Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[N:23][CH:24]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:31](=[O:32])[C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][N:23]=5)=[CH:30][CH:29]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)nc1
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc4nc(C5CC5)c(C)n4c3)cc2)nc1

Procedure:
Operations similar to Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(5-methoxy-2-pyridyl)benzenecarboxylic acid, to provide the title compound as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11]1[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=1.O1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2nccc(C(F)(F)F)n2)cc1Br
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To 3-bromo-4-fluoroaniline (0.76 g, 4.0 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (0.73 g, 4.0 mmol) was added dioxane (13.33 mL) and p-TSA (0.761 g, 4.0 mmol). The reaction was sealed and was heated at reflux overnight. The reaction was cooled to room temperature and was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and the organic was dried over sodium sulfate and filtered before concentration. The crude product was purified by flash chromatography (25:75 ethyl acetate:hexanes) to afford N-(3-bromo-4-fluorophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (1.2 g, 3.57 mmol, 89%) as a pale yellowish solid. 1H NMR (500 MHz, CDCl3): δ 8.68 (d, J=4.9 Hz, 1H); 7.99-7.96 (m, 1H); 7.51 (d, J=8.4 Hz, 1H); 7.29 (s, 1H); 7.14 (t, J=8.5 Hz, 1H); 7.10 (d, J=4.9 Hz, 1H). rhSYK activity=+
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Product: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CHLOROFORM-D): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.O>CN(C)C=O>[O:9]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCCOc1ccccc1
Yield: 100 %

Procedure:
60% Sodium hydride (1.16 g) was suspended in dimethylformamide (40 ml), and phenol (3 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and a solution of 1,6-dibromohexane (7.78 g) in dimethylformamide (10 ml) was dropwise added, which was followed by stirring at room temperature for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 8.2 g of 6-phenoxyhexyl bromide.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=3[S:29]([NH:32]C(C)(C)C)(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.BrC1C=CC(CN2C=CN=C2)=CC=1>C1(OC)C=CC=CC=1>[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=3[S:29]([NH2:32])(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CCCCc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: Brc1ccc(Cn2ccnc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reaction time: 30 h
Yield: 49 %

Procedure:
Trifluoroacetic acid was added (10 mL) to the crude 3-(4-imidazol-1-ylmethylphenyl)-5-butyl-N-tert-butylthiophene-2-sulfonamide from step (c) above, and one drop (ca. 0.05 mL) of anisol was added to the mixture. The reaction mixture was stirred under N2 atmosphere for 30 hours and then evaporated and co-evaporated with acetonitrile. The crude product was purified by column chromatography (CH2Cl2:MeOH (20:1)) to give sub-title compound (232 mg, 0.62 mmol) in 49% yield (from 1-(4-bromobenzyl)-1H-imidazole).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([NH:20][CH:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:25]4[C:29](=[O:30])[C:28]5=CC=CC=[C:27]5[C:26]4=[O:35])[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH2:39].NN.C(O)C.[OH-:45].[K+]>CCOCC>[C:29]([OH:30])(=[O:45])/[CH:28]=[CH:27]\[C:26]([OH:35])=[O:39].[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([NH:20][CH:21]([CH3:36])[CH2:22][CH2:23][CH2:24][NH2:25])[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O
Reactant: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nc(OCc3ccc(Cl)cc3)ccc2c1
Agent: NN
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(NC(C)CCCN)c2nc(OCc3ccc(Cl)cc3)ccc2c1
Product: O=C(O)/C=C\C(=O)O
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 7.5 g (0.014 mole) 2-(4-chlorobenzyloxy)-6-methoxy-8-(4-phthalimido-1-methylbutylamino)quinoline (crude), 6.0 ml 85% hydrazine hydrate, and 100 ml 95% ethanol was refluxed 3 hr. After standing overnight, the mixture was stirred with ether and 20 g 50% aq. KOH. The ether layer was washed with water and sat'd. brine. The aqueous portions were extracted with ether and the washing process repeated. A sat'd solution of 2.0 g maleic acid in methanol was added to the dried (MgSO4) ether solution. There was obtained 5.10 g (71%) of an off-white solid, mp 173°-177°. Recrystallization of the crude maleate from 120 ml 95% ethanol (charcoal) afforded 3.55 g, mp 174°-178°. Further recrystallization from ethanol gave the analytical sample, mp 176°-177.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Agent: Cl
Solvent: c1ccncc1
Product: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NS(C)(=O)=O)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 39 h
Yield: 98.7 %

