Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])C1C=CC=CC=1.CO.C(O)C>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:21]=[CH:20][C:19]([S:16]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 100 %

Procedure:
tert-Butyl 4-(trifluoromethyl)phenylsulfonylcarbamate was prepared by a method analogous to the method disclosed in Tet. Lett. 2004, 45, 8483-8487. tert-Butyl benzyl(4-(trifluoromethyl)phenylsulfonyl)carbamate (Intermediate 86, 520 mg) was hydrogenated (1 atm H2) over 20 wt % Pd(OH)2 (52 mg) in 1:1:1 methanol:ethanol:ethyl acetate (8 ml) for 16 hours. The reaction was filtered over celite and concentrated to yield the title compound (407 mg). MS M−H 324.3
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N+:3]=1[O-].[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][NH:18]2.C(=O)([O-])[O-:24].[K+].[K+].CN(C)C=O>[Cl-].[Na+].O>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N+:18]2([O-:24])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Reactant: O=C([O-])[O-]
Reactant: Clc1cccc2[nH]ncc12
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [O-][N+]1(c2ccc(C(F)(F)F)cn2)N=Cc2c(Cl)cccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine N-Oxide (1.8 g, 0.009 mol), 4-chloroindazole (1.1 g, 0.007 mol), anhydrous potassium carbonate (1.5 g, 0.0105 mol) and dimethylformamide (20 ml) was stirred and warmed to 70° C. Within 1 hour the reaction was complete based on thin-layer chromatographic analysis. The solution was poured into brine (300 ml) and the precipitate was collected by suction filtration and was washed with water until the filtrate was clear. The brick-red solid was air dried to yield 1.6 g (73%) of the desired product, m.p. 154° C. (dec).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:22][O:23][C:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])([CH3:26])[CH3:25])[C:12]([NH:14][CH:15]2[CH:18]([C:19]#[N:20])[NH:17][C:16]2=[O:21])=[O:13])[N:10]=1)=[O:4].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:19]([C@H:18]1[NH:17][C:16](=[O:21])[C@H:15]1[NH:14][C:12](=[O:13])[C:11]([C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])[S:7][CH:8]=1)=[N:22][O:23][C:24]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([CH3:26])[CH3:25])(=[O:40])[NH2:20]
Reactant: CC(C)(ON=C(C(=O)NC1C(=O)NC1C#N)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C(N)=O)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 2 ml of dimethyl sulfoxide is dissolved 0.38 g of (3S,4S)-b 3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-4-cyano-2-azetidinone and, following addition of 0.1 ml of 30% aqueous hydrogen peroxide and 0.1 ml of 1N sodium hydroxide, the mixture is stirred at approx. 25° C. for 30 minutes. The reaction mixture is chromatographed on an XAD-II column (eluant: 30% ethanol) to give 0.12 g of (3S,4S)-4-carbamoyl-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-2-azetidinone.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:5](=[O:32])[NH:6][C@@H:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=[O:9].CO>O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:1][CH2:2][CH2:3][N:4]([CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:5](=[O:32])[NH:6][C@@H:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)=[O:9]
Reactant: CN1CCN(C(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)N(CCO)CCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NC(=O)N(CCO)CCc2ccccc2)CC1
Reaction time: 72 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, 20% palladium hydroxide on carbon (200 mg) is added to a solution of 1-[(2S)-2-[3-(2-hydroxyethyl)-3-phenethylureido]-3-[4-(benzyloxy)phenyl]propionyl]-4-methylpiperazine (Compound No. 18-40, 1.09 g) in tetrahydrofuran (2 ml)-methanol (2 ml). The mixture is stirred under a hydrogen atmosphere for three days. Palladium hydroxide on carbon is filtered out with Celite, and the filtrate is concentrated under reduced pressure to give 685 mg (75%) of the titled compound (Compound No. 23-1) as noncrystalline powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:19][C:2]2[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]3=[N:10][CH:11]=[CH:12][C:3]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Product: CSc1nc(NC2CCCCC2)c2ccnc-2[nH]1

