Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH:13][C:14]2[CH:25]=[CH:24][C:17]([CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH2:20])=[CH:16][CH:15]=2)=[O:12])=[CH:3][CH:2]=1.[CH3:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29](O)=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl.CO.CN(C)C=O.CN1CCCC1=O>[CH3:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29]([NH:20][C@H:19]([C:21]([OH:23])=[O:22])[CH2:18][C:17]1[CH:24]=[CH:25][C:14]([NH:13][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[O:12])=[CH:15][CH:16]=1)=[O:30]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: N[C@@H](Cc1ccc(NC(=O)c2ccnc3ccccc23)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(NC(=O)c2ccnc3ccccc23)cc1)C(=O)O
Reaction time: 2 h

Procedure:
4-[[(4-Quinolinyl)carbonyl]amino]-L-phenylalanine on Wang resin (300 mg, 0.20 mmol) was washed with dichloromethane (2×10 mL), methanol (2×10 mL) and dimethylformamide (2×10 mL). To the resin was added a solution prepared from 2,6-dimethylbenzoic acid (150 mg, 1.0 mmol), BOP (450 mg, 1.02 mmol) and diisopropylethylamine (0.23 mL) in 4 mL of N-methylpyrrolidone at room temperature. The resulting mixture was agitated for 2 hr. The reaction mixture was then filtered and washed with dichloromethane (2×10 mL), methanol (2×10 mL) and dichloromethane (2×10 mL). Cleavage was effected by treatment with 90% trifluoroacetic acid (TFA) in dichloromethane for 5 minutes. The mixture was filtered and the TFA was removed under high vaccum. Addition of ether (25 mL) effected precipitation of N-[(2,6-dimethylphenyl)carbonyl]-4-[[(4-quinolinyl)carbonyl)amino]-L-phenylalanine (0.16 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH:22]1[C:23]2[C:18](=[C:17]([N:6]3[C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=4[C:4]4[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]3=4)[CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][N:21]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1cccc2cnccc12
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc3cnccc23)CCN(C)C1
Temperature: 25 °C

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 1 mmol), 5-bromoisoquinoline (208 mg, 1 mmol), K3PO4 (318 mg, 1.5 mmol), L-Proline (11.5 mg, 0.2 mmol) and CuI (9.5 mg, 0.05 mmol) in dry DMF (2 mL) was stirred at 150° C. for 24 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-isoquinolin-5-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (20 mg). 1H NMR (Oxalate salt, CD3OD) δ (ppm): 9.42 (s, 1H), 8.40 (m, 2H), 7.90 (m, 2H), 7.40 (s, 1H), 7.08 (d, 1H), 6.99 (d, 1H), 6.70 (d, 1H), 4.65 (m, 2H), 3.70 (m, 2H), 3.18 (s, 3H), 3.0 (m, 1H), 2.72 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][CH:7](Br)[C@@H:6]1[N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(=O)C.[CH2:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])[CH:33]=[CH2:34].N1C(C)=CC(C)=CC=1C.[Br-].C[O-].[Na+]>ClCCl.CO.FC(F)(F)S([O-])(=O)=O.[Ag+].C(N(CC)CC)C.C(OCC)(=O)C>[C:25]1(=[O:26])[N:21]([C@@H:6]2[C@@H:5]([OH:4])[C@H:10]([OH:11])[C@@H:9]([CH2:15][OH:16])[O:8][C@H:7]2[O:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:32][CH:33]=[CH2:34])[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]12
Reactant: C=CCOCCCCCO
Reactant: CC(=O)OC[C@H]1OC(Br)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ag+]
Agent: C[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: C=CCOCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A solution of 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-D-glucopyranosyl bromide 230 (5.0 g, 10.0 mmol) in dichloromethane (5 mL) was added dropwise to a mixture of the alcohol 229 (1.33 mL, 10 mmol), silver trifluoromethanesulphonate (2.57 g, 10.0 mmol) and collidine (1.23 mL, 9.0 mmol) in dichloromethane (10 mL) at -70° C. After stirring for 3 hours at -70°, t.l.c. (2:1-toluene and ethyl acetate) indicated that the starting bromide and the reaction product had the same Rf. After addition of some triethylamine, the reaction mixture was diluted with dichloromethane and worked up as usual. The syrupy residue was chromatographed on silica gel using a 5:1 mixture of toluene and ethyl acetate providing compound 231 (4.0 g, 71%). 