Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[N:1]1([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCN(C(=O)N2CCCc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)N2CCCc3ccccc32)CC1
Temperature: 50 °C
Yield: 93.1 %

Procedure:
11.2 g of ethyl 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperidine-4-carboxylate, 443 ml of ethanol and 163 ml of 1N aqueous sodium hydroxide solution are introduced into a 1 l round-bottomed flask. The reaction medium is heated at 50° C. for 4 h 30. The ethanol is evaporated under reduced pressure and a 1N aqueous hydrochloric acid solution is subsequently added. The precipitate is filtered off, washed with water and then dried under reduced pressure. 9.5 g of 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperidine-4-carboxylic acid are obtained.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15](Cl)[C:14]2[C:18](=[O:32])[N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[CH2:20][C:13]=2[C:12]=1[F:33].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15]([C:38]2[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=2)[C:14]2[C:18](=[O:32])[N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[CH2:20][C:13]=2[C:12]=1[F:33]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Temperature: 80 °C

Procedure:
A microwave vial was charged with 6-(cis-2-amino-3,3-difluorocyclohexylamino)-4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (13.7 mg, 0.028 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.82 mg, 0.042 mmol) and bis(triphenylphosphine)palladium chloride (3.97 mg, 5.65 μmol) and placed under an inert environment. DME (283 μL) was added to the mixture and the resulting yellow slurry was degassed for 5 min. Sodium carbonate was added (56.5 μL, 0.113 mmol) and the slurry degassed for an additional 3 min. The vessel was capped and the mixture was heated at 80° C. for 4 h, cooled to ambient temperature, diluted with EtOAc (5 mL), and washed with water (3 mL) and brine (3 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to give the title compound as a dark brown residue which was used in the next step without further purification (21 mg). [M+H] calc'd for C26H29F3N6O3, 531. found, 531.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11](=[O:13])[CH3:12].[OH-].[Na+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[NH2:1])(=[O:13])[CH:12]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1oc2ccccc2c1N
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(C(=O)C=Cc2ccccc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of 1A (114 mmol) in MeOH (200 mL) was added NaOH (18.2 g, 445 mmol). The reaction was exothermic. After cooled to room temperature, benzaldehyde (14.5 g, 137 mmol) was added. The mixture was stirred overnight under N2. TLC monitored the reaction. After the reaction completed, the reaction mixture was poured into ice-water under stirring. The solids precipitated out and were collected by filtration, and dried to give 1B (26 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]=2[CH3:22])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]([CH3:22])=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: CCCn1c(C)c(-c2ccc(OC)cc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(-c2ccc(OC)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with the procedure of Example 10, the above compound was prepared from 3-(4-methoxy-phenyl)-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([OH:18])=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:25][NH2:26]>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([NH:26][CH3:25])=[O:18])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)O)(CC1)CC2
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Carboxylic acid 10-4 (810 mg, 2.96 mmol) was dissolved in 12 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 4.4 mL, 8.8 mmol) and subsequently with 5 drops of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 mnin. The acid chloride was dissolved in anhydrous methylene chloride (12 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 8.9 mL, 17.8 mmol). Upon addition of the amine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 200 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to chromatography on silica gel eluting with a gradient from 0 to 3.5% methanol in methylene chloride to give 4-[2-(ethylsulfonyl)ethyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide 10-5 as a white powder. MS (ESI+)=288 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15](O)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:19]>>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([Cl:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Product: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Yield: 99.5 %

Procedure:
A mixture of 26.2 g (106 mmol) of (4-benzylpiperidin-1-yl)oxoacetic acid and 50 ml of thinyl chloride is refluxed for 2 h, then cooled and concentrated to yield 28.0 g (99.5%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH2:25]O)[CH:20]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH2:25][N:31]4[C:27](=[O:37])[C:28]5[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:30]4=[O:32])[CH:20]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cc(CCO)no1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cc(CCN2C(=O)c3ccccc3C2=O)no1
Reaction time: 0.58 h
Yield: 123.4 %

