Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]Br)=[CH:4][CH:3]=1.C1COCC1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: BrCCc1ccc(Br)cc1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CCc2ccc(Br)cc2)cc1

Procedure:
4-Bromophenethyl bromide (261.4 mg, 1.0 mmol) and a THF solution (1.42 mL, 1.06 M, 1.5 mmol) of 4-methoxyphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 4-methoxyphenylmagnesium bromide was added dropwise at 40° C. over 3 hours. After thin-layer chromatography (hexane/ethyl acetate=92/8), the title compound was obtained as a colorless liquid (0.226 g, yield 78%).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[Br-].C1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[CH2:38][C:37](=O)[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:40]([O:42][CH3:43])=[O:41])[CH:35]=2)O1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:5])[CH2:3][C:37](=[CH2:38])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:40]([O:42][CH3:43])=[O:41])[CH:35]=2)[O:4]1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(C)(C)O2
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Agent: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C1CC(C)(C)Oc2ccc(C(=O)OC)cc21
Temperature: -30 °C

Procedure:
Potassium tert-butoxide (96.0 mg, 0.85 mmol) was added to a suspension of triphenylmethylphosphonium bromide (305 mg, 0.85 mmol) in toluene (3.00 mL) while stirring at −30° C. under N2 atmosphere. After stirring for 1 hour at −30° C., a solution of methyl 2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromene-6-carboxylate (100 mg, 0.43 mmol) in toluene (2.00 mL) was added slowly via a syringe. The suspension was stirred for a further 30 minutes at −30° C. and then heated to reflux overnight. The mixture was allowed to cool to room temperature, diluted with EtOAc (50.0 mL) and washed with water (10.0 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-25% EtOAc/hexanes to give the desired product as a pale-yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:19][NH2:20].C1COCC1.[BH4-].[Na+].[ClH:28]>CC#N.CCOC(C)=O>[ClH:28].[ClH:28].[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH2:15][CH2:19][NH2:20])=[CH:13][CH:12]=3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Oc2cnc(C3CC3)nc2)cc1
Reactant: CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NCCc1ccc(Oc2cnc(C3CC3)nc2)cc1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-[(2-cyclopropylpyrimidin-5-yl)oxy]benzaldehyde (0.240 g, 1.0 mmol) in MeCN (0.50 mL) was added 2M methylamine in THF (2.0 mL, 4.0 mmol) followed by sodium borohydride (0.120 g, 3.2 mmol) and MeCN (0.50 mL). The slurry was stirred for 30 minutes. The solvents were removed by evaporation, water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine and evaporated onto silica gel. This gel was applied onto a 20 g silica gel column. Column chromatography using a gradient of 10% to 60% EtOAc in heptanes eluted impurities. Elution with 10% MeOH in EtOAc (100 mL) followed by 5% concentrated NH3 in MeOH (100 mL) gave the product in the basic fractions. These fractions were combined, concentrated and re-dissolved in water. The pH was adjusted to 13 to 14 using sodium hydroxide solution and the mixture was extracted several times with EtOAc. The organic extracts were washed with brine, dried over potassium carbonate, filtered and concentrated to give an oily residue. This oil was dissolved in EtOAc and an excess of a 1.5M solution of hydrogen chloride in EtOAc was added. The solvent was removed by evaporation to give 0.186 g (56% yield) of the crude subtitle compound. The salt obtained was 93.9% pure and was used without further purification.
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([OH:9])[CH:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].C(=O)([O-])[O-].[Ca+2]>P([O-])([O-])([O-])=O>[CH2:5]([OH:6])[C@@H:4]([C@H:3]([C@@H:2]([CH2:1][OH:10])[OH:9])[OH:8])[OH:7]
Reactant: OC[C@@H](O)C(O)[C@H](O)CO
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 27 h

Procedure:
D-arabitol was dissolved in 0.1M phosphate buffer solution(pH 6.0) to a final concentration of 5% (w/v), and 5 ml each of the solution was dispensed in a test tube. To this reaction mixture were added the bacterial cells prepared in the same manner as in Example 6 in a wet weight of about 10% (w/v) and 2% (w/v) of calcium carbonate, and a reaction with shaking was run at 30° C. After 6 hours' reaction, 5% (w/v) of various sugars and sugar alcohols were added as shown in Table 2 for further reaction. After the reaction was continued for 27 hours, the bacterial cells were removed by centrifugation and then the amount of xylitol produced was determined by HPLC. As shown in Table 2, an increase in the amount of xylitol produced was recognized by addition of various sugars and sugar alcohols.
Reaction SMILES: C1(C([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)=[CH:30][CH:29]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:43]>C(O)C.C(Cl)Cl>[ClH:43].[NH2:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:32][CH:33]=1
Reactant: c1ccc(C(N[C@@H]2CCC[C@H]2OCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: N[C@@H]1CCC[C@H]1OCc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 8 h

