Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:31]1[CH2:36][CH2:35][N:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([C:37]([N:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)=[O:38])=[CH:44][CH:43]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCOCC3)cc2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C(=O)N3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 67.6 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.63 mmol) and morpholino(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (260 mg, 0.82 mmol) in dioxane (10 mL), aqueous 2M Na2CO3 solution (1.13 mL, 2.27 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (250 mg, 68%). LCMS: 587.35 (M+1)+; HPLC: 93.85% (@254 nm) (Rt:4.535; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (bs, 1H), 8.21 (t, 1H), 7.69-7.71 (m, 2H), 7.45-7.49 (m, 3H), 7.26 (s, 1H), 5.86 (s, 1H), 4.29 (d, 2H, J=4 Hz), 3.82-3.84 (m, 2H), 3.48-3.60 (m, 8H), 3.23-3.25 (m, 2H), 3.09-3.11 (m, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.52-1.68 (m, 4H), 0.83 (t, 3H, J=6.8 Hz).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][S:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].CN(C)[CH:28]=[O:29]>>[CH:28]([C:10]1[O:6][C:7]([CH2:11][S:12][CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])=[CH:8][CH:9]=1)=[O:29]
Reactant: O=C1c2ccccc2C(=O)N1CCSCc1ccco1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(CSCCN2C(=O)c3ccccc3C2=O)o1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Phosphorus oxychloride (6.4 g) was added to a stirred solution of 2-[2-[(2-furanylmethyl)thio]ethyl]-1H-isoindole-1,3(2H)-dione (6.0 g) in dry dimethylformamide. After stirring for 2 hr at 0° C. and at room temperature for 12 hr, the mixture was poured into stirred ice-cold water (500 ml). The precipitated solid was collected and crystallised from propan-2-ol yielding the title compound as brown micro-needles (5.6 g) m.p. 77°-79°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:23]1[C:27]2C=CC=C[C:26]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N)C>CN(C=O)C.CCOC(C)=O>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([OH:14])[C:11]([NH:23][CH2:27][CH3:26])=[O:13])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)C(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
(5)(3S)-3-(tert-Butoxycarbonylamino)-2-hydroxy-4-phenylbutanoic acid (6.3 g, 21 mmol) and 1-hydroxybenzotriazole (HOBt) (3.0 g, 22.4 mmol) were dissolved in DMF (45 mL) and cooled in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (4.6 g, 24 mmol) was added, followed by aqueous ethylamine solution (3.0 mL). The solution was stirred for 18 hours. The solution was diluted into EtOAc (200 mL) and washed with 1M HCl, saturated aqueous NaHCO3, and saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to yield ((1S)-1-benzyl-3-ethylamino-2-hydroxy-3-oxo-propyl)carbamic acid 1,1-dimethylethyl ester (5.8 g, 84%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[Na+].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[CH2:14]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[N:24][C:25](Cl)=[C:26]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[N:27]=2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[F:38][C:39]1[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:40]=1[O:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1(C)C=CC=CC=1.CN(C=O)C.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[N:24][C:25]([N:45]3[CH2:44][CH2:43][CH:42]([O:41][C:40]4[CH:48]=[CH:49][C:50]([F:52])=[CH:51][C:39]=4[F:38])[CH2:47][CH2:46]3)=[C:26]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[N:27]=2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: Fc1ccc(OC2CCNCC2)c(F)c1
Reactant: CC(C)(C)Nc1nc2c(nc1Cl)CN(Cc1ccccc1)CC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(Cc1ccccc1)CC2

