Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][CH2:20][OH:21])[C:3]1=[O:22].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32](Cl)=[O:33].C(N(CC)CC)C>C(Cl)Cl>[OH:21][CH2:20][CH2:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:32]([C:24]2[NH:23][C:31]3[C:26]([CH:25]=2)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:33])[C:3]1=[O:22]
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CCO)C1=O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCO)C1=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(RS)-Amino-1,3-dihydro-1-(2-hydroxyethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (69.0 mg, 0.234 mmole), indole-2-carbonyl chloride (43.1 mg, 0.240 mmole) and triethylamine (33.3 μl, 0.240 mmole) were combined in CH2Cl2 (3 ml). The reaction was stirred for 10 minutes at room temperature then chromatographed on silica gel (14% acetone in CH2Cl2). The product fractions were combined and evaporated to dryness in vacuo. The residue was triturated with Et2O to yield the title compound: (m.p. 160°-171° C.).
Reaction SMILES: [O:1]1[CH:9]2[CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]2.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>C(Cl)Cl>[CH2:10]([NH:17][C@@H:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][C@H:9]1[OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1=CCCC2OC2CC1
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Product: O[C@@H]1CCC=CCC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a stirred solution of 5,6-epoxycyclooctene III (10.0 g, 0.081 mol) in dry CH2Cl2 (100 ml) kept under nitrogen atmosphere, benzylamine (10.35 g, 0.097 mol) and Ytterbium(III) trifluoromethanesulfonate (4.96 g, 0.008 mol) were added and the mixture was stirred for 24 hrs at room temperature. Extractive work-up of the reaction mixture with water and CH2Cl2 gave the title product as a white solid (yield 83%). m.p.: 70-71° C., b.p:140° C./1 mm Hg. 1H NMR (CDCl3): δ 7.59-7.56 (m, 2H, ArH), 7.38-7.35 (m, 3H, ArH), 5.64-5.44 (m, 2H, CH=CH), 5.42-5.00 (bs, D2O exchangeable, OH) 4.07 (AB syst, 2H, J=12.57 Hz, PhCH2), 3.75-3.65 (m, 1H, CHOH), 3.00-3.15 (m, 1H, CHNH--), 2.35-2.02 (m, 6H), 1.95-1.42 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C@H:11]1[N:21]2[C@@H:15]([S:16][CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]2=[O:22])[CH2:14][CH2:13][CH2:12]1)(=O)[NH2:9].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[C:8]([C@H:11]1[N:21]2[C@@H:15]([S:16][CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:20]2=[O:22])[CH2:14][CH2:13][CH2:12]1)#[N:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(N)=O)N2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C#N)N2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
Triethylamine (58.8 mg, 0.581 mmol) was added to a 0° C. solution of tert-butyl (4S,7S,10aS)-7-carbamoyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (57 mg, 0.17 mmol) in DCM (1.2 mL). TFAA (52.3 mg, 0.249 mmol) was then slowly added to the reaction. The ice bath was removed and the reaction mixture was left to stir at rt for 1 hr. The reaction was diluted with DCM (2 mL) and quenched by the addition of aqueous 10% Na2CO3 (2 mL). The aqueous phase was isolated and extracted with DCM (2 mL). All organic phases were combined, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give tert-butyl (4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (36 mg, 0.11 mmol, 67% yield) as a light yellow solid. Anal. Calcd. for C15H23N3O3S m/z 325.4. found: 326.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[O-:13]C1C=CC=CC=1.[K+]>C(O)COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:13]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: [O-]c1ccccc1
Agent: [K+]
Solvent: OCCOCCO
Product: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Temperature: 160 °C

Procedure:
3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium phenoxide (8.66 g) in diethylene glycol (66 mL) and the mixture is heated to 160° C. for approximately 15 hours. The resulting dark brown solution is cooled to room temperature, poured. onto 100 mL cold water, and extracted twice with diethyl ether. The pooled organic extracts are washed with water, 10% aqueous sodium hydroxide, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus to provide a yellow oil that solidifies on standing. Recrystallization from ethanol-water provides the desired product as a pale yellow solid.
Reaction SMILES: COC(=O)[NH:4][CH2:5][C@H:6]([CH2:11][C:12](=[O:14])N)[CH2:7][CH:8]([CH3:10])[CH3:9].[OH-:16].[Na+]>Cl>[CH3:9][CH:8]([CH2:7][C@H:6]([CH2:5][NH2:4])[CH2:11][C:12]([OH:14])=[O:16])[CH3:10]
Reactant: COC(=O)NC[C@H](CC(N)=O)CC(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 25 °C
Yield: 21.5 %

