Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][C:14]2=O>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[C:14](=[O:15])[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([F:10])[CH:12]=3)[C:16]2=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: Cc1c(N)cccc1Br
Solvent: CC(=O)O
Product: Cc1c(Br)cccc1N1C(=O)c2ccc(F)cc2C1=O
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A mixture of 3-bromo-2-methylaniline (200 mg, 1.075 mmol) and 5-fluoroisobenzofuran-1,3-dione (179 mg, 1.075 mmol) in acetic acid (2 mL) was heated at 100° C. for 4.5 h. The mixture was concentrated and the residue was purified by column chromatography (eluting with a gradient from hexane to 60:40 hexane-EtOAc) to give 2-(3-bromo-2-methylphenyl)-5-fluoroisoindoline-1,3-dione as a white solid (235 mg, 59%). Mass spectrum m/z 334, 336 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:7]=1)/[CH:2]=[CH:3]/[CH3:4].C(N(CC)CC)C.[C:29](Cl)(=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:31]([O:30][C:29]([N:19]1[CH2:20][CH2:21][N:16]([C:8]2[N:7]=[C:6]([O:5][CH2:1]/[CH:2]=[CH:3]/[CH3:4])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:17][CH2:18]1)=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C/C=C/COc1nc(N2CCNCC2)nc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C/COc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12

Procedure:
To a solution of 4-[trans-(2-buten-1-yl)oxy]-2-(1-piperazinyl) quinazoline (1.20 g) in dry methylene chloride (12 ml) is added triethylamine (1.77 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (0.73 ml) in dry methylene chloride (5 ml). The mixture is stirred under ice-cooling for 3 hours. The reaction mixture is diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (elutant, chloroform) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[trans-(2-buten-1-yl)oxy]quinazoline (1.57 g) as crystals.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>C(N(CC)CC)C.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>[CH3:9][C:4]1[N:3]=[C:2]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: Cc1ccc(N)c(Br)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#C[Si](C)(C)C)n1
Yield: 37.6 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (800 mg, 4.28 mmol) reacted with (PPh3)2PdCl2 (150 mg, 0.21 mmol), Cul (41 mg, 0.21 mmol) and ethynyltrimethylsilane (840 mg, 8.55 mmol) in triethylamine (30 ml). The crude residue was purified by flash chromatography (hexane/ethyl acetate 8:2) to yield 330 mg (1.61 mmol, 38%) of (6-methyl-2-trimethylsilanylethynyl-pyridin-3-yl)amine as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:9])[C:6]=1[CH2:7]O.[Br-:10].[C:11]1([PH+:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(#N)C>C(OCC)C>[Br-:10].[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:9])[C:6]=1[CH2:7][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1csc(C)c1CO
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1csc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4.4 G of 2,4-dimethyl-3-hydroxymethylthiophene and 10.7 g. of triphenylphosphonium bromide was dissolved in 40 ml. of acetonitrile and stirred at 40° C. for 1 hour. The resulting solution was cooled and 150 ml. of ethyl ether was added. The white precipitate which formed was filtered and washed with cold acetone to yield (2,4-dimethyl-3-thenyl)triphenylphosphonium bromide, m.p. 262°-265° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([CH2:15][CH3:16])[C:11]([O:13]C)=[O:12])=[CH:5][C:4]=1[C:17](=[O:36])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)=[CH:22][CH:21]=1.[OH-].[Li+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([CH2:15][CH3:16])[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:17](=[O:36])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=2)=[CH:22][CH:21]=1
Reactant: CC[C@@H](Cc1ccc(OC)c(C(=O)NCc2ccc(Oc3cc(F)c(F)c(F)c3)cc2)c1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC[C@@H](Cc1ccc(OC)c(C(=O)NCc2ccc(Oc3cc(F)c(F)c(F)c3)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a solution of compound (465 mg, 0.927 mmol) of Example 16 in methanol (9 mL) were added 1 mol/L aqueous solution of lithium hydroxide (2.04 mL) and water (3 mL), and the mixture was stirred for 4 hours at room temperature. The reaction mixture was allowed to stand statically for 2 days and then stirred for 18 hours at 50° C. Water was added to the reaction mixture, which was filtered. After the filtrate was cooled to 0° C., it was brought to pH 4 with 3 mol/L hydrochloric acid. The precipitated powder was collected by filtration, dried and submitted to silica gel column chromatography (hexane:ethyl acetate=10:1→2:1) to afford 289 mg of crude powder. This was purified by recrystallization (acetonitrile) to afford 183 mg of white powdery title compound. Yield 40%.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:27])[CH:18](OC(C)(C)C)N(C)C>CN(C=O)C>[Si:1]([O:8][CH2:9][CH2:10]/[C:11](=[CH:16]\[N:17]([CH3:27])[CH3:18])/[C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCO[Si](C)(C)C(C)(C)C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/N(C)C)CCO[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 87 %

Procedure:
A mixture of methyl 4-[tert-butyl(dimethyl)silyl]oxybutanoate (6.8 g, 29.31 mmol) and N,N,N′,N′-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine (5.1 g, 29.31 mmol) in DMF (14 mL) in sealed tube was heated to 100° C. overnight. Added water to the mixture at 0° C. and extracted with ethyl acetate twice. The organic phase was separated and washed with water (2×) and brine and dried with anhydrous Na2SO4. The organic phase was concentrated to give the title compound (7.33 g, 91%). [M+H] Calc'd for C14H29NO3Si, 288. Found, 288.
