Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25](OC)([O:27]C)[CH3:26].[ClH:31]>C(#N)C.CCOCC.C(O)C>[ClH:31].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25](=[O:27])[CH3:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COC(C)(CBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (7.45 g, 33.4 mmol), K2CO3 (5.5 g) and bromo-2,2-dimethoxypropane (6.84 g, 37.6 mmol) in acetonitrile (200 ml) was heated and stirred at reflux for 4 hours. An additional charge of bromo-2,2-dimethoxypropane (5.1 g, 28 mmol) was added and the mixture was refluxed overnight. After being cooled to room temperature, the mixture was filtered, and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column (SiO2, 100 g; eluted with dichloromethane, DCM, and 1% CH3OH in DCM). The oil product thus obtained weighed 2.2 g (24%). The oil product was dissolved into ethanol (10 ml) then was treated with HCl in ether solution (1M, 9 ml) at room temperature. The crystals were collected, 2.08 g, m.p.=220°-223° C. dec.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.[CH2:16]([O:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH:27][CH3:28])[CH:21]=1)[CH3:17].[CH2:30](Cl)CCl>CN(C=O)C>[CH2:16]([O:18][C:19]([C:20]1[CH:25]=[CH:24][C:23]2[N:26]=[C:28]([NH:11][C:9]3[S:10][C:6]4[CH:5]=[C:4]([O:3][C:2]([F:1])([F:14])[F:15])[CH:13]=[CH:12][C:7]=4[N:8]=3)[N:27]([CH3:30])[C:22]=2[CH:21]=1)=[O:29])[CH3:17]
Reactant: CCOC(=O)c1ccc(N)c(NC)c1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2c1
Yield: 59.3 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid ethyl ester (2.8 g) was prepared by following General Procedure D starting from 6-trifluoromethoxy-benzothiazol-2-ylamine (2.9 g), 4-amino-3-methylamino-benzoic acid ethyl ester (2.1 g), thioCDI (2.2 g) and EDC (2.4 g) in DMF (30 mL).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[O:15]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](Cl)=O)=[CH:16]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[O:15]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:16]1
Reactant: O=C(Cl)/C=C/c1ccoc1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccoc1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-(3-furyl)acryloyl chloride (Shizuri, Y.; Ojika, M.; Yamada, K. Tetrahedron Lett., 1981, 22, 4291) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 287.32; mp: 162.5-164.0° C.; 1H-NMR (CDCl3) δ: 8.79-8.75 (1H, m), 7.99 (1H ddd, J=7.7, 7.7, 1.8 Hz), 7.87 (1H, d, J=15.8 Hz), 7.83-7.78 (1H, m), 7.64-7.62 (1H, m), 7.53-7.39 (4H, m), 7.37-7.22 (2H, m), 6.85 (1H, d, J=15.8 Hz), 6.55 (1H, d, J=1.8 Hz).
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1.N.[NH2:22][C:23]([NH2:25])=[O:24]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=3)[CH2:11][O:24][C:23]([NH2:25])=[N:22]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NC(N)=O
Reactant: C=C(c1cccc(Br)c1)c1ccc(OC)c(Cl)c1
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C2(c3cccc(Br)c3)COC(N)=N2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
A solution of iodine (3.76 g, 14.83 mmol) in ethyl acetate (40 mL) was added dropwise over 25 min to a mixture of 4-[1-(3-bromo-phenyl)-vinyl]-2-chloro-1-methoxy-benzene (4.36 g, 13.49 mmol) and silver cyanate (2.42 g, 16.18 mmol) in acetonitrile (38 mL) and ethyl acetate (18 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 80 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 60° C. for 4 hours. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline. Dichloromethane (40 mL) was added to the crude and the two phases were separated; organic layer was collected, dried over magnesium sulfate anhydrous, filtered and evaporated under reduced pressure. The solid obtained was washed with cyclohexane to give 2.89 g of desired product as a pale-yellow solid (56%)
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1>CCO.[Pd]>[CH:14]1([C:9]2[NH:10][S:11](=[O:12])(=[O:13])[C:6]3[C:5]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:4][CH:3]=[CH:2][C:7]=3[N:8]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(-c3ccccn3)c21
Agent: [Pd]
Solvent: CCO
Product: O=S1(=O)NC(C2CCCCC2)=Nc2cccc(-c3ccccn3)c21
Yield: 82.2 %