Procedure:
To a stirred solution of 45 mg (0.1 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of ether-CH2Cl2 was added 0.5 mL of pyridine followed by 0.020 mL (0.26 mmol) of methanesulfonyl chloride. The solution was stirred 39 h at ambient temperature and poured into 1 N aq. HCl. The mixture was extracted with EtOAc, then hexanes. The combined organic extracts were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure to afford 52 mg of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-methanesulfonylaminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. Mass spec. (ESI+): 526 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([C:38]3[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=3)[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:17]=12.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClC(Cl)C.O>[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([N:22]3[C:18]4=[N:19][CH:20]=[N:21][C:16]([NH2:15])=[C:17]4[C:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[N:23]3)=[CH:39][CH:40]=2)[CH2:49][CH2:48]1
Reactant: CN1CCNCC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(-n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)cc2)CC1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
Sodium triacetoxyborohydride (67 mg, 0.319 mmol) was added to a mixture of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde (100 mg, 0.245 mmol), 4-methylpiperazine (37 mg, 0.369 mmol), glacial acetic acid (35 mg, 0.589 mmol) in dichloroethane (4 mL). After stirring at room temperature over night, more sodium triacetoxyborohydride (67 mg, 0.319 mmol) was added and the reaction mixture was stirred over night. Water (2 mL) was added and followed by sodium bicarbonate (250 mg). After stirring vigorously for 1 hour, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichlromethane/methanol (97:3 to 80:20) as mobile phase to give 1-{4-[(4-methylpiperazino)methyl]phenyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 21%). 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 2.48 (bm, 8H), 3.56 (s, 3H), 5.75 (bs, 2H), 7.11 (d, J=8.50, 2H), 7.18 (m, 3H), 7.40 (m, 2H), 7.48 (d, J=8.50 Hz, 2H), 7.29 (d, J=8.63 Hz, 2H), 8.12 (d, J=8.50 Hz, 2H), 8.47 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=492.2, Rt=2.97 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH:27]([NH:30][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:3])([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC(C)C)nn1
Yield: 53 %

Procedure:
As described for example 81, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) was converted, using isopropylamine instead of aminomethylcyclopropane, to the title compound (49 mg, 53%) which was obtained as a white foam. MS: m/e=370.3 [M+H]+.
Reaction SMILES: OC1C=CC([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=CC=1.[H-].[Na+].Br[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN([CH:45]=[O:46])C>>[CH:27]1[C:28]2[C:23](=[CH:22][C:21]([NH:20][C:18](=[O:19])[CH:8]([C:23]3[CH:22]=[CH:21][CH:30]=[CH:29][C:45]=3[O:46][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:30][CH:29]=2)[CH:24]=[CH:25][N:26]=1
Reactant: BrCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccccc1OCCc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E249) in DMF cooled to −35° C. was added NaH and the solution was stirred at −40° C. for 30 min. Then, 2-bromoethylbenzene was added and the solution was warmed and stirred at room temperature for 2 h. The solution was poured into NaHCO3(sat)/EtOAc and further extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3-4% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(phenethoxyphenyl)propylcarbamate (E289).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Combine 4-hydroxy-3-methyl-benzaldehyde (0.502 g, 3.69 mmol), 6-chloro-nicotinonitrile (0.510 g, 3.68 mmol), and potassium carbonate (1.28 g, 9.26 mmol) in dimethylacetamide (18 mL) and warm to 100° C. After 1 h. cool to ambient temperature, dilute reaction mixture with water (40 mL), and extract with ethyl acetate (3×50 mL). Wash combined organic extracts with water and brine successively, dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography (hexanes→ethyl acetate gradient/1.5 L) to provide 0.784 g (89%) of the title compound as a light brown solid: mass spectrum (electrospray): m/z=239.0 (M+1); 1H NMR (CDCl3): 10.01 (s, 1H), 8.44 (d, 1H, J=2.4 Hz), 7.99 (dd, 1H, J=2.0, 8.3 Hz), 7.86 (s, 1H), 7.81 (dd, 1H, J=1.5, 8.3 Hz), 7.23 (d, 1H, J=8.3 Hz), 7.13 (d, 1H, J=8.8 Hz), 2.25 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O.C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([Cl:10])[CH:3]=1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(Br)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cc(Br)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
4-Bromo-2-chlorobenzaldehyde (1 g, 4.56 mmol), morpholine (0.457 mL, 5.24 mmol), acetic acid (0.300 mL, 5.24 mmol) and sodium triacetoxyborohydride (1.45 g, 6.84 mmol) were mixed with THF (4 mL) in a sealed microwave vial. The mixture was stirred at r.t. for 2 hrs. The mixture was diluted with EtOAc, washed with H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude was purified on BIOTAGE® with 0-20% of EtOAc in hexane. The fractions containing the desired product was collected and concentrated to give 1.01 g titled product. MS (ESI) m/z 289.9 (M+H)+.
Reaction SMILES: [Cl-].[Li+].O.[CH2:4]([C:11]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])(C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]>CS(C)=O>[F:37][C:26]([F:38])([C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])[CH2:25][CH2:24][CH2:23][CH2:22][CH:11]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reaction time: 12 h
Yield: 49.5 %