Procedure:
To a solution of 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)isoxazol-3-yl)ethanol (S5, 5.3 mg), phthalimide (10.9 mg) and triphenylphosphine (19.4 mg) in tetrahydrofuran (1 mL), a 1.9 mol/L solution of diisopropyl azodicarboxylate in toluene (39 μL) was added under ice cooling, and the mixture was stirred at the same temperature for 35 minutes, and then stirred at room temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 84 to 35% hexane in ethyl acetate) to obtain 2-(2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)isoxazol-3-yl)ethyl)isoindoline-1,3-dione (S6, 8.9 mg) as white solid.
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[OH-].[K+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)C>[I-:1].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:9][CH:4]2[N:5]([CH3:8])[CH:6]=[CH:7][NH+:3]2[CH3:2])=[CH:16][CH:15]=1
Reactant: CC1N(C)C=C[NH+]1C
Reactant: COc1ccc(C=O)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=CC2N(C)C=C[NH+]2C)cc1

Procedure:
A mixture of 10 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2.0 g of potassium hydroxide and 10 ml of 4-methoxybenzaldehyde is refluxed in 50 ml of absolute ethanol for 15 minutes during which time a precipitate is formed. The reaction mixture is cooled and the solid is filtered off. Crystallization from absolute ethanol yields 9.1 g of the title compound, melting point 289°-291° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Yield: 41.1 %

Procedure:
2,5-dihydroxyacetophenone (5.00 g, 0.0329 mol), benzyl bromide (3.72 ml, 0.031 mol), potassium carbonate (4.31 g, 0.031 mol) and acetone (150 ml) were added to a 500 ml round bottom flask. The reaction mixture was heated overnight at reflux and then was cooled to ambient temperature. When cool, deionized water (150 ml) was added to the reaction mixture and the reaction mixture was extracted three times with 100 ml portions of diethyl ether. The combined ether layers were dried with sodium sulfate and concentrated in vacuo yielding a dark solid. This dark solid was recrystallized from 50:50 (ethanol:water) yielding 3.09 g of 2-hydroxy-5-benzyloxyacetophenone as yellow needles.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: Cc1nc2ccccc2s1
Reactant: O=S(=O)(O)Cl
Product: Cc1nc2c(S(=O)(=O)Cl)cccc2s1

Procedure:
2-Methylbenzothiazole (50 g) was added in a slow, dropwise manner to 86 mL of chlorosulfonic acid at room temperature. When the addition was complete, the dark reaction mixture was heated at 140°-145° C. for about 3 hours. The solution was allowed to cool and was slowly added to a large excess of ice. Insoluble solids were removed by filtration and the aqueous layer was extracted with benzene. Drying and evaporation of the solvent gave an off-white solid which was shown by 1H NMR analysis to consist of a mixture of sulfonyl chlorides, presumably the 4-, 6-, and 7-isomers. This crude material was recrystallized three times from hexane to remove the 6-isomer as a white solid, m.p. 100°-102° C. The combined mother liquors were concentrated to give a dark yellow oil which was carried on to the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[C:9]1([CH2:15][S:16][CH:17]([C:21](O)=[O:22])[C:18](O)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[OH:22][C:21]1[CH:2]=[C:1]([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)[O:3][C:18](=[O:19])[C:17]=1[S:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccsc1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Product: O=c1oc(-c2ccsc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared from the condensation of the trimethylsilyl enol ether of 3-acetylthiophene and the diethyl ester of [(phenylmethyl)thio]propanedioic acid following the same procedure outlined in Method A; m.p. 150-151° C. NMR (DMSO-d6) δ3.98 (s, 2 H), 6.58 (s, 1 H), 7.20 (m, 5 H), 7.48 (m, 1 H), 7.72 (m, 1 H), 8.13 (d, 1 H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[N:29]=[CH:30][N:31]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[CH:32]=4)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[N:29]=[CH:30][N:31]([CH2:33][CH:34]5[CH2:35][CH2:36]5)[CH:32]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cn(CC4CC4)cn3)nc12)C(=O)N1CCC(C#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](NC(=O)c1c[nH]c2ncc(-c3cn(CC4CC4)cn3)nc12)C(=O)N1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
To a solution of 2-(1-cyclopropylmethyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (160 mg, 0.26 mmol) in CH2Cl2 (2.25 mL) was added trifluoroacetic acid (0.75 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated. The residue was dissolved in a mixture of ammonium hydroxide, MeOH and CH2Cl2 (1:10:60, 3.0 mL) and stirred at room temperature for 30 min. The reaction mixture was then concentrated and the residue purified twice by SiO2 chromatography (0-5% MeOH/EtOAc then 0-10% MeOH/CH2Cl2) to afford 27 mg (21%) of 2-(1-cyclopropylmethyl-1H-imidazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a white powder. MS: (M+H)+=489.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:3][CH2:2]1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH2:19][CH:18]([O:21][CH2:24][C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:2][CH2:3]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: OC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(COC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1)N1CCOCC1
Reaction time: 1 h