Procedure:
5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.268 g, 0.713 mmol) was dissolved in 99% EtOH (50 ml) and hydrogenated using Pd/C (10%, 10 mg) at 4 bar pressure for 24 h. The mixture was filtered through a pad of Celite™ and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 ml) and washed with phosphate buffer (pH=7, 10 ml), dried (Na2SO4) and the solvent was removed under reduced pressure, yielding 200 mg (82%) of 3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals. The product was further transformed by Method F. M.p. 200-203° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].[C:17]([CH2:21][CH:22](C)[C:23](Cl)=[O:24])([O:19][CH3:20])=[O:18].[C:27](=S)=S>>[C:17]([CH:21]([CH3:27])[CH2:22][C:23]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[N:2]([CH3:1])[CH2:11]2)=[O:24])([O:19][CH3:20])=[O:18]
Reactant: CN1Cc2ccccc2NC1=O
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: S=C=S
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C(C)CC(=O)c1ccc2c(c1)CN(C)C(=O)N2
Temperature: 25 °C

Procedure:
3,4-Dihydro-3-methyl-2(1H)-quinazolinone (2.5 g) is added to a stirred suspension of anhydrous aluminum chloride (10.5 g) in carbon disulfide (120 ml) under nitrogen. 3-Carbomethoxy-2-methyl-propionyl chloride (2.5 g) is added dropwise to the stirred suspension, which is refluxed for about 18 hours and cooled to RT. The liquid phase is decanted and the residue treated with H2O (120 ml) and extracted with methylene chloride. The organic extract is dried, filtered and concentrated in vacuo, affording the desired product as a solid, which is used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30](=O)[O:31]C(C)(C)C)([CH3:28])([CH3:27])[CH3:26]>CO.C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
3.31 g of 1-cyclopropyl-6-fluoro-7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in a mixture of 30 ml of methanol and 20 ml of chloroform, and the resulting solution was stirred at 50° C. for 5 hours after addition of 2.29 g of di-t-butylcarbonate thereto. The solvent was removed under reduced pressure to obtain 4.2 g of the object compound
Reaction SMILES: [Cl:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[C:17]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[ClH:25]>[Fe].CO>[ClH:1].[ClH:25].[NH2:21][C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:24])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N)c3Cl)c2n1
Reaction time: 1 h

Procedure:
To a mixture of 8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylquinoline (1.0 g), concentrated hydrochloric acid (5.2 ml) and methanol (5.2 ml)) was added iron powder (666 mg). The mixture was heated under reflux for 2 hours and stirred in an ice-water bath for 1 hour. The precipitate was collected by vacuum filtration and washed with 1 N hydrochloric acid and water to give 8-(3-amino-2,6-dichlorobenzyloxy)-2-methylquinoline dihydrochloride (635 mg) as a brownish powder.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].[Cl:25][C:26]1[N:31]=[N:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C>C(=O)(O)[O-].[Na+].C(Cl)Cl>[Cl:25][C:26]1[N:31]=[N:30][C:29]([S:32]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nn1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)nn1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 24 h
Yield: 34.2 %