Procedure:
A solution of sodium tert-butoxide (81 mg, 0.843 mmol), 6-benzyl-N-(tert-butyl)-3-chloro-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (125 mg, 0.281 mmol), Pd2(dba)3 (12.86 mg, 0.014 mmol), 4-(2,4-difluorophenoxyl)piperidine hydrochloride (84 mg, 0.337 mmol), and BINAP (17.50 mg, 0.028 mmol) in toluene (937 μL) was stirred at 90° C. overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give 6-benzyl-N-(tert-butyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine as a TFA salt (155 mg).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2/[N:10]([C@H:20]3[CH2:25][CH2:24][C@@H:23]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH2:22][CH2:21]3)[C:11]3[CH:16]=[C:15]([O:17]C)[N:14]=[CH:13][C:12]=3[NH:19]/2)=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].[Si](Cl)(C)(C)C.O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2/[N:10]([C@H:20]3[CH2:21][CH2:22][C@@H:23]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:25]3)[C:11]3[CH:16]=[C:15]([OH:17])[N:14]=[CH:13][C:12]=3[NH:19]/2)=[O:7])=[CH:32][CH:33]=1
Reactant: COc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(O)cc32)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a RT suspension of (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-methoxy-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (30 mg, 0.066 mmol) and sodium iodide (69.4 mg, 0.463 mmol) in ACN (0.6 mL) was added TMS-Cl (0.059 mL, 0.463 mmol) and water (10 μL), and the mixture was heated at 60° C. After 2 hours and 4 hours, additional TMS-Cl portions (0.059 mL, 0.463 mmol) were added, and the mixture was stirred at 60° C. for a total reaction time of 20 hours. The material was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 10% to 90% over 15 minutes. The combined fractions were freebased with saturated aqueous NaHCO3 and extracted with 10% IPA/DCM, dried over Na2SO4, filtered and evaporated. The title compound was obtained as a white solid (8 mg, 21% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=8 Hz, 6H) 1.50-1.60 (m, 2H) 1.62-1.82 (m, 2H) 2.05-2.08 (m, 2H) 2.49-2.51 (m, 1H) 2.55-2.74 (m, 2H) 3.97-4.02 (m, 1H) 4.60-4.70 (m, 1H) 6.38 (s, 1H) 7.20-7.30 (m, 2H) 7.48-7.52 (m, 1H) 7.64 (d, J=7.63 Hz, 1H) 8.29 (dd, J=8.22, 5.97 Hz, 2H) 11.10 (br. s., 1H) 12.26 (br. s., 1H). M/Z calc'd for C23H26FN5O3: 439.48. found 440 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH2:16]([NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20])[CH3:17].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19]([NH:18][CH2:16][CH3:17])=[O:20])=[CH:27][CH:26]=3)[N:7]=1)[CH2:9]2
Reactant: Clc1nccc(N2CC3CCC(C2)O3)n1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(-c2nccc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
3-(2-chloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3,2,1]octane (intermediate 24) (100 mg, 0.44 mmol) was stirred with 1-ethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (141 mg, 0.48 mmol), Pd(dppf)Cl2:DCM (18 mg, 0.002) and Na2CO3(140 mg, 1.3 mmol) in DME:Water (4:1) for 30 minutes at 130° C. in microwave conditions. The reaction mixture was filtered through a celite545 cake and washed with methanol. The reaction mixture was concentrated in vacuo. The resulting oil was purified by prep HPLC at low pH to afford the title compound as a white solid. (20 mg, 13%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]Cl)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:11]([O:14][CH2:15][C:16]1[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=1)(=[O:13])[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(#N)C>[C:11]([O:14][CH2:15][C:16]1[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:18]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OCc1nc(C(C)C)cn1Cc1ccncc1
Reactant: ClSc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
To a solution of the compound (3) (0.97 g, 4.5 mmol) in toluene (1.88 g) was added dropwise a solution of the compound (10a) (0.87 g, 3.2 mmol) in acetonitrile (4 ml) under ice-cooling for 30 minutes. A solution of triethylamine (0.46 g, 4.5 mmol) in acetonitrile (0.5 ml) was added dropwise thereto for 15 minutes, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed with water, concentrated under reduced pressure and purified by column chromatography on silica gel (elution ethyl acetate) to yield the objective (11) (1.17 g) as a crystal. Yield 82%. Mp 133–135° C.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[C:44]([NH2:52])[CH:43]=1>C(#N)C>[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[C:44]([NH:52][C:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:7]=[CH:8]3)=[O:17])[CH:43]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CCCCCn1ccc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CCCCCn1ccc2cc(C(=O)Nc3cnc4ccccc4c3)ccc21