1H-n.m.r. (CDCl3): 5.80 (m, 2 H, --CH= and H-3), 5.36 (d, 1 H, J1,2 8.5 Hz, H-1), 5.18 (m, 3 H, =CH2 and H-4), 2.13, 2.06, 1.87 (3 s, 3 H each, 3 OAc), 1.40 (2 H) and 1.15 (m, 4 H): methylenes. A 0.2M solution of sodium methoxide in methanol (0.500 mL) was added dropwise to a solution of compound 231 (4.00 g, 7.1 mmol) in dry methanol (30 mL) cooled at 0° C. The mixture was stirred at 0° C. for 2 hours until t.l.c. (10:1-chloroform and methanol) indicated the disappearance of the starting material. The reaction mixture was de-ionized with Dowex 50 (H+ form, dry) at 0° C. Filtration and evaporation of the solvent left a residue which was purified by chromatography on silica gel using a 100:5 mixture of chloroform and methanol as eluant providing compound 232 (2.36 g, 76%). 1H-n.m.r. (CDCl3): 7.70 and 7.80 (m, 4 H, aromatics), 5.82 (m, 1 H, --CH=), 5.17 (m, 3 H, =CH2 and H-1), 1.38 and 1.10 (m, 6 H, methylenes); 13C-n.m.r. (CDCl3): 134.9 and 116.6 (ethylenics), 98.3 (C-1), 56.6 (C-2).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[C:22]([F:34])=[C:23]([C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C1COCC1>[Cl:20][C:21]1[C:22]([F:34])=[C:23]([C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)[C:24]([N:12]=[C:6]1[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]1)=[O:25]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1c(C(F)(F)F)ccc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)sc1=NC(=O)c1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a suspension of the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF was added Et3N (0.37 mL, 2.7 mmol). This mixture was cooled to 0° C. and 3-chloro-2-fluoro-6-trifluoromethyl benzoyl chloride (Alfa Aesar, 0.35 g, 1.3 mmol) in 5 mL THF was added dropwise via syringe. The mixture was allowed to stir at ambient temperature for 1 hour, then was warmed to reflux and was allowed to stir for 8 hours. The mixture was then cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and purified via flash column chromatography (SiO2, 7:3 hexanes:EtOAc) to provide the title compound (0.20 g, 0.50 mmol, 46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.27 (s, 3H), 2.28 (s, 3H), 3.27 (s, 3H), 3.68 (t, J=4.7 Hz, 2H), 4.28-4.37 (m, 2H), 7.37-7.43 (m, 1H), 7.44-7.52 (m, 1H); MS (DCI/NH3) m/z 411 (M+H)+; Anal. calculated for C16H15ClF4N2O2S: C, 46.78; H, 3.68; N, 6.82. Found: C, 46.83; H, 3.30; N, 6.65.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[N:14][NH2:15])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.[Ag]=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N+:14]=[N-:15])=[CH:4][CH:3]=1
Reactant: NN=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=[Ag]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: [N-]=[N+]=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred ice-cold solution of 4,4'-dichlorobenzophenone hydrazone (1.303 g) in dry methylene chloride (20 ml) was added magnesium sulfate (590 mg), silver oxide (1.196 g) was added in one portion followed by potassium carbonate (30 mg). The mixture was stirred at ice-temperature for 1 hour, then at room temperature for an additional hour, filtered through Celite to give a dark purple solution which was directly used for the cycloaddition reaction.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.[OH-:21].[K+].O.CO>C(O)(=O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:21])=[CH:16][C:3]1=2
Reactant: [OH-]
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1S2
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1cccnc1S2
Temperature: 0 °C
Yield: 29.9 %

Procedure:
A mixture of 50 mg of (5,6-dihydro-6-oxo benzo[b]pyrido-[3,2-f]thiepin-8-yl)-acetamide, 200 mg of potassium hydroxide, 2 ml of water and 15 ml of methanol was refluxed under a nitrogen atmosphere for 4 hours. After the completion of the reaction, the solvent was distilled off to obtain a residue, to which was added ice water. The mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain an oil, which was chromatographed over silica gel and eluted with chloroform/ethanol (200/1) to obtain a solid. This solid was recrystallized from ethanol to give 15 mg (yield: 30%) of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetic acid as colorless needle crystals having a melting point of 212°-213.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][N+:15]([O-:17])=[O:16].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]([F:12])([F:11])[F:10])=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])C=C(c1ccc(Br)cc1)C(F)(F)F