Procedure:
A 0.2 l reactor was loaded with 6N hydrochloric acid (100 ml) containing compound 27 (12 g, 0.055 mole), and was heated to 100°-110° C. for 12-24 hours, and then cooled to room temperature, i.e., about 20° to about 25° C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 37 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 21.5% yield. Purity: 99.9% area by HPLC.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:24]>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:24]
Reactant: COc1ccc(-c2cc(=O)c3cc(Br)ccc3o2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cc(-c2ccc(O)cc2)oc2ccc(Br)cc12

Procedure:
A dichloromethane solution (12 ml) that contained boron tribromide was slowly added to a dichloromethane solution (215 ml) that contained compound 15 (400 mg, 1.21 mmol) while stirring under cooling on ice, and the obtained mixture was then reacted. After completion of the reaction, purified water (100 ml) was added to the reaction solution, and the dichloromethane layer was extracted. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate/hexane (2/5) as an elution solvent, so as to obtain a product of interest, 6-bromo-4′-hydroxyflavone (compound 16). Yield: 50 mg (yield constant: 13.1%) 1H NMR (300 MHz, CDCl3) δ10.38 (s, 1H), 8.09 (s, 1H), 7.97-8.00 (m, 3H), 7.76 (d, J=9.0 Hz, 1H), 6.93-6.96 (m, 3H).
Reaction SMILES: B.C1COCC1.C1COCC1.[CH3:12][S:13][CH2:14][CH2:15][N:16]([C:30](=O)[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=O)[CH3:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[CH3:12][S:13][CH2:14][CH2:15][N:16]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH2:27][CH3:28])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: CSCCN(C(=O)c1ccc(F)cc1)c1ccc(S(=O)(=O)NC(C)=O)cc1
Agent: B
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1ccc(N(CCSC)Cc2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 60.6 %

Procedure:
A solution of 1 M BH3.THF/THF (7.0 mL, 7.0 mmol) was added to a stirring solution of 4-[(2-methylthio-ethyl)-(4-fluoro-benzoyl)-amino]-N-acetyl-benzenesulfonamide (0.29 g, 0.69 mmol) in THF (8 mL). After 18 h, the excess BH3 was quenched by addition of 0.1 M HCl; followed by partitioning the mixture between CH2Cl2 and NaHCO3. The organic layer was dried (Na2SO4), filtered, evaporated in vacuo, and the residue was purified by MPLC (CH2Cl2 to 90:10 CH2Cl2/EtOAc) to afford 0.16 g (59%) of 4-[(2-methylthio-ethyl)-(4-fluoro-benzyl)-amino]-N-ethyl-benzenesulfonamide as a colorless glass; 1H NMR δ 1.09 (t, 3H, J=7.5), 2.16 (s, 3H), 2.74 (m, 2H), 2.96 (m, 2H), 3.67 (m, 2H), 4.37 (t, 1H, J=6.0), 4.62 (s, 2H), 6.69 (d, 2H, J=9.0), 7.04 (dd, 2H, J=4.5, 7.5), 7.15 (dd, 2H, J=6.0, 9.0), 7.66 (d, 2H, J=7.5).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20](OC)=[O:21])[CH2:18][N:17]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.CCOCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([CH2:20][OH:21])[CH2:18][N:17]([CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2CO)cc1OC1CCCC1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of trans-3-(3-Cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (2.7 g, 6.6 mmol) in 27 mL of THF at 0° C. was added LiAlH4 (4.0 mmol, 4 mL of 1M toluene solution). After stirring for 2 hr the reaction mixture was then successively treated dropwise with H2O (0.15 mL), 15% NaOH (0.15 mL), and H2O (0.46 mL). The resulting suspension was diluted with ether, stirred for 1 hr, filtered through Celite, and concentrated under reduced pressure to an oil. Silica gel chromatography (graded elution: CH2Cl2 then 9:1, CH2Cl2 :methanol) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-hydroxymethyl-1-(phenylmethyl)pyrrolidine (2.0 g, 80%) as an oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[CH2:18]1)[CH3:15].[CH3:28][O:29][C:30]1[CH:45]=[CH:44][C:33]([CH2:34][O:35][C:36]2[CH:43]=[CH:42][C:39]([CH2:40]O)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:15][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:40][C:39]3[CH:42]=[CH:43][C:36]([O:35][CH2:34][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:45][CH:44]=4)=[CH:37][CH:38]=3)[CH:23]=2)[CH2:18]1)[CH3:13]
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Reactant: COc1ccc(COc2ccc(CO)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Reaction time: 12 h
Yield: 41.2 %

