Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[O:1]=[C:2]1[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([NH:24][CH:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
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: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid, obtained in Example 1E (0.95 g, 3.08 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (CAS 87120-72-7) in dichloromethane (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.171 g, 3.08 mmol) and diisopropylethylamine (2.6 mL, 13.86 mmol). The reaction mixture was stirred at ambient temperature overnight, then diluted with dichloromethane and washed with 1 N HCl (10 mL), water, 1 N NaOH (10 mL), water, dried over MgSO4, and evaporated to yield tert-butyl 4-(2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamido)piperidine-1-carboxylate (0.8 g, 60%). To a solution of this product in methanol (10 mL) was added 4 N HCl/dioxane (2 mL), and the reaction mixture was stirred at room temperature for 3 hours. It was concentrated in vacuo and partitioned between 1 N NaOH and dichloromethane. The organic layer was concentrated and chromatographed on an Analogix 15-24 g silica column, eluting with a 2-5% gradient of methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.19-7.35 (m, 10H), 6.99 (d, J=6.4 Hz, 1H), 4.01 (s, 2H), 3.75-3.95 (m, 1H), 3.52 (t, J=6.6 Hz, 2H), 3.04-3.14 (m, 2H), 2.63-2.72 (m, 2H), 2.57-2.64 (m, 2H), 1.77-1.95 (m, 4H), 1.37-1.53 (m, 2H); MS (ESI+) m/z 392 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1>C1COCC1.O>[Cl:17][C:18]1[N:19]=[C:20]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:21]=[N:22][CH:23]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Cl)n2)C1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Sodium hydride (225.6 g, 5.64 mol) is dispersed into THF (3 L) and the temperature is lowered to 0-5° C. A solution of (R)-3-hydroxy-1-boc piperidine (891.6 g, 4.43 mol) in THF (3 L) is added over 1 h while maintaining the temperature between 0-5° C. The reaction is stirred for 1 h. 2,6-Dichloropyrazine (600 g, 4.03 mol) as a solution in THE (3 L) is added dropwise over 1.5 h maintaining the same temperature. The reaction is stirred for 2 h at 25-30° C., and then poured onto ice. The mixture is diluted with water and extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate, filtered, and concentrated. The residual oil is triturated with 5% dichloromethane in hexane to give the product as a white solid. The solid is collected by filtration and dried, to give 1538 g crude material. The crude product is retriturated with 5% dichloromethane in hexanes to give a white solid in quantitative yield. ES/MS m/z 314.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:26][CH2:27][CH2:28][C@H:29]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42])[CH2:30][F:31])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:52]([O:55][C@@H:56]([CH3:60])[C:57](Cl)=[O:58])(=[O:54])[CH3:53]>ClCCl>[C:52]([O:55][C@H:56]([CH3:60])[C:57]([N:26]([C@@H:21]([C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[S:12][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:27][CH2:28][C@H:29]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42])[CH2:30][F:31])=[O:58])(=[O:54])[CH3:53]
Reactant: CC(C)(C)C(NCC[C@@H](CF)N1C(=O)c2ccccc2C1=O)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)O[C@H](C)C(=O)N(CC[C@@H](CF)N1C(=O)c2ccccc2C1=O)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-((2S)-4-(1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)-1-fluorobutan-2-yl)isoindoline-1,3-dione (65 mg, 0.125 mmol) in dichloromethane (1 mL, 0.1 M solution) at room temperature was added DIEA (65.3 μL, 0.375 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (35 μL, 0.276 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude diastereomers were purified by preparative reverse phase HPLC. The combined fractions of each diastereomer were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The nonpolar diastereomer, (R)-1-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)((S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-1-oxopropan-2-yl acetate, was obtained in 23% (10 mg). LC/MS (uplc) MH+ 706.2, 1.37 min. The polar isomer, (R)-1-(((S)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)((S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-1-oxopropan-2-yl acetate, was obtained in 12% (5 mg). LC/MS (uplc) MH+ 706.2, 1.36 min.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=3[Cl:29])=[C:19]([F:30])[C:15]3[N:16]=[CH:17][S:18][C:14]=3[CH:13]=2)=[O:11])[CH2:4][O:3]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:15]2[N:16]=[CH:17][S:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2cc3scnc3c(F)c2Nc2ccc(Br)cc2Cl)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOCC(O)CO)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Yield: 76.4 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxamide (490 mg, 0.92 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) to afford the desired product (white solid, 345 mg, 58.6% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 9.54 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.60 (d, 1H), 7.34 (d, 1H), 6.46 (m, 1H), 4.84 (d, 1H), 4.60 (m, 1H), 3.88 (m, 1H), 3.74 (m, 2H), 3.36 (m, 2H). MS APCI (+) m/z: 491.9 [M+H].
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Se](=O)=O>O1CCOCC1.C(O)C>[OH:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(CO)n1
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(O)c(C=O)n1
Yield: 57.3 %