Procedure:
A stirred solution of 4′-bromo-2,2,2-trifluoroaceto-phenone (0.392 g, 2.00 mmol) and CH3NO2 (0.488 g, 8.0 mmol) in dry toluene (70 mL) containing N,N-diethylenediamine (30 mmol) is heated at reflux with a Dean and Stark trap until complete removal of H2O. The cooled solution is washed with 5% aqueous HCl, dried over MgSO4, filtered, evaporated in vacuo and the resulting residue when purified by chromatography gives the title compound.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][N:70]=[C:69]([N:73]3[CH2:77][CH2:76][CH2:75][CH2:74]3)[CH:68]=2)[C:56]=1[CH3:78].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][N:70]=[C:69]([N:73]5[CH2:74][CH2:75][CH2:76][CH2:77]5)[CH:68]=4)[C:56]=3[CH3:78])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccnc(N3CCCC3)c2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccnc(N3CCCC3)c2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.044 mmol), 2,5-dimorpholinopyridin-3-amine (0.088 g, 0.33 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)quinoline (0.1 g, 0.28 mmol) and Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.067 g, 0.70 mmol) in toluene (2.8 mL) at 100° C. for 1.0 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (1H, dd, J=2.3, 0.6 Hz), 7.84 (1H, dd, J=8.8, 2.5 Hz), 7.73 (1H, d, J=5.5 Hz), 7.59 (1H, dd, J=9.9, 1.7 Hz), 7.55 (1H, d, J=2.7 Hz), 7.35-7.43 (1H, m), 6.58 (1H, d, J=8.6 Hz), 6.39 (1H, d, J=2.5 Hz), 3.59-3.81 (8H, m), 3.47 (4H, t, J=6.5 Hz), 3.15 (2H, br. s.), 2.94-3.05 (4H, m), 2.83 (2H, br. s.), 2.13 (3H, s), 1.93-2.04 (4H, m). Mass Spectrum (ESI) m/e=588.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2.F[B-](F)(F)F.C([PH+](CCCC)CCCC)CCC.Br[Zn][CH2:33][CH:34]1[O:38][CH2:37][CH2:36][O:35]1.CC1CCCO1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:35]1[CH2:36][CH2:37][O:38][CH:34]1[CH2:33][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2
Reactant: Br[Zn]CC1OCCO1
Reactant: O=c1occc2cc(Br)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[PH+](CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Product: O=c1occc2cc(CC3OCCO3)ccc12
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of 6-Bromo-1H-isochromen-1-one (980 mg, 4.4 mmol), tributyl phosphonium tetrafluoroborate (25 mg, 0.087 mmol), palladium (II) acetate (9.8 mg, 0.044 mmol) was suspended in DMF (10 ml) then added bromo(1,3-dioxolan-2-ylmethyl)zinc (9.58 ml, 4.79 mmol) and purged with nitrogen. The reaction was heated to 85° C. for 10 hours and then stirred at RT overnight. Methyl tetrahydrofuran was added and the mixture was washed with brine. The organic layer was dried over MgSO4, filtered and evaporated to dryness. The residue was purified thru a 80 g ISCO Redi-sep column and eluted with 0-100% EtOAc/hexane to yield the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[N:12]=1.C(OCC)(=O)C>C1COCC1.O>[C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[N:12]=1)#[N:18]
Reactant: Sc1ccncc1
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Sc2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-Mercaptopyridine (0.88 g, 7.94 mmol) and sodium hydride (60% in oil, 0.35 g, 8.66 mmol) were dissolved in THF (30 ml), and the mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.22 mmol) in THF (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.54 g, ca. 100%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2([CH3:16])[CH3:15])#[CH:2].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.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.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]3([CH3:16])[CH3:15])=[CH:25][CH:26]=1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure F and using 6-ethynyl-2,2,4,4-tetramethylchroman (synthesis described in U.S. Pat. Nos. 5,045,551 and 5,616,597 incorporated herein by reference) (0.060 g, 0.28 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.078 g, 0.28 mmol), triethyl amine (4 mL), tetrahydrofuran (4 mL), copper(I)iodide (0.030 g, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.11 g, 0.16 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent the title compound was obtained (0.047 g, 46%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH:18]([CH3:19])[CH2:17][CH:16]([OH:20])[CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH:18]([CH3:19])[CH2:17][C:16](=[O:20])[CH2:15]3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CC1CC(O)CN1S(=O)(=O)c1cccc2cnccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1CC(=O)CN1S(=O)(=O)c1cccc2cnccc12

