Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([CH3:12])[N:3]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([CH3:12])[N:3]=1
Reactant: CCOC(=O)c1cc(O)nn1C
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCCN(C)C)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a stirred solution of ethyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (10 g, 58.8 mmol), 2-(dimethylamino)ethanol (5.76 g, 64.7 mmol) and PPh3 (21.6 g, 82.3 mmol) in anhydrous THF (200 mL) was added dropwise DIAD (16.6 g, 82.3 mmol) at 0° C. After the addition, the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (CH2Cl2/MeOH 30:1) to give the title compound (5.6 g, 40% yield) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH:4]([OH:5])[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of tert-butyl 4-(2,4-difluorobenzoyl)piperidine-1-carboxylate (1.28 g, 3.93 mmol) in MeOH (15.7 mL) was added NaBH4 (0.372 g, 9.84 mmol). The ice bath was removed and the reaction mixture stirred for 2 h at room temperature then was quenched with saturated aqueous NH4Cl. The organic layer was extracted with EtOAc, washed with H2O and dried over MgSO4. The solvent was removed under reduced pressure gave tert-butyl 4-((2,4-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate as a white hygroscopic solid.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1([N:23]([CH3:25])[CH3:24])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14](C)[C:15](=O)OC(C)(C)C)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].CO.C(Cl)(Cl)[Cl:29]>C(Cl)(Cl)Cl>[ClH:29].[ClH:1].[ClH:29].[CH2:2]([C:6]1([N:23]([CH3:24])[CH3:25])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][CH3:15])[CH2:10][CH2:11]1)[CH2:3][CH2:4][CH3:5]
Reactant: ClC(Cl)Cl
Reactant: CCCCC1(N(C)C)CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CCCCC1(N(C)C)CCN(CCNC)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
HCl gas was passed through a solution of 10.5 g (1 eq) tert-butyl 2-(4-butyl-4-(dimethyl-amino)piperidin-1-yl)ethyl(methyl)carbamate in 1000 ml chloroform at 0° C. for ˜1 h. The reaction mixture was then stirred for 12 hours at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure and the residue washed with hexane (3×50 ml) and ethyl acetate (3×50 ml) and dried. 9 g (87%) of product were obtained in the form of a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C1C(=O)N([Br:21])C(=O)C1>>[Br:1][CH:2]([Br:21])[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: BrCc1cc(Br)c2ncccc2c1
Product: Brc1cc(C(Br)Br)cc2cccnc12

Procedure:
A mixture of 6-bromomethyl 8-bromoquinoline (2) and 6-dibromomethyl 8-bromoquinoline (4) (2:4=3:1 mole ratio, with about 30 wt % succinimide) was obtained by bromination of the compound 1 in the presence of NBS and was carried through the sulfonation reaction. The presence of succinimide did not affect the sulfone formation and did simplify the isolation of the bromination product. To a slurry of the above mixture (15.0 g) in 48 mL of 20% water-DMAC was added sodium methane sulfinate (6.6 g, 64.8 mmol) in one portion at room temperature. The resulting solution was aged at room temperature until 2 was consumed (about 2h, by HPLC). Then, the reaction solution was allowed to warm up to 90° C. After 4h aging, the 6-dibromomethyl 8-bromoquinoline (4) was completely converted to product 3 (by HPLC). Then, the reaction solution was allowed to cool to room temperature and ½ saturated NaHCO3/H2O solution (160 mL) was added over 1 h. The slurry was cooled to 0° C. and aged for 1 h before filtration. The wet cake was washed with a solution of 5:1 DMAC:H2O (2×20 mL) and then H2O (2×20 mL). After drying, 3 was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:31])=[N:15][C:16]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[N:17][CH:18]=1)=[O:12].CCOCC>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:31])=[N:15][C:16]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:17][CH:18]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)CCC(=O)Nc1ncc(C(=O)NCc2ccc(Cl)cc2Cl)c(O)n1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)Nc1ncc(C(=O)NCc2ccc(Cl)cc2Cl)c(O)n1
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
A solution of tert-butyl 4-({5-[(2,4-dichlorophenyl)methylcarbamoyl]-4-hydroxypyrimidin-2-yl}amino)-4-oxobutanoate (425 mg) in trifluoroacetic acid (3 mL) was left standing at room temperature for 30 minutes. Ether (60 mL) was added to the reaction solution, and the resulting suspension was filtered. The product collected by filtration was washed with ether, dried under reduced pressure, and then purified by reverse phase high performance liquid chromatography (acetonitrile/water, containing 0.1% formic acid) to obtain the title compound (144 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:34][C:35]=1[F:36].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CC1(C)OB(c2ccc(F)c(F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(F)c(F)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.5 g, 0.1 mmol), 2-(3,4-Difluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.24 g, 0.1 mmol), Na2CO3 (2 M, 2.45 mL), and Pd(PPh3)2Cl2 (9.7 mg, 0.084 mmol) in toluene/ethanol (1:1, 8.0 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-(3,4-Difluoro-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 65% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([O:24][CH3:25])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([O:24][CH3:25])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C)ccc1S(=O)(=O)Nc1ccsc1C(=O)O
Temperature: 77.5 °C
Yield: 78.3 %