Procedure:
To a mixture of trans-2-triphenylmethylamino-[4-(benzoxazol-2-yl)benzyloxy]-cyclopentane (3.67 g; 6.67 mmol)in ethanol (100 ml) and CH2Cl2 (20 ml) is added ethanolic HCl until pH≈2. This is stirred overnight, concentrated in vacuo, washed with CH2Cl2, dried under vacuum and flash chromatographed using 3:1; CH2Cl2:EtOH. The product is rechromatographed using 3:1; CH2Cl2 :EtOH to obtain trans-2-amino-[4-(benzoxazol-2-yl)benzyloxy]cyclopentane hydrochloride (m.p. >200° C.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl>[Br:33][C:9]1[N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:12][CH2:11]3)[C:6]2=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCn2cccc2C12CCN(C(=O)OCc1ccccc1)CC2
Solvent: ClCCl
Product: CN1CCn2c(Br)ccc2C12CCN(C(=O)OCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To benzyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (3.00 g, 8.84 mmol) in CH2Cl2 (30 mL) at 0° C. was added NBS (1.57 g, 8.84 mmol) portionwise. The reaction mixture was stirred at 0° C. for 2 h. Additional NBS (157 mg) was added and the reaction mixture was stirred at 0° C. for 15 minutes (repeated 6 additional times until starting material was consumed). The reaction mixture was diluted with 0.5 M Na2S2O3 (30 mL) and the aqueous phase was removed. The organic phase was washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography utilizing a gradient of 0-30% ethyl acetate in CH2Cl2 to yield benzyl 6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (2.34 g, 63%) as a cream solid. ESI-MS m/z calc. 417.1, found 418.1 (M+1)+; Retention time: 1.49 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.43-7.26 (m, 5H), 6.09 (d, J=3.7 Hz, 1H), 5.99 (d, J=3.7 Hz, 1H), 5.08 (s, 2H), 3.89-3.74 (m, 2H), 3.68 (t, J=5.8 Hz, 2H), 3.27 (t, J=5.8 Hz, 2H), 3.22-2.99 (m, 2H), 2.21 (s, 3H), 2.09-1.94 (m, 2H), 1.73-1.52 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]([CH2:18][CH2:19][CH3:20])([CH2:12][C:13](OCC)=[O:14])[C:7](OCC)=[O:8])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+].P([O-])(O)(O)=O.[K+].P([O-])([O-])(O)=O.[K+].[K+]>CCOCC.O.C(O)(=O)C>[OH:3][CH2:4][C:6]([CH2:7][OH:8])([CH2:18][CH2:19][CH3:20])[CH2:12][CH2:13][OH:14]
Reactant: CCCC(CC(=O)OCC)(C(=O)OCC)C(=O)OCC
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Al+3]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CCCC(CO)(CO)CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diethyl 2-ethoxycarbonyl-2-n-propyl-succinate (55.8 g) in dry ether (50 ml.) was added slowly to a stirred suspension of lithium aluminium hydride (14.7 g.) in dry ether (150 ml.) at 0°, under a current of nitrogen. The mixture was stirred at room temperature for three hours and then refluxed, with stirring for four hours. A solution of potassium hydroxide (30.0 g.), potassium dihydrogen phosphate (22.0 g.) and potassium monohydrogen phosphate (22.0 g.) in water (200 ml.) was added to the cooled reaction mixture. The pH was adjusted to 5.0 with glacial acetic acid. The solid was removed by filtration and washed with water (40 ml.) The combined filtrates and washings were evaporated in vacuo. The residue was washed with acetone (3×100 ml). The acetone washings were evaporated in vacuo. The residue was washed with chloroform (3×100 ml.) and the washings were evaporated in vacuo, Toluene was added and the residue was evaporated in vacuo. 3,3-Di-(hydroxymethyl)-hexan-1-ol was obtained as a colourless oil and was used without further purification.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[N+:18]([C:21]1[CH:31]=[CH:30][C:24]([CH2:25][O:26][C:27](Cl)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][O:26][C:27]([N:4]([CH:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]2)[CH2:1][CH2:2][CH3:3])=[O:28])=[CH:30][CH:31]=1)([O-:20])=[O:19]
Reactant: CCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1

