Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[Br:3][C:4]1[N:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC.C([O-])([O-])=O.[Na+].[Na+]>>[Br:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[N:9]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cccc(Br)n2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(6-bromo-pyridin-2-yl)-ethanone (1880 mg, 9.40 mmol) in ethylene glycol (10.00 mL, 179.32 mmol) was treated with trimethylorthoformate (2.10 mL, 19.16 mmol) followed by LiBF4 (180 mg, 1.88 mmol). The reaction mixture was heated at 95° C. for 5 h. Sat. aq. Na2CO3 was added and the mixture was extracted twice with ether and the combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (50:50 hept-EA)=0.57.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]1[CH:12]2[C:13]([CH3:15])([CH3:14])[CH:10]([CH2:11]2)[CH2:9][CH:8]=1>C(Cl)CCl.[Cl-].[Zn+2].[Cl-]>[C:13]([C:10]12[CH2:11][CH:12]([C:7]([CH3:6])=[CH:8][CH2:9]1)[C:1](=[O:4])[CH2:2][CH2:3]2)([CH3:15])=[CH2:14]
Reactant: CC1=CCC2CC1C2(C)C
Reactant: C=CC(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: C=C(C)C12CC=C(C)C(C1)C(=O)CC2
Yield: 0.8 %

Procedure:
A mixture of 20.0 g acryloyl chloride (0.22 mol) and 3.01 g zinc chloride (0.02 ml, 0.1 eq.) in 150 ml ethylene chloride was treated with a soln. of 350 ml α-pinene ((1S-(−)/(1R)-(+) 90:10, 2.20 mol, 10 eq.) in 250 ml ethylene chloride and the resulting mixture was stirred 1 h at 25° C. and 4 h at 50° C. After cooling, the reaction mixture was washed with aq. sat. NaCl soln. and aq. sat. NaHCO3 soln. The aq. phases were extracted with Et2O, dried (Na2SO4), and concentrated. The crude product (48 g) was filtered (SiO2, hexane/Et2O 200:6→200:10) and the residue (1.42 g) treated with 300 mg LiOH.H2O in 15 ml MeOH at 25° C. for 7 h. The resulting mixture was poured into aq. sat. NaCl soln., extracted with hexane and the org. phases dried with Na2SO4, FC (SiO2, hexane/Et2O 30:1) gave 347 mg (0.8%) of compound 10. Boiling point: 80° C. at 0.07 torr (0.09 mbar).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[CH:15]=[CH:14]2)[N:22]=[CH:21][CH:20]=[CH:19]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pd].C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[CH2:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[CH:19]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2C=Cc3ccc4ncccc4c3O2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4ncccc4c3O2)cc1

Procedure:
Treatment of 2H-pyrano[2,3-f]quinolin-2-yl-methyl 4-methylbenzene-sulfonate with palladium on carbon (10 wt. %) in ethanol following the procedure described for Example 1c affords 3,4-dihydro-2H-pyrano[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate.
Reaction SMILES: [I-:1].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(C)=O>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][I:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: ClCCCCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCc1ccccc1
Temperature: 70 °C
Yield: 0.1 %

