Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>CN(C=O)C.C(Cl)Cl>[OH:27][C:15]1[C:14]([CH2:13][CH:12]=[C:11]([CH3:34])[CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[C:22]([O:23][CH3:24])[C:21]([CH3:25])=[C:20]2[C:16]=1[C:17](=[O:26])[O:18][CH2:19]2
Reactant: CCOP(=O)(CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCP(=O)(O)O)C(=O)OC2
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a solution of {5-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonic acid diethyl ester (20 mg, 0.039 mmol) in DMF (0.5 mL) and DCM (0.5 mL) was added TMSBr (50.5 μL, 0.39 mmol) followed by 2,6-lutidine (45.3 μL, 0.39 mmol). The reaction was allowed to proceed for one hour when it was complete, as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse-phase HPLC. The fraction containing the desired product was concentrated and treated with 10% TFA/DCM for 5 minutes. After concentration, the residue was purified by preparative reverse-phase HPLC to provide 7 mg (50%) of [5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonic acid as a solid. 1H NMR (300 MHz, CD3OD) δ 1.66-1.78 (m, 5H), 2.10 (s, 3H), 2.16-2.22 (m, 2H), 3.34 (d, J=7.2 Hz, 2H), 3.72 (s, 3H), 5.16 (s, 2H), 5.20 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CD3OD) δ 31.57 ppm; MS (m/z) 355 [M−H]−, 357 [M+H]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[C:18]([Cl:29])[N:17]=[CH:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[OH-].[Na+]>O>[Cl:29][C:18]1[N:17]=[CH:16][N:15]([C:12]2[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=2)[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=1
Reactant: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(N)(=O)=O)cc2)cc1F
Yield: 97 %

Procedure:
A mixture of N-tert-butyl-4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (37.0 g, 85 mmol, obtained in example 4), concentrated HCl (200 mL) and H2O (200 mL) is heated at reflux for 3 h. The mixture is allowed to cool and is brought to pH 6 with 6N NaOH. A white precipitate appears, which is collected by filtration and washed with plenty of H2O and then with CHCl3. 31 g of the title compound of the example is obtained (yield: 97%), which are recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([CH:12]=O)=[CH:10][CH:9]=[C:8]([C:14]([F:17])([F:16])[F:15])[N:7]=1.[CH3:18][O:19][C:20](=[O:41])[CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:18][O:19][C:20](=[O:41])[CH:21]=[CH:12][C:11]1[C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:9][CH:10]=1
Reactant: COCCCc1nc(C(F)(F)F)ccc1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COCCCc1nc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 80 %

Procedure:
N-Methoxy-2-(3-methoxy-propyl)-N-methyl-6-trifluoromethyl-nicotinamide (156 mg, 0.509 mmol) was reacted with 1M-LAH in THF solution to give 2-(3-methoxy-propyl)-6-trifluoromethyl-pyridine-3-carbaldehyde quantitatively as oil. The crude product was used directly in the following reaction. 2-(3-Methoxy-propyl)-6-trifluoromethyl-pyridine-3-carbaldehyde was reacted with methyl(triphenylphosphoranylidene)acetate (204 mg, 0.61 mmol) to give 3-[2-(3-methoxy-propyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid methyl ester (124 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[C:17]([CH2:19][N:20]2[CH2:25][CH:24]3[CH2:26][CH:21]2[CH2:22][N:23]3[CH:27]([CH3:29])[CH3:28])[CH:16]=[C:15]2[C:10]=1[CH2:11][N:12](CC1C=CC(OC)=CC=1)[C:13](=[O:38])[N:14]2[C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37].[OH-].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[C:17]([CH2:19][N:20]2[CH2:25][CH:24]3[CH2:26][CH:21]2[CH2:22][N:23]3[CH:27]([CH3:29])[CH3:28])[CH:16]=[C:15]2[C:10]=1[CH2:11][NH:12][C:13](=[O:38])[N:14]2[C:30]1[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: COc1ccc(CN2Cc3c(-c4ccc(F)cc4Cl)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CC2CC1CN2Cc1cc(-c2ccc(F)cc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 25 °C

