Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18]#[CH:19])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>C(N(CC)CC)C.C(OCC)(=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.[Cu](I)I>[NH2:1][C:2]1[C:17]([C:18]#[C:19][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C#Cc1cccc(C(=O)OCc2ccccc2)c1N
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1c(C#Cc2nccs2)cccc1C(=O)OCc1ccccc1
Yield: 82 %

Procedure:
A solution of benzyl 2-amino-3-ethynylbenzoate (3.06 g), 2-bromothiazole (1.65 mL), bis(triphenylphosphine)palladium(II) dichloride (0.704 g) and copper iodide (0.232 g) in triethylamine (60 mL) was stirred under a nitrogen atmosphere at 60° C. for 1.5 hr with heating. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (3.32 g, yield 82%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([N:32]=[C:33]=[O:34])[CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH2:28]([NH:32][C:33](=[O:34])[O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:3]=[C:2]2[CH3:1])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN=C=O
Reactant: CCCN(c1ccncc1)n1cc(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCNC(=O)Oc1ccc2c(c1)c(C)cn2N(CCC)c1ccncc1
Reaction time: 2 h

Procedure:
To a stirred solution consisting of 3-methyl-1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.11 g) and tetrahydrofuran (50 ml) was added milled K2CO3 (1.09 g), followed by dropwise addition of butyl isocyanate (0.93 ml) at room temperature under nitrogen. Stirring was continued for 2.0 hours at which time the reaction mixture was filtered through a pad of celite and the solids washed with EtOAc. Concentration afforded the crude product. Purification via flash column chromatography (silica gel, 2% Et3N/EtOAc) afforded 2.65 g of the desired carbamate as an oil. This oil was dissolved in a small amount of EtOAc and diluted with ether, whereupon the product crystallized as a white powder, m.p. 120°-122° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)[OH:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[C:23]([C:29]([F:30])([F:32])[F:31])[CH:22]=2)=[O:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(C(O)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CSc1ccc(C(=O)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a 250 mL round bottomed flask charged with (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanol (4.78 g, 10 mmol) and dichloromethane (50 mL) was added Dess-Martin periodinane (10.65 g, 25 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h before quenching with saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with ethyl acetate (250 mL), washed with saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanone as a light yellow solid (3.8 g, 80%) which was used for the next step without further purification: LC/MS m/e calcd for C22H16F3N2O3S2 [M+H]+ 477.05, observed 477.0.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH:22]1[N:26]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C@H:38]3[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@@H:42]([O:48][C:49](=[O:51])[CH3:50])[C@H:41]([O:52][C:53](=[O:55])[CH3:54])[C@@H:40]([C:56]([O:58][CH3:59])=[O:57])[O:39]3)=[C:33]([NH:60][C:61](=[O:82])[CH2:62][CH2:63][NH:64][C:65]([O:67][CH2:68][CH:69]3[C:81]4[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=4[C:75]4[C:70]3=[CH:71][CH:72]=[CH:73][CH:74]=4)=[O:66])[CH:32]=2)=[O:28])[CH2:25][CH2:24][O:23]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[OH:18][CH2:19][CH2:20][CH2:21][CH:22]1[N:26]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C@H:38]3[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@@H:42]([O:48][C:49](=[O:51])[CH3:50])[C@H:41]([O:52][C:53](=[O:55])[CH3:54])[C@@H:40]([C:56]([O:58][CH3:59])=[O:57])[O:39]3)=[C:33]([NH:60][C:61](=[O:82])[CH2:62][CH2:63][NH:64][C:65]([O:67][CH2:68][CH:69]3[C:70]4[CH:71]=[CH:72][CH:73]=[CH:74][C:75]=4[C:76]4[C:81]3=[CH:80][CH:79]=[CH:78][CH:77]=4)=[O:66])[CH:32]=2)=[O:28])[CH2:25][CH2:24][O:23]1
