Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]([C:16]#[N:17])=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:18]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=[O:31].[K+].[K+].OO>CS(C)=O.O>[C:1]1([N:7]2[C:11]3[C:12]([C:16]([NH2:17])=[O:31])=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:18]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(C#N)c2n1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(C(N)=O)c2n1-c1ccccc1
Reaction time: 2 h
Yield: 121.4 %

Procedure:
3-Phenyl-2-[(S)-1-(9H-purin-6-ylamino)ethyl]-3H-benzoimidazole-4-carbonitrile (70 mg, 0.18 mmol) was dissolved in DMSO (2 mL) and to this solution was added a solution of K2CO3 (10 mg) in water (0.1 mL). H2O2 (0.2 mL, 30% in water) was added dropwise and the resulting solution stirred for 2 h. Very slow hydrolysis occurred as observed by LCMS. The solution was heated at 60° C. over 2 days with additional aliquots of H2O2 (2×0.2 mL). The cooled mixture was poured onto water. The resulting aqueous solution was passed through an SCX cartridge, the cartridge was washed with water and MeOH and the product eluted with 2M NH3 in MeOH. The product fractions were combined and evaporated and the residue purified by chromatography (Si—PCC, 0-10% 2M methanolic NH3 in DCM). The product fractions were concentrated in vacuo to give white solid. This was triturated in ether, filtered and dried in vacuo to give 311 as a white solid (35 mg, 50%). 1H NMR (DMSO-d6, 400 MHz): δ 8.18-8.00 (2H, m), 7.87-7.77 (1H, m), 7.66 (1H, d, J=7.4 Hz), 7.55-7.27 (6H, m), 7.23-7.13 (2H, m), 6.95 (1H, s), 5.38-5.18 (1H, m), 1.46 (3H, d, J=6.7 Hz). LCMS (Method K): RT 1.99 min; m/z 399 [M+H]+
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][C:10]2=[O:20])=[CH:5][CH:4]=1.B(Br)(Br)Br.CCCCCC>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][C:10]2=[O:20])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2C[C@@H](c3ccccc3)OC2=O)cc1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C1O[C@H](c2ccccc2)CN1c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
4.10 g (15.2 mM) of (5R)-3-(4-methoxyphenyl)-5-phenyl-2-oxazolidinone synthesized in Example 1 was dissolved in 100 ml of methylene chloride and cooled to -75° to 70° C. on a dry ice-acetone cooling bath. To the solution, 31.5 ml of 1.0M-solution of boron tribromide in methylene chloride was added dropwise in 43 minutes, followed by stirring for 1 hour at -75° to -70° C. and further stirring for 2 hours at room temperature. After the reaction, the reaction mixture was poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with water and dried with anhydrous sodium sulfate, followed by evaporation under reduced pressure to obtain a residue. To the residue, an appropriate amount of hexane was added to precipitate a crystal. The crystal was recovered by filtration, thus obtaining 3.13 g of (5R)-3-(4-hydroxyphenyl)-5-phenyl-2-oxazolidinone (Yield: 80.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:17])[C:10]3[CH:16]=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1C(=O)N([Br:29])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:17])[C:10]3[CH:16]=[C:15]([Br:29])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2c3sccc3C(C)C2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC2c3sc(Br)cc3C(C)C2C1

Procedure:
A solution of the product from step i) (204 mg, 0.81 mmol) in AcOH (2 ml) and CHCl3 (2 ml) was treated with NBS (152 mg, 0.85 mmol) at 22° C. for 30 minutes. Next, the reaction was carefully quenched with sat. NaHCO3 (10 ml), extracted with EtOAc (2×75 ml) and the combined organic layers were dried (MgSO4). The crude product was filtered through a plug of silica gel using hexanes:EtOAc (50:50) to give the subtitle compound. MS calculated for C13H16BrNO2S+H 330, observed 332.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:23]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([Cl:16])[CH:24]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(OCc2ccccc2)c1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Temperature: 0 °C