Procedure:
Sodium iodide (8.9 g, 59.2 mol) and 4-phenyl-1-chlorobutane (5.0 g, 29.6 mol) were added to acetone (29.6 mL) at rt. The mixture was heated to 70° C. for 12 h. The resulting solution was gravity filtered to remove salts. The solvent was removed under reduced pressure and excess salts were dissolved in water (100 mL). Hexane (100 mL) was added to the aqueous mixture. The phases were separated and the organic phase was washed with saturated sodium bisulfite solution (3×50 mL), treated with decolorizing carbon, and gravity filtered. The organic layer was then dried (MgSO4), filtered, and concentrated in vacuo to afford 4-phenyl-1-iodobutane (6.94 g, 90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=1.[CH2:16]([NH:18][C:19](=[O:36])[NH:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:19]([NH:18][CH2:16][CH3:17])=[O:36])=[CH:26][CH:25]=2)[CH:7]=1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
(S)-4-(4,6-dichloropyrimidin-2-yl)-3-methylmorpholine (Intermediate 1B) (992 mg, 4.0 mmol), 4-(3-ethylureido)phenyl boronic acid pinacol ester (1.05 g, 3.6 mmol), cesium carbonate (3.9 g, 12.0 mmol) and bis(diphenylphosphino)-ferrocenedichloropalladium(II)-DCM-complex (163 mg, 0.2 mmol) in dioxane/water (1:3, 2.4 mL) were irradiated in a Biotage microwave for 40 min at 110° C. The reaction mixture was concentrated in vacuo, the residue suspended in water (150 mL) and the pH adjusted from 10 to 7 with HCl (2M aq solution). EtOAc (150 mL) was added and aqueous layer removed. The organic layer was washed with brine (70 mL) and then concentrated in vacuo to leave a brown solid which was purified by flash chromatography (0-5% MeOH in DCM over 30 min) to yield an orange solid, 630 mg, 42%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]([CH3:22])[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(=CCCCC(=O)O)CC1
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCC(=O)O)CC1

Procedure:
5.0 g (16.1 mmol) 5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexylidene]-pentanoic acid in 50 ml methanol were hydrogenated with 0.5 g 10% Pd/C in the presence of 0.94 ml (16.9 mmol, 1.05 eq) sodium methanolate for 1 h at RT. After filtration and evaporation of the solvent, the residue was dissolved in ether and acidified by adding 1M HCl. The organic phase was extracted with water, dried over MgSO4 and evaporated to give 5.3 g (quant) trans-5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-pentanoic acid as light yellow oil, MS: (312 MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH:12]#[C:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:14]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1])[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(trifluoromethyl)phenol (50.0 g, 0.31 mol) and progargyl bromide (44.0 g, 0.37 mol) in ACN (500 mL) was added K2CO3 (51.0 g, 0.37 mol) and the mixture was stirred overnight at rt, concentrated, diluted with water and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA=40/1) to give compound P33a (59.7 g, 97%) as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=[O:15])[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.[CH2:23](O)[CH2:24][CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[CH2:23][CH2:24][CH2:25][O:26][CH:14]1[C:13]1[CH:12]=[C:11]([N:10]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][C:8]([C:19]([F:20])([F:22])[F:21])=[N:9]2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(C3OCCCO3)c2)n1
Yield: 78.5 %

Procedure:
To a stirred solution of 122 (3.25 g, 10.62 mmol) in PhMe (53 ml) was added 1,3-propanediol (1.616 g, 21.24 mmol) followed by p-toluenesulfonic acid monohydrate (0.202 g, 1.062 mmol) and the resulting solution was allowed to stir at reflux with a Dean-Stark trap for 16 h. The solution was evaporated to dryness, and saturated NaHCO3 aqueous solution was added and the mixture was extracted with EtOAc and the extracts were dried over Na2SO4 and evaporated. The residue was purified via Biotage (5% to 40% EtOAc/Hexane; 40+M column). The title product 146 (3.04 g, 8.34 mmol, 79% yield) was obtained as an off-white solid. LRMS (ESI): (calc.) 364.3; (found) 365.2 (MH)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[CH:3]=1>S(=O)(=O)(O)O>[OH:9][C:4]1[CH:5]=[C:6]2[C:7]([CH:4]=[CH:5][C:6](=[O:8])[O:8]2)=[CH:2][CH:3]=1
Reactant: Oc1cc(O)cc(F)c1
Agent: O=S(=O)(O)O
Product: O=c1ccc2ccc(O)cc2o1
Temperature: 0 °C
Reaction time: 24 h
Yield: 146.9 %