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc(COC(=O)N3CCOC3CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2NC(=O)CCNC(=O)OCC2c3ccccc3-c3ccccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(COC(=O)N3CCOC3CCCO)cc2NC(=O)CCNC(=O)OCC2c3ccccc3-c3ccccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a mixture of the silyl ether 13 (52 mg, 0.042 mmol) in THF (2 mL) and pyridine (2 mL) was added HF-pyridine complex (400 μL). The reaction mixture was stirred for 3 h and was poured into saturated aqueous sodium bicarbonate and was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water and brine and dried over sodium sulfate, before being filtered and concentrated. The resulting oil was purified via radial chromatography on a 1 plate eluting with 5% methanol in dichloromethane to give 36 mg (86%) of a solid residue: 1H NMR (CD3OD); δ1.55 (bs, 2H), 1.68 (m, 1H), 1.87 (m, 1H), 1.95 (s, 3H), 2.01 (m, 6H), 2.67 (oct, 2H, J=6.8 Hz), 3.30 (m, 1H), 3.50 (m, 3H), 3.65 (m, 1H), 3.69 (m, 3H), 3.82 (q, 1H, J=8.0 Hz), 4.01 (m, 1H), 4.23 (m, 1H, J=7.0 Hz), 4.25-4.40 (m, 2H), 4.47 (d, 1H, J=10.0 Hz), 5.0-5.15 (m, 3H), 5.19 (t, 1H, J=9.8 Hz), 5.28 (dd, 1H, J=6.0, 9.6 Hz), 5.39 (d, 1H, J=7.6 Hz), 5.49 (m, 3H), 7.11 (m, 2H), 7.17-7.32 (m, 3H), 7.34 (t, 2H, J=7.4 Hz), 7.62 (d, 2H, J=7.6 Hz), 7.77 (d, 2H, J=7.6 Hz), 8.07 (s, 1H); LC-MS m/z (ES+), 927.87 (M+Na+)+, 9.79 min.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C([N:18]1[CH:22]=[CH:21]N=C1)(N1C=CN=C1)=O.O>CN(C)C=O>[CH3:4][C:3]1[CH:2]=[C:22]([NH:18][C:4]([C:3]2[C:2](=[S:1])[NH:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH:21]=[C:8]([CH3:9])[CH:7]=1
Reactant: O=C(O)c1cccnc1S
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-Mercaptonicotinic acid (90 g, 0.58 mol) was suspended in N,N-dimethylformamide (660 mL) under ice-cooling, then carbonyldiimidazole (110 g, 0.70 mol) was added thereto, and the whole was stirred for 2 hours at room temperature. Water (5.4 mL) was added thereto, and the whole was stirred for 40 minutes, and then 3,5-xylydine (76 mL, 0.61 mol) was added thereto and the resulting mixture was stirred at 60° C. for 16 hours. The mixture was allowed to stand, and then water (1.3 L) was added, and the precipitated solid was filtered off. The solid was dried at 45° C. under reduced pressure to give 130 g of the title Reference Compound as a yellow solid (Yield: 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:35]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN(C(=O)c1ccccc1)C2Cc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol), 4-dimethylaminopyridine (0.2 g), and triethylamine (1.5 mL) in CH2Cl2 (8 mL) at room temperature under nitrogen was added neat benzoyl chloride (0.42 g, 3.0 mmol) dropwise. The reaction was stirred overnight, quenched with a solution of saturated sodium bicarbonate, and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, 30-50% ethyl acetate/hexane) to provide the title compound (0.835 g, 90% yield): ES-MS (m/z) 464 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(F)c(F)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(CCCBr)c(F)c1F
Reaction time: 1 h
Yield: 81.4 %

Procedure:
Compound 70-2 (2.90 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (4.40 g) and N-bromosuccinimide (2.99 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.14 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:12][C:13]([F:17])=[C:14](F)[F:15]>>[Cl:12][C:13]([F:17])=[C:14]([C:10]1[S:9][CH:8]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:11]=1)[F:15]
Reactant: CCCCCCc1ccsc1
Reactant: FC(F)=C(F)Cl
