Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:22]([OH:23])=[CH:21][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)=[O:10])=[CH:7][O:8][C:4]=2[C:3]=1[Br:24].[N+]([O-])(O)=[O:26].O.C(Cl)(Cl)Cl.CO>C(O)(=O)C>[Br:1][C:2]1[C:22](=[O:23])[C:21](=[O:26])[C:5]2[C:6]([C:9](=[O:10])[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)=[CH:7][O:8][C:4]=2[C:3]=1[Br:24]
Reactant: COc1ccc(C(=O)c2coc3c(Br)c(Br)c(O)cc23)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C(Br)=C3Br)cc1OC
Temperature: 60 °C

Procedure:
To a suspension of compound 14 (100 mg, 0.22 mmol) in glacial acetic acid (2 mL) at room temperature was added nitric acid (0.1 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 60° C. for 30 min, allowed to cool to room temperature, and poured into cold water. The resulting precipitate was filtered and recrystallized to obtain compound SKC-BF-12 (40 mg, 40%) as an orange solid. TLC Rf=0.7 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 7.87 (s, 1H), 7.57 (app s, 1H), 7.37 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.84 (d, J=8.3, 1H), 3.95 (s, 6H); MS (ES) m/z 471 (M+H)+.
Reaction SMILES: C1CCCCC=1.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([N+:27]([O-])=O)[CH:15]=2)[CH2:10][CH2:9]1>[Pd].C(O)C>[NH2:27][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Temperature: 80 °C
Yield: 96.1 %

Procedure:
0.160 g (1.500 mmol) of palladium on carbon (10%) and 15.19 ml (150 mmol) of cyclohexene are added to a solution of 4.82 g (15 mmol) of tert-butyl 4-(4-methylpiperazin-1-yl)-2-nitrobenzoate in 100 ml of ethanol. The reaction mixture is heated at a temperature of 80° C. for 8 hours. The reaction mixture is filtered and then rinsed with ethanol to yield 4.2 g (yield=96%) of tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](C)[CH:5]=[CH:4][N+:3]=1[O-].[CH3:10][C:11]([O:13]C(C)=O)=[O:12]>>[C:11]([O:13][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:12])[CH3:10]
Reactant: Cc1cc[n+]([O-])c(C)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccccn1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
Compound 2,4-Dimethylpyridine N-Oxide (4.47 g, 36.3 mmol) was dissolved in Ac2O (11 mL) and added dropwise to acetic anhydride (108 mL) heated to 110° C. The resulting solution was stirred at 110° C. for 1 hour and 15 minutes. Excess reagent was evaporated leaving the corresponding 2-[(acetyloxy)-methyl]pyridine which was used without further purification. To a solution of the protected alcohol in MeOH (5 mL) was added NaOH 2N (15 mL) at room temperature. The mixture was stirred at room temperature for 1.5 hours, extracted with EtOAc and washed with water. The solvent was evaporated giving a residue that was purified by column chromatography (4% MeOH in CH2Cl2) affording 1.54 g (34% overall yield) of colorless oil. 1H NMR (CD3OD) δ 8.29 (d, 1H, J=4.2 Hz, H-6); 7.40 (s, 1H, H-3); 7.11 (d, 1H, J=4.2 Hz, H-5); 5.10 (s, 1H, OH); 4.68 (s, 2H, CH2); 2.38 (s, 3H); 13C NMR (CD3OD) δ 162.4 C-2), 151.0 (C-4), 149.4 (C-6), 125.0 (C-3), 123.3 (C-5), 65.8 (CH2), 21.7 (Me).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Li]CCCC.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C>C1COCC1>[CH3:17][CH:16]([CH3:18])[CH2:15][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cn1c2ccccc2c2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c2ccccc2c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Into a solution of 3 (4.2 g, 13.9 mmol) in THF (80 ml) was added BuLi (2.5 M in hexane, 6.95 ml, 17.4 mmol) dropwise at −78° C. The mixture was stirred at this temperature for 3 hours before 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (4.05 g, 21.75 mmol) was added in one portion. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours, quenched with water, and then extracted with ether. The organic extracts were combined, washed with brine and water, and dried over MgSO4. Upon evaporating off the solvent, the crude product was purified by column chromatography on silica gel with hexane/methylene chloride 3:1 (v/v) as the eluent to yield 4 (3.95 g, 81%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.60 (s, 1H), 8.15-8.10 (d, 1H), 7.90-7.85 (d, 1H), 7.45-7.35 (m, 3H), 7.25-7.15 (m, 1H), 4.10-4.09 (d, 2H), 2.42-2.30 (m, 1H), 1.39 (s, 12H), 0.97-0.95 (d, 6H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.CC[O-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
12 ml of diethyl malonate were introduced into 120 ml of ethanol and then 5.5 grams of sodium ethylate at 98% were added over 10 minutes at 0° to +5° C. The mixture was stirred for 15 minutes at 0°+5° C. and then 8.8 ml of ethyl bromoacetate were added over 30 minutes. The mixture was stirred for 48 hours at ambient temperature and then the mixture was poured into 600 ml of water and extracted 3 times with 300 ml of methylene chloride. The organic phase was washed twice with 300 ml of water, then evaporated to dryness. The oil obtained was distilled under reduced pressure to obtain 12.4 grams of the expected product with a boiling point of 110° to 120° C. at 1.0 mm of Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[NH:15][N:14]=[C:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH:12]=1)=O>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:11]1[CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[NH:14][N:15]=1
Reactant: Nc1ccccc1NC(=O)c1cc(/C=C/c2ccc(O)cc2)n[nH]1
Solvent: CC(=O)O
Product: Oc1ccc(/C=C/c2cc(-c3nc4ccccc4[nH]3)n[nH]2)cc1
Temperature: 100 °C
Yield: 2.4 %

