Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1>C1COCC1>[CH3:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:17](=[O:18])[O:11][C:3]=2[CH:4]=1
Reactant: COc1cc(N)c(O)cc1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc2[nH]c(=O)oc2cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of 2-amino-5-methyl-4-(methyloxy)phenol (1.54 g, 10 mmol) in THF (60 mL) was added carbodiimidazole (1.94 g, 12 mmol). The reaction mixture was stirred for 3 hours at room temperature, concentrated, diluted with EtOAc (100 mL), washed with 1N HCl, H2O, brine, and dried (Na2SO4). The solvent was removed via rotovap to give the title compound (1.76 g, 98%) as a white solid. MS (ES) m/e 180 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]([O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[C:5]2=[CH:6][CH:7]=1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.[Cl-].[Li+]>O1CCCC1>[CH:31]([C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]([O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])=[O:23])[C:5]2=[CH:6][CH:7]=1)=[CH2:32]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(Br)cc12
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Reaction time: 21 h
Yield: 80.9 %

Procedure:
The 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (1.00 g, 2.01 mmol) obtained in Step 2 of Example 383 was dissolved in tetrahydrofuran (20 mL). Thereafter, tributyl(vinyl)tin (1.40 mL, 4.79 mmol), tetrakistriphenylphosphine palladium (240 mg, 0.21 mmol), and lithium chloride (260 mg, 6.13 mmol) were added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred for 21 hours while heating under reflux. Thereafter, the reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-vinylspiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (723 mg, 81%) in the form of a light yellow solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C@H:19]1[C@@H:26]2[C@@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[O:21][C@:20]1([CH2:38][OH:39])[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@@H:26]2[C@@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[O:21][C@@:20]1([CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:38]=[O:39])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1(C)O[C@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H]2O[C@](C=O)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O1
Reaction time: 0.5 h

Procedure:
DMSO (1.65 mL, 23.6 mmol) was added drop-wise to a cold (−78° C.) solution of oxalyl chloride (1.05 mL, 12.0 mmol) in dichloromethane (50 mL). After stirring for 30 min, a solution of compound 2 (3 g, 7.5 mmol) in dichloromethane (25 mL) was added to the reaction. The stirring was continued for 45 min at −78° C., and triethylamine (3.5 mL, 25.0 mmol) was added to the reaction. The reaction was stirred at −78° C. for 15 min, after which the ice-bath was removed and the reaction was allowed to gradually warm over 45 min. The reaction was diluted with dichloromethane and the organic phase was sequentially washed with 5% aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, dried (Na2SO4) and concentrated under reduced pressure to provide 3 (2.2 g, crude), which was used without any further purification. LC-MS (M+H)+=399.1
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44]Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]
Reactant: ClCc1ccccn1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccccn2)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (200 g, 529 mol), prepared as described by Bigge et al. (Tetrahedron Let 1989, 30, 5193), in tetrahydrofuran (200 mL) and DMF (1.5 L) was cooled to about −78° C., and a 0.5 M solution of potassium bis(trimethylsilyl)amide in THF (1.27 L) was added. After the above solution had stirred for about one hour, the free base of 2-picolyl chloride was generated by extracting the corresponding hydrochloride salt (217 g, 1.32 mol) from saturated sodium bicarbonate solution with methylene chloride. The combined organic extracts were dried (MgSO4), concentrated, immediately dissolved in DMF (100 mL), and then added dropwise to the enolate containing solution. The reaction was stirred for about 4 hours at about −78° C., then slowly warmed to room temperature and stirred overnight. The toluene and THF were removed under reduced pressure. The residue was extracted from water (1.5 L) with ethyl acetate (3×1 L), the combined extracts were then washed with water (1.5 L), dried (MgSO4) and then concentrated in vacuo to give 240 g of crude product of the title compound of part 3-A which was carried on to the next step: +APcI MS (M+H)+ 470, (M−tBu+H) 436; 1H NMR=400 MHz (methanol-d4) δ: 8.4 (arom, m, 1H), 7.65-7.2 (arom, m, 7H), 6.94 (arom, m, 1H), 5.18 (CbzNCHH, m, 1H), 5.05 (CbzNCHH, m, 1H), 2.54 (m, 1H), 1.41 (Boc, s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:24][C:25]1[C:26](F)=[C:27]2[C:33]([NH:34][C:35](=[O:40])[C:36]([OH:39])([CH3:38])[CH3:37])=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1.CC#N.O>CCCCO.O>[Br:24][C:25]1[C:26]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:27]2[C:33]([NH:34][C:35](=[O:40])[C:36]([OH:39])([CH3:38])[CH3:37])=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C)(O)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CC#N