Product: CCCCCCc1csc(C(F)=C(F)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-hexylthiophene (30 g, 0179 mol) in anhydrous petrol (40-60 C., 100 ml) was cooled to −10 C. and diisopropylamine (freshly distilled, 18.1 g, 0179 mol) and tetramethylethylenediamine (TMEDA) (33 g, 028 mol) were added. N-BuLi (1.6M in hexanes, 113 ml, 0.18 mol) was added dropwise over 30 min at −10 C. The solution was warmed to 0 C. over 1 h, and then added via cannula to a solution of chlorotrifluorethylene at −78 C. The reaction was warmed to RT over 2 h and stirred for a further 16 h. The reaction was quenched with sat, ammonium chloride and extracted with THF (3×50 ml). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a yellow oil (47 g). High vacuum distillation through a packed column with a reflux ratio head (0.1 mbar, 70-71 C.) afforded 13.0 g of product. Purity (HPLC) >99%. MS (EI) 264 (d, M+). 19F NMR revealed the expected signals, 1H and 13C NMR were complicated by the presence of cis/trans isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Product: COc1cccc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The method of example 3.1 was used with 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 3-methoxy-benzoyl chloride (2 mmol) to obtain a residue. The residue was chromatographed on silica gel eluting sequentially with ethyl acetate and then 6% methanol in dichloromethane to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[C@H:50]12[CH2:56][C@H:53]([NH:54][CH2:55]1)[CH2:52][N:51]2C(OC(C)(C)C)=O.C(O)(=O)C>CS(C)=O>[C@H:50]12[CH2:56][C@H:53]([NH:54][CH2:55]1)[CH2:52][N:51]2[CH2:46][C:42]1[CH:41]=[C:40]([C:35]2[C:36]([F:39])=[CH:37][CH:38]=[C:33]([CH2:32][NH:31][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([NH:20][CH2:19][C:10]4[C:11]([NH:12][CH:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]5=[N:8][C:9]=4[CH2:48][CH3:49])=[O:22])[N:24]=3)=[O:30])[CH:34]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)n1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (50.0 mg. 0.075 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.226 mmol) and acetic acid (4.52 mg, 0.075 mmol) and fitted magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.753 mmol, 176 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and to the filtrate was added MeOH (2.0 mL) and 1 drop of concentrated HCl. This solution was heated at 60° C.° for 12 h. Purification was completed via a Gilson HPLC (basic conditions) to afford 10.26 mg (18.4%) of the title compound. LC-MS m/z 746 (M+H)+, 0.69 min (ret time).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)=[O:15]>>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)=[CH:21][CH:20]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: Oc1ccc(-c2cc3c(O)cc(O)cc3o2)cc1
Yield: 93 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(4-methoxyphenyl)ethanone: Yield 93% following procedures A.2 and A.5; m.p. 216-217° C.; IR 3309, 1613, 1510, 1439, 1241, 1134, 1064 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.76 (5, 1H), 9.67 (s, 1H), 9.28 (s, 1H), 7.59 (d, J=8.7 Hz, 2H), 6.97 (s, 1H), 6.83 (d, J=8.7 Hz, 2H), 6.39 (d, J=0.8 Hz, 1H), 6.16 (d, J=1.8 Hz, 1H); 13C-NMR (126 MHz, δ ppm, CD3OD) 158.7, 158.4, 157.3, 154.8, 152.1, 126.8, 124.3, 116.7, 113.1, 98.8, 97.4, 90.9.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([CH3:22])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[ClH:23]>O1CCOCC1.C(OCC)C>[ClH:23].[CH3:22][C@@H:11]1[NH:12][CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: C[C@H]1CN(c2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@H]1CN(c2ccc(C#N)cc2)CCN1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
(S)-tert-butyl 4-(4-cyanophenyl)-2-methylpiperazine-1-carboxylate (0.404 g, 1.340 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford a white solid (300 mg, 94%). [M+H] calc'd for C12H15N3, 201; found, 201.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:4](=[O:6])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1c(F)cccc1F
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1c(F)cccc1F
Temperature: 4 °C