Procedure:
3-Hydroxy-6-methyl-2-pyridine methanol (20.0 g, 0.14 mol) and selenium dioxide(8.0 g, 72 mmol) were dissolved in 140 mL of 1,4-dioxane and 280 mL of absolute ethanol. The resulting mixture was heated at 80°-85° C. for 12 h. The selenium precipitate was removed by filtration and the filtrate was concentrated to dryness in vacuo. The dark red residue was sublimed at 90° C. and 14 mmHg for 6 h to obtain 11.0 g (56%) of pure product, m.p. 101°-102° C.; 1H NMR (CDCl3) δ: 10.50 (br s, 1H), 10.03 (s, 1H), 7.27 (s, 2H); 2.53 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[CH:15]1([NH:21][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Yield: 91.3 %

Procedure:
A solution of 4-chloro-3-nitro-benzene sulfonamide (5.49 g, 23.2 mmol), cyclohexylamine (4.00 mL, 35.0 mmol), and triethylamine (5.0 mL, 35 mmol) in acetonitrile (75 mL) was refluxed overnight under nitrogen atmosphere. The reaction mixture was concentrated almost to dryness. The residue was diluted in ethyl acetate and washed with 1N hydrochloric acid (1×) and saturated NaHCO3 (1×). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was filtered and washed with hexane to give the product as a yellow solid (6.34 g, 91%). ESI-MS m/e 300.1 (M+1).
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[CH2:7][C:8]1[N:13]=[C:12]([C:14]([O:16]C)=[O:15])[C:11]([OH:18])=[C:10]([OH:19])[N:9]=1>O.C1COCC1>[Br:4][C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[CH2:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: COC(=O)c1nc(Cc2ccc(F)cc2Br)nc(O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(Cc2ccc(F)cc2Br)[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
A solution of lithium hydroxide monohydrate (23.5 mg, 560 μmol) in water (1 ml) was added to a stirred solution of methyl 2-(2-bromo-4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxylate (50 mg, 140 μmol) in THF (4 ml). The resulting mixture was stirred at room temperature for 24 h. The mixture was then acidified by the addition of Amberlyst resin, filtered and evaporated to dryness. The residue was triturated with Et2O to give the title compound as a white solid (0.02 g; 41%). LCMS: m/z=344 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].I[CH3:14]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CI
Reactant: Clc1nc[nH]c2nccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (15.2 g, 99 mmol) in N,N-Dimethylformamide (DMF) (100 mL) at 0 C was added 60% NaH (5.15 g, 129 mmol) portionwise. After H2 bubbling stopped, iodomethane (6.81 mL, 109 mmol) was added dropwise, and then the reaction mixture was allowed to warm to room temperature. After 3 hours, the reaction mixture was poured slowly onto water (˜800 mL; Caution: H2 evolution due to quenching excess NaH). The resulting solid was filtered and washed with water followed by hexanes to afford 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (12.2 g) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20]C([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:68])[C:5]([C@@:7]1([CH3:67])[C@@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[O:57][C@@H:58]1[O:63][CH2:62][C@@H:61]([OH:64])[C@H:60]([OH:65])[C@H:59]1[OH:66])=[O:6].CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:68])[C:5]([C@@:7]1([CH3:67])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[O:57][C@@H:58]1[O:63][CH2:62][C@@H:61]([OH:64])[C@H:60]([OH:65])[C@H:59]1[OH:66])=[O:6]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@@H]21)C3(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Reaction time: 15 h
Yield: 103 %