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C(C)(C)O)c23)C1
Temperature: 150 °C
Yield: 54.5 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (538 mg, 2.69 mmol) and N,N-diisopropylethylamine (347 mg, 0.468 mL, 2.69 mmol) were added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamide (283 mg, 0.895 mmol) in n-BuOH (3 mL). The resulting mixture was heated at 150° C. in a sealed tube for 24 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layers were dried over MgSO4 and filtered, and the filtrate concentrated to an oil and purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-75% CH3CN/water, 25CV) to give (R)-tert-butyl 1-(5-bromo-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (242 mg, 55% yield) as a solid. LCMS (APCI+) m/z 496.2, 498.2 (M+H)+, Retention time=3.53 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:25])[CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: CCCC(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CCCC(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and n-butyric acid as starting materials, MS (LC/MS): 373.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[C:3]=1[C:17]([O:19]CC)=O.[C:22]([NH:35][NH2:36])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[C:22]([NH:35][NH:36][C:17]([C:3]1[C:4](=[O:16])[N:5]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2ccccc2n(CC(C)C)c1=O
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccccc2n(CC(C)C)c1=O

Procedure:
Reagents: Comp 30 (0.52 mmols, 0.15 g); dodecanoyl hydrazine (0.78 mmols, 0.17 g). Yield: 0.05 g (21%), white solid, m.p.=112° C.-113° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][C:13]2[C:14]([C:26](O)=[O:27])=[N:15][N:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[NH4+:29].[OH-]>O1CCCC1.C(Cl)(=O)C(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]([NH:12][C:13]2[C:14]([C:26]([NH2:29])=[O:27])=[N:15][N:16]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(CSc1ccc(Br)cc1)Nc1cn(CCc2ccccc2)nc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1nn(CCc2ccccc2)cc1NC(=O)CSc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
113 mg (0.3 mM) of the compound obtained in Example 23 was dissolved in 1 ml of tetrahydrofuran to which 60 μl (0.7 mM) of oxalyl chloride was added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. Subsequently, 70 μl of NH4OH was added thereto, and the resulting mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 21 mg (19%) of the title compound.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:25])[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=[O:24])=[CH:14][CH:13]=1)=[O:10])C>CO.C1COCC1.O>[O:24]=[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]1[C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:7]([OH:25])=[O:6])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(-n2ccccc2=O)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC(=O)Nc1ccc(-n2ccccc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
LiOH.H2O (56 mg, 1.3 mmol) was added to a solution of N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-malonamic acid ethyl ester (200 mg, 0.6 mmol) in methanol (0.5 mL), THF (1 mL) and H2O (0.5 mL) and the resulting mixture was stirred for 1 hour at room temperature then concentrated. The residue was diluted with water and acidified with concentrated HCl. The resulting precipitate was isolated by filtration to afford 156 mg (86%) of N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-malonamic acid. 1H NMR: (DMSO-d6): δ 12.8 (s, 1H), 10.3 (s, 1H), 7.78-7.6 (m, 3H), 7.5 (t, 1H), 7.4-7.3 (m, 2H), 6.5 (d, 1H), 6.38 (t, 1H), 3.4 (d, 2H).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:22]2[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[CH:24][CH:23]=2)[O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[NH2:67][CH2:68][CH2:69][C:70]([O:72][CH3:73])=[O:71]>CO.O>[CH:1]1([CH2:4][CH:5]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([NH:67][CH2:68][CH2:69][C:70]([O:72][CH3:73])=[O:71])=[O:27])=[CH:24][CH:23]=2)[O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[N:14]3)=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CCN
Reactant: COC(=O)c1ccc(C(CC2CC2)Oc2ccc(-n3cc(C(F)(F)F)cn3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(C(CC2CC2)Oc2ccc(-n3cc(C(F)(F)F)cn3)cc2)cc1
Reaction time: 8 h
Yield: 109.2 %

Procedure:
To a mixture of (+/−)-methyl 4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl)benzoate (104 mg, 0.242 mmol) in methanol (1.2 mL) and water (0.2 L) was added lithium hydroxide monohydrate (50.08 mg, 1.21 mmol) at room temperature. The resulting mixture was stirred overnight. The reaction mixture was poured into water and acidified to pH=6 with 1N hydrochloric acid. The solution was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (0.84 mL) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (95.8 mg, 0.252 mmol) was added, followed by N-methylmorpholine (50.9 mg, 0.504 mmol). The reaction mixture was stirred for 30 minutes at room temperature. Methyl 3-aminopropionate (23.4 mg, 0.168 mmol) was then added and the reaction was stirred for 48 hours. The reaction mixture was partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/−)-methyl 3-(4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl)benzamido)propanoate (92 mg, 76%). MS (M+Na): 524.1.