Procedure:
1-Fluoro-3,5-dihydroxybenzene (1.0 g, 7.8 mmol) and ethyl 2-benzyl acetoacetate 1.72 g, 7.8 mmol) are suspended in 20 mL of 70% sulfuric acid at room temperature. The reaction mixture is stirred for 24 hours and poured into ice water. The solid is filtered and washed with water. The yellowish crude product is re-crystallized from hot ethanol to afford the 7-hydroxy coumarin intermediate (929 mg, 42%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]([CH3:45])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:34]=[C:33]3[C:28]([C:29]([C:36](=[O:44])[NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:30][C:31]([CH3:35])=[N:32]3)=[CH:27][CH:26]=2)=[CH:21][N:20]=1)[C:14]([OH:16])=[O:15]>C(Cl)Cl>[C:14]([C:13]([CH3:45])([CH3:12])[CH2:17][O:18][C:19]1[N:20]=[CH:21][C:22]([C:25]2[CH:34]=[C:33]3[C:28]([C:29]([C:36](=[O:44])[NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:30][C:31]([CH3:35])=[N+:32]3[O-:6])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)([OH:16])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)O)nc3)cc2n1
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)O)nc3)cc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
m-Chloroperoxybenzoic acid (30.0 mg, 0.20 mmol) was added at room temperature to a solution of 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoic acid B-17 (45.5 mg, 0.10 mmol) in methylene chloride (7 mL). The reaction mixture was stirred at room temperature overnight, then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 7-(6-(2-carboxy-2-methylpropoxy)pyridin-3-yl)-2-methyl-4-(phenylcarbamoyl)quinoline 1-oxide B-23 (16.0 mg, Yield=40%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.28 (s, 6H), 2.66 (s, 3H), 4.34 (s, 2H), 7.17 (d, J=6.0 Hz, 1H), 7.40-7.46 (m, 3H), 7.80 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.5 Hz, 1H), 7.99 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.41 (d, J=8.5 Hz, 1H), 8.83 (s, 1H), 8.87 (s, 1H), 10.78 (s, 1H). MS (ESI) [M+1]+ 474.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[N:21][CH:22]=2)=[CH:13][C:12]([C:36]2[CH:41]=[C:40]([Cl:42])[C:39]([OH:43])=[C:38]([Cl:44])[CH:37]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[N:21][CH:22]=2)=[CH:13][C:12]([C:36]2[CH:37]=[C:38]([Cl:44])[C:39]([OH:43])=[C:40]([Cl:42])[CH:41]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cnc(N2CCNCC2)nc1)C1CC1
Yield: 13.8 %

Procedure:
Following general procedure A-2, tert-butyl 4-(5-((3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-yl)amino)pyrimidin-2-yl)piperazine-1-carboxylate (0.10 mmol) was reacted with TFA (2 mL) to afford the desired product (7.4 mg, 14% over two steps) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.24 (s, 1H), 8.30 (s, 2H), 7.93 (d, J=1.3 Hz, 2H), 7.83 (d, J=1.3 Hz, 1H), 7.21 (s, 2H), 3.98 (t, J=5.2 Hz, 4H), 3.06 (t, J=5.2 Hz, 4H), 2.94-2.86 (m, 1H), 1.24-1.08 (m, 4H). ESI MS m/z 535 [C27H24Cl2N6O2+H]+; HPLC>99% (AUC), tR=11.54 min.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:7]([CH3:14])=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=1>C1(C)C=CC=CC=1>[Br:2][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[CH3:14]
Reactant: BrP(Br)Br
Reactant: Cc1c(Cl)cccc1CO
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 203.8 %