Procedure:
Cells were prepared as described in Example 4. 1 mg 7-xylosyl-10-deacetyltaxol, 200 mg (108 milliunits) C-13 deacylase (described in Example 4), 0.2 ml methanol, 0.2 ml 1 M potassium phosphate buffer pH 7, and 3.6 ml water were mixed end-over-end at 48 rpm for 17 hours at 24° C. After 15 hours, HPLC analysis by Method 1 showed complete removal of C-13 side chain from the substrate. 2 ml of the solution now containing 7-xylosyl-10-deacetylbaccatin-III was added to 1 ml of the above Moraxella sp. cells (0.24 g wet cell weight) in 50 mM potassium phosphate buffer pH 7 and mixed end-over-end for 24 hours at 48 rpm. Reaction mixtures were extracted with 6 ml CH2Cl2. Extracts were dried and redissolved in methanol for HPLC analysis by Method 1. 0.099 mg/ml 10-deacetylbaccatin-III was found (103% yield based on initial 7-xylosyl-10-deacetyltaxol concentration).
Reaction SMILES: I[C:2]1[C:3](=[O:15])[O:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[As](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>C1C=CC=CC=1.[OH-].[Na+]>[C:16]1([C:2]2[C:3](=[O:15])[O:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ccc(C2=C(I)C(=O)OC2)cc1
Reactant: OB(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)OC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4 g of the product of Step 3, 3.7 g of PhB(OH)2, 0.4 g of Ph3As, 0.4 g of PdCl2 (PhCN)2 in 100 mL of benzene and 15 mL of 2N NaOH is refluxed for 6 h. After cooling to r.t., Et2O (200 mL) is added to the reaction mixture and the mixture is washed with 100 mL of saturated NaHCO3. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([C:9]([NH2:11])=[NH:10])[S:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:13]C(=O)C(C)(C)C>>[C:1]([C:4]1[N:5]=[C:6]([C:9]([NH2:11])=[NH:10])[S:7][CH:8]=1)([CH3:2])([CH3:3])[CH3:13]
Reactant: CC(C)(C)C(=O)CBr
Reactant: N=C(N)c1nc(C2CC2)cs1
Product: CC(C)(C)c1csc(C(=N)N)n1

Procedure:
4-tert-Butyl-thiazole-2-carboxamidine (Compound N) was prepared in analogy to Compound M with procedure shown in Example 10 by using 1-bromo-3,3-dimethyl-butan-2-one instead of 2-bromo-1-cyclopropyl-ethanone. MS: calc'd (MH+) 184, measured (MH+) 184.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].O.O.O.O.O.O.O.S([O-])([O-])(=O)=[O:27].[Mg+2].O.[K]>CC(C)=O>[F:18][C:2]([F:1])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:27])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(N[C@@H]1CCCc2ccc(F)cc21)C(F)(F)F
Reactant: O=S(=O)([O-])[O-]
Agent: [K]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC[C@@H](NC(=O)C(F)(F)F)c2cc(F)ccc21
Yield: 96 %

Procedure:
To a solution of (R)-2,2,2-trifluoro-N-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (3.51 g, 13.4 mmol, 1 equiv) in acetone (217 mL) was added magnesium sulfate heptahydrate (9.92 g, 40.3 mmol, 3 equiv) with water (167 mL). The mixture was stirred in ice bath. Potassium permangnate (6.37 g, 40.3 mmol, 3 equiv) was added in portions within 1 hour period. After addition, the reaction mixture was stirred at RT for 16 h. The resulting black solid was filtered off and washed with acetone. The combined filtrate and washings were diluted with CH2Cl2 (200 mL). The aqueous phase was separated and washed with CH2Cl2. The CH2Cl2 solution was washed with saturated Na2S2O7 solution (150 mL). The resulting black solid was filtered off The filtrate was evaporated to remove organic solvents. The concentrate was diluted with CH2Cl2 (400 mL). The aqueous phase was separated and washed with CH2Cl2. The combined CH2Cl2 phase was concentrated to give a white solid product (3.54 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.00 (q, 1H), 7.30-7.36 (m, 1H), 7.15 (dd, 1H), 5.32-5.38 (m, 1H), 2.60-2.85 (m, 2H), 2.16-2.30 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].O>CCOCC>[NH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCN
Reaction time: 2 h