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-5-ol (3.44 g) and 4-(chloroacetyl)morpholine (2.95 mL) in THF (30 mL) was added potassium tert-butoxide (2.55 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (4.36 g).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Li]CCCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[CH3:1][C:2]1([C:8]2[CH:13]=[C:12]([B:26]([OH:27])[OH:25])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1C1(C)CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1C1(C)CCCCC1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a mixture of 2-(1-methylcyclohexyl)-4-bromoanisole (13.66 g, 0.0482 mol) in THF (121 mL) cooled to −75° C. under an atmosphere of argon was added n-BuLi (33.2 mL, 1.6 M, 0.053 mol) dropwise maintaining a temperature below −70° C. The resulting suspension was stirred for 30 minutes and triisopropylborate (34.2 mL, 27.87 g, 0.148 mol) was added dropwise. The mixture was allowed to warm to RT overnight. The resulting mixture was cooled to 0° C. and 1.0 N HCl (150 mL) was slowly added. After warming to RT the mixture was diluted with ether and the layers separated, the aqueous layer was extracted ether (3×) and the organic layers combined. The resulting organic layer was washed with water, brine and dried (Mg2SO4). The mixture was filtered, evaporated and the resulting yellow oil was purified on silica gel (eluent: CH2Cl2:MeOH, 100 to 92:2) to afford 3-(1-methylcyclohexyl)-4-methoxyphenyl boronic acid (7.72 g, 64%) as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 120 (s, 3H), 1.40–1.85 (m, 8H), 2.00–2.10 (m, 2H), 3.75 (s, 3H), 6.90 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.66 (brs, 1H), 7.81 (s, 2H).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH3:18].[CH2:19]1[O:21][CH2:20]1.B(F)(F)F.CCOCC>C1COCC1>[CH3:18][C:14]1[S:15][CH:16]=[CH:17][C:13]=1[CH2:19][CH2:20][OH:21]
Reactant: C1CO1
Reactant: Cc1sccc1Br
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1sccc1CCO
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1.6M BuLi in hexane (98.4 mL, 157.5 mmol) and THF (150 mL) was added at −78° C. a solution of 3-bromo-2-methyl-thiophene (CAS 30319-05-2, 26.6 g, 150 mmol) in THF (50 mL) and stirring at −78° C. was continued for 1 h. 2.0M ethylene oxide in THF (112.5 mL, 225 mmol) and then BF3-Et2O (20.4 mL, 165 mmol) was added dropwise at −70° C. and the yellow solution was stirred at −78° C. for 1 h. After warming to 0° C. the reaction mixture was quenched with 10% brine (400 mL) and extracted with ethyl acetate (400+200 mL). The organic layers were washed with 10% brine, dried (Na2SO4) and evaporated affording 18.6 g crude product as a yellow oil. Purification by chromatography over silica with hexane-ethyl acetate 5:1 gave 14.9 g (70%, GC 94.7%) yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:27]([CH3:28])=[CH:26][C:8]([C:9]([NH:11][NH:12][C:13](=O)[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])=[N:16][CH:15]=2)=[O:10])=[CH:7][C:6]=1[CH3:29])[CH:2]=[CH2:3].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CC(=O)OCC>[CH2:1]([O:4][C:5]1[C:27]([CH3:28])=[CH:26][C:8]([C:9]2[O:10][C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:23])[CH3:24])=[N:16][CH:15]=3)=[N:12][N:11]=2)=[CH:7][C:6]=1[CH3:29])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C)cc(C(=O)NNC(=O)c2cnc(CC(C)C)c(C)c2)cc1C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOc1c(C)cc(-c2nnc(-c3cnc(CC(C)C)c(C)c3)o2)cc1C
Yield: 94.6 %