Procedure:
Glacial acetic acid (1.0 mL) was added to a sealed tube charged with a solution of N-(2-aminophenyl)-3-[(E)-2-(4-hydroxyphenyl)ethenyl]-1H-pyrazole-5-carboxamide (0.044 g, 1.36 mmol) in xylenes (1.0 mL) and heated to 100° C. After twelve hours the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the title benzimidazole (10 mg, 25% yield) as a white solid: 1H NMR (400 MHz, CD3OD): δ 7.59 (bs, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 7.16 (d, J=16.4 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J=16.4 Hz, 1H), 6.79 (m, 2H); MS (EI) for C18H14N4O: 303.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:12]=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][N:38]([CH3:46])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].Br[C@H]1CCN(C(OC(C)(C)C)=O)C1.OCCN(C)C(=O)OC(C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:36][CH2:37][N:38]([CH3:46])[C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:17][CH2:16]2)[N:12]=[C:11]([C:21]([F:22])([F:23])[F:24])[CH:10]=1)=[O:8]
Reactant: CN(CCBr)C(=O)OC(C)(C)C
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1CC1CCNCC1
Agent: CC(C)(C)OC(=O)N1CC[C@H](Br)C1
Agent: CN(CCO)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1CC1CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 11.6 %

Procedure:
To a stirred solution of 83 (87 mg, 0.171 mmol) in DMF (855 μl) was added potassium carbonate (59.1 mg, 0.428 mmol). The mixture was cooled to 0° C., then followed by the addition of tert-butyl 2-bromoethyl(methyl)carbamate (44.8 mg, 0.188 mmol) [made by following the procedure described above for the synthesis of 72 (scheme 10, example 8, step 1), except using tert-butyl 2-hydroxyethyl(methyl)carbamate in place of N-Boc-(R)-3-hydroxypyrrolidine]. The mixture was stirred at room temperature for 16 h, and then more tert-butyl 2-bromoethyl(methyl)carbamate (44.8 mg, 0.188 mmol) was added. The mixture was stirred at room temperature for 30 min, then at 80° C. for 1 hour. The mixture was quenched with water and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of methanol (0-10%) in dichloromethane to afford 84 (11 mg, 12%) as a white solid. LRMS (ESI): calc. 553.3; found 554.2 (MNa)+.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[C:18]([O:19][CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:22][CH:23]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(O)cccc1F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1OCCO

