, 1.4 mmol), p-methoxyphenol (2.8 mmol) and cesium carbonate (0.91 g, 2.8 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was evaporated and the residue was purified by chromatography on silica gel to give the title product as an oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])=[CH:5][CH:4]=1.[BrH:21].BrBr.S(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl.O>[Br:21][CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:20])[F:1])=[CH:8][CH:7]=2)[C:13]1=[O:18]
Reactant: Br
Reactant: O=C1CCc2c1cccc2-c1ccc(C(F)(F)F)cc1
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1c2cccc(-c3ccc(C(F)(F)F)cc3)c2CC1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2.76 g (10 mmol) of 4-(4-trifluoromethylphenyl)-1-indanone are dissolved in 20 ml of glacial acetic acid and, after addition of 10 μl of a 48% strength solution of HBr in glacial acetic acid, while stirring a solution of 0.516 ml (10.05 mmol) of bromine in glacial acetic acid is added. After 3 h at room temperature, the reaction mixture is poured into a mixture of 100 ml of water with 100 g of ice and 100 mg of sodium bisulfite, and the resulting suspension is shaken with dichloromethane. The organic phase is washed 3× with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on silica gel with dichloromethane/n-heptane 3/1. 2-Bromo-4-(4-trifluoromethylphenyl)-1-indanone is obtained with a melting point of 102-105° C., in addition to a little 2,2-dibromo compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:32])[C@:4]1([OH:31])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27]1(C)[CH2:29][O:28]1.I(O)(=O)(=O)=O>O1CCCC1.O>[Cl:1][CH2:2][C:3](=[O:32])[C@:4]1([OH:31])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27](=[O:28])[CH3:29]
Reactant: CC1(CO[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@@]2(O)C(=O)CCl)CO1
Agent: [O-][I+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
A solution of 21-chloro-11β,17-dihydroxy-16α-[(2-methyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione (12 mmoles) in 200 ml of tetrahydrofuran is stirred with a solution of 10 g of periodic acid in 20 ml of water for 3 hours. The slurry is diluted with water and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to give the title compound.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:28]O2)[N:21]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:15]([O:14][C:12]([C@@H:11]1[CH2:28][C@H:26]1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[N:21]=1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: Fc1cccc(C2CO2)n1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.3 %

Procedure:
To a suspension of NaH (60% oil dispersion, 320 mg, 8 mmol) in toluene (10 mL) was added dropwise t-butyl diethylphosphonoacetate (1.92 g, 7.6 mmol). The resulting mixture was stirred at rt for 10 min., then a solution of 2-fluoro-6-oxiranyl-pyridine (530 mg, 3.8 mmol) in toluene (5 mL) was added dropwise to the reaction mixture. The resulting mixture was then heated at reflux for 12 h. The mixture was cooled to rt and diluted with EtOAc and washed with NH4Cl (saturated) and water. The EtOAc layer was dried (Na2SO4). The solvent was removed and the residue was subjected to ISCO (40 g column, hexane 3 min. then 0-60% EtOAc in hexane over 60 min.) to give the desired product (165 mg). MS (MH+ 238).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])(=[O:11])[CH3:10].[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C1COCC1>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30](=[O:31])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])=[O:11])=[CH:33][CH:34]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC(C)CCCC(C)(C)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)CCCC(C)(C)OC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (121.0 mL of a 2.0M solution, 0.243 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is placed in a dry ice-acetone bath. 2,6-Dimethyl-7-octen-2-yl acetate (22.66 g, 0.114 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 4-nitrobenzoyl chloride (20.00 g, 0.108 mol) dissolved in THF (25 mL) over 30 min. The mixture is warned to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (70 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][C:24]([OH:26])=O)[CH:6]=[C:7]([C:9]([CH3:17])([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=1.CC(N)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:17])([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[C:5]2[C:4]=1[C:24](=[O:26])[CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]12
Reactant: CCCCCCC(C)(C)c1cc(OC)cc(N2CCCC2CC(=O)O)c1
Agent: CC(N)c1ccccc1
Product: CCCCCCC(C)(C)c1cc(OC)c2c(c1)N1CCCC1CC2=O