Procedure:
To 100 mg of 4-chloro-2-methylthiopyrrolo[2,3-d]-pyrimidine was added 2 ml of cyclohexylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of EtOH up to 40% EtOH. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from EtOH/H2O to afford white crystals of product, yield 67 mg (51%), m.p. 189°-190°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1([CH2:18][CH3:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[ClH:20].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3([CH2:18][CH3:19])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCC1(CCCCCCBr)C(=O)Nc2ccccc21
Product: CCC1(CCCCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H starting from 3-(6-bromohexyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)-piperazine and the reaction mixture is processed according to method 2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C=O)C.O.CC(OC)(C)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:12]([C:13](=[O:15])[CH3:14])[CH2:25][CH:24]=[CH2:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc(NC(C)=O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(C)=O)c1cc(C(=O)OCC)cc(Cl)n1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 6.0 g (25 mmol) 2-acetylamino-6-chloro-isonicotinic acid ethyl ester, 10.36 g (75 mmol) potassium carbonate and 4.23 ml (50 mmol) allyl bromide in 25 ml DMF is stirred at 60° C. for 24 h. The cooled mixture is diluted with water and TBME. The organic phase is washed with water, dried over Na2SO4 and evaporated. The product is purified by chromatography on silica gel (hexane/EtOAc 9/1) to yield the title compound as a yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1([CH3:22])[CH:17]=[C:16](B(O)O)[NH:15][C:14](=[O:21])[O:13]1>O>[CH3:11][C:12]1([CH3:22])[O:13][C:14](=[O:21])[NH:15][C:16]2[CH:3]=[CH:2][C:7]([C:2]3[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=3)=[CH:6][C:17]1=2
Reactant: N#CCc1cccc(Br)c1
Reactant: CC1(C)C=C(B(O)O)NC(=O)O1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)c3)cc21

Procedure:
Prepared from 3-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-oxazin-6-yl)boronic acid. White solid: mp 188-190° C.; 1H-NMR (DMSO-d6) δ10.33 (s, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.48 (d, 1H, J=8.00 Hz), 7.33 (d, 1H, J=7.57 Hz), 6.99 (d, 1H, J=8.81 Hz), 4.09 (s, 2H), 1.67 (s, 6H); MS m/z 291(M−H). Anal. Calc. For C18H16N2O2.0.3 H2O: C, 72.61; H, 5.62; N, 9.41. Found: C, 73.00; H, 5.43; N, 8.81
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:24])[CH2:4][CH2:3]1.[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.[C:38]([BH3-])#N.[Na+]>>[CH2:23]([S:20]([C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:24])[N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:36][C:34]4[CH:33]=[CH:32][C:29]5[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=5[N:35]=4)[CH2:3][CH2:4]3)[C:15]=2[CH:16]=1)(=[O:22])=[O:21])[CH3:38]
Reactant: [BH3-]C#N
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: CS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [Na+]
Product: CCS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Yield: 19 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 103), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 19% yield.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: CC[C@@H]1C(=O)Nc2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (0.21 g, 0.64 mmol) in acetone (5 mL) was added potassium carbonate (0.12 g, 0.87 mmol) followed by iodomethane (0.20 mL, 0.46 g, 3.2 mmol). The reaction vessel was flushed with nitrogen and sealed. The mixture was stirred at room temperature for 16 h, after which time additional iodomethane (0.20 mL, 0.46 g, 3.2 mmol) and potassium carbonate (0.11 g, 0.80 mmol) were added. Stirring was continued at 40° C. for an additional 20 h. The solvent was then evaporated, and the resulting residue was partitioned between water and ethyl acetate, separated, washed with water and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (quantitative) as an oil that was used without further purification. MS (ESI) m/z 343 ([M+H]+); HRMS: calcd for C19H19FN2O3, 342.13804; found (ESI+), 343.14463.