Procedure:
3-Benzyloxybenzenethiol (13) (75.0 g, 347 mmol) and 2-chloro-4-fluorobenzaldehyde (55.0 g, 347 mmol) were dissolved in dimethylformamide (DMF) (350 mL) while the solution was being stirred. The solution was then placed in a water bath at 30° C. and potassium carbonate (62.3 g, 451 mmol) and dimethylformamide (25 mL) were added. This mixture was stirred for 30 min at an internal temperature of 40 to 42° C. Tap water (125 mL) was then added and the mixture was cooled in ice water. To the cooled mixture, additional tap water (625 mL) was added dropwise for crystallization. The mixture was stirred for 30 min and the resulting crystals were collected by filtration and washed with 10% aqueous 2-propanol (188 mL). The moist crystals were dissolved in ethyl acetate (750 mL) and the solution was washed twice with tap water (375 mL×2). The organic layer was concentrated under reduced pressure and acetone (900 mL) was added to the resulting residue. Purified water (386 mL) was then added dropwise at an internal temperature of 23° C. The mixture was stirred for 30 min and the resulting crystals were collected by filtration and washed with 50% aqueous acetone (400 mL). The washed crystals were air-dried overnight. Subsequently, the product was dried by blowing an air stream at 45° C. for 1 hour. This gave 4-(3-benzyloxyphenylthio)-2-chlorobenzaldehyde (1) as a colorless prism crystals (115 g, 94%).
Reaction SMILES: C(C1C2C(=CC=CC=2)N(CC(N2C[C@H](F)C[C@H]2C(NCC2C=C(C=C(Cl)C=2F)C(O)=O)=O)=O)C=1)(=O)C.C[O:38][C:39](=[O:73])[C:40]1[CH:45]=[C:44]([Cl:46])[C:43]([F:47])=[C:42]([CH2:48][NH:49][C:50]([C@@H:52]2[CH2:57][C@@H:56]3[C@@H:54]([CH2:55]3)[N:53]2[C:58](=[O:72])[CH2:59][N:60]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]([C:69](=[O:71])[CH3:70])=[CH:61]2)=[O:51])[CH:41]=1>>[C:69]([C:62]1[C:63]2[C:68](=[CH:67][CH:66]=[CH:65][CH:64]=2)[N:60]([CH2:59][C:58]([N:53]2[C@H:52]([C:50]([NH:49][CH2:48][C:42]3[CH:41]=[C:40]([CH:45]=[C:44]([Cl:46])[C:43]=3[F:47])[C:39]([OH:73])=[O:38])=[O:51])[CH2:57][C@@H:56]3[C@H:54]2[CH2:55]3)=[O:72])[CH:61]=1)(=[O:71])[CH3:70]
Reactant: COC(=O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@H]3C[C@H]3N2C(=O)Cn2cc(C(C)=O)c3ccccc32)c1
Agent: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cc(C(=O)O)cc(Cl)c2F)c2ccccc12
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cc(C(=O)O)cc(Cl)c2F)c2ccccc12

Procedure:
The title compound was prepared according to procedure described for the preparation of 3-[({(2S,4R)-1-[2-(3-acetyl-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carbonyl}-amino)-methyl]-5-chloro-4-fluoro-benzoic acid Example 605 starting from 3-[({(1R,3S,5R)-2-[2-(3-acetyl-indol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carbonyl}-amino)-methyl]-5-chloro-4-fluoro-benzoic acid methyl ester Example 480. MS: 512.0 [M+H]+; tR (HPLC conditions c): 4.41 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=O.C([BH3-])#N.[Na+]>C(O)C.CO>[OH:8][CH2:7][C@H:5]([NH:6][CH:11]1[CH2:10][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[C:4]([O:3][CH3:2])=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COC(=O)[C@H](CO)NC1Cc2ccccc2C1
Reaction time: 0.5 h

Procedure:
L-serine methyl ester hydrochloride (0.05 moles, 7.78 g) is dissolved in absolute ethanol (400 ml) and methanol (40 ml), added with 2-indanone (0.05 moles, 6.74 g) and sodium cyanoborohydride (0.55 moles, 3.64 g) under stirring in 30 minutes. The mixture is stirred at r.t. for 5 hours, then evaporated to dryness under vacuum and the residue is taken up into water (150 ml) and ethyl acetate (150 ml). The phases are separated and the aqueous phase is further extracted with ethyl acetate (200 ml). The combined organic phases are extracted with a 0.2 N HCl solution (2×200 ml). The aqueous solution is separated, adjusted to pH=8 with sodium bicarbonate and extracted with ethyl acetate (2×300 ml). The organic solution is separated, dried over sodium sulfate and evaporated under vacuum. The resulting product is dried under vacuum at r.t. Yield: 8.4 g (71.4%)
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:19]1([C:25]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:43]1([C:25]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH:32]3[C:15](=[O:16])[CH2:14][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2C(C(=O)Cc3ccccc3)NCC21
Reaction time: 24 h