Procedure:
To a solution of 32 (0.25 g; 0.65 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL) was added aqueous sodium hydroxide (10 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL, 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a white solid (188 mg).
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[CH2:15]([Mg]Br)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:15]([CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Product: CCOC(=O)c1cc2c([nH]1)C(CCc1ccccc1)CC2

Procedure:
The title compound was synthesized from ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.3 g, 1.55 mmol) and phenethylmagnesium bromide (7.5 mL, 0.5 M in THF, 3.7 mmol) according to General Procedure 3 to afford 96.5 mg of (E/Z)-ethyl 6-(2-phenylethylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by General Procedure 6 to give 87.3 mg of ethyl 6-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate in 90% purity. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.55 (br. s., 1H), 7.29-7.35 (m, 2H), 7.19-7.26 (m, 3H), 6.64 (d, J=1.59 Hz, 1H), 4.23-4.33 (m, 2H), 3.02-3.13 (m, 1H), 2.51-2.82 (m, 5H), 1.94-2.14 (m, 2H), 1.78-1.90 (m, 1H), 1.34 (t, J=7.13 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1-c1ccc(F)cc1F
Temperature: 100 °C

Procedure:
To a stirred solution of 2-chloro-3-methyl-5-nitropyridine (prepared according to the procedure of Hawkins and Roe, J. Am. Chem. Soc., page 330, 1948) (17.6 g, 102 mmol, 1 eq.) in DMF (220 mL) was added 2,4-difluorobenzeneboronic acid (16.16 g, 102 mmol, 1 eq.) followed by Cs2CO3 (41.1 g, 122.7 mmol, 1.2 eq). The mixture was degassed with argon. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2 mmol, 0.02 eq). The mixture was degassed with argon and then heated to 100° C. under argon. After 18 h the mixture was cooled. The mixture was filtered and the filtrate concentrated under reduced pressure. The filtrate was partitioned between water and ethyl acetate. The aqueous layer was extracted several times with ethyl acetate. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The material was purified by flash column chromatography eluting with 5:1 hekanes/acetone giving 7.5 g 2-(2,4-difluorophenyl)-3-methyl-5-nitropyridine. Mass spectrum (ESI) 251.3 (M+1). 1H NMR (500 MHz, CDCl3) δCHCl3: 9.35 (1H, s); 8.42 (1H, s); 7.47 (1H,m); 7.07 (1H, m); 6.97 (1H, m); 2.41 (3H, s).
Reaction SMILES: C1[O:6][C:5]([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=[O:9])[C:3](=[O:4])[O:2]1.C(N(CC)CC)C.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(O)C>[CH2:33]([CH:7]([C:5]([CH2:11][C:12]([OH:14])=[O:13])([C:3]([OH:2])=[O:4])[OH:6])[C:8]([OH:10])=[O:9])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)CC1(CC(=O)O)OCOC1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCCCC(C(=O)O)C(O)(CC(=O)O)C(=O)O