Procedure:
Diethyl azodicarboxylate (40% toluene solution, 1.91 g) was added dropwise to THF solution (6 ml) of 2-[(N,N-dimethylamino)methyl]-6-hydroxytetralin (300 mg), 4-[(4-methoxybenzyl)oxy]benzylalcohol (1.07 g) and triphenylphosphine (1.15 g) at room temperature, which was stirred for 12 hours. The reaction mixture was concentrated, and the residue was purified using alumina column chromatography (development solvent; hexane˜hexane:ethyl acetate=10:1), and recrystallized (ethyl acetate-hexane) to give the titled compound (260 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][N:7]=[CH:6]2.C1(C(N)C2CCCCC2)CCCCC1.[CH3:28][Si:29]([CH2:32][CH2:33][O:34][CH2:35]Cl)([CH3:31])[CH3:30].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:5](=[CH:6][N:7]([CH2:35][O:34][CH2:33][CH2:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[N:8]=2)[CH:4]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc2cn[nH]c2cc1OC
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2cn(COCC[Si](C)(C)C)nc2cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared in a similar manner as described by G. Luo et al., J. Org. Chem. 2006, 71, 5392-5395: To a solution of 5,6-dimethoxyindazole [7746-30-7] (356 mg, 2.00 mmol) in THF (20 mL) was added dicyclohexylmethylamine (0.51 mL, 2.40 mmol) followed by SEM-Cl (0.43 mL, 2.40 mmol). The mixture was stirred at RT for 24 h, followed by dilution with EtOAc and quench with 1N aqueous NaOH solution. The layers were separated and the organic layer was washed with water and brine, then dried (Phase separator) and evaporated. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 4:1 to 1:1) to separate from the regioisomer 5,6-dimethoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and to provide the title compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.37; MS (LC/MS): 309 [M+H; tR (HPLC conditions k): 3.70 min.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:7]1[NH:17][C:16](=[O:18])[CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:6])[CH3:5]>CCOCC>[C:4]([C:7]1[N:17]=[C:16]([O:18][CH3:3])[CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:6])[CH3:5]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OC)nc1C(C)=O

Procedure:
An ethereal solution of diazomethane (excess) is added to a stirred suspension of ethyl 1,6-dihydro-2-acetyl-6-oxonicotinate (2.20 g, 10.5 mmol) in 10 ml of ether. The ether and excess diazomethane are removed under vacuum, and the crude product is purified by column chromatography, eluting with 30% ethyl acetate/hexane to give ethyl 2-acetyl-6-methoxynicotinate.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[CH3:38].[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43]>CN(C)C=O.C(#N)C.C(O)C>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[CH3:38])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[CH3:38])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: CC(=O)c1ccc(OCCCBr)c(C)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCO
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(C)c1
Temperature: 95 °C

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (3.0 g; 11.7 mmol), K2CO3 (3.0 g), and 1-[4-(3-bromopropoxy)-3-methylphenyl]-ethanone (3.19 g) in dimethylformamide (20 ml) and acetonitrile (50 ml) was heated at 95° C. for 4 hours. At the end of the reaction, the solvent was concentrated down to about 30 ml, then partitioned between water (200 ml) and dichloromethane (300 ml). The dichloromethane solution was separated and washed with water and brine, then dried over MgSO4. The crude product from the evaporated solution was purified by flash chromatography over a silica gel column (SiO2, 60 g, eluted with 1% methanol in dichloromethane, 600 ml; 2% methanol in dichloromethane, 600 ml). The material thus obtained was a light yellow oil, weight: 2.07 g (43%). This oil was dissolved in ethanol and treated with a solution of fumaric acid (585 mg) in ethanol. The 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylphenyl]-ethanone hemifumarate crystals formed on cooling at 0° C. This was collected and weighed 1.5 g, m.p.=185°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C(OC(C)C)(C)C>[CH3:19][N:20]([CH3:25])[S:21]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:23])=[O:22]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis Inc., Windham, N.H. 03087) in 64.6 g (0.640 mole) of triethylamine and 40 ml of methylene chloride was added in a thin stream to a solution of 83.3 g (0.580 mole) of dimethylsulfamoyl chloride (Aldrich) in 60 ml of methylene chloride stirred at ambient temperature in a water bath. The reaction mixture was stirred for 8 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a viscous residue. The residue was partitioned between water and ethyl ether (300 ml each). The organic layer was washed with two 200 ml portions of 2N hydrochloric acid. Once with 200 ml of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a viscous residue. The residue was treated with 65.0 g (0.63 mole) of triethylamine and the reaction mixture was stirred for 5 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure and the viscous residue was partitioned between water and ethyl ether (450 ml each). The organic layer was washed with four 300 ml portions of water (pH neutral to pH paper), dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a brown viscous oily residue. The oil was purified by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride). Fractions containing the title compound were combined and the solvent evaporated under reduced pressure to yield a viscous oil. The oil was dissolved in 150 ml of isopropyl ether and filtered to remove some insolubles. The filtrate was concentrated to a viscous oil. The oil was triturated with isopropyl ether-petroleum ether (bp range 30°-60° C.), cooled (refrigerator) and the resulting solid was collected by filtration. The solid was recrystallized from isopropyl ether to give 18.5 g (45%) of white solid, mp 54°-57° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH3:18])[C:11]2[O:15][C:14](S)=[N:13][C:12]=2[CH:17]=1.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.O>[Cl:7][C:8]1[CH:9]=[C:10]([CH3:18])[C:11]2[O:15][C:14]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[N:13][C:12]=2[CH:17]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(Cl)cc2nc(S)oc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Cl)cc2nc(N3CCNCC3)oc12
Yield: 34.2 %