Procedure:
0.35 cm3 of triethylamine and then 0.33 cm3 of phenylacetyl chloride are added to a suspension of 1.1 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry methylene chloride at room temperature. The reaction mixture is stirred at this temperature for 24 hours, diluted with 200 cm3 of methylene chloride, washed with 100 cm3 of a saturated solution of sodium bicarbonate, with 100 cm3 of water (twice) and then with an aqueous saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 11 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallised in 70 cm3 of acetonitrile and the crystals are filtered off and dried. 0.5 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-phenylacetyl-perhydroisoindol-4-ol is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:20]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[CH3:19])[CH2:23][CH2:22][CH2:21]1
Reactant: Cc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-methylphenyl]acetic acid (0.5 g, 1.951 mmol) was dissolved in DMF (1 ml). Azetidine (0.167 g, 2.93 mmol), DIEA (0.511 ml, 2.93 mmol), and HATU (1.484 g, 3.90 mmol) were added and the mixture stirred at RT for 1 hr. The reside was purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid to afford the title compound. LC/MS (m/z): 296 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:18])=[C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15]OC2=O)[CH:8]=1.Br.C1(OC)C=CC=CC=1.C(N(CC)CC)C>C(O)(=O)C.C(O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:18])=[C:7]([N:9]2[CH2:10][CH2:11][NH:12][CH2:16][CH2:15]2)[CH:8]=1
Reactant: COc1ccc(C)c(NCCN2CCOC2=O)c1
Agent: Br
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C)c(N2CCNCC2)c1
Temperature: 90 °C

Procedure:
To 505 mg (2.0 mmol) of 3-[2-(5-Methoxy-2-methyl-phenylamino)-ethyl]-oxazolidin-2-one in a flask was added 2 mL of 48% HBr in acetic acid, 1 mL of acetic acid, and 1 mL of anisole, and the mixture was heated at 90° C. for six hours. The solution was allowed to cool to room temperature, and 5 mL of CH2Cl2 was added. The product crystallized and was isolated by filtration. The solids were dissolved in 55 mL of ethanol, 201 mg (2 mmol) of triethylamine were added, and the solution was heated at reflux for 3 hours. The solution was then concentrated in vacuo to give a residue that was partitioned between ether and water. The phases were separated, and the aqueous phase as basified with 1M NaOH. The aqueous phase was then extracted twice with ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over Na2SO4, filtered, and acidified with 2M HCl in ether. The product was isolated via filtration.
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[S:12][C:11]([S:13]([NH:16][C@H:17]([C:24](O)=[O:25])[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])(=[O:15])=[O:14])=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[S:12][C:11]([S:13]([NH:16][CH:17]([CH2:24][OH:25])[CH2:18][CH2:19][C:20]([F:21])([F:22])[F:23])(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: O=C(O)[C@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)s1
Agent: B
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)CCC(F)(F)F)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 48 %

Procedure:
Borane-THF (1 M, 15 mL, 14.21 mmol) was added dropwise over 30 min at 0° C. to a solution of N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoronorvaline (1.0 g, 2.84 mmol) in THF (10 mL). The reaction was allowed to warm to 25° C. for 18 h and then was quenched by addition of 50 mL of 10% acetic acid in methanol. After solvent evaporation, the crude product was dissolved in EtOAc and washed with 1N HCl, H2O and saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated to produce a crude oil (0.83 g) that was purified via flash chromatography, eluent: 1:6 ethyl acetate-hexane. This produced the title compound 5-chloro-N-[4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as a colorless oil (0.46 g, 48%). Mass Spectrum (−ESI): 337 (M−H)−.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:43]1[CH:48]=[N:47][CH:46]=[CH:45][N:44]=1)CCC>O1CCOCC1.C(OCC)(=O)C.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].[Cu]I>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:48]=[N:47][CH:46]=[CH:45][N:44]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4cnccn4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C
Yield: 43.9 %