Procedure:
A mixture of 2 (10 g), triethylamine (15 ml) and dodecanol (22 ml) in ethanol-free chloroform (100 ml) was refluxed for 22 hours. Workup in the usual fashion gave the crude product (15.3 g, 86%) as a semi-solid. GC analysis indicated the mixture contained an 89:6 mixture of the major and minor isomers together with about 4% of unreacted 2. Crystallization of this material gave 11.8 g of 3c with mp 74.8°-75.6° C. Recrystallization gave 3c with mp 74.7°-75.3° C., which migrated as a single spot on TLC and as a broad peak, Rt 10.88-10.93, by GC, after derivatization.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][CH:25]([OH:42])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=2)[CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[C:8]([O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][C:25](=[O:42])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=2)[CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2cc(C(=O)OC(C)(C)C)c3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cc(C(=O)OC(C)(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.02 g (19.8 mmol) acetic anhydride are mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.237 g (0.494 mmol) tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-3-carboxylate in 10 ml absolute DMSO. Having stirred for 2 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a yellowish oil.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:7])[NH:5][CH:6]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.CCN(CC)CC>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:5]2[CH:6]=[C:2]([I:1])[N:3]=[C:4]2[CH3:7])=[CH:11][CH:10]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(I)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
4-Iodo-2-methyl-1H-imidazole (200 mg, 1.0 mmol), 4-fluorophenylboronic acid (215 mg, 1.6 mmol), copper(II)acetate (210 mg, 1.2 mmol) and Et3N (0.16 ml, 1.2 mmol) were suspended in 10 ml THF and oxygen was bubbled through the reaction mixture for 40 min. The reaction mixture was stirred for 48 hours at RT and then filtrated over dicalit. The filtrate was concentrated and then purified by flash chromatography to yield 1-(4-fluoro-phenyl)-4-iodo-2-methyl-1H-imidazole (120 mg, 0.40 mmol, 41%).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[CH:3][C:4](=[N:6][OH:7])[NH2:5].[CH:15]([O-])([O-])OCC>B(F)(F)F.CCOCC>[CH3:1][C:2]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[CH:3][C:4]1[N:5]=[CH:15][O:7][N:6]=1
Reactant: CCOC([O-])[O-]
Reactant: CC(=CC(N)=NO)c1ccc(Cl)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=Cc1ncon1)c1ccc(Cl)cc1

Procedure:
β-Methyl-p-chlorocinnamamidoxime (4.64 g.) was refluxed with ethyl orthoformate (50 ml.) and two drops of boron trifluoride etherate for 45 min. Ethyl orthoformate was removed under reduced pressure and the residual brown oil was dissolved in chloroform (100 ml.) and washed consecutively with 2N-hydrochloric acid (20 ml.), saturated sodium hydrogen carbonate solution (20 ml.), and water (20 ml.). The chloroform solution was evaporated to a brown oil (ca. 4.6 g.) which was chromatographed on silica gel. Elution with benzene gave 3-(β-methyl-p-chlorostyryl)-1,2,4-oxadiazole, 2.90 g. (60%), m.p. 56°-57°, λmax (EtOH) 273 nm (ε 20760) (Found: C 59.95; H, 4.2; Cl, 15.9; N, 12.7. C11H9ClN2O requires C, 59.85; H, 4.1; Cl, 16.1; N, 12.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=O)[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5]2.P(Br)(Br)[Br:19]>>[Br:19][C:7]1[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: BrP(Br)Br
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1C(F)(F)F
Product: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Br
Temperature: 140 °C

