Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@:6]1([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][Si](C(C)(C)C)(C)C)=[CH:36][CH:35]=2)[CH:27]=1)OC)(=[O:3])[CH3:2].O.C([SiH](CC)CC)C.C(OC(=O)C)C>C(#N)C>[C:16]([O:15][C@H:9]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH2:33][C:34]3[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=3)[CH:27]=2)[O:7][C@@H:8]1[CH2:19][O:20][C:21](=[O:23])[CH3:22])(=[O:18])[CH3:17]
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a solution of (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-2-(3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-4-chlorophenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (44.0 g, 0.064 mol) in acetonitrile (200 mL), water (1.15 mL, 0.064 mol), triethylsilane (32.45 mL, 0.203 mol) and borontrifluoroetherate (15.94 mL, 0.127 mol) were added at 10° C. The resulting mixture was stirred at r.t. for 16 h. Additional amounts of triethylsilane (3.25 mL, 0.020 mol) and borontrifluoroetherate (1.59 mL, 0.013 mol) were added at 10° C. and heated at 30° C. for 6 h. Ethylacetate (1 L) was added to the reaction mixture, washed it with saturated NaHCO3 solution (2×500 mL), water (500 mL) and brine (500 mL) successively. The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 4:6 Ethyl acetate:Pet.Ether) to provide title compound (30 g, 86.27%) as off-white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:27]=[N:28]O.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I.C(N(CC)CC)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=1[C:27]#[N:28])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: C=NO
Reactant: CCN(CC)c1ccc(N=Nc2c(C)cc(Br)cc2Br)c(NC(C)=O)c1
Agent: [Cu]I
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(N=Nc2c(C)cc(Br)cc2C#N)c(NC(C)=O)c1
Temperature: 90 °C

Procedure:
A stirred mixture of 3-acetylamino-4-(2', 4'-dibromo-6'-methylphenylazo)-N,N-diethylaniline (4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.8 parts), triethylamine (1.5 parts), and nitrobenzene (100 parts) was heated to 90° C. for 11/2 hours when thin layer chromatography showed reaction to be complete. Isolation by the method of Example 3 gave 3-acetylamino-4-(2'-cyano-4'-bromo-6'-methylphenylazo)-N,N-diethylaniline, infra red spectrum identical with that of authentic material.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[C:7]1([CH:13]([CH3:16])[C:14]#[N:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.ClCCl>[C:7]1([CH:13]([CH3:16])[C:14](=[NH:2])[NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CC(C#N)c1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C(=N)N)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Ammonium chloride (535 mg, 10.0 mmol) was suspended in toluene (3 ml), cooled to 0° C., under nitrogen then trimethylaluminium (5 ml, 2M in toluene) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 2 h. Then 2-phenylpropionitrile (1.33 ml, 10.0 mmol) in toluene (2 ml) was added and heated to 80° C. for 17 h. The reaction mixture was poured onto a slurry of silica (20 g) in dichloromethane (20 ml) and stirred for 5 min. It was filtered and the filtrate concentrated in vacuo. Trituration of the residue with diethyl ether afforded the title compound as a solid in 95% yield, 1.75 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:13]1[CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=[CH:11][N:12]=1
Reactant: COc1ccc(-c2cc[n+]([O-])cc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2ccnc(Cl)c2)cc1