Procedure:
To a solution of lithium aluminium hydride (600 mg, Aldrich) in ether (50 mL) was added dropwise the product (3.8 g) from Example 4 in ether (50 mL). After 1-3 h, the mixture was poured into water and stirred for 30 min. The insoluble aluminum hydroxide was filtered through a celite pad, and the aqueous layer was extracted with ether three times. The ether extracts were washed with brine solution, dried and concentrated. The crude product was distilled at 0.25 Torr and 82° C. High resolution mass spectrum for C13 H31 O N Si: calculated 245.2175, found 245.2159.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[S:25][C:26]([CH2:29]Cl)=[CH:27][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:29][C:26]3[S:25][C:24]([Cl:23])=[CH:28][CH:27]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3ncccc23)CC1
Yield: 100.3 %

Procedure:
This compound was prepared following the procedure described in example 7, part E, starting with 2 g (6.6 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester and 0.94 ml (8 mmol) of 2-chloro-5-(chloromethyl)thiophen. After standard work-up and purification, 2.86 g of 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester were obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[N:33]=[C:32](B(O)O)[CH:31]=[CH:30][CH:29]=1>CCCCCCC.CCOC(C)=O>[CH3:26][O:27][C:28]1[N:33]=[C:32]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(B(O)O)n1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide and 6-methoxypyridin-2-ylboronic acid (CAS RN 372963-51-4) and using a gradient of n-heptane:EtOAc (100:0 to 60:40) for the chromatographic purification. The product was purified a second time by preparative HPLC (Phenomenex Gemini® column) eluting with a gradient of acetonitrile:water (50:50 to 95:5). Colorless oil (17%). MS (ESI): m/z=456.114 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][OH:11])[O:7]2)[O:3]1.N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][O:11][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[O:7]2)[O:3]1
Reactant: CC1(C)O[C@H]2O[C@H](CO)[C@H](O)[C@H]2O1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@H](O)[C@H]2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of 1,2-O-isopropylidene-α-D-xylofuranose 1 (30 g, 0.15 mol) in 360 mL of CH2Cl2 was cooled to 0° C. and to it was added 20 mL (0.23 mol) of pyridine and a catalytic amount (1.0 g) of N, N-dimethylaminopyridine. The resulting mixture was stirred at 0° C. for 10 min, at which time 20 mL (0.17 mol) benzoyl chloride was added to it dropwise over a period of 30 min. The reaction mixture was stirred at 0° C. for an additional 30 min and then quenched by the addition of 200 mL a saturated solution of NH4Cl. The reaction was allowed to warm to room temperature, the layers were separated, and the aqueous layer was extracted with 3×50 mL of CH2Cl2. The combined organic extracts were washed with 3×50 mL of a 10% aqueous solution of CuSO4, 2×50 mL of water and brine. The organic solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product mixture was purified by chromatography on silica gel to afford 44.3 g (95% yield) of 2 as a colorless liquid: Rf 0.54 (60% EtOAc/hexane); 1H-NMR (CDCl3) δ 8.03 (m, 2H), 7.40-7.68 (m, 3H), 5.97 (d, 1H, J=3.6 Hz), 4.80 (m, 1H), 4.61 (d, 1H, J=3.4 Hz), 4.37 (m, 2H), 4.20 (s, broad, 1H), 3.35 (broad, 1H), 1.50 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:26][C:25](=[O:27])[NH:24][CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:26][C:25](=[O:27])[NH:24][CH2:23]1)=[O:19]
Reactant: O=C1C[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CN1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1C[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CN1
Yield: 93.4 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-N-{[(3R)-5-oxopyrrolidin-3-yl]oxy}-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 129 (0.22 g, 0.59 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated at 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)-6-hydroxy-7-oxo-N-{[(3R)-5-oxopyrrolidin-3-yl]oxy}-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 130 (0.156 g, 93%) as a white foam.