Procedure:
To a solution of phosphorus tribromide (0.422 mL, 4.47 mmol) in Toluene (30 mL) was added (3-chloro-2-methylphenyl)methanol (2 g, 12.77 mmol). The reaction was stirred at RT overnight. The solvent was removed and the residue was partitioned between EtOAc and brine. The organic layer was concentrated and the residue was purified by biotage (5% EA/hexane) to give the product (2.0 g, 71%). 1H NMR (400 MHz, CDCl3) δppm 7.36 (m, 1H), 7.24 (m, 1H), 7.12 (m, 1H), 4.56 (s, 2H). 2.48 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([C:5]2[C:4]([OH:10])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[CH:6]=2)[C:4]=1[OH:10]
Reactant: COc1cc(C)ccc1O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)cc(-c2cc(C)cc(OC)c2O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Bu3MeNMnO4 (10.9 g, 34.1 mmol) was dissolved in CH2Cl2 (250 mL) placed in an ice bath and allowed to cool. Then 2-methoxy-4-methylphenol (9.95 g, 72.0 mmol) was added dropwise to the CH2Cl2 solution and allowed to react with stirring for 1 h at 0° C. under N2. The reaction mixture was diluted with H2O (˜200 mL) and the mixture stirred for an additional 30 min. The mixture was filtered through a glass-wool plug to remove the MnO2 and the organic layer separated. The organic layer was washed with 0.1 M HCl (3×150 mL), brine (50 mL), and then dried over MgSO4. Removal of the solvent under reduced pressure afforded 1 as a yellow powder (5.97 g, 60% yield). Purification of 1 was achieved using column chromatography on silica gel and elution with ethyl acetate/hexanes (1/4, v/v) to afford a 50% overall yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[CH2:23][NH:24][CH2:25][CH3:26].C1(C)C=CC=CC=1>C(OCC)C>[CH2:25]([N:24]([CH2:23][CH:19]1[O:20][CH2:21][CH2:22][O:18]1)[C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[CH3:26]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCNCC1OCCO1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(CC1OCCO1)c1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 72 h
Yield: 68.7 %

Procedure:
4-t-Butyl-2,6-dinitrochlorobenzene (1.8 grams; 0.007 mole), N-(1,3-dioxolan-2-yl)methyl ethylamine (1.83 grams; 0.014 mole) and toluene (50 ml) were placed in a glass reaction vessel equipped with a stirrer, heating mantle, reflux condenser and thermometer. The reaction mixture was heated to 90° C. and maintained at this temperature with stirring for 72 hours. Diethyl ether (50 ml) was added to the cooled reaction mixture, which was filtered and evaporated to a volume of 10 cc. The residue was chromatographed on silica to remove unreacted starting material. The product (1.7 grams) was obtained as an oil which solidified on standing (73°-74° C. melting point). The product was analyzed for C16H23N3O6 :
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4](COCC[Si](C)(C)C)[CH:3]=1.[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([C:59]2[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=2)(=[O:58])=[O:57])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([C:59]2[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=2)(=[O:58])=[O:57])[CH:43]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[NH:4][CH:3]=2)[CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Nc2cc(O)cc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2cc(O)cc(-c3c[nH]c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)cc1
Yield: 33 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.12 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methoxybenzenesulfonamide (229 mg, 0.57 mmol), sodium carbonate (60 mg, 0.57 mmols), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (17 mg, 0.02 mmol) and 1.12 ml 1,2-dimethoxyethane and 0.28 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 40 mg (33% yield, 77% purity) of the title compound.
Reaction SMILES: Cl.[C:2](=[NH:9])([NH2:8])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:10]1([C:16]#[C:17][CH:18]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:3]([C:2]1[N:8]=[C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][N:9]=1)[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCC(=N)N
Reactant: O=CC#Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCCCc1nccc(-c2ccccc2)n1
Yield: 20.7 %