Procedure:
To a 20 mL vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.35 g, 0.87 mmol, Example 91), 6-chloropyridazine-3-sulfonyl chloride (0.20 g, 0.96 mmol, Archiv der Pharmazie and Berichte der Deutschen Pharmazeutischen Gesellschaft 1966, 229, 646), CH2Cl2 (10 mL) and triethylamine (0.61 mL, 4.4 mmol). After 24 h at room temperature, an additional 100 mg of 6-chloropyridazine-3-sulfonyl chloride was added and the solution was stirred for an additional hour. The reaction was diluted with saturated aqueous sodium bicarbonate and CH2Cl2. This was stirred for 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was purified by silica gel chromatography (0 to 70% EtOAc in hexanes). The resulting oil was dissolved in EtOAc/heptanes, concentrated and dried under reduced pressure to afford 2-(4-(4-((6-chloropyridazin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.15 g) as a yellow solid.
Reaction SMILES: O=C1N([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)CC(C(N2CCC(C(O)=O)CC2)=O)O1.Cl.[O:31]1CCCC1>>[N:10]1([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:11][CH2:12][C:7](=[O:31])[CH2:8][CH2:9]1
Reactant: O=C(O)C1CCN(C(=O)C2CN(C3CCN(c4ccncc4)CC3)C(=O)O2)CC1
Reactant: C1CCOC1
Agent: Cl
Product: O=C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 79.7 g of the ketal prepared in a) in 2 l tetrahydrofuran is admixed with 1 l 6 n hydrochloric acid and the reaction mixture is stirred for 2 h at room temperature. Subsequently the tetrahydrofuran is removed in a vacuum on a rotary evaporator, the hydrochloric acid is made alkaline with semi-concentrated ammonium hydroxide solution and extracted four times with 100 ml methylene chloride each time. After drying the combined organic extracts over sodium sulfate and removing the solvent, the residue is purified by means of column chromatography on silica gel. 64.2 g (100% yield) 2,3,5,6-tetrahydro-[1,4']bipyridinyl-4-one is obtained in this manner as a grey powder. m/e=176; f.p.=102° C.
Reaction SMILES: Br.C(O)(=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@H:20]([OH:21])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][N:25](C(OCC3C=CC=CC=3)=O)[CH3:26])[C:17]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:16]=3[S:15]2)=[CH:10][CH:9]=1.CCOCC>C1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[C@@H:20]([OH:21])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][NH:25][CH3:26])[C:17]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:16]=3[S:15]2)=[CH:12][CH:13]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Agent: Br
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
1.7 ml of 25% hydrogen bromide-acetic acid are added to a solution of 1.07 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in 2 ml of benzene under ice-cooling, and the mixture is stirred at room temperature for 2 hours. Then, ether is added to the mixture, and the precipitates are collected by filtration and washed with ether. Water and benzene are added to said precipitates, and the mixture is alkalized with potassium carbonate. The benzene layer is collected, washed with water, dried and then evaporated to remove solvent. Ether is added to the residue, and crystalline precipitates are collected by filtration and recrystallized from a mixture of ethyl acetate and n-hexane. 0.47 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.
Reaction SMILES: [C:1]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16](Cl)=[O:17])[CH2:12][CH2:11]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1.C(Cl)(=O)C(Cl)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[C:1]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:17])[C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[F:32])[CH2:12][CH2:11]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1
Reactant: O=C(Cl)C1CCN(CC2=Cc3ccccc32)CC1
Reactant: Fc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1F)C1CCN(CC2=Cc3ccccc32)CC1
Yield: 35 %

Procedure:
0.025 mole of 1-(benzocyclobuten-1-ylmethyl)-4-piperidinecarbonyl chloride (prepared by the action of oxalyl chloride on the acid described above), dissolved in 50 ml of dichloromethane, is introduced into a suspension of 0.025 mole of 1,3-difluorobenzene and 0.026 mole of aluminum trichloride in 10 ml of dichloromethane. When the gaseous evolution has ceased, the mixture is hydrolyzed with ice, settling is allowed to take place and the product is extracted with 1N hydrochloric acid. The aqueous phase is then alkalinized and extracted with dichloromethane. After evaporation of the solvent, the expected product is obtained.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>CO>[Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCCCO)C(=O)C1
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
700 mg (2.13 mmoles) of 4(RS)-t-butyldimethylsilyloxy-2-(6-hydroxyhexylthio)-2-cyclopentenone, 1020 mg (10 mmoles) of acetic anhydride and 1580 mg (20 mmoles) of pyridine were mixed, and stirred at room temperature for 2 hours. After the reaction, methanol was added. The solvent was removed to give 795 mg of 4-t-butyldimethylsilyloxy-2-(6-acetoxyhexylthio)-2-cyclopentenone as a nearly pure product.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[NH2:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11].[S-:14][C:15]#[N:16].[K+].II>C(#N)C>[C:2]([C:3]1[S:14][C:15](=[NH:16])[N:8]([CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)CC=O
Reactant: N#C[S-]
Reactant: CC(C)(O)CN
Agent: II
Agent: [K+]
Solvent: CC#N
Product: CC(C)(O)Cn1cc(C(C)(C)C)sc1=N
Yield: 94.6 %

Procedure:
A mixture of 3,3-dimethylbutanal (7.7 mL, 62 mmol), 1-amino-2-methylpropan-2-ol (5.0 g, 56 mmol), 4 Å molecular sieves (5 g, 8-12 mesh beads), potassium thiocyanate (7.3 g, 75 mmol) and iodine (14 g, 56 mmol) in acetonitrile (100 mL) were processed as described in Example 18A to provide the title compound (12 g, 53 mmol, 94% yield). MS (DCI/NH3) m/z 229 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C@H:9]1[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH:19][CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[C:27]([OH:31])=[CH:28][CH:29]=[CH:30][C:22]=2[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClCCl>[CH2:12]([N:19]([CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[C:27]([OH:31])=[CH:28][CH:29]=[CH:30][C:22]=2[CH2:21]1)[CH2:10][C@H:9]([OH:11])[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: Oc1cccc2c1CCCC(NCc1ccccc1)C2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: Oc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.6 %