Procedure:
The dl-2-[1-[3-methoxy-5-(1,1-dimethylheptyl)phenyl]pyrrolidin-2-yl]acetic acid provided in Example 54, Part A is resolved into dextrorotatory and levorotatory isomers via the alpha-methylbenzylamine salt by the methods of Examples 18 and 19. The resolved isomeric acids are then cyclized to provide the d- and l-isomers of 6-methoxy-8-(1,1-dimethylheptyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]quinolin-5-one. Cleavage of the methyl ether with hydrobromic acid/acetic acid by the procedure of Example 21 affords the title compounds.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[S:12][C:13]2[C:14](=[C:16]([C:20](Cl)=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:15]=1.[NH2:23][CH2:24][C@@H:25]1[CH2:30][C@H:29]2[C@H:27]([CH2:28]2)[N:26]1[C:31]([C:33]1[N:34]=[C:35]([CH3:45])[S:36][C:37]=1[C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1)=[O:32]>C(#N)C>[CH3:45][C:35]1[S:36][C:37]([C:38]2[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=2)=[C:33]([C:31]([N:26]2[C@H:25]([CH2:24][NH:23][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:13]4[S:12][C:11]([Cl:10])=[N:15][C:14]=34)=[O:21])[CH2:30][C@H:29]3[C@@H:27]2[CH2:28]3)=[O:32])[N:34]=1
Reactant: O=C(Cl)c1cccc2sc(Cl)nc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3cccc4sc(Cl)nc34)C[C@@H]3C[C@@H]32)c1
Reaction time: 0.5 h

Procedure:
DIPEA (0.61 mmol) and 2-chloro-benzothiazole-4-carbonyl chloride (0.31 mmol) are added successively to a solution of ((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone (0.31 mmol) in acetonitrile (1.0 mL). The mixture is stirred for 30 min and purified by prep. HPLC to give the desored product. LC-MS (acidic): tR=1.06 min; [M+H]+=523.0.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C([O-])(O)=O.[Na+].[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:21](ON1C(=O)CCC1=O)=[O:22])[CH:18]([CH3:20])[CH3:19]>O.CC#N>[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:21]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:22])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 5 °C

Procedure:
H-Gln-OH (2 eq.) and NaHCO3 (2 eq.) were dissolved under stirring in water at maximum 45° C. and then cooled to about 5° C. Z-Val-OSu (1 eq.) was dissolved in MeCN and added in the aqueous solution in such way that the temperature did not rise above 10° C. The mixture was stirred for at least 1 h at ±5° C. before being warmed to room temperature for at least two hours. The peptide solution was concentrated under vacuum, diluted with water and washed twice with AcOEt. The aqueous phase was then diluted with i-BuOH and the pH was adjusted to 2.5 with a solution of KHSO4. DCM was then added to extract the peptide into the organic phase which was washed with a 5% weight NaCl solution and finally with water. The organic phase was collected and concentrated under reduced pressure until water content in the evaporates was <1% weight. The concentrate was diluted with hot isopropyl acetate and left to cool to 25° C. under gentle stirring to crystallize the peptide. The solid was recovered by filtration, once washed with AcOiPr at 25° C. and dried under vacuum until AcOiPr content in the peptide was ≦5% weight. After drying under vacuum not less than 70% of Z-Val-Gln-OH was recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14].[OH-].[K+].Cl>O1CCCC1.O.CO>[Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:12]/[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1C=O
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ncc(Br)cc1/C=C/C(=O)c1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 6.5 g of 5-bromo-2-methoxypyridine-3-carboxaldehyde in 30 ml of tetrahydrofuran under nitrogen was added 200 ml of methanol followed by 4.6 g of 4-chloroacetophenone. Then, a solution of 6.6 g of 85% potassium hydroxide in 15 ml of water was added. The mixture warmed, became yellow, and deposited a thick precipitate. It was then stirred mechanically for about 1.5 hours until the temperature fell back to about 25° C. It was then further cooled in an ice bath and neutralized by the addition of 20 ml of aqueous 5M hydrochloric aid in small portions. The resulting pasty mixture was poured into 400 ml of water, acidified to a pH of 1 with aqueous 1N hydrochloric acid and then filtered. The moist product was boiled with 2-propanol/ethyl acetate (3:1), cooled and filtered. The filter cake was dried under reduced pressure to give (E)-3-(5-bromo-2-methoxy-3-pyridinyl)-1-(4-chlorophenyl)-2-propen-1-one as a pale yellow solid melting at about 168.5°-171.5° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:4]=1[SH:12].[C:13]([CH2:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#N>ClC1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:9][C:8]1[C:3]2[N:2]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:12][C:4]=2[C:5]([F:11])=[CH:6][C:7]=1[F:10]
Reactant: CCOC(=O)c1cccc(CCC#N)c1
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CCOC(=O)c1cccc(CCc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 30.3 %