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O.[NH2:42][C@@H:43]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([CH:71]2[S:75](=[O:77])(=[O:76])[NH:74][C:73](=[O:78])[CH2:72]2)=[C:67]([F:79])[CH:66]=1)[C:44]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=1[C:55]([O:57][CH3:58])=[O:56])=[O:45].C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]([F:7])([CH3:6])[C:3]([NH:42][C@@H:43]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([CH:71]2[S:75](=[O:76])(=[O:77])[NH:74][C:73](=[O:78])[CH2:72]2)=[C:67]([F:79])[CH:66]=1)[C:44]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=1[C:55]([O:57][CH3:58])=[O:56])=[O:45])=[O:4]
Reactant: CC(F)(F)C(=O)O
Reactant: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)NC(=O)C(C)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
2,2-Difluoropropanoic acid (2.31 mg, 0.0210 mmol) in DMF (1.00 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (9.97 mg, 0.0225 mmol). The solution was stirred at ambient temperature for 5 minutes. Methyl 2-[5-((2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-fluorophenyl]-propanoylamino)pentyl]oxy-6-hydroxybenzoate trifluoroacetate (10.0 mg, 0.0150 mmol) in DMF (1.00 mL) was added followed by N,N-diisopropylethylamine (13.1 μL, 0.0751 mmol). The solution stirred at rt for 2 h. The product was directly purified by preparative LCMS to afford product as a white solid (7.1 mg, 73%). LCMS found for C28H33F3N3O9S (M+H)+: m/z=644.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[CH2:16]([NH2:18])[CH3:17].Cl>C(O)C>[CH2:16]([NH:18][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1)[CH3:17]
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: CCN
Agent: Cl
Solvent: CCO
Product: CCNc1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 2.26 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 30 ml of ethanol, 4.05 ml of 70%-ethylamine aqueous solution was added, and the mixture was heated for 24 hours at 80°-90 ° C. in a sealed tube. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.66 g of the desired compound as pale yellow needles, m.p. 272°-273.5 ° C. (decomp.).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:5](=[O:7])[CH3:6])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCN)c1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCCC(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
At 0° C., acetic anhydride (0.59 g, 5.75 mmol) was added dropwise into a mixture of 3-(4-bromophenyl)butan-1-amine (0.57 g, 2.5 mmol), triethylamine (1.16 g, 11.5 mmol) and 4-dimethylamino-pyridine (1.0 mg, 0.008 mmol) in anhydrous dichloromethane (10 mL) the mixture was stirred at room temperature for 1.5 hours, water (20 mL) was added and extracted with dichloromethane (10 mL×3), combined and concentrated the organic layers, the residue was purified by column chromatography (silica gel, dichloromethane/Methanol=50:1) to give N-(3-(4-bromophenyl)butyl)acetamide (0.66 g, 94.4%). LRMS (M+H+) m/z: calcd for 270.17. found 270.1.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)=[O:7]>C(O)C.[Pd]>[F:29][C:2]([F:1])([F:28])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(NCC(=O)N1CCN(C(=O)OCCC(F)(F)F)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCC(=O)N1CCN(C(=O)OCCC(F)(F)F)CC1
Reaction time: 12 h

Procedure:
To a solution of 1.63 g 4-(2-Benzyloxycarbonylamino-acetyl)-piperazine-1-carboxylic acid 3,3,3-trifluoro-propyl ester in 40 ml ethanol were added 200 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethanol and concentrated. Yield: 1.02 g colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C@H:12]1[CH2:14][O:13]1)[CH2:6][CH2:5]2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([CH2:15][N:22]=[CH:14][C@H:12]([C@@H:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[O:8]2)[OH:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc2c(c1)CC[C@@H]([C@H]1CO1)O2
Solvent: CO
Product: O[C@H](C=NCc1ccccc1)[C@@H]1CCc2cc(F)ccc2O1