Procedure:
The solution of 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (136 mg, 0.20 mmol) in trifluoroacetic acid (1.5 mL) was stirred at 60° C. for 1 h. It was cooled to rt and treated with 5N NaOH solution to pH 9˜10. The resulting mixture was extracted with methylene chloride. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 8% of 2N ammonium in methanol/methylene chloride as eluent provided the 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.03 (d, 3H, J=5.7 Hz), 1.08 (d, 3H, J=5.7 Hz), 1.66 (m, 2H), 2.37 (t, 1H, J=8.2 Hz), 2.43 (t, 1H, J=11.9 Hz), 2.56 (brs, 1H), 2.83 (t, 1H, J=9.2 Hz), 2.90 (d, 1H, J=8.7 Hz), 3.14 (s, 1H), 3.54 (m, 2H), 3.64 (t, 1H, J=13.0 Hz), 4.33 (abq, 2H, J=14.2 Hz), 5.12 (s, 1H), 6.24 (s, 1H), 6.84 (s, 1H), 7.08 (t, 1H, J=8.0 Hz), 7.28 (m, 2H), 7.39 (d, 1H, J=8.0 Hz), 7.54 (t, 1H, J=8.0 Hz). MS (API-ES+): 573 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.CO>O1CCCC1>[NH2:12][C:3]1[C:2]([F:1])=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: Cc1nc2cc(F)c([N+](=O)[O-])cc2o1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2cc(F)c(N)cc2o1
Reaction time: 1.5 h

Procedure:
5-Fluoro-2-methyl-6-nitrobenzoxazole (16 g, 81.57 mMole), was dissolved in tetrahydrofuran (150 mL), and methanol (50 mL). Raney-Nickel which had been pre-washed with water (×3) and tetrahydrofuran (×3), was added and the mixture was then hydrogenated at room temperature and 50 psi of hydrogen. The reaction is complete in approximately 1.5 hours. After this period, the catalyst is filtered off and the solution concentrated under reduced pressure. The residue is triturated with heptane, cooled and the solid filtered off. Yield 12 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:7].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.C(Cl)Cl.[BH4-].[Na+]>O1CCCC1.CO>[C:13]1([CH:6]([NH2:7])[C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C#N)cc1OC
Reactant: Br[Mg]c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(N)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a stirring solution of 3,4-dimethoxybenzonitrile (1.63 grams, 10.0 mmol) in tetrahydrofuran (25 milliliters) was added phenyl magnesium bromide (3.7 milliliters, 3M, 11.0 mmol) and the resulting solution was refluxed for 40 minutes. The progress of the reaction was monitored by TLC (30% ethyl acetate/methylene chloride, UV), after 40 minutes the reaction was complete. The reaction mixture was allowed to cool and methanol (25 milliliters) was added slowly. When the effervescence had ceased sodium borohydride (0.40 grams, 10.5 mmol) was added slowly and the reaction mixture was stirred at room temperature overnight. The resulting dark purple mixture was extracted with ether (3 times with 50 milliliters) and the combined ether extracts back extracted into aqueous 3N hydrochloric acid (150 milliliters). The pH of the aqueous layer was then adjusted to 14 using sodium hydroxide (5 Molar) and the mixture was extracted with methylene chloride (2 times with 50 milliliters). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford 1.76 grams (72%) of product as an orange oil: 1H NMR (CDCl3) δ7.43-7.16(m, 5H), 6.95-6.74(m, 3H), 5.17(s, 1H), 3.85(s, 3H), 3.84(s, 3H), 1.78(s, 2H).
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:10][C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=1>[OH-].[Na+].C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]([CH3:21])=[C:9]([CH3:20])[N:10]=[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:6]1=[O:5]
Reactant: OCCCl
Reactant: Cc1nc(O)c(Cc2ccc(Cl)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(Cc2ccc(Cl)cc2)c(=O)n(CCO)c1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
Ethylene chlorohydrin (16.11 g, 0.20M) was added to a solution of 2-hydroxy-3-p-chlorobenzyl-5,6-dimethylpyrazine (11.06 g, 40 mM) in aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. Dilute aqueous K2CO3 was added to the residue, the resulting mixture being extracted three times with chloroform, dried wit anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 300 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 641 (9.73 g, yield: 75.9%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[CH2:4][CH2:5][O:6][CH2:7][C:2]1=[O:1])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCOCC1=O