Procedure:
A mixture of 4-(4-methoxyphenyl)pyridine 1-oxide (1.68 g) and phosphorus oxychloride (15 mL) is heated under reflux for six hours and concentrated under reduced pressure. Toluene is added and the mixture concentrated under reduced pressure. The residue is dissolved in hot toluene (20 mL) and the organic phase washed with water (twice 10 mL) a saturated aqueous sodium hydrogenocarbonate solution (10 mL), dried over magnesium sulphate and concentrated under reduced pressure to give 1.45 g of 2-chloro-4-(4-methoxyphenyl)pyridine as an orange coloured crystalline material.
Reaction SMILES: N(CC)CC.S([O-])([O-])(=O)=O.C1C2C(COC([N:28]3[CH2:33][CH2:32][CH:31]([C:34]4[N:38]=[C:37]([C@@H:39]5[CH2:45][CH2:44][C@@H:43]6[CH2:46][N:40]5[C:41](=[O:52])[N:42]6[O:47][S:48]([OH:51])(=[O:50])=[O:49])[O:36][N:35]=4)[CH2:30][CH2:29]3)=O)C3C(=CC=CC=3)C=2C=CC=1.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[S:48]([OH:51])([O:47][N:42]1[C:41](=[O:52])[N:40]2[CH2:46][C@H:43]1[CH2:44][CH2:45][C@H:39]2[C:37]1[O:36][N:35]=[C:34]([CH:31]2[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]2)[N:38]=1)(=[O:49])=[O:50]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OS(=O)(=O)O)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Solvent: CCNCC
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2c2nc(C3CCNCC3)no2)N1OS(=O)(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Et2NH (6.1 mL, 60.0 mmol) was added to a solution of tetrabutylammonium (9H-fluoren-9-yl)methyl 4-(5-((2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate sulfate (1.0 g, 1.2 mmol) in dried CH2Cl2 (30 mL). The mixture was stirred under N2 atmosphere at rt. for 12 hrs, then evaporated under vacuum. The residue was purified by prep-HPLC using the ammonium formate conditions. E SI-MS (EI+, m/z): 314.2. 1H NMR (300 MHz, D2O) δ 4.82 (d, J=8.0 Hz, 1H), 4.17 (br s, 1H), 3.47-3.45 (m, 2H), 3.25-3.12 (m, 3H), 2.96-2.92 (m, 1H), 2.39-1.94 (m, 8H).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7](=[O:18])[N:6]([CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].O=P(Cl)(Cl)Cl.[CH3:26]N(C=O)C>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:3]3[NH:1][N:2]=[CH:26][C:4]=3[C:5](=[O:20])[N:6]([CH3:19])[C:7]2=[O:18])=[CH:11][CH:12]=1
Reactant: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn[nH]c32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 6-hydrazinyl-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (4.0 g, 14.5 mmol) in anhydrous DMF (200 mL) is added POCl3 (16 mL) dropwise with IPA-dry ice bath cooling. After the completion of the addition, the mixture is allowed to warm up to room temperature and stirred at r.t. overnight. DMF is removed under reduced pressure, and the residue is treated with cold water very carefully. The generated precipitate is filtered, washed with water to give pure product as white solids (3.74 g, yield: 90%). MS (ESI) m/z 287.1 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:65]=[CH:64][C:53]2[NH:54][C:55]([CH:57]([NH2:63])[C:58]([O:61][CH3:62])([CH3:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:65]=[CH:64][C:53]2[NH:54][C:55]([CH:57]([NH:63][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[C:58]([O:61][CH3:62])([CH3:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: COC(C)(C)C(N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(C)(C)C(NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 76 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-2-methylpropylamine in tetrahydrofuran. Yield: 76%; Rf value: 0.50 (silica gel; dichloromethane/ethanol=9:1); C25H29ClN4O3 (468.98); mass spectrum: (M+H)+=469/471 (chlorine isotope) and (M−H)−=467/469 (chlorine isotope).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[NH:13][C:9]=2[CH:8]=[CH:7][N:6]=1.[C:15]1([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH2:23]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:21]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:13]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([O:4][CH3:3])[C:10]=2[CH:11]=[C:12]1[CH3:14]
Reactant: COc1nccc2[nH]c(C)cc12
Reactant: BrCc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (98 mg, 2.5 mmol, 60% in mineral oil) in THF (10 mL), 4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine 3 (280 mg, 1.72 mmol) in THF (3 mL) was added. The mixture was stirred at room temperature for 30 min, and then 2-phenylbenzyl bromide (0.40 mL, 2.2 mmol) was added, stirring was continued for 18 h. The reaction mixture was quenched with saturated NH4Cl (20 mL), extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water (40 mL), brine (40 mL), dried over Na2SO4 and evaporated. Flash chromatography of the residue over silica gel, using 10% EtOAc in hexanes to 25% EtOAc in hexanes) gave product 4 as a yellow foam. Yield: 375 mg (66%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:6]([O:8]CC)=[O:7]>S(=O)(=O)(O)O>[CH3:3][C:4]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C=C(C)C(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CC(=CC(=O)O)C(C)C
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of aqueous potassium hydroxide solution (0.5 N, 92 mL) and ethyl 3,4-dimethyl-2-pentenoate (XI, 5.5 g) was stirred at 80° C. for 17 hours until the oily supernatent layer disappeared. The reaction mixture was cooled, acidified with aqueous sulfuric acid, (0.5 N, ca. 100 mL), and extracted with ether. The ethereal layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to afford 3,4-dimethyl-2-pentenoic acid as a yellow liquid (X, 4.1 g, 91%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[ClH:8].[Cl:9][C:10]([N:12]1[C:18]2[S:19][C:20]([CH2:22][CH3:23])=[CH:21][C:17]=2[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[N:15][CH2:14][CH2:13]1)=[O:11]>O1CCCC1>[ClH:9].[ClH:8].[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:16]1[C:17]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=2[N:12]([C:10](=[O:11])[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH2:13][CH2:14][N:15]=1
Reactant: CN(C)CCCN
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc2c(s1)N(C(=O)NCCCN(C)C)CCN=C2c1ccccc1Cl
Temperature: 0 °C