Yield: 65.1 %

Procedure:
(S)-6-fluoro-3,4-dihydro-2-((R)-oxiran-2-yl)-2H-chromene (30 mg, 0.154 mmol) was dissolved in methanol (2 ml) and kept under stirring. benzylamine (40 mg, 0.374 mmol) was added and the reaction mixture left to stir. After checking the reaction outcome, the solution was concentrated under reduced pressure and the crude residue further dried at 30° C. in vacuo to furnish 30 mg of (R)-2-(phenylmethylimino)-1-((S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol as a white solid (64% yield).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N+:35]([O-])[CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40]([NH2:44])([CH3:43])([CH3:42])[CH3:41].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>FC(F)(F)C1C=CC=CC=1.CCOC(C)=O>[C:40]([NH:44][C:36]1[N:35]=[CH:34][C:33]([C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]2[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=3)[N:11]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:38][CH:37]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc[n+]([O-])c3)N2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc(NC(C)(C)C)nc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(1-oxidopyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (0.049 g, 0.087 mmol) in trifluorotoluene (2 mL) was cooled to 0° C. Tert-butylamine (0.046 mL, 0.44 mmol) was added, followed by p-toluenesulfonic anhydride (0.057 g, 0.18 mmol). After 1 hour, the reaction was diluted with EtOAc (50 mL) and washed with water (15 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography with 0-45% EtOAc/hexanes to afford 47 mg of impure tert-butyl (2R,5S)-2-[(R)-[6-(tert-butylamino)pyridin-3-yl]{[tert-butyl(dimethyl)silyl]oxy}methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate. LC-MS=6123 (M−H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1>CN1C(=O)CCC1>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:26]1[CH:27]=[CH:28][N:29]=[C:25]1[CH3:24])=[N:3][C:4]=2[NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Reactant: Cc1ncc[nH]1
Solvent: CN1CCCC1=O
Product: Cc1nccn1-c1nc(NCCc2ccc(O)cc2)c2ncn(C(C)C)c2n1
Temperature: 240 °C

Procedure:
A microwave reaction tube was charged with 4-(2-(2-chloro-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol (30 mg, 0.091 mmol), 2-methyl-1H-imidazole (59 mg, 0.73 mmol) and 0.5 ml of NMP. The sealed tube was heated under microwave irradiation at 240° C. for 2 hr. The reaction mixture was purified by reverse-phase HPLC(C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[F:34][C:30]1[CH:29]=[C:28](/[C:26](/[CH3:27])=[CH:25]\[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1cccc(F)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 40 mg as the TFA salt. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.22 (d, 1H), 7.18 (s, 1H), 7.10 (m, 2H), 6.85 (t, 1H), 6.70 (s, 1H), 6.62 (d, 2H), 4.65 (d, 1H), 4.05 (d, 1H), 3.50 (m, 1H), 3.15 (m, 1H), 2.80 (s, 3H), 2.60 (m, 1H), 2.42 (s, 3H), 2.38 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([N+:11]([O-:13])=[O:12])[C:4]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].S(N)(=O)(=O)[OH:21].C(O)(C)C.Cl([O-])=O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([OH:21])=[O:8])=[C:5]([N+:11]([O-:13])=[O:12])[C:4]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NS(=O)(=O)O
Reactant: CCCCCOc1c(OC)ccc(C=O)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCCCOc1c(OC)ccc(C(=O)O)c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