Procedure:
A solution of 3-oxo-morpholine (6.5 g, 4 mmol) (Willey, Alan David; Kott, Kevin Lee; Miracle, Gregory Scot; Gosselink, Eugene Paul; Burckett-St. Laurent, James Charles Theophile Roger. Bleaching compositions containing bleach activators having alpha-modified lactam leaving-groups. PCT Int. Appl. (1996), WO 9622350 A1) in DMF (45 mL) was treated at rt in 3 portions with sodium hydride (3.34 g, 60% dispersion in mineral oil, 84 mmol). After 30 min a solution of ethyl bromoacetate (11.8 g, 71 mmol) in DMF (20 mL) was added dropwise. After 3 h the solvent was evaporated, the residue was taken up with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, concentrated and chromatographed (SiO2, dichloromethane:methanol=1000:0 to 995:5). The title compound was obtained as a light yellow oil (3.34 g, 28%). 1H-NMR (300 MHz, DMSO): δ=1.19 (t, J=7 Hz, 3H), 3.40 (mc, 2H), 3.85 (mc, 2H), 4.05-4.28 (m, 6H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Reaction time: 18 h
Yield: 61.4 %

Procedure:
A solution of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (3.0 g, 10.54 mmol) and 4-azetidin-3-ylmorpholine (1.8 g, 12.66 mmol) in DCE (200 mL) was stirred at ambient temperature for 2 h. Sodium triacetoxyborohydride (3.5 g, 16.5 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (50 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 99:1 to 98:2 to 95:5) to afford 4-(5-chloro-2-((3-morpholinoazetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine as a cream solid (2.66 g, 61%). LCMS (Method C): RT=2.68 min, [M+H]+ 411.3
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(Br)cn1
Reaction time: 15 h
Yield: 58.5 %

Procedure:
In 100 ml of pyridine was dissolved 10.13 g of N-t-butoxycarbonylglycine and the solution was added with 5 g of 2-amino-5-bromopyridine, 13.85 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 7.06 g of 4-dimethylaminopyridine, individually at room temperature. Stirring was conducted for 15 hours at the same temperature. Water was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated under vacuum to give 5.58 g of 2-(N-t-butoxycarbonylglycinylamino)-5-bromopyridine. This compound was dissolved, along with 5.82 g of (S)-[N-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, in 70 ml of dimethylformamide and added with 4.9 ml of triethyl amine and 2.97 g of dichlorobistriphenylphosphine palladium (II) at room temperature. Reaction was performed at 100° C. for 4 hours with stirring. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated under vacuum. Recrystallization of the concentrate provided 5.13 g of (S)-[N-3-(4-(2-(N-t-butoxycarbonylglycinylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl)methyl acetamide. This product was reacted with 1.65 ml of trimethylsilyl iodide in chloroform at room temperature for 30 min under a nitrogen atmosphere with stirring. Following the addition of chloroform, the organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo. The concentrate was purified through column chromatography to provide the title compound. 550 mg.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].CC(C)([O-])C.[K+].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].C(OCC)(=O)C>CN(C)P(N(C)C)(N(C)C)=O>[C:33]1(=[O:42])[N:32]([CH2:31][CH2:30][CH2:29][O:4][C:3]2[CH:2]=[CH:1][C:17]3[CH2:16][C@H:15]4[N:18]([CH3:19])[CH2:20][CH2:21][C@:7]56[C:6]=3[C:5]=2[O:9][C@H:8]5[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]46)[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]12
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 25.0 g (87.7 mmol) of morphine in 350 ml of hexamethylphosphoramide was cooled in an ice-water bath and 10.3 g (92.0 mmol) of potassium tertiary butoxide was added through a Gooch tube over a period of 10 minutes. After stirring at room temperature for 0.5 hr, 23.5 g (87.7 mmol) of N-(3-bromopropyl)-phthalimide was added and stirring was continued at this temperature for 21 hrs. The reaction mixture was poured into 500 ml of ice-water and then 500 ml of ethyl acetate was added. The organic phase was separated and the aqueous solution was extracted with 500 ml of ethyl acetate. The combined ethyl acetate extracts were washed with water (3 × 250 ml), 2 N sodium hydroxide, and with water (3 × 300 ml). After drying, the solvent was removed in vacuo to give 31.0 g of crude product, which after recrystallization from isopropanol--ether, yielded pure 3-(3-phthalimidopropoxy)-7,8-didehydro-4,5 α-epoxy-17-methylmorphinan-6 α-ol, m.p. 121°-123°, [α]D25 -76.63° (c 1.03, MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si](C(C)(C)C)(C)C)[CH:18]=[CH:17]3)[CH:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[CH:17]3)[CH:10]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(ccn3[Si](C)(C)C(C)(C)C)c2)C(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]ccc3c2)C(Cc2ccccc2)C1
Yield: 93.4 %