Procedure:
A solution of 6-isobutyl-5-methyl-nicotinic acid N′-(4-allyloxy-3,5-dimethyl-benzoyl)-hydrazide (89 mg, 0.224 mmol) and Burgess reagent (162 mg, 0.68 mmol) in THF (4 mL) is heated in a microwave oven at 110° C. for 6 min. The mixture is diluted with EA (15 mL) and washed with 1M aq. NaH2PO4 (5 mL), 1M aq. NaOH (5 mL) and water (5 mL). The org. phase is dried (MgSO4), filtered and evaporated to provide crude 5-[5-(4-allyloxy-3,5-dimethyl-phenyl)-[1,3,4]oxadiazol-2-yl]-2-isobutyl-3-methyl-pyridine (80 mg); LC-MS: tR=1.07 min, [M+1]+=378.3.
Reaction SMILES: B.C1COCC1.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([CH:16]2[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)=O)[CH:8]=1>C1COCC1>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][CH2:14][CH:16]2[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(=O)Nc2cccnc2)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCNC(CNc2cccnc2)C1
Temperature: 25 °C

Procedure:
Borane-THF complex (1.0 M solution in THF, 3.4 mL, 3.4 mmol) was added to a solution of tert-butyl 3-(pyridin-3-ylcarbamoyl)piperazine-1-carboxylate (522 mg, 1.70 mmol) in THF (4 mL). The reaction mixture was heated to reflux for 5 h. Upon cooling to rt, the reaction mixture was carefully quenched by the dropwise addition of MeOH. After gas evolution ceased, MeOH (10 mL) was added, and the reaction mixture was heated to reflux overnight. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure, yielding the title compound which was used without further purification. LC-MS: RT=2.90 min, [M+H]+=293.1.
Reaction SMILES: [Cl-].[Li+].[CH:3]([O-:5])=[O:4].[Li+].[F:7][C:8]1[CH:13]=[N:12][C:11]2[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=[C:16](I)[C:10]=2[C:9]=1[CH:28]=[O:29].C(OC(=O)C)(=O)C.C(N(C(C)C)C(C)C)C>CO.C(Cl)Cl.C(O[Pd]OC(=O)C)(=O)C.CN(C=O)C>[F:7][C:8]1[C:9]([CH:28]=[O:29])=[C:10]2[C:16]([C:3]([OH:5])=[O:4])=[CH:15][N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]2=[N:12][CH:13]=1
Reactant: O=C[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(C=O)c(F)cnc32)cc1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(C=O)c(F)cnc32)cc1
Temperature: 56 °C
Yield: 85.5 %

Procedure:
Lithium chloride (0.472 g, 11.14 mmol) and lithium formate (0.579 g, 11.14 mmol) were combined in a sealable dried tube. DMF (10 mL), 5-fluoro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (1.650 g, 3.71 mmol), acetic anhydride (0.702 mL, 7.43 mmol) and diacetoxypalladium (0.083 g, 0.371 mmol) were added. N-Ethyl-N-isopropylpropan-2-amine (1.294 mL, 7.43 mmol) was added and the mixture was sealed and heated at 56° C. for 3 h. The reaction mixture was taken up in MeOH/DCM (20%) and filtered. The yellow solution was concentrated and the residue was dissolved in MeOH/DCM (10%) and washed with aqueous HCl (0.1N). The aqueous phase was extracted two more times. The organics were combined, dried over MgSO4 and concentrated to an orange oil, which was triturated in ether (300 mL). The precipitate was filtered and dried in vacuo to afford the title compound as light yellow solid (1.15 g, 77%). 1H NMR (400 MHz, DMSO-d6) δ 2.37 (s, 3H) 7.47 (d, J=8.08 Hz, 2H) 8.10 (d, J=8.10 Hz, 2H) 8.54-8.65 (m, 2H) 10.60 (s, 1H) 13.45 (br. s., 1H). [M+H] calc'd for C15H10FIN2O3S, 363; found, 363.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([N:17]([CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)NCCNC(C)C
Product: CC(C)NCCN(C(C)C)S(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Following the procedure of Example 1, m-nitrobenzenesulfonyl chloride was reacted with N,N'-diisopropyl ethylene diamine to give N-(1-methylethyl)-N-[2-[(1-methylethyl)amino]ethyl]-3-nitrobenzene sulfonamide.