Procedure:
Piperazine (4.3 g, 0.05 mol) was added to a suspension of 5-chloro-2-mercapto-7-methylbenzoxazole (5.0 g, 0.25 mol) in toluene (100 mL) with stirring. The reaction mixture was stirred for 7 hours under reflux, then cooled, and the mixture was added to a mixture of ethyl acetate (45 mL) and water (80 mL). The mixture was adjusted to pH 7.5 by gradually adding 5 N hydrochloric acid. The separated organic layer was washed with water (80 mL), added with water (80 mL) again, and adjusted to pH 1–1.5 with 5 N hydrochloric acid. The organic layer was removed by phase separation. The remaining aqueous layer was added with ethyl acetate, adjusted to pH 8.0 with 5 N aqueous sodium hydroxide, and then extracted. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (4.3 g). This compound may be converted into 5-chloro-7-methyl-2-(1-piperazinyl) benzoxazole hydrochloride by treatment with 4 N hydrochloric acid/ethyl acetate in ethyl acetate.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C@H:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][O:9][S:26]([CH3:25])(=[O:28])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H](COS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethanol (85 mg, 0.337 mmol) in dichloromethane (2 mL) were added triethylamine (61 μl, 0.44 mmol) and methanesulfonyl chloride (27 μl, 0.35 mmol) in the order, followed by stirring at room temperature for 20 min. The solution was washed with an aqueous saturated sodium bicarbonate solution to separate an organic layer. The organic layer was dried over sodium sulfate and filtrated. The filtrate was concentrated and dried for 30 min in a vacuum to give methanesulfonic acid (R)-2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethyl ester. Methanesulfonic acid (R)-2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethyl ester, 1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (5-3) (60 mg, 0.112 mmol) and potassium carbonate (77 mg, 0.560 mmol) were dissolved at 70° C. for 12 hrs in DMF (1 ml) in a nitrogen atmosphere with stirring. The solution was cooled to room temperature, washed with an aqueous saturated sodium bicarbonate solution and concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 5/1) and dried in a vacuum to afford 83 mg of the compound as a white solid (yield 97%). 1H NMR (300 MHz, CDCl3) δ −0.23 (3H, s), −0.11 (3H, s), 0.80 (9H, s), 2.25 (2H, m), 2.33 (3H, s), 2.47 (2H, m), 2.80 (2H, m), 3.50-3.70 (2H, m), 3.62 (2H, s), 3.83 (1H, dd), 4.36 (1H, dd), 5.13 (1H, dd), 5.26-5.50 (2H, m), 6.30 (1H, d), 6.73 (1H, m), 7.16-7.43 (7H, m), 7.53 (1H, d)
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.Cl.[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:16]2[N:24]=[C:4]([OH:14])[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:23]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Product: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1

Procedure:
The title compound was prepared from 3-oxo-3-phenyl-propionic acid ethyl ester and benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 6.92 (s, 1H), 7.50-7.65 (m, 6H), 8.15-8.20 (m, 2H), 8.26 (d, J=7.2 Hz, 2H), 12.80 (br s, 1H); MS: m/z (ESI) 247 (M−H).