Procedure:
To a solution of zinc chloride (26 mg, 0.19 mmol) in chlorobenzene (3 ml) was added a solution of 2-amino-3,4,6-trifluorothiophenol hydrochloride (269 mg, 1.2 mmol) in chlorobenzene (1 ml) and a solution of ethyl 3-(2-cyanoethyl)benzoate (254 mg, 1.2 mmol) in chlorobenzene (1 ml) and the mixture was heated to reflux for 40 hours. The reaction mixture was evaporated followed by addition of methylene chloride. The resulting mixture was washed with water, dried and evaporated to yield a residue, which was purified on a silica gel column to give ethyl 3-[2-(4,5,7-trifluorobenzothiazol-2-yl)ethyl]benzoate (133 mg, 30%) as an oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26])=[C:20]([Cl:31])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.O>CN(C)C=O>[Cl:31][C:20]1[CH:19]=[C:18]([O:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][CH2:1][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26]
Reactant: C1COCCN1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCN4CCOCC4)cc23)cc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A starting compound (N-(4-{[6-(3-propoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-propyl-urea, 54 mg), potassium carbonate (138 mg), and morpholine (0.017 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give 42 mg (yield 77%) of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:12][NH:13][CH3:14]>>[CH2:1]([N:5]1[CH2:10][CH2:9][C:8]([N:13]([CH3:14])[CH3:12])=[CH:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCN1CCC(=O)CC1
Product: CCCCN1CC=C(N(C)C)CC1
Yield: 77.9 %

Procedure:
1-Butyl-4-piperidone is reacted with dimethylamine gas as described in Example 1, affording 1-butyl-4-dimethylamino-1,2,5,6-tetrahydropyridine with a yield of 77.9%, bp.: 103°-106° C./1.5 kPa. The tetrahydropyridine derivative so obtained is freshly distilled and reacted with acrolein as described in Example 1, to give a light yellow oil with a yield of 44.2%, consisting of 75% of 6α-, and 25% of 6β-dimethylamino-3-butyl-3-azabicyclo[3.3.1]nonan-9-one, bp.: 110°-116° C./7 Pa; nD20 =1.4933.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[C:25]4[C:21](=[N:22][O:23][N:24]=4)[CH:20]=[CH:19][C:18]=3[OH:26])[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:25]4[C:21](=[N:22][O:23][N:24]=4)[CH:20]=[CH:19][C:18]=3[OH:26])[C:9]2=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)ccc2nonc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2c(O)ccc3nonc23)c2ccccc2N1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A mixture of 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one (21.8 g, 48.5 mmol), triethylsilane (50 mL) and trifluoroacetic acid (100.mL) was stirred at ambient temperature for 16 h, then heated to 45° C. for 1.5 h. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated with diethyl ether to afford 1-(diphenylmethyl)-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one (10.94 g, 52%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ10.90-10.00 (br s, 1H), 7.61-7.31 (m, 10H), 7.18 (s, 1H), 7.06-6.89 (m, 4H), 6.55 (d, J=8.4 Hz, 1H), 6.45 (d, J=9.6 Hz, 1H), 5.57 (s, 1H); MS (ES+) m/z 456.0 (M+23).