4-Methoxy-2-nitro-3-pentyloxybenzaldehyde (70 g, 261.9 mmol), amidosulfuric acid (76.3 g, 785.7 mmol) and isopropanol (210 ml) were mixed, an aqueous sodium chlorite (38.5 g, 340.5 mmol) solution (350 ml) was added dropwise to this solution while cooling in a water bath. After stirring for 20 minutes, ethyl acetate (300 ml) was added to separate the organic layer. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (150 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration to give 4-methoxy-2-nitro-3-pentyloxybenzoic acid (59.02 g, 80%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH2:1]([CH:8]1[CH2:10][N@@:9]1[S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@H]2CN2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)S(=O)(=O)[N@@]1CC1Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)[N@]1CC1Cc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a cooled (−10° C.) solution of (S)-2-benzylaziridine (100 g, 0.751 mol) and N,N-dimethylsulfamoyl chloride (84.5 mL, 0.787 mol) in dichloromethane (100 mL) was added N,N-diisopropylethylamine (131 mL, 0.751 mol). The resulting yellow solution was stirred at −10° C. for a minimum of 16 hours. After this period, a 0.5M solution of citric acid (500 mL) was added and the phases were separated. The organic phase was then washed with 1.0 M sodium bicarbonate solution (500 mL). The organic phase was then solvent exchanged into tent-butyl methyl ether (500 mL). The solution was then cooled to 0° C., and heptane (100 mL) was added dropwise over a period of 2 hours. The mixture was then aged for an additional 2 hours at 0° C., and then cooled (−10° C.), to allowed compound IIa to precipitate out as a white, crystalline solid (27.8 g, 77%). Tlc assay: Rf: 0.53 (SiO2; 1:1 heptane:ethyl acetate, KMnO4). 1H NMR (400 MHz, CDCl3): δ 7.20-7.29 (m, 5H), 2.94 (dd, J=14, 5 Hz, 1H), 2.80-2.88 (m, 1H), 2.70 (dd, J=14, 7 Hz, 1H), 2.66 (s, 6H), 2.56 (d, J=7 Hz, 1H), 2.14 (d, J=4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 137.4, 129.3, 128.9, 127.2, 40.6, 38.3, 38.1, 33.0.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5](=O)[C:6]([CH3:31])([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:11][N:12]=1)[CH3:7])=[O:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:30][C:15]1[CH:16]=[C:17]([NH:19][C:20]2[N:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][N:21]=2)[CH:18]=[C:13]([C:10]2[S:9][C:8]([C:6]([C:5]3[O:2][CH:1]=[N:3][N:4]=3)([CH3:31])[CH3:7])=[N:12][CH:11]=2)[CH:14]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)C(=O)NNC=O)s2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)c3nnco3)s2)c1
Yield: 41.7 %

Procedure:
The product from Step 2 (80 mg, 0.172 mmol) was taken up in THF (2 mL) in a microwave vial, and Burgess reagent (82 mg, 0.344 mmol) was added. The reaction was irradiated in the microwave at 100° C. for 30 min. The yellow reaction mixture was concentrated to dryness, and the resulting residue was purified by column chromatography on silica (0-100% ethyl acetate in hexanes) to provide N-(3-methyl-5-{2-[2-(1,3,4-oxadiazol-2-yl)propan-2-yl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (32 mg, 42%) as an off-white solid. MS ESI: [M+H]+ m/z 447.0. 1H NMR (600 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.20 (s, 1H), 8.81 (d, J=4.9, 1H), 7.97 (s, 2H), 7.44 (s, 1H), 7.26 (d, J=4.9, 1H), 7.14 (s, 1H), 2.29 (s, 3H), 1.87 (s, 6H). rhSYK activity=+++
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:16]([OH:17])[OH:15])[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1cnc2ccccc2c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromoquinoline (Sigma-Aldrich, St. Louis, USA) (1 eq, 14.0 mmol, 1.94 ml) in toluene/THF (4:1, 25 ml), triisopropylborate (1.2 eq, 16.8 mmol, 3.94 ml) is added. The mixture is cooled to −40° C., then n-butyl lithium (1.6 M in THF, 1.2 eq, 17 mmol, 10.5 ml) is added within 30 min. After stirring for additional 30 min at this temperature, the cooling bath is removed and the reaction mixture is allowed to to warm up to −20° C. before quenching with aqueous HCl solution (2 N). The mixture is adjusted to pH 7 by using aqueous NaOH solution (4 N), then it is saturated with NaCl, and extracted with THF. The organic layer is concentrated in vacuo, and the resulting solid is recrystallized in MeCN yielding the title compound, [M+H]+=173.