Procedure:
In analogy to example 16.4 (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-6-hydroxy-phenyl)-2-methoxy-acetamide (example 80.4) was reacted with 2-bromoethanol in the presence of cesium carbonat in DMF to give N-(4-cyano-benzyl)-2-[2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-2-methoxy-acetamide. White solid. MS 359.2([M+H]+)
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)(=O)=O)=CC=1.[I-:24].[Na+]>CC(=O)CC>[C:13]12([CH2:12][CH2:11][I:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCC23CC4CC(CC(C4)C2)C3)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: ICCC12CC3CC(CC(C3)C1)C2
Yield: 57.6 %

Procedure:
A solution of 2-(1-adamantyl)ethyl p-toluene-sulfonate (4.0 g) and sodium iodide (2.5 g) in 2-butanone (20 ml) is heated for 2 hours under reflux. The cooled solution is filtered and concentrated to a residue which is partitioned between dichloromethane and water. The organic layer is washed with aqueous sodium thiosulfate and water. The dried solution is evaporated to a crystalline mass which is recrystallized from ethanol to give 2-(1-adamantyl)ethyl iodide (2.0 g), m.p. 93°-94°. An analytical sample is obtained by recrystallization from the same solvent, m.p. 97°-98°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][N:11]2C(C)=CC=C2C)[N:5]=[C:4]([N:18]2C(C)=CC=C2C)[CH:3]=1.Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:18][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][NH2:11])[N:5]=1
Reactant: Cc1cc(CCCn2c(C)ccc2C)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)nc(CCCN)c1

Procedure:
By analogy to Example 56, Step B, 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(3-(2,5-dimethylpyrrol-1-yl)propyl)pyridine was treated with 9.2 equivalents of hydroxylamine hydrochloride and 5.4 equivalents of potassium hydroxide in refluxing ethanol/water to yield 2-amino-6-(3-aminopropyl)-4-methylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1B(O)O.Cl[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][N:17]=1.C(P(C(C)(C)C)C[Si](C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][N:17]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)P(C[Si](C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccnc(-c2cc(C(F)(F)F)ccc2F)c1

Procedure:
10.0 g (0.0481 mol) of 2-fluoro-5-(trifluoromethyl)phenylboronic acid, 6.86 g (0.0433 mol) of 2-chloro-4-nitro-pyridine, 1.10 g (0.0012 mol) of tris(dibenzylideneacetone) dipalladium (0), 0.67 g (0.00289 mol) of di-tert-butyl-trimethylsilylmethyl-phosphane, 15.67 g (0.0481 mol) of cesium carbonate and 100 ml of dioxane were stirred at room temperature for 24 hours. The resultant mixture was poured into 200 ml of water and extracted twice with 200 ml of methylene chloride. The organic phase was dried over magnesium sulfate overnight and filtered. The solvent was removed on a rotovapor and the residue was purified by chromatography on silica gel with petroleum ether/ethyl ether (10/0.5) as eluent. Yield of 2-(2-fluoro-5-trifluoromethyl-phenyl)-4-nitro-pyridine: 3.58 g (28.92%) as a white solid with m.p. 58.11° C. 1H NMR (CD2Cl2) 7.10-8.90 (m, 6H, arom-H). 19F NMR (CD2Cl2) −62.98 (s, 3F, CF3), −111.85 (s,1F, F-arom). LC/MS calculated for C12H6F4N2O2 286.04; found 286.04.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH2:21][O:20][CH3:19])[O:23][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: COCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: COCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methoxymethyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7]1[N:12]2[N:13]=[C:14]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:15]=[C:11]2[C:10]([CH:23]=[O:24])=[CH:9][CH:8]=1.[Cl-].[NH4+]>O1CCCC1>[OH:24][CH:23]([C:10]1[C:11]2[N:12]([N:13]=[C:14]([C:16]([F:22])([F:21])[C:17]([F:18])([F:19])[F:20])[CH:15]=2)[C:7]([O:6][CH3:5])=[CH:8][CH:9]=1)[CH2:1][CH3:2]
Reactant: COc1ccc(C=O)c2cc(C(F)(F)C(F)(F)F)nn12
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(OC)n2nc(C(F)(F)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an argon atmosphere, ethyl magnesium bromide (5.44 mL, 0.91 mol/L tetrahydrofuran solution) was added to a solution of the compound of Example 354 (1.24 g) in tetrahydrofuran (30 mL) at −78° C. The mixture was allowed to gradually warm to room temperature and was stirred at room temperature for 1 hour. Subsequently, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (100 mL). The extract was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The extract was then concentrated and purified by amino-silica gel column chromatography (ethyl acetate) to afford the title compound as a pale yellow oil (1.41 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([OH:15])=[O:14].C([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C.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>[F:9][C:8]([F:11])([F:10])[C:7]([C:5]1[S:6][C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C(c1ccc(Br)s1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Temperature: 90 °C
Yield: 77.5 %