Procedure:
To a solution of 9.2 g of 3-dimethylaminopropylamine in 50 ml of tetrahydrofuran is added 7.8 g of 1-chlorocarbonyl-5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride by portions with cooling and stirring. After the mixture is reacted for two and half hours at room temperature, the reaction substance is poured into 200 ml of ice-cold water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 5-o-chlorophenyl-7-ethyl-1-(3-dimethylaminopropylcarbamoyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine dihydrochloride as yellow crystals. This product, when recrystallized from a mixture of methanol and ethyl acetate, melts at 223°-224° C with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:17])[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.4 %

Procedure:
A solution of 5-bromo-2-methoxybenzaldehyde (100 g, 0.46 mol) in chloroform (250 ml) was cooled with an ice bath and 3-chloroperoxybenzoic acid (50-60% purity) (146 g, 0.51 mol) in chloroform (1000 ml) added. The reaction mixture was allowed to warm slowly to room temperature and stirred for 72 h. The white solid was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in ether (200 ml) and washed with 1M sodium sulphite solution (2×200 ml) then sodium hydrogen carbonate [half saturated] (3×200 ml). The ether layer was washed with 10% aqueous sodium hydroxide (3×100 ml) and the combined basic extract was acidified with concentrated hydrochloric acid and extracted with Et2O (3×100 ml). The combined organic extract was dried (MgSO4) and florisil (10 g) filtered and the solvent removed under reduced pressure to give the title compound (90 g) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.[C:13]([O-:16])([O-])=O.[K+].[K+].[Cl-].O>C(Cl)Cl>[OH:12][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[C:2]([NH:1][C:13](=[O:16])[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1)=[CH:11][CH:10]=[CH:9]2
Reactant: O=C([O-])[O-]
Reactant: Nc1cccc2cc(O)ccc12
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc2cc(O)ccc12)c1ccccc1

Procedure:
To a round bottom flask containing 1.00 g (6.3 mmol) 5-amino-naphthalene-2-ol in 10 mL CH2Cl2, was added 2.61 g (0.0189 mmol) K2CO3, followed by 1.46 mL (0.0126 mmol) benzolyl chloride. The solution mixture was stirred under inert atmosphere until completion. After stirring for 18 h, water was added into the mixture and diluted with CH2Cl2. The organics were separated by sep. funnel, while extracting the organics 3× with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered and concentrated in-vacuo. The crude was purified by crystallization in CH2Cl2/Hexanes. A gray colored powder was collected, which was titled compound. MS (ESI pos. ion) m/z: 264 (M+H)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[O:3]=[C:4]1[N:9]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(F)(F)F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Sodium hydride (840 mg, 24.5 mmol) was gradually added to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (4.1 g, 20.4 mmol) in DMF (30 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 30 minutes. A solution of 4-trifluoromethylbenzyl chloride (5 g, 20.9 mmol) in DMF (5 ml) was added dropwise to the mixture while cooling in an ice-bath, which was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to afford tert-butyl 3-oxo-4-(4-trifluoromethylbenzyl)piperazine-1-carboxylate (6.7 g, yield 91%) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2.[CH2:19]([Mg]Br)C>CCOCC>[CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][C:11]([CH3:19])([OH:16])[CH2:12]2
Reactant: CCC(CCCCC1CCC2CC(=O)CC12)OC
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCC(CCCCC1CCC2CC(C)(O)CC12)OC