Procedure:
The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 (600 mg) was dissolved in 1,4-dioxane (11 ml). Added thereto were tri-n-butyl(pyrazinyl)tin 72 (720 mg), tetrakis(triphenylphosphine)palladium (0) (206 mg) and copper (I) iodide (51 mg), and the mixture was stirred under heating at 100° C. for 1.5 hours, under irradiation by a microwave (500 W). The mixture was diluted with ethyl acetate, the insoluble materials were filtered off, and the filtrate was washed with water. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25-30:70), and crystallized from hexane-diethyl ether to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienylmethyl)benzene 73 (263 mg) as pale yellow crystals. APCI-Mass m/Z 617/619 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)#[N:7].C([O-])([O-])=O.[Na+].[Na+].O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]#[N:7])[CH2:9][CH2:10]1)=[O:4]
Reactant: N#CC1CCNCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CC1CCN(C(=O)CCl)CC1
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (0.43 mL) was added to a mixture of a solution of 4-cyanopiperidine (500 mg) in CH2Cl2 (5 mL) and an aqueous 2 M Na2CO3 solution (5.7 mL) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. After the reaction mixture was further stirred at room temperature for 4 hours, CH2Cl2 and water were added thereto, then, extraction was performed on the mixture using CH2Cl2, and the extract was washed with saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure, whereby 1-(chloroacetyl)piperidine-4-carbonitrile (845 mg) was obtained as a light yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])[CH2:15][CH2:16]2)=[O:10])=[CH:28][CH:29]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
1-[1-(4-Methoxycarbonylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (6.33 g) and sodium hydroxide (1.94 g) are dissolved in methanol (100 ml) and the mixture is stirred at room temperature overnight. After the solvent is concentrated, water is added to the residue and the mixture is extracted with diethyl ether. The aqueous layer is adjusted to pH 1 by adding conc. hydrochloric acid and extracted with ethyl acetate. The extract is dried with magnesium sulfate, concentrated and recrystallized from n-hexane/ethanol to give 1-[1-(4-carboxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (4.5 g) as white powder, m.p.: 232°-235° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.O.NN>C(O)C.CO.[Ni]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(O)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
4-Hydroxy-3-nitrobenzonitrile (0.5 g, 3.05 mmol) was dissolved in ethanol (20 mL) and methanol (10 mL), and Raney-Nickel (1 mL, 10% aqueous solution) was added at rt followed by hydrazine mono hydrate (0.296 mL, 6.09 mmol). The mixture was stirred at rt overnight. The mixture was then filtered through celite and concentrated by rotary evaporation. The residue was purified via chromatography (silica, n-hexane to ethyl acetate) to give 3-amino-4-hydroxybenzonitrile (D19, 200 mg, 49%) as an orange solid.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:20][CH:21]([CH3:25])[CH2:22][CH:23]=[O:24]>O1CCCC1>[OH:24][CH:23]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)[CH2:22][CH:21]([CH3:25])[CH3:20]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of ethyl 4-iodobenzoate (20 g, 72 mmol) in tetrahydrofuran (200 mL) at −40° C. was added isopropylmagnesium chloride lithium chloride (62 mL, 80 mmol, 1.3 M in THF) dropwise, maintaining the internal temperature below −30° C. The mixture was stirred for 30 minutes and 3-methylbutanal (8.68 g, 101 mmol) was then added dropwise, maintaining the internal temperature below −35° C. Following the addition, the reaction was allowed to stir for 15 minutes at −35° C. and was then allowed to warm to room temperature. The reaction was quenched with 1 N aqueous hydrochloric acid (400 mL), and the mixture was extracted with ethyl acetate (2×200 mL). The organics were washed with brine (200 mL) and water (200 mL), dried over sodium sulfate, filtered and concentrated to give ethyl 4-(1-hydroxy-3-methylbutyl)benzoate (16 g, 93%) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.95 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.73-4.76 (m, 1H), 4.28-4.33 (m, 2H), 1.60-1.71 (m, 2H), 1.41-1.46 (m, 1H), 1.31-1.39 (m, 3H), 0.87-0.92 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:40][N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[C:44]([CH3:55])[CH:43]=[N:42]1>O1CCOCC1.O.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>[CH3:40][N:41]1[C:45]([C:2]2[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[CH2:11][N:12]3[C:13](=[O:22])[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]3=[O:21])=[O:8])[S:5][CH:6]=2)=[C:44]([CH3:55])[CH:43]=[N:42]1
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 80 °C
Yield: 93.9 %

Procedure:
To a solution of 4-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (200 mg, 0.37 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (0.17 g, 1.23 mmol), tetrakistriphenylphosphine Pd(0) (42 mg, 0.036 mmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (413 mg, 1.86 mmol) [from Preparation 17]. The reaction mixture was heated to 80° C. in a sealed tube for 2 h. The reaction solution was concentrated under vacuum, and purified on silica gel (10-50% EtOAc/Hex) to give the title compound (192 mg, 94%) as a white solid: LC-MS (ES) m/z 553 (M+H)+.