Procedure:
1-(5-Bromothiophen-2-yl)-2,2,2-trifluoroethanone (0.8 g, 3.09 mmol) and 3-carboxyphenylboronic acid (0.5 g, 3.01 mmol) were dissolved in DMF (10 mL) and the solution was purged with argon for 10 min. 2M aqueous solution of Na2CO3 (0.65 g, 6.17 mmol) and catalytic Pd(PPh3)4 (178 mg, 0.15 mmol) were added to the reaction mixture and heated to 90° C. for 10 h. The reaction mixture was cooled to room temperature, diluted with water and acidified to pH˜6 with 1.5 N HCl. The crude product was extracted with EtOAc. The combined extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was triturated with diethyl ether to get 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid (700 mg, yield 79%). 1H NMR (400 MHz, DMSO-d6) δ 13.35 (br s, 1H), 8.31-8.30 (m, 1H), 8.16-8.11 (m, 2H), 8.04-8.02 (d, J=7.6 Hz, 1H), 7.93-7.92 (d, J=4.3 Hz, 1H), 7.67-7.63 (t, J=7.8 Hz, 1H). MS (ESI) m/z: Calculated for C13H7F3O3S: 300.01. found: 299.0 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:39][OH:40]>O1CCCC1>[OH:40][NH:39][C:13](=[O:14])[CH2:12][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:25]
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2Cc3ccccc3C2=O)cc1OC
Yield: 78.3 %

Procedure:
N-Hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (5.00 g, 14.7 mmol), carbonyldiimidazole (2.49 g, 15.4 mmol) and hydroxylamine hydrochloride (1.30 g, 19.1 mmol) in tetrahydrofuran (15 mL) to afford N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide as a white solid (4.1 g, 79% yield): mp, 188.5-189.5° C.; 1H NMR (DMSO-d6) δ2.82-2.87 (m, 2H, CH2), 3.71 (s, 3H, CH3), 3.74 (s, 3H, CH3), 4.15 (d, J=17.5 Hz, NCHH), 4.63 (d, J=17.5 Hz, 1H, NCHH), 5.74 (t, J=7.7 Hz, 1H, NCR), 6.85-6.93 (m, 3H, Ar), 7.45-7.69 (m, 4H, Ar), 8.83 (br s, 1H, OH), 10.60 (1H, NH); 13C NMR (DMSO-d6) δ35.11, 46.26, 51.25, 55.50, 111.09, 111.76, 119.19, 122.79, 123.43, 127.84, 131.29, 131.91, 132.27, 141.68, 148.27, 148.69, 166.03, 166.84; Anal Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 64.08; H, 5.55; N, 7.86.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:22][CH:23]([NH2:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:28][CH:23]([CH3:22])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CC(N)C(C)(C)C
Reactant: COc1cc(NC(SC)=C(C#N)S(C)(=O)=O)cc(OC)c1
Product: COc1cc(NC(NC(C)C(C)(C)C)=C(C#N)S(C)(=O)=O)cc(OC)c1