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([OH:9])[CH:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19](CO)[OH:20])[OH:18])[OH:16])[OH:14].C(=O)([O-])[O-].[Ca+2].C(O)C>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].[CH2:19]([OH:20])[C@@H:17]([OH:18])[CH:15]([OH:16])[C@H:13]([OH:14])[CH2:12][OH:11]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: OC[C@@H](O)C(O)[C@H](O)CO
Solvent: CCO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 27 h

Procedure:
D-arabitol and D-glucose were dissolved in 0.1 M phosphate buffer (pH 6.0) to 5% (w/v) and 1%, respectively. The resulting mixture was distributed into test tubes in 10-ml portions each, and inoculated with the microbial cell in an amount of 10% (w/v) by a wet weight. In addition, calcium carbonate was added thereto to 2% (w/v). The resulting medium was cultured at 30° C. with shaking. For comparison, ethanol or glucose was added to the culture medium six hours after the commencement of culturing in such a manner as shown in Table 4. After 27 hours, the microbial cells were removed by centrifugation and xylitol thus produced was determined by HPLC. The results are shown in Table 4. As shown in Table 4, the amount of xylitol produced from D-arabitol was increased by addition of the carbon source.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:13]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[CH2:23]([S:22][C:13]1[C:12]([NH:11][CH:1]=[O:2])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(N)c1SCc1ccccc1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(NC=O)c1SCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
27.0 g (0.586 mol) of formic acid are added dropwise to 48.6 g (0.476 mol) of acetic anhydride at 0° C. After the mixture has been stirred at 50°-60° C. for 2 h it is cooled to 0° C. and a solution of 50.0 g (0.183 mol) of methyl 3-amino-2-benzylmercaptobenzoate in 150 ml of THF is added. The reaction solution is then stirred at room temperature for 4 h. The mixture is concentrated under reduced pressure (60° C., 0.1 torr). The resulting oily residue (61.77 g) is employed in subsequent reactions without further purification (cf. Example e)).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Mg+].[Br-]>C(Cl)Cl.CCOCC.O=[Mn]=O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]2[CH:21]=[CH:22][C:23]([CH:26]([OH:27])[CH3:28])=[CH:24][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(-c2sccc2-c2ccccc2OCc2ccccc2)cc1
Reactant: C[Mg+]
Agent: O=[Mn]=O
Agent: [Br-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(O)c1ccc(-c2sccc2-c2ccccc2OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol of example 4 (200 mg, 0.536 mmol) in CH2Cl2 is added MnO2 (467 mg, 5.36 mmol) and the mixture is stirred overnight. The reaction is then filtred throught a plug of celite and the crude mixture diluted in ether (5.0 mL) and cooled at −78° C. MeMgBr was then added (3M in ether, 0.22 mL, 0.66 mmol) and the reaction was warmed to room temperature and stirred for 1 h. The mixture was quenched with saturated NH4Cl, diluted with Et2O and washed successively with HCl 10%, aq. NaHCO3 and brine. The ether layer was dried with anh. MgSO4, filtered and concentrated under reduced pressure to give a residue which was separated in two and one part was purified by flash chromatography (70% Hexanes/30% AcOEt) to provide the title compound (19.4 mg). 1H nmr (400 MHz, acetone-d6) δ ppm 7.45 (1H, d, J=7.5 Hz), 7.32-7.05 (13H, m), 6.91 (1H, t, J=7.5 Hz), 4.97 (2H, s), 4.80 (1H, m) 4.12 (1H, d, J=5.0 Hz), 3.95 (3H, d, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH:12]2[CH2:18][C:19]([NH:21][C@@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH:32]=O)[CH:28]=3)[CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34](O)(C)(C)C.C1COCC1.O.C[N+]1([O-])CCOCC1.P([O-])([O-])([O-])=O>CCOC(C)=O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH:12]2[CH2:18][C:19]([NH:21][C@@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH:32]=[CH2:34])[CH:28]=3)[CH2:23]2)=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(c1)CC[C@@H](NC(=O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1)C2