Procedure:
Then, in substantially the same manner as in Example 9, 2.34 g of the thus obtained 1-(5-isoquinolinesulfonyl)-3-hydroxy-5-methylpyrrolidine was reacted in dichloromethane with 1.08 g of oxalyl chloride, 0.67 g of dimethylsulfoxide and 0.60 g of triethylamine to obtain 1-(5-isoquinolinesulfonyl)-5-methyl-3-pyrrolidone.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[Cl:24][C:4]1[CH:3]=[C:2]([NH:1][C:39]([C:34]2[C:33](=[O:42])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[C:37]([CH3:38])=[CH:36][CH:35]=2)=[O:40])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[N:15]=2)[CH:12]=1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(Cl)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of N-[6-(4-amino-2-chlorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.292 mmol) and 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (94 mg, 0.38 mmol) in N,N-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (100 μL, 0.583 mmol) and HATU (144 mg, 0.380 mmol), and the mixture was stirred at 60° C. for 4 hr. Ethyl acetate, tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate alone) to give a white solid. The obtained solid was washed with ethyl acetate and collected by filtration to give the title compound (120.2 mg, 72%) as a white solid.
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([NH2:22])[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C(C)(C)C.CCO.C1COCC1>O>[NH2:22][C:20]1[S:21][C:17]2[C:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[C:15]([C@H:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:8][OH:7])[C:24]([CH3:25])=[CH:23][C:18]=2[N:19]=1
Reactant: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A flask was charged with (S)-2-(2-Amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (2.15 g, 4.52 mmol), LiOH monohydrate (2.00 g, 47.4 mmol), H2O (4 mL), EtOH (absolute, 4.0 mL), and THF (8.0 mL). The reaction was placed under N2 and heated to 100° C. After 2 h, the reaction was cooled to 23° C., diluted with H2O, and extracted with EtOAc several times. The combined organic phases were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene and purified via chromatography on silica gel (80 g “gold” ISCO column; Hex/EtOAc) giving (S)-2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethanol (1.10 g, 62% yield). LCMS-ESI+: calc'd for C20H23ClN2O2S: 391.1 and 393.1 (M+H+); found: 391.2 and 393.2 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: 7.49-7.41 (m, 2H), 7.36-7.32 (m, 2H), 7.20 (d, J=7.3 Hz, 1H), 5.39 (s, broad, 2H), 4.52-4.50 (m, 1H), 3.85-3.70 (m, 2H), 2.63 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2I)=[N:11][N:12]=1.F[C:32]([B])=[C:33](F)F.[K].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CCC=1>C(O)CC.Cl[Pd]Cl.[Fe].ClCCl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:32]=[CH2:33])=[N:11][N:12]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4I)o3)n2)cc1
Reactant: [B]C(F)=C(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: C1=CC(P(c2ccccc2)c2ccccc2)=CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCO
Product: C=Cc1ccccc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Temperature: 100 °C
Yield: 53.5 %

Procedure:
A solution of 4-[5-amino-6-[5-(2-iodophenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (100 mg, 0.1952 mmol), potassium trifluoro-vinyl-boron (31.37 mg, 0.2342 mmol), triethyl amine (81.63 μL, 0.5857 mmol) and cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (31.88 mg, 0.03904 mmol) in propanol (2.000 mL) was degassed and flushed with nitrogen (3×) and the resulting solution heated at 100° C. for 1 h. The reaction mixture cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate. Product fractions were combined and concentrated in vacuo to leave the product as a yellow solid (43.1 mg, 53% yield); 1H NMR (400.0 MHz, DMSO) d 2.97 (m, 6H), 5.51 (m, 1H), 5.98 (m, 1H), 7.54 (m, 2H), 7.58-7.70 (m, 3H), 7.78 (br s, 2H), 7.89 (m, 1H), 8.06 (m, 2H) and 9.00 (s, 1H) ppm; MS (ES+) 413.15