Procedure:
To a stirring solution of 3-benzyl-4-[1-(tert-butyl-dimethyl-silanyl)-1H-indol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.61 g, 3.2 mmol) in 20 mL THF at 0° C. was added TBAF (3.5 mL, 1.0 M in THF, 3.5 mmol). After 15 minutes the solution was quenched by the addition of water, concentrated under reduced pressure, and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification via flash chromatography (5% to 40% EtOAc in hexanes) afforded 3-benzyl-4-(1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 93%) as a white foam; MS (M+H)=392.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[Br:14][C:15]1[S:19][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:14][C:15]1[S:19][C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:24][CH2:25]2)=[N:17][CH:16]=1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: Brc1cnc(N2CCNCC2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ncc(Br)s3)CC2)cc1
Yield: 82.7 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (0.9 g), 1-(5-bromothiazol-2-yl)piperazine (1.1 g) and potassium carbonate (0.9 g) in dimethylformamide (10 ml) was stirred at 70° C. for 9 hr. Water (100 ml) was poured into the reaction mixture to allow precipitation of crystals. The crystals were collected by filtration and washed with water to give the title compound (1.5 g) as yellow crystals, m.p.=160-163° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:8]([Cl:15])=[C:7]([N+:16]([O-])=O)[CH:6]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([NH:4][C:5]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:8]([Cl:15])=[C:7]([NH2:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1NC(C)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cc(N)c(Cl)cc1NC(C)=O
Yield: 94 %

Procedure:
To a solution of 4 g (14.7 mmol) of 4,5-diacetamido-1-chloro-2-nitrobenzene in 200 ml of ethanol were added a solution of 0.4 g of copper(II) sulfate×5H2O in 2 ml of water and subsequently, a little at a time, 1.1 g (29.4 mmol) of sodium borohydride. The mixture was refluxed for 3 hours and subsequently filtered. The filtrate was concentrated, and the crude product was washed with water and methylene chloride. Workup of the organic phase gave a yield of 94% of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:10]([Cl:9])[CH:11]=2)[CH:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)O
Product: Clc1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 84 °C
Yield: 61 %

Procedure:
250 mg of 4,6-dichloropyrimidine and 165 mg of m-chloroaniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl were added. The mixture obtained was refluxed (84° C.) for 2.5 hours under nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-(3-chlorophenyl)pyrimidin-4-amine hydrochloride in the form of colorless crystals was obtained.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])(O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1CCC(O)(c2cccc(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC1CC=C(c2cccc(F)c2F)CC1
Temperature: 30 °C
Yield: 58.8 %

Procedure:
The compound (47) (130.1 g), p-toluenesulfonic acid (1.3 g), and toluene (500 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (500 ml) and toluene (500 ml) were added, and mixed thereto. The mixture was allowed to stand until it had separated into organic and aqueous phases, and an extractive operation into an organic phase was carried out. The organic phase obtained was fractionated, washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder, and dried, giving 71.6 g of 4-butoxy-(2,3-difluorophenyl)cyclohexene (48). The compound (48) obtained was a colorless oil, having the boiling point at 131° C./3 mmHg to 132° C./3 mmHg, and the yield based on the compound (6) was 66.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:36])([F:37])[F:38])=[CH:29][CH:28]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(NCc2ccc(OCC(F)(F)F)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(OCC(F)(F)F)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 36.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.64 g) and (4-isopropylphenyl){[4-(2,2,2-trifluoroethoxy)phenyl]methyl}amine (1.0 g) as starting materials, N-(4-isopropylphenyl)-7-methoxy-N-{[4-(2,2,2-trifluoroethoxy)phenyl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained. melting point: 125-127° C.