Procedure:
A solution of 1-pentyl-1H-indole-5-carboxylic acid (0.687, 2.97 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (1.18 g, 3.11 mmol) and N,N-diisopropylethyl (1.14 mL, 6.53 mmol) in acetonitrile (20 mL) was stirred at ambient temperature for 5 minutes. Quinolin-3-ylamine (1.93 g, 13.4 mmol) was added, and the solution was heated at reflux for 18 hours. The solvent was evaporated in vacuo, and the residue was partitioned between dichloromethane and water. The product was preabsorbed onto silica gel and purified by flash chromatography using ethyl acetate in hexane as the eluant, to give the product, 0.40 g (38%). MS: m/z 358 (MH+). 1H NMR (DMSO-d6): 0.84 (t, 3 H), 1.23-1.34 (m, 4 H), 1.73-1.83 (m, 2 H), 4.24 (t, 2 H), 6.64 (d, 1 H), 7.53 (d, 1 H), 7.56-7.69 (m, 3 H), 7.86 (d, 1 H), 7.98 (t, 2 H), 8.37 (s, 1 H), 8.89 (d, 1 H), 9.21 (d, 1 H) and 10.60 (s, 1 H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17].[OH-].[NH4+]>C(Cl)Cl.O.C(#N)C>[N+:16]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2ccccc2n1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
Quinoline (Formula (1), 12.9 g, 0.10 mole) was added dropwise over 5 min. with good agitation to a solution of 50 mL of concentrated sulfuric acid in a 250 mL round bottom flask. No attempt was made to control the exotherm and on this scale the final temperature was 77° C. The mixture was heated to 100° C. and 71% nitric acid (13.3 g, d. 1.42, 9.4 mL, 0.15 mole) was added at such a rate to keep the temperature between 100° C. and 110° C. Stirring was continued for an additional 30 minutes or until an HPLC (Zorbax® SB-C18 HPLC column, from Mac-Mod Analytical, Inc. of Chadds Ford, Pa. U.S.A.; dimensions 4½ mm (inside diameter) by 25 cm (length); HPLC conditions: 40:60 acetonitrile:water-0.5% ammonium acetate, 220 nm, flow 0.5 mL/min.) sample showed the reaction was complete. The mixture was cooled slightly and poured onto a mixture of 200 mL methylene chloride and 300 mL (by volume) of ice. The two phase mixture was placed in an ice bath and the temperature was kept below 25° C. while the pH was increased to 10 with concentrated ammonium hydroxide. The mixture was vacuum filtered through paper and transferred to a separatory funnel. The lower organic phase was separated and the aqueous layer was extracted with an additional 100 mL of methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered and evaporated affording 15.8 g (91% yield) of a clear light amber oil which crystallized on standing. HPLC Analysis was conducted for 5-nitroquinoline and 8-nitroquinoline only: 45% 8-nitroquinoline (Formula (3), rt 9.0 min.) and 55% 5-nitroquinoline (Formula (2), rt 12.8 min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]2[NH:11][CH:12]=[CH:13][C:5]=12)([O-:3])=[O:2].C[Si](C)(C)N[Si](C)(C)C.[Cl:23]C(OC)=O>C1COCC1>[Cl:23][C:8]1[N:7]=[C:6]2[NH:11][CH:12]=[CH:13][C:5]2=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: COC(=O)Cl
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2[nH]ccc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 5.00 g (27.9 mmol) of 4-Nitro-1H-pyrrolo[2,3-b]pyridine 7-oxide and 11.8 ml (55.8 mmol) of hexamethyldisilazane are initially charged in 290 ml of THF. At RT, 10.8 ml (140 mmol) of methyl chloroformate are added. The solution is stirred at RT overnight. The reaction solution is filtered through a silica gel cartridge and the cartridge is washed with dichloromethane/methanol 10:1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[N:11]1([S:16]([CH:19]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])[CH3:20])(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:1][C:25](=[O:26])[NH:24][S:21]([CH:19]([S:16]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:17])=[O:18])[CH3:20])(=[O:22])=[O:23])[N:7]=1
Reactant: CC(S(=O)(=O)N=C=O)S(=O)(=O)N1CCCC1
Reactant: COc1cc(Cl)nc(N)n1
Solvent: ClCCl
Product: COc1cc(Cl)nc(NC(=O)NS(=O)(=O)C(C)S(=O)(=O)N2CCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 701.1 %

Procedure:
1.6 g (0.01 mol) of 2-amino-4-chloro-6-methoxypyrimidine are dissolved in 30 ml of dichloromethane, and 2.7 g (0.01 mol) of 1-pyrrolidinosulfonylethylsulfonyl isocyanate (Example 3b) in 30 ml of dichloromethane are added dropwise at room temperature. After the mixture has been stirred for 3 hours at room temperature, the organic phase is washed with 2N HCl and water, dried and evaporated. Trituration of the crude product with diethyl ether gives 30 g (70% of theory) of 3-(4-chloro-6-methoxypyrimidin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea of melting point 158°-160° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(CCCOCc1ccccc1)N1CCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(CCCO)N1CCCC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar, a suspension of 4-(benzyloxy)-1-(pyrrolidin-1-yl)butan-1-one (284 mg, 1.15 mmol) and Pd/C (10% Pd, 122 mg) in dry MeOH (10 mL) was stirred at rt under a H2 atmospheric pressure until completion of the reaction. The mixture was then filtered, and the filtrate concentrated under reduced pressure to give the title compound as a colorless oil. LC-MS-conditions 08: tR=0.41 min; [M+H]+=158.07.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([N:20]4[CH2:24][CH2:23][C@@:22]5([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=6[C:26](=[O:33])[O:25]5)[CH2:21]4)=[O:19])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.O1CCOCC1.Br[C:42]1[CH:43]=[CH:44][C:45]([F:48])=[N:46][CH:47]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>C(OCC)(=O)C.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]>[F:48][C:45]1[N:46]=[CH:47][C:42]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([N:20]4[CH2:24][CH2:23][C@@:22]5([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=6[C:26](=[O:33])[O:25]5)[CH2:21]4)=[O:19])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:43][CH:44]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)OC1(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccc(F)nc5)cc4)CC3)C2)c2ccccc21
Temperature: 110 °C