Procedure:
A suspension of (2S)-3-phenoxy-1,2-epoxypropane (300 mg) (IL FARMACO, 50 (10), 643 (1995)), N-benzyl-(1-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (535 mg), and ytterbium(III) trifluoromethanesulfonate (372 mg) in dichloromethane (15 ml) was stirred at room temperature for 3 days and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol) over silica gel (16 g) to afford (2S)-1-[N-benzyl-(6,7,8,9-tetrahydro-1-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (747 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][S:4][C:5]1[C:6]([CH3:14])=[CH:7][C:8]([F:13])=[C:9]([NH:11][NH2:12])[CH:10]=1.[C:17](O[C:21](=[O:23])[CH3:22])(=[O:19])[CH3:18].[CH2:24](OCC)C>>[CH:21]([O:23][CH:9]([CH3:8])[CH3:10])([CH3:24])[CH3:22].[F:13][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]([S:4][CH2:3][C:2]([F:1])([F:15])[F:16])=[CH:10][C:9]=1[NH:11][NH:12][C:17](=[O:19])[CH3:18]
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Product: CC(=O)NNc1cc(SCC(F)(F)F)c(C)cc1F
Product: CC(C)OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.6 g of 1-(5-(2,2,2-trifluoroethylthio)-2-fluoro-4-methylphenyl)hydrazine was dissolved in 100 mL of diethyl ether, and 1.85 g of acetic anhydride was dropwise added under cooling with ice, followed by stirring at room temperature for one hour. The obtained crystals were collected by filtration and washed with a solution of hexane:diisopropyl ether=3:1 (mass ratio) to obtain 4.41 g of N′-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}acetohydrazide in the form of colorless crystals. Then, to 4.4 g of this hydrazide, 1.93 g of ethyl acetoacetate and 4.02 g of phosphorus tribromide were added, followed by stirring at 50° C. for 2 hours. Then, after stirring under cooling with ice for 10 minutes, ice was put, and the pH was adjusted to 5 with a 1N sodium hydroxide aqueous solution. Then, extraction with ethyl acetate was carried out, followed by washing with a saturated salt solution, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2.03 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxy-5-methylpyrazole in the form of colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][S:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:28][N:27]([CH2:24][CH2:25][CH3:26])[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[CH2:12][S:11][CH2:10][C:9]2=3)=[CH:4][CH:3]=1
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CSCC1=Cc1ccc(Cl)cc1
Solvent: CC(Cl)Cl
Product: CCCN1NC(c2ccc(Cl)cc2)C2=C1C(=Cc1ccc(Cl)cc1)CSC2
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A mixture of tetrahydro-3,5-bis-(4-chlorophenylmethylene)-4H-thiopyran-4-one (6 g, 16.6 mmole) and N-propylhydrazine (1.3 g, 16.6 mmole) in dichloroethane (100 ml) is heated at reflux temperature for 2.5 hours and cooled to room temperature overnight. The reaction mixture is washed with dilute HCl and water, then dried over CaCl2. After the solvent is removed in vacuo, the residue (yellow solid) is chromatographed on a dry-packed Al2O3 column (neutral, activity I). The fractions eluted with 0-5% EtOAc/hexane give the major product. Further elution of the column with EtOAc, then with CHCl3, and after crystallization from acetoneacetonitrile, gives 0.6 g (9%) of the title compound in crystalline form (99% pure) m.p. 192°-194.5°.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[Br-].[Li+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN1CCCC1=O>[NH2:1][CH:2]([CH2:3][OH:4])[C:5]([O:7][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: N[C@@H](CO)C(=O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: NC(CO)C(=O)OCc1ccccc1

Procedure:
In a similar manner 1.09 grams (0.0105 mole) of serine, 1.76 grams (0.02 mole) of lithium bromide, 2.02 grams (0.0118 mole) of benzyl bromide and 16 grams of N-methylpyrrolidinone were stirred together at 25° C. for 16 hours and at 50° C. for 3 hours to obtain the desired benzyl α-amino-β-hydroxypropionate product. High pressure liquid chromatographic assay indicated a 86 percent yield of the desired product.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=O.[NH2:14]N.O>C(O)C>[O:10]1[CH2:11][CH2:12][CH:7]([C:5]2[CH:4]=[CH:3][NH:2][N:14]=2)[CH2:8][CH2:9]1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)C1CCOCC1
Solvent: CCO
Solvent: O
Product: c1cc(C2CCOCC2)n[nH]1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-3-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one (compound 294.1, 4.3 g, 23.4 mmol) in ethanol (20 mL) was added NH2NH2.H2O (1.41 g, 28.2 mmol). The reaction mixture was stirred for 3 h at 80° C. The resulting mixture was concentrated under reduced pressure to yield 4.45 g (crude) of the title compound as a light yellow solid.