Procedure:
6,7-Dichloro-3-trifluoromethyl-1H-quinoxalin-2-one (500 mg, 1.8 mmol) was dissolved in phosphorus tribromide (2.0 ml), and the solution was heated at 140° C. for 16 hours. The reaction mixture was cooled to room temperature, before it was poured out on ice (100 g) and extracted with dichloromethane. The organic phase was separated and dried with anhydrous sodium sulphate, then taken to dryness by rotary evaporation to leave a pale brown powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:28])([CH3:27])[CH2:9][N:10]2[CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:6][CH:5]=1)([O-])=O>CO>[CH3:27][C:8]1([CH3:28])[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:10]([CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Solvent: CO
Product: CC1(C)CN(CC2CCNCC2)c2cc(N)ccc21
Reaction time: 8 h

Procedure:
tert-Butyl 4-[(6-nitro-3,3-dimethylindolinyl)-methyl]piperidinecarboxylate (Step A, 900 mg) was dissolved in 10 mL MeOH, the mixture was bubbled with H2 for 10 min. 10% Pd/C (30 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 Hexane:EtOAc to afford a colorless oil. MS: 360 (M+1). Calc'd. for C21H33N3O2−359.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH:25]1([B-](F)(F)F)[CH2:27][CH2:26]1.[K+].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:25]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)[CH2:27][CH2:26]1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O/N=C(\CC(c1ccccc1)c1ccc(C2CC2)cc1)c1ccncc1
Temperature: 100 °C
Yield: 47.9 %

Procedure:
To a solution of (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5, 100 mg) in toluene (0.9 mL) and water (0.1 mL) was added potassium cyclopropyltrifluoroborate (47 mg), tri-potassium phosphate monohydrate (199 mg) and tetrakis(triphenylphosphine) palladium (0) (6 mg). The mixture was heated to 100° C. overnight. After cooling to rt a saturated aqueous solution of NaHCO3 was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:1) to yield (E)-3-(4-cyclopropyl-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (43 mg, 49%) as a white foam, MS (ESI+): m/z=343.3 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.O.CO>CCOC(C)=O.[OH-].[Na+]>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]#[C:21][C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:9]=1
Reactant: C[Si](C)(C)CCOCn1nc(C#Cc2ccccn2)c2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(C#Cc2ccccn2)c2ccc(N)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 6-Nitro-3-pyridin-2-ylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (2 mmol), SnCl2 (1.37 g, 6.0 mmol), water (0.5 mL), and MeOH (10 mL), were stirred in a 60 deg C oil bath for 30 min at which time HPLC indicated complete reduction. The resulting mixture was stripped of methanol, suspended in EtOAc (50 mL) and diluted with 1M NaOH (18 mL). The resulting emulsion was gently extracted EtOAc (10×25 ml). The combined organics were extracted with 1M Na2CO3, brine, dried over MgSO4, concentrated and filtered through a pad of silica eluted with EtOAc. The yield of crude product for two steps was 701 mg, 96% mass recovery. ESIMS (M+H+): 365.1.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>C(O)C.C(OCC)(=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>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:3]2[O:4][C:5]3[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=3[C:7](=[O:8])[C:2]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CS(=O)(=O)c1ccc(-c2oc3ccccc3c(=O)c2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2oc3ccccc3c(=O)c2-c2ccccn2)cc1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A solution of 3-bromo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one (0.5 g, 1.32 mmol) from Example 22, Step 2 and 2-tributylstannylpyridine(0.58 g, 1.58 mmol) and tetrakis(triphenylphosphine)palladium(0.15 g, 0.13 mmol) in N-methyl-2-pyrrolidine(50 ml) and ethanol(1 ml) was heated at a temperature of 100° C. for 24 hours. Then the mixture was cooled to room temperature and diluted with ethyl acetate and filtered through a pad of celite. The mixture was washed with 5% aqueous KF, dried and concentrated. The residue was subjected to flash chromatography to yield the title compound as a pale yellow solid(0.27 g).