Procedure:
To a solution of (1R)-1′-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (130 mg, 0.00029 mol) in 1,4-dioxane (1 mL, 0.01 mol) were added 5-bromo-2-fluoropyridine (0.060 mL, 0.00058 mol), tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.000001 mol), tri-tert-butylphosphine (0.71 mg, 0.0000035 mol) and potassium fluoride (56 mg, 0.00096 mol). The mixture was heated at 110° C. under nitrogen for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and brine successively, dried and concentrated. The product was purified by CombiFlash using CH2Cl2/EtOAc (max.EA 30%). LC-MS: 429.2 (M+H+)
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH2:25])[C:17]=1[F:26])(=[O:12])[CH3:11].[F:27][C:28]([F:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH:25][C:29](=[O:30])[C:28]([F:27])([F:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:17]=1[F:26])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Reactant: O=C(Cl)C(F)(F)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccccc2)c1F
Reaction time: 24 h
Yield: 92.1 %

Procedure:
To a solution of DIEA (1.49 mL, 8.55 mmol) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethyl acetate (690 mg, 2.85 mmol), as prepared in the preceding step, in DCM (6 mL) was added a solution of 2,2-difluoro-2-phenylacetyl chloride (0.99 g, 5.20 mmol), as prepared according to the procedure of step 3 of Example 1, in DCM (3 mL). After stirring for 24 hours, the mixture was concentrated, and partitioned between DCM and H2O. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 2.5, and 5%) to give the title compound (1.04 g, 92% yield) as an orange oil. 1H-NMR (400 MHz, CDCl3) δ 8.49-8.43 (m, 2H), 7.87 (d, J=9.2 Hz, 1H), 6.68 (d, J=7.1 Hz, 2H), 7.55-7.49 (m, 3H), 4.35 (t, J=6.4 Hz, 2H), 3.37 (dt, J=6.3, 2.3 Hz, 2H), 2.01 (s, 3H).
Reaction SMILES: [CH2:1]([S:7][C:8]1[C:25]([S:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19]([S:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:20]([S:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:21]=3)[C:16]3[C:11](=[CH:12][C:13](Br)=[C:14]([S:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:15]=3)[C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>CN1C(=O)N(C)CC1>[CH2:1]([S:7][C:8]1[C:25]([S:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19]([S:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:20]([S:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:21]=3)[C:16]3[C:11](=[CH:12][C:13]([S:7][CH2:8][CH2:9][CH2:10][CH2:23][CH2:22][CH2:21][CH:20]=[CH2:19])=[C:14]([S:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:15]=3)[C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSc1cc2c(cc1Br)c1cc(SCCCCCC)c(SCCCCCC)cc1c1cc(SCCCCCC)c(SCCCCCC)cc21
Solvent: CN1CCN(C)C1=O
Product: C=CCCCCCCSc1cc2c3cc(SCCCCCC)c(SCCCCCC)cc3c3cc(SCCCCCC)c(SCCCCCC)cc3c2cc1SCCCCCC
Reaction time: 3 h

Procedure:
A mixture of 400 mg of 2,3,6,7,10-pentakis-(hexylthio)-11-bromotriphenylene, 70 mg of sodium (7-octenyl)thiolate and 60 ml of DMEU is stirred for 3 hours at 90° under N2 and worked up in the usual manner, giving 2,3,6,7,10-pentakis-(hexylthio)-11-(7-octenylthio)-triphenylene.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[S:24][CH:23]=[CH:22][N:18]2[C:19](=[O:21])[CH:20]=1.[I:27]N1C(=O)CCC1=O.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>C(#N)C>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[S:24][CH:23]=[CH:22][N:18]2[C:19](=[O:21])[C:20]=1[I:27]
Reactant: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)(C)C
Reactant: O=C1CCC(=O)N1I
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)(C)C

Procedure:
A solution of Step 1 intermediate (275 mg, 5.816 mmol) was treated with N-iodosuccinimide (143 g, 6.327 mmol) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2 to afford a crude product which was purified by column chromatography using 2% ethyl acetate in chloroform as eluent to afford 510 mg of the desired compound as a yellow solid; 1H NMR (300 MHz, DMSO-d6) 1.08 (s, 9H), 3.58 (m, 2H), 3.81 (m, 3H), 7.07-7.12 (m, 2H), 7.30-7.33 (m, 2H), 7.41-7.48 (m, 1H), 7.94-7.96 (m, 1H), 8.23-8.29 (m, 1H); ESI-MS (m/z) 497.21 (M+H)+.