Procedure:
A mixture of 5-hexenimidamide hydrochloride (P4, 500 mg), 3-phenyl-2-propynal (398 mg), and sodium carbonate (786 mg) in acetonitrile (15 mL) was irradiated in a microwave synthesizer at 120° C. for 40 min and then allowed to cool. The solution was filtered and evaporated in vacuo. The residue was dissolved in dichloromethane and the organic layer was washed with H2O, dried over Na2SO4, filtered and evaporated in vacuo. The crude was purified by column chromatography (eluting with ciclohexane/ethyl acetate 9/1) to give 142 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:15]=[CH:16][C:17]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:13][C:12]=1[O:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (15.0 g, 94.5 mmol) and tert-butyl (3-hydroxy-4-methylphenyl)carbamate (20.0 g, 90.0 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (18.6 g, 135 mmol), and the mixture was stirred at 70° C. for 18 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water (400 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (400 mL×2). The combined organic layer was washed with saturated brine (300 mL×2), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure. The residue was triturated with hexane to give the title compound (28.6 g, 92%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[OH:17])=[CH:6]/[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][N:10]=[C:9](Cl)[CH:8]=1)[CH3:2].[CH:19]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4](=[O:18])/[C:5](/[OH:17])=[CH:6]/[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][N:10]=[C:9]([N:27]2[CH2:28][CH2:29][N:24]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:25][CH2:26]2)[CH:8]=1)[CH3:2]
Reactant: C1CCC(N2CCNCC2)C1
Reactant: CCOC(=O)/C(O)=C/c1cc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(O)=C/c1cc(N2CCN(C3CCCC3)CC2)ncc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
A mixture of 3.16 g (Z)-3-(2-chloro-5-nitro-pyridin-4-yl)-2-hydroxy-acrylic acid ethyl ester in 40 mL DMF was treated with 2.96 g (192 mmol) 1-cyclopentyl-piperazine and heated to 110° C. for 1.5 h. The mixture was diluted with 1N NaHCO3 aq. and extracted with DCM. The combined organic layers were dried with MgSO4 and evaporated to dryness to yield the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([O:29]C)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)OC)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)n1
Yield: 86 %

Procedure:
A 2.0 g (4.9 mmol) sample of the methyl ester product compound from Example 1 was dissolved in 80 ml of ethanol and treated with 80 ml of 10% NaOH at ambient temperature for 3 days. The ethanol was removed in vacuo and the aqueous phase acidified to pH 1 with hydrochloric acid which caused the product to precipitate; filtration and drying in vacuo gave 1.65 g (86%) of colorless compound: mp 134–135° C.; NMR (DMSO-d6) δ 0.85 (t, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H), 1.23–1.39 (m, 4H), 1.53–1.68 (m, 4H), 2.59 (t, J=7 Hz, 2H), 2.78 (t, J=7 Hz, 2H), 5.37 (s, 2H), 5.37 (s, 2H), 7.18–7.26 (m, 2H), 7.28–7.37 (m, 3H), 7.42–7.48 (m, 1H), 7.53–7.60 (m, 1H), 7.70–7.75 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([OH:19])[CH2:16][CH:15]3[CH2:17][CH2:18][CH:8]2[CH2:9][C:10]23OCC[O:11]2)[CH:2]=1.Cl>C1COCC1.C([O-])(O)=O.[Na+].O>[OH:19][C:7]1([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:16][CH:15]2[CH2:17][CH2:18][CH:8]1[CH2:9][C:10]2=[O:11]
Reactant: OC1(c2cccnc2)CC2CCC1CC21OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC2CCC1CC2(O)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Alcohol of step A (higher Rf isomer, 0.290 g, 1.11 mmol) was dissolved in THF (10 mL) under nitrogen. Hydrochloric acid (2.0 mL, 4.0 M aqueous solution, 8.0 mmol) was added and the mixture stirred for 4 hours at room temperature. The mixture was then diluted with NaHCO3/H2O and extracted twice with ethyl acetate. The extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide a light yellow solid, 0.204 g (85%). The crude product 2 was used directly for the next step without further purification. 1H NMR (CDCl3) □δ□□ 8.74 (s, 1H), 8.52 (d, 1H), 7.72 (dt, 1H), 7.30 (dd, 1H), 2.66 (dt, 1H), 2.53 (m, 2H), 2.41 (t, 1H), 2.18 (t, 1H), 2.13 (d, 1H), 2.09 (m, 1H), 1.99 (m, 1H), 1.89 (m, 1), 1.62 (m, 2H). Step C