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:4]=1[C:5]#[N:6].C(N(CC)CC)C.[C:34](Cl)(=[O:37])[O:35][CH3:36]>C(Cl)Cl>[CH3:36][O:35][C:34]([N:22]1[CH2:23][CH2:24][C@H:20]([O:19][C:18]2[C:13]3[CH2:12][N:11]([C:8]4[CH:9]=[N:10][C:3]([O:2][CH3:1])=[C:4]([C:5]#[N:6])[CH:7]=4)[CH2:26][CH2:25][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:21]1)=[O:37]
Reactant: COC(=O)Cl
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](Oc2ncnc3c2CN(c2cnc(OC)c(C#N)c2)CC3)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
To a solution of 2-methoxy-5-[4-((S)-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]py rimidin-6-yl]-nicotinonitrile (prepared using intermediate 11 and method 1b, process step 2, example 1) (25.0 mg, 0.071 mmol) and triethylamine (0.04 mL, 0.29 mmol) in CH2Cl2 (2 mL) was added methyl carbonochloridate (0.006 mL, 0.078 mmol) and the mixture stirred at room temperature for 18 h. Diluted with CH2Cl2 (2 mL) and washed with sat. NaHCO3(aq) (1 mL). The organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification was performed by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo gave (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid methyl ester (10 mg, 35% yield) as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.09-2.31 (m, 2H) 2.91 (t, 2H) 3.45-3.75 (m, 9H) 3.93 (s, 3H) 4.17 (s, 2H) 5.58-5.65 (m, 1H) 8.09 (d, 1H) 8.27 (d, 1H) 8.61 (s, 1H) LCMS: [M+H]+=411.1, Rt(1)=1.58 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:14]N.[N:16]1C=CC=[CH:18][CH:17]=1>>[CH3:18][C:17]1[N:7]2[CH:6]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:4]=[CH:3][C:2]2=[N:14][N:16]=1
Reactant: c1ccncc1
Reactant: Clc1ccc(-c2cccnc2)cn1
Reactant: NN
Product: Cc1nnc2ccc(-c3cccnc3)cn12
Temperature: 110 °C

Procedure:
A 90 mg portion of 6-chloro-3,3'-bipyridine and 0.15 ml of anhydrous hydrazine were dissolved in 20 ml of pyridine and heated at 110° C. for 48 hours. The volatiles were removed at reduced pressure and the residue dissolved in 20 ml of triethyl orthoacetate and heated at 110° C. for 12 hours. The volatiles were removed at reduced pressure and the residue purified by chromatography on silica gel, eluting with ethyl acetate:methanol (9:2). The obtained tan solid was recrystallized from ethyl acetate-methanol, giving the desired product as off-white flakes, mp 199°-201.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13]N3C=CN=N3)[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[N:20]1[CH:25]=[CH:24][C:23](=[O:26])[CH2:22][CH2:21]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C[O:40]CC1>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:40])[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[N:20]1[CH:25]=[CH:24][C:23](=[O:26])[CH2:22][CH2:21]1
Reactant: O=C1C=CN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1C=CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of the product of step 1 above (1 g, 2.9 mmol, 1 equiv) in THF anhydrous (15 mL) is cooled down to −78° C. and lithium bis(trimethylsilyl)amide 1.0 M in THF (3.2 mL, 3.2 mmol, 1.1 equiv) is added dropwise. The reaction mixture is stired at −78° C. for 1 h. (R)-(−)-Glycidal butyrate (466 mg, 0.46 mL, 3.2 mmol, 1.1 equiv) is added dropwise and the reaction mixture is allowed to gradually warm to room temperature and is left to stir over weekend. The mixture is quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The washed organics with brine are dried over (MgSO4) and concentrated. The product is purified by flash chromatography on silica gel using 1–3% MeOH in DCM as eluant to give the title compound as a solid (380 mg, 1.24 mmol, 42.8%). HPLC Rt=4.36, MS=(M+H)+=307.