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1ccc2c(c1)CC[C@@H](NC(=O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetic acid (332 mg, 1 mmol), crude 48999-36 (190 mg, 1.1 mmol), II (135 mg, 1 mmol) and III (191 mg, 1 mmol) in 1 mL of DMF was stirred overnight at room temperature. After quenching with sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:3 to 100:5 to 100:6) gave the title compound as a white solid. E. Preparation of (R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide. To a solution of the procuct of step D. (280 mg, 0.575 mmol) in 13 mL of a mixture solvent t-butanol/THF/water (10:2:1) was added NMO (135 mg, 1.15 mmol), followed by OsO4 (2.5% w/w in t-butanol, 175 mg, 0.017 mmol). After stirring overnight at room temperature, 4 mL of pH 7.2 phosphate buffer was added, followed by NaIO4 (615 mg, 2.875 mmol). After stirring for 5 h at room temperature, the reaction solution was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness in vaco. Flash chromatography (SiO2, EtOAc/hexane=1:1) afforded the title compound as a white solid. Preparation of (R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)C=O.[OH:11][C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:15]([C:16]([NH2:18])=O)=[CH:14][N:13]=1>O>[C:16]([C:15]1[CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:12]([OH:11])=[N:13][CH:14]=1)#[N:18]
Reactant: NC(=O)c1cnc(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(O)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
Phosphorus oxychloride (2.99 mL) was added dropwise to N,N-dimethylformamide (49 mL) at 0° C., and the mixture was stirred at the same temperature for 15 minutes. Then 6-hydroxy-5-nitronicotinamide (4.9 g) was added portionwise to the mixture, and the reaction mixture was stirred at 50° C. for an hour. Water was added to the reaction mixture at 0° C., and the resulting precipitate was collected by filtration in vacuo. The obtained solid was washed with water to give 5-cyano-2-hydroxy-3-nitropyridine (3.17 g) as a pale brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2ccccc2[nH]1
Temperature: -40 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To the SEM-protected indole prepared in step 1 (0.99 g, 4.0 mmol) in THF (10 mL) at −40° C. was added n-BuLi (2.5 M in hexanes, 1.9 mL, 4.8 mmol). The mixture was stirred at −40° C. for 1 h and then triisopropyl borate (1.2 mL, 5.2 mmol) was added. The mixture was allowed to warm to room temperature while stirring for 18 h. To the reaction mixture was added 1N HCl (aq). The mixture was stirred at room temperature for 30 minutes. The mixture was then adjusted to pH˜5 using saturated NaHCO3 (aq) The mixture was extracted with ether. The combined ether extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 30 minutes) to provide the indole boronic acid (0.20 g, 17%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]([NH2:20])=O)[CH2:14][CH2:13]1.O.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][NH2:20])[CH2:16][CH2:17]1
Reactant: COCCCN1CCC(C(N)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCN1CCC(CN)CC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
To a suspension of lithium aluminum hydride (3.32 g, 70.0 mmol) in tetrahydrofuran (200 ml) was added dropwise a solution of 1-[3-(methyloxy)propyl]-4-piperidinecarboxamide (step 1, 7.00 g, 35.0 mmol) in tetrahydrofuran (50 ml) at 0° C. over 15 minutes. The mixture was stirred at 0° C. for 30 min and at 40° C. for 1.5 h. After cooling to 0° C., water (3.3 ml), 15% aqueous sodium hydroxide (3.3 ml) and water (10 ml) were carefully added dropwise. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give 6.31 g (97%) of the title compound as a pale yellow oil.