Procedure:
The title compound was prepared by the reaction of 4-(N-(prop-1-yl)amino)-1-tert-butoxycarbonylpiperidine (from Example 17, Step A) with (4-nitrobenzyl)chloroformate, followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 322.2 (M+H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]3[CH2:27][CH2:26][CH2:25][C:14]4([O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15]4)[CH2:13]3)[C:6]=2[CH:5]=[C:4]([C:28]#[N:29])[CH:3]=1.[CH3:30][Zn]C.C(O)(C(F)(F)F)=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]3[CH2:27][CH2:26][CH2:25][C:14]4([O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:15]4)[CH2:13]3)[C:6]=2[CH:5]=[C:4]([C:28]#[N:29])[CH:3]=1
Reactant: C[Zn]C
Reactant: CC(C)(C)CN1CC2(CCCC(Cn3cnc4c(Br)cc(C#N)cc43)C2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c1ncn2CC1CCCC2(C1)CN(CC(C)(C)C)C(=O)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
4-bromo-1-((3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.100 g, 0.218 mmol) was dissolved in THF (1.00 mL) and treated with tetrakis(triphenylphosphine)palladium(0) (0.503 g, 0.044 mmol) followed by dimethylzinc (1.09 mL, 2.18 mmol). Addition of the dimethylzinc resulted in an exotherm with gas evolution and a color change from brownish-yellow to bright yellow. The reaction mixture was purged with nitrogen and capped. The reaction was allowed to stir at rt for 18 h. The reaction mixture turned dark brown over the course of the reaction. The reaction was quenched with sat. aq. ammonium chloride solution and diluted with EtOAc. The layers were separated, and the organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 15 min run; 50 mL/min elution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 35-69% solvent A) to afford the title compound (0.035 g, 31% yield) as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (br. s., 1H), 8.19 (s, 1H), 7.44 (s, 1H), 4.21 (d, J=7.03 Hz, 2H), 3.31 (dd, J=8.78, 18.57 Hz, 2H), 2.85 (s, 2H), 2.56 (s, 3H), 2.06-2.21 (m, 1H), 1.81 (d, J=11.04 Hz, 1H), 1.73 (d, J=13.80 Hz, 1H), 1.40-1.58 (m, 4H), 1.25-1.35 (m, 1H), 0.95-1.08 (m, 1H), 0.83 (s, 9H). MS (m/z) 395.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([O:47]C)=[O:46])=[CH:41][C:40]=4[F:49])[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O>O1CCOCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:39]4[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][C:40]=4[F:49])[C:33]([F:38])=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:52])([F:51])[F:1])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)c(-c2ccc(C(=O)O)cc2F)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2,6′-difluoro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (50 mg, 0.067 mmol), lithium hydroxide monohydrate (28 mg, 0.67 mmol), water (1 mL) and 1,4-dioxane (2 mL) were stirred at room temperature for 2.5 hours. LCMS of aliquot indicated formation of the desired product and complete consumption of starting material. Crude mixture was acidified (1N HCl, aq.). Volatiles were removed under reduced pressure. Pot residue was dissolved in MeCN and purified by a reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v). Corresponding fractions were pooled and evaporated in vacuo to afford a mixture. The resulting mixture was extracted with EtOAc. The separated organic phases were back washed w/water, separated, dried/Na2SO4, filtered and evaporated to afford the title compound. LCMS (ESI) calc.=733.13; found=734.14 (M+1)+. 1H NMR (CDCl3, 500 MHz, 1:1 mixture of atropisomers): δ 7.95 (t, J=6 Hz, 1H), 7.89-7.83 (m, 2H), 7.73 (s, 0.5H), 7.71 (s, 1H), 7.68-7.64 (m, 2H), 7.62 (s, 0.5H) 7.58 (t, J=7 Hz, 0.5H), 7.53 (t, J=7.5 Hz, 0.5H), 7.42 (d, J=8 Hz, 0.5H), 7.39 (d, J=8 Hz, 0.5H), 7.31-7.23 (m, 1H), 6.89 (d, J=4 Hz, 0.5H), 6.87 (d, J=3.5Hz, 0.5H), 5.61 (d, J=8 Hz, 0.5H), 5.29 (d, J=8 Hz, 0.5H), 5.05 (d, J=16 Hz, 0.5H), 4.93 (d, J=16 Hz, 0.5H), 4.16 (d, J=16.5 Hz, 0.5H), 3.94 (d, J=16 Hz, 0.5H), 3.89 (s, 1.5H), 3.87 (s, 1.5H), 3.85-3.72 (m, 1H), 0.59 (d, J=7 Hz, 1.5H), 0.43 (d, J=6 Hz, 1.5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:24])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:9])=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:11]([NH:10][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=2)[CH3:9])=[O:24])=[CH:19][CH:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)cc1)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a pyridine (5.0 ml) solution of N-[(1R)-1-(4-aminophenyl)ethyl]-2-(4-tert-butylphenoxy)acetamide (420 mg, 1.0 mmol), methanesulfonyl chloride (114 mg, 1.0 mmol) was added at 0° C. and the mixture was stirred for 3 hours at 0° C. The reaction mixture was then quenched with 2 M HCl and then crude products were extracted with methylene dichloride The organic layer was then washed with brine, dried over Na2SO4. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with methylene dichloride/ethylacetate=1/1 to furnish 120 mg (29% yield) of the title as a white solid.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:21])[C:7]([NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=1)=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH3:21])[C:7]([NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=1)=[O:8]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)CSC(C)=O)nc1
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)C(C)CS)nc1