Reaction SMILES: C[C:2]([O:15][CH3:16])([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].O.O.[OH-].[Li+]>CO.O1CCCC1>[CH3:16][O:15][CH:2]([C:6]([CH3:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: COC(C)(C(=O)O)C(C)(C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(C(=O)O)C(C)(C)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
According to General Procedure II, methyl 2-methoxy-3-methyl-3-phenylbutanoic acid (0.49 g, 2.2 mmol, from Reference Example 38) is dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). To this solution is added water (5 mL) and lithium hydroxide monohydrate (0.18 g, 4.4 mmol), and the resulting mixture is stirred at 60° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 10% aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a light orange oil, which solidified to a straw colored crystalline solid (0.46 g, 100%). MS (ES−): (M−H)=207.0
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.ClC(OCC)=O.Cl.[CH3:26][NH:27][OH:28]>ClCCl.C(N(CC)CC)C>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([N:27]([OH:28])[CH3:26])=[O:18])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CNO
Reactant: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)N(C)O)cc1
Reaction time: 16 h

Procedure:
A solution of 12.05 g of (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-2-propenoic acid in 350 ml of dichloromethane and 9.7 ml triethylamine, is cooled in an ice bath. To this stirred solution is added 7.0 ml of ethyl chloroformate dropwise. After four hours at ice-bath temperature, 20.7 ml of triethylamine is added, followed by 12.6 g of N-methylhydroxylamine hydrochloride and the mixture is kept at room temperature for 16 hours. This mixture is washed with cold 0.3 N aqueous hydrochloric acid, ice cold sodium bicarbonate and brine. The organic phase is dried over MgSO4, treated with charcoal and filtered. The solvent is evaporated at 50° under reduced pressure and the product is crystallized from ether to give (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-hydroxy-N-methyl-2-propenamide, m.p. 143°-145°, the compound of formula IV wherein R1 and R2 represent methyl at the 2 and 5 positions, R4 represents methyl, and R3, R8 and R9 represent hydrogen; the compound may also be named (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-methyl-2-propenohydroxamic acid. The product can also be recrystallized from ethyl acetate (with charcoal and silica gel).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:30](=O)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(Cc5csc(C(C)C)n5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C
Yield: 24 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-isopropylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.066 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), p-anisaldehyde (0.023 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.019 g, 24%); 1H-NMR (500 Mz, DMSO-d6): δ 1.33 (d, J=7.0 Hz, 6H, iPr—CH3), 2.68 (m, 4H, piperazine N(CH2)2), 3.22-3.34 (m, 1H), 3.62-3.70 (m, 6H, piperazine N(CH2)2 and NCH2), 3.84 (s, 3H, OMe), 7.10 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 7.35 (s, 1H, thiazole 5-H), 8.14 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.33 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.71 min—527/529 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 527.1232, calculated for C24H28BrN6OS (M+H)+: 527.1229.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([O-:15])=[O:14]>>[Cl:1][C:2]1[C:3]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccccc1O
Product: O=[N+]([O-])c1ccccc1Oc1ncc(C(F)(F)F)cc1Cl
Yield: 63 %

Procedure:
This material was prepared in 63% yield from 3-chloro-2-fluoro-5-trifluoromethylpyridine and 2-nitrophenol following the general procedure outlined in Example 104. The product was isolated as an amber oil which was characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:37]=[CH:36][C:33](C=O)=[CH:32][CH:31]=1.[Cl-].[NH4+].C1C[O:45][CH2:44]C1>>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:44]([C:37]1[CH:36]=[CH:33][CH:32]=[CH:31][C:30]=1[O:29][C:28]([F:27])([F:38])[F:39])[OH:45])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: OC(c1ccccc1OCc1ccccc1)c1ccccc1OC(F)(F)F
Reaction time: 0.25 h
Yield: 77 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 8.7 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (3.3 g, 12.64 mmol) in THF (126 mL) at −78° C. and the mixture solution was stirred at the same temperature for 15 minutes. To this solution, a solution of 4-trifluoromethoxybenzaldehyde (2.0 g, 10.52 mmol) in THF (42 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for 40 minutes and at 0° C. for 45 minutes, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (3.03 g, 77%) as a colorless oil.