Procedure:
2-(5-Methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} (4 g, 0.0158 moles) diluted in ether is added dropwise to a stirring solution of ethyl magnesium bromide (0.0158 moles) dissolved with diethyl ether. The mixture is cooled in an ice bath during the addition. The ice bath is removed and the solution stirred for an additional hour. The reaction is quenched with water and a 15% sulfuric acid solution. The organic phase is separated and the solvent removed under vacuum. The aqueous layer is extracted with ether (2×200 ml) and the extracts are combined with the organic layer and dried over anhydrous sodium sulfate. The solid is filtered off and the remaining solvent removed leaving a clear, pale yellow oil. The crude product is subsequently chromatographed on silica gel yielding desired product as a clear colorless oil (1.7 g, 6.3 mmoles).
Reaction SMILES: [C:1]([C:3]1[O:4][CH:5]=[CH:6][CH:7]=1)#[CH:2].[Li]CCCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH:18]=[O:19]>C1COCC1>[O:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1]#[C:2][C:18]([C:17]1[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:19]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C#Cc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)C#Cc2ccco2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-Ethynylfuran (200 mg, 2.17 mmol) was dissolved in dry THF (10 ml) and cooled to −78° C. under N2 atmosphere. BuLi (1.2 ml, 2.4 mmol) was added slowly and stirred at −78° C. for 10 min and then 3,4,5-trimethoxybenzaldehyde (500 mg, 2.6 mmol) was added and reaction mixture was stirred for 1 h at −78° C. and then reaction temp raised to room temp. The reaction was quenched by addition of aqueous NH4Cl solution and extracted with EtOAc. The colorless oil was dissolved in dichloromethane and excess of MnO2 was added to it and stirred overnight at room temp. The reaction mixture was filtered through celite plug and evaporated to dryness. 3-(2-furyl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-one was precipitated from ether by slow addition of hexane as off-white powder (65%). 1H NMR (300 MHz, CDCl3) δ 3.93 (s, 9H), 6.50-6.52 (m, 1H), 7.01 (d, J=3.6 Hz, 1H), 7.45 (s, 2H), 7.24 (s, 1H), 7.55 (d, J=1.5 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[S:8][CH2:7]1.[ClH:17].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:19]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[ClH:17].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[S:8][CH2:7]3)[CH2:31][CH2:32]2)=[N:19]1
Reactant: O=C1C(CC(F)(F)F)SCN1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C1C(CC(F)(F)F)SCN1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 70 °C
Yield: 46.5 %

Procedure:
A mixture of 3-(4-bromobutyl)-5-(2,2,2-trifluoroethyl)-4-thiazolidinone (3.20 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (2.81 g), K2CO3 (4.83 g) and NaI (250 mg) in acetonitrile (280 ml) was heated at 70° C. for 15 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.30 g of crystals, m.p. 188°-200° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:32]=[CH:31][C:10]([C:11]([NH:13]/[C:14](/[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:15]\[C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[O:12])=[CH:9][CH:8]=2)C[CH2:2]1.O1C=CNC1=O>>[CH:4]1([CH2:5][O:6][C:7]2[CH:32]=[CH:31][C:10]([C:11]([NH:13]/[C:14](/[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:15]\[C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:1]1
Reactant: O=C(NCCO)/C(=C/c1ccc(C2CC2)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Agent: O=c1[nH]cco1
Product: O=C(NCCO)/C(=C/c1ccc(C2CC2)cc1)NC(=O)c1ccc(OCC2CC2)cc1

Procedure:
A reaction similar to that described in Example 1 (1c) was conducted using N-[4-(cyclopropylmethoxy)benzoyl]glycine (299 mg) prepared in Example 18 (18b) and 4-cyclopropylbenzaldehyde (184 mg) to give the corresponding oxazolone (366 mg). A reaction similar to that described in Example (1 (1d) was conducted using all this oxazolone to give 385 mg of 4-(cyclopropylmethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (white powder).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]2[C:28]3[CH:29]=[C:30]([CH:33]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[C:34]4[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=4)[CH:31]=[CH:32][C:27]=3[NH:26][C:25](=O)[CH2:24][S:23]2)[CH:19]=[CH:20][CH:21]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]2[C:28]3[CH:29]=[C:30]([CH:33]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[C:34]4[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=4)[CH:31]=[CH:32][C:27]=3[NH:26][C:25](=[S:2])[CH2:24][S:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=O)N2
Solvent: C1CCOC1
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=S)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Tetraphosphorus decasulfide (0.0097 mol) was added at room temperature to a solution of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (see Example B13) (0.0081 mol) in THF (50 ml). The mixture was stirred at room temperature for 2 hours and poured out into ice water. The precipitate was filtered off and taken up in K2CO3 10%. The mixture was extracted with DCM and a small amount of methanol. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 3.2 g (77.5%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepine-2(3H)-thione.