Procedure:
Following the procedure of Example 2, but substituting an equivalent amount of ethyl 6-(2-acetylthiomethyl-propionamido)-nicotinate, obtained as disclosed in Example 6, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate, ethyl 6-(2-mercaptomethyl-propionamido)-nicotinate is obtained; m.p. 58°-61° C. from petroleum ether.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:21])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:8][C:7]=1O)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O1CCCC1.O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]2[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[O:21][C:7]=2[CH:8]=1
Reactant: CCNC(=O)Nc1ccc(CCc2ccccn2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNc1nc2ccc(CCc3ccccn3)cc2o1
Reaction time: 1.5 h
Yield: 16.2 %

Procedure:
A mixture of 2-[2-{4-(3-ethylureido)-3-hydroxyphenyl}ethyl]pyridine (3.3 g) and polyphosphate ester (30 g) was stirred at 90° to 100° C. for 1.5 hours. The reaction mixture was dissolved in a mixture of ethyl acetate, tetrahydrofuran and water and the resultant solution was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography eluting with a solution of chloroform and methanol (39:1 V/V). The eluted fractions containing desired product were evaporated to give 6-[2-(2-pyridyl)ethyl]-2-ethylaminobenzoxazole (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[CH2:29]([O:28][C:26]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([F:18])([F:16])[F:17])[CH:4]=2)([OH:14])[CH2:13][CH2:12]1)=[O:27])[CH3:30]
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidine (ACROS Co., 2.0 g) was dissolved in methylene chloride (10 ml), and pyridine (0.6 ml) and ethyl chloroformate (0.8 ml) were added thereto. The mixture was stirred at room temperature for 5 hr. After completion of the reaction, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (1:2)) to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid ethyl ester (2.03 g, yield 81%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[NH:13][C:12]1=[O:19].C(O[Cl:25])(C)(C)C>CO>[Cl:25][N:13]1[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]1=[O:19]
Reactant: COCCOCCOCCN1C(=O)NC(C)(C)C1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: COCCOCCOCCN1C(=O)N(Cl)C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.9 %

Procedure:
To a 0° C. solution of 3-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-5,5-dimethylimidazolidine-2,4-dione (900 mg, 3.3 mmol) in methanol (80 ml) was added tert-butylhypochlorite (220 mg, 2.0 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was checked for completion by high pressure liquid chromatography. The reaction mixture was concentrated in vacuo, and crude material was purified by preparative-high pressure liquid chromatography to give 30 mg (3%) of the title compound. 1H NMR (D2O, 400 MHz) δ 3.79 (t, J=4.8 Hz, 2H), 3.73 (t, J=4.8 Hz, 2H), 3.69-3.58 (m, 8H), 3.37 (s, 3H), 1.49 (s, 6H); LRMS (ESI/APCI) m/z 309 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[O:18][CH3:19])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: COc1ccccc1Nc1nc2c(-c3ccc(S(C)(=O)=O)cc3)cccn2n1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methoxy-phenyl)-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (100.0 mg, 0.3133 mmol) and (4-methylsulfonylphenyl)boronic acid (75.0 mg, 0.375 mmol) in a manner analogous to Step 2c and was isolated as a pale yellow solid (0.097 g, 78%). MP=211-213° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.53-8.49 (m, 1H), 8.38 (dd, J=8.0, 1.3 Hz, 1H), 8.24 (d, J=8.4 Hz, 2H), 8.10 (d, J=8.5 Hz, 2H), 7.66-7.62 (m, 1H), 7.61 (s, 1H), 7.08-6.89 (m, 4H), 3.92 (s, 3H), 3.11 (s, 3H). MS=395 (MH)+.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH:14]1([C@@:17]2([OH:24])[C@H:21]([CH3:22])[NH:20][C:19](=[O:23])[CH2:18]2)[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:14]1([C@:17]2([OH:24])[CH2:18][C:19](=[O:23])[N:20]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=3)[C@H:21]2[CH3:22])[CH2:16][CH2:15]1
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Reactant: C[C@@H]1NC(=O)C[C@@]1(O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C[C@@]1(O)C1CC1

Procedure:
Using 4-iodo-2-(trifluoromethyl)benzonitrile (558 mg), (4R,5S)-4-cyclopropyl-4-hydroxy-5-methylpyrrolidin-2-one (350 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (166 mg), tris(dibenzylideneacetone)dipalladium(0) (86 mg) and cesium carbonate (902 mg), and in the same manner as in Example 62, the title compound was obtained as a yellow powder (yield: 123 mg, 20%).