Yield: 48.2 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2,6-difluorobenzoic acid (12.1 g), N,N'-carbonyldiimidazole (12.3 g) and 2-amino-7-chloro-1,8-naphthyridine (8.5 g). The product produced by precipitation in water (6.8 g; m.p. 215° C.) is dissolved in boiling ethanol (450 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration washed with ethanol (3×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-2,6-difluorobenzamide (7.3 g) is produced, m.p. 242° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: O=C(O)c1ccncc1Cl
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(SC(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 80 °C
Yield: 63.3 %

Procedure:
A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of 3-chloroisonicotinic acid, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](O[Si](C(C)(C)C)(C)C)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.Cl>O>[N:13]1[CH:12]=[CH:11][C:10]([C:9]2[C:31]3[C:26](=[N:27][CH:28]=[CH:29][N:30]=3)[NH:25][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1cnccn1
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccc(F)cc1)c1ccncc1
Agent: Cl
Solvent: O
Product: Fc1ccc(-c2[nH]c3nccnc3c2-c2ccncc2)cc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
1-(4-Fluorophenyl)-2-t-butyldimethylsiloxy-2-(4-pyridyl)ethanone (16) (5.44 g, 15.77 mmol), 2-aminopyrazine (1.00 g, 10.5 mmol), and concentrated HCl (30 mL) were heated in a sealed tube to 190° C. behind an explosion shield. After 3 h at 190° C., the reaction was allowed to cool to 23° C. then diluted with water (100 mL). After further dilution with concentrated ammonium hydroxide to pH of 12, the reaction was extracted with methylene chloride (3×200 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by applying flash chromatography (100% ethyl acetate) to afford 3-(4-pyridyl)-2-(4-fluorophenyl)-4,7-diaza-indole (62): Mass Spectrum (CI) 291 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(CCN(C)C)C.[Li]C(CC)C.CN([CH:31]=[O:32])C>CCOCC>[C:1]([N:8]1[C@@H:13]([CH:31]=[O:32])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C)C=O
Reactant: CC1CCCCN1C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: C[C@H]1CCC[C@H](C=O)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of N-Boc-2-Methyl-Piperidine (9.4 g, 46.9 mmol) in 94 mL of ether was cooled to −60° C. and treated with TMEDA (7.1 mL, 46.9 mmol) followed by sec-BuLi (49.2 mL, 51.66 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 30 min and then cooled to −78° C. The mixture was treated with a solution of DMF (5.5 mL, 70.44 mmol) in 16 mL of ether via syringe, stirred for 10 min, and then quenched with 75 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an oil which was chromatographed on silica with hexanes:EtOAc (4:1) to afford 6.5 g (66%) of the trans isomer and 2.1 g (21%) of the cis isomer. Both products were homogeneous by TLC analysis, with the cis isomer positiioned just above the trans isomer. 1H NMR (250 MHz) δ9.28-9.26 (d, 1 H), 4.25 (br. d, 1 H), 3.64-3.57 (m, 1H), 1.74-1.46 (m, 15 H), 1.09-1.04 (d, 3 H); 13C NMR (62.7 MHz) 196.3 (s), 155.1 (s), 77.4 (s), 59.2 (s), 47.3 (s), 29.3 (s), 28.2 (s), 25.4 (s), 16.3 (s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:26])[CH:11]=1.[Cl:27]N1C(=O)CCC1=O>CN(C=O)C>[Cl:27][C:11]1[C:12](=[O:26])[N:13]2[C:17](=[C:18]([C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[CH2:16][CH2:15][CH2:14]2
Reactant: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)cc(=O)n2c1CCC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c(Cl)c(=O)n2c1CCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
Example 9 (22 mg, 0.047 mmol) was dissolved in DMF (2 mL) and N-chlorosuccinimide (8 mg, 0.056 mmol) was added and the reaction was allowed to stir at r.t. for 4 hr. The mixture was concentrated in vacuo and purified by preparative HPLC (25/35 water/acetonitrile) to give 5 mg (21%) of the title compound. 1H NMR (400 MHz, MeOD): δ 7.98 (s, 1H), 7.50 (dd, 1H, J=10.0, 1.6 Hz), 7.44 (m, 1H), 6.87 (t, 1H, J=8.6 Hz), 4.17 (t, 2H, J=7.8 Hz), 3.59 (m, 2H), 3.34 (m, 2H), 3.17 (t, 2H, J=7.4 Hz), 2.43 (m, 2H). MS (ES) [m+H] calc'd for C17H16 ClFIN3O4, 508. found 508.