Procedure:
3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-methylsulfany-2-propenenitrile (0.263 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) gave the title compound as a syrup, 262 mg (86%). 1H NMR (200 MHz, CDCl3): δ=0.85 (s, 9H), 1.01 (d, 3H), 3.12 (s, 3H), 3.26 (m, 1H), 3.78 (s, 6H), 6.25 (d, 2H), 6.35 (t, 1H); EI SP/MS: 381 (M+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][CH3:22])=[C:10]([CH2:19]O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.S(Cl)(Cl)=O>[N:23]([CH2:19][C:10]1[C:9]([CH2:21][CH3:22])=[N:8][C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[C:11]=1[NH:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N+:24]=[N-:25]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=S(Cl)Cl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 218.1 %

Procedure:
To [1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (24.9 g, 82 mmol) was added thionyl chloride (90 mL, 1.23 mmol) and the mixture was heated to 80° C. under an atmosphere of nitrogen. After 2 h the mixture was cooled, concentrated and the residue azeotroped with toluene. The residue was then dissolved in a solution of sodium azide (7.98 g, 123 mmol) in DMSO (120 mL). The mixture was stirred for 16 h. The above procedure was repeated on the same scale and the 2 reactions combined for work-up. The combined DMSO mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous phase was extracted thoroughly with ethyl acetate and the combined organics were washed with water, then brine, dried and concentrated to afford 58.9 g of a brown solid. The product was purified by flash chromatography on 1.5 kg of silica using a step gradient from 3:1 to 2:1 cyclohexane/ethyl acetate to afford 39.94 g of the title compound. LC-MS m/z 330 (M+H)+, 2.21 min (ret time).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]#[N:11].[CH2:12]([NH2:14])[CH3:13].Cl>CO>[CH2:12]([NH:14][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]#[N:11])[CH3:13]
Reactant: CCN
Reactant: Cc1cc(Cl)c(C#N)c(=O)[nH]1
Agent: Cl
Solvent: CO
Product: CCNc1cc(C)[nH]c(=O)c1C#N
Yield: 62.2 %

Procedure:
To a 10 ml microwave vial added 4-chloro-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (750 mg, 4.45 mmol) and methanol (1 mL) then added ethylamine (5.56 mL, 11.12 mmol). One drop on conc. HCl was added and the vial was capped and the reaction was microwaved to 120° C. for 1 hr. The reaction was cooled and the solid was filtered and washed with cold MeOH. Gave 4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (500 mg, 2.77 mmol, 62.2% yield)1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (br. s., 1H) 7.11 (br. s., 1H) 5.78 (br. s., 1H) 3.22-3.32 (m, 2H) 2.11 (s, 3H) 1.10 (t, J=7.07 Hz, 3H)_MS(ES) [M+H]+ 177.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][OH:11])[C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CC(C)=O>[CH2:20]([O:12][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCc1cc(F)cc(F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OCCc1cc(F)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a solution of 2,4-difluoro-6-(2-hydroxyethyl)phenol (450 mg, 2.58 mmol) in Acetone (10 mL) was added K2CO3 (714 mg, 5.17 mmol) followed by (bromomethyl)benzene (0.461 mL, 3.88 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford 2-(2-(benzyloxy)-3,5-difluorophenyl)ethanol (540 mg, 2.043 mmol, 79% yield) as viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.48-7.36 (m, 5H), 6.84-6.72 (m, 2H), 5.07 (s, 2H), 3.78 (q, J=6.3 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H), 1.53 (t, J=5.5 Hz, 1H).