Procedure:
Lithium chloride (0.75 g, 17.72 mmol) and water (0.16 ml, 8.86 mmol) were added to a solution of diethyl 2-(6-heptenyl)-2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)malonate (4.7 g, 8.86 mmol) in dimethyl sulfoxide (100 ml) followed by stirring for 12 hours at a temperature of 170° C. to 180° C. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ethyl acetate (100 ml). The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/50) to give ethyl 2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)-8-nonenoate (2.01 g, Yield 49.5%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]#N)=[N:4][CH:5]=[CH:6][CH:7]=1.C[O-:11].[Na+].Cl.[C:14](=O)([O-])[OH:15].[Na+]>CO>[Br:1][C:2]1[C:3]([C:8]([O:15][CH3:14])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C([O-])O
Reactant: N#Cc1ncccc1Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncccc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.01 g of 3-bromo-2-cyanopyridine was added to methanol (18 mL) solution of 1.55 g of sodium methoxide, and in a nitrogen atmosphere, this was stirred at room temperature for 1.5 hours and then at 70° C. for 2.5 hours. The reaction liquid was cooled to room temperature, and 30 mL of 2 N hydrochloric acid was added thereto and stirred at room temperature for 4 hours. Then, aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 4/1) to obtain 135 mg of the entitled compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=O>CCCCCCC.C(OCC)(=O)C>[Cl:12][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[F:20])=[N:1][C:2]=2[C:10]([Cl:11])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1c(Cl)ccc(Cl)c1C(=O)O
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=c1oc(-c2ccccc2F)nc2c(Cl)ccc(Cl)c12
Temperature: 25 °C

Procedure:
2-Amino-3,6-dichlorobenzoic acid (0.5 g) and triethyl amine (20 ml) were mixed. 2-Fluorobenzoyl chloride (0.77 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT and stirred until disappearance of starting material was seen on TLC (silicagel) using heptane/ethyl acetate (4/1) as eluent. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness. The residue was partitioned between methylene chloride and potassium carbonate (2N), the organic layers separated, dried over magnesium sulfate and evaporated to dryness. The raw product was purified by column chromatography on silicagel using heptane/ethyl acetate as eluent. Yield 0.31 g. m.p. 140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1/[CH:23]=[CH:24]/[C:25]([NH:27][NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1/[CH:23]=[CH:24]/[C:25]1[O:38][C:29]([C:30]2[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=2)=[N:28][N:27]=1
Reactant: CS(=O)(=O)c1ccc(-c2nnc(/C=C/C(=O)NNC(=O)c3ccc(C#N)cc3)n2-c2ccccc2Cl)nc1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2nnc(/C=C/c3nnc(-c4ccc(C#N)cc4)o3)n2-c2ccccc2Cl)nc1
Reaction time: 2 h

Procedure:
(E)-N′-(3-(4-(2-chlorophenyl)-5-(5-(methylsulfonyl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)acryloyl)-4-cyanobenzohydrazide 10 was dissolved into dichloromethane (10 mL) and triphenyl phosphine (0.27 g, 1.0 mmol), carbon tetrabromide (0.34 g, 1.04 mmol) and triethylamine (0.18 mL, 1.30 mmol) was added. The reaction was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1:3) to give (E)-4-(5-(2-(4-(2-chlorophenyl)-5-(5-(methylsulfonyl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)vinyl)-1,3,4-oxadiazol-2-yl)benzonitrile as a yellow solid. Yield: 0.035 g, 12.7%.
Reaction SMILES: [C:1](=[O:14])(OC(Cl)C(Cl)(Cl)Cl)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:3]([O:2][C:1]([C:16]1[NH:15][CH:19]=[CH:18][N:17]=1)=[O:14])([CH3:4])([CH3:5])[CH3:6]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)OC(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ncc[nH]1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
5 g (17.5 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonate dissolved in 10 ml of THF are added at 0° C. to a solution of imidazole (1.2 g; 17.6 mmol) in THF (20 ml) in the presence of 5M aqueous potassium carbonate solution (5 ml). The mixture is stirred for 1 hour at 20° C., and the organic phase is decanted and washed with 10 ml of saturated aqueous NaCl solution.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:4][CH:3]=1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[N:28]=1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([NH:21][C:19]([C:8]1[C:6]2=[N:7][C:2]([C:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[N:28]=3)=[CH:3][N:4]=[C:5]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cn1nc(I)c2cccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cccnc21
Temperature: 125 °C
Yield: 68.2 %

Procedure:
To a solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (400 mg, 936 μmol) and 3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine (364 mg, 1.4 mmol) in DMF (8 mL) was added hexabutylditin (814 mg, 709 μL, 1.4 mmol) then the mixture was purged with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium (0) (54.1 mg, 46.8 μmol) was added and the reaction mixture was heated at 125° C. After 18 h the mixture was filtered through a pad of Celite to remove catalyst, then the filtrates were concentrated in vacuo and purified by chromatography (silica, 10-70% ethyl acetate in hexanes) to obtain N-tert-butyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (306 mg, 638 μmol, 68%) as an off-white powder. MS (M+H)+=480.