Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:22]([CH2:24]Br)=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([OH:36])[CH3:35]>>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:22]([CH2:24][O:36][CH2:34][CH3:35])=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCO
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Product: CCOCC(=O)[C@H](CCc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 3 h

Procedure:
In a 100 ml round bottom flask equipped with an argon line was placed Nu-Phe-HPhe-CH2-Br (300 mg, 0.582 mmol), potassium fluoride (150 mg, 2.4 mmol), and potassium carbonate (150 mg, 1.2 mmol), and 8 ml of 200 proof ethanol. The reaction was stirred 3 hours, filtered and the solvents were removed under vacuum and the residue chromatographed on a short silica gel column (CHCl3:MLEOH 95:5) and then recrystallized from ether.
Reaction SMILES: O=C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:17][C:18](=[O:40])[NH:19][C@H:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:22][C:23]([O:25]CC1C=CC=CC=1)=[O:24])OCC1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:17][C:18](=[O:40])[NH:19][C@H:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 142 %

Procedure:
A suspension of (9S,13S)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate (4.30 g, 6.64 mmol), 10% Pd/C (1.0 g) and ammonium formate (4.0 g) in EtOH (70 mL) under a empty balloon was stirred at room temperature overnight. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The solvent was evaporated to give (S)-4-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (4.07 g, 70%) which was used without further purification. ESMS m/z: 432.3 (M/2+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:10]2[CH:9]=[C:8]([CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:1][C:37](=[O:39])[CH3:38]
Reactant: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(N)CC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(3-(7-Amino-8-(3-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl)propyl)propane-1-sulfonamide (cf. example 209: 45 mg, 0.108 mmol) and triethylamine (15 μL, 0.108 mmol) were dissolved in dichloromethane (2 mL). Acetylchloride (7.64 μL, 0.108 mmol) were added. The reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with dichloromethane and successively washed with hydrochloric acid, water and saturated sodium chloride solution. The organic layer was dried and concentrated in vacuo. The crude product was purified by flash-chromatography (silica gel, dichloromethane, methanol). Yield: 37 mg (0.08 mmol, 75%).
Reaction SMILES: C(SC1C=C2C(C(C3C=CC=CC=3OC)=NNC2=O)=CC=1)C1C=CC=CC=1.ClN1C(C)(C)C(=O)N(Cl)C1=O.S(Cl)(Cl)(=O)=O.[Cl:44][C:45]1[CH:46]=[CH:47][C:48]([O:66][CH3:67])=[C:49]([C:51]2[C:60]3[C:55](=[CH:56][C:57]([S:61](Cl)(=[O:63])=[O:62])=[CH:58][CH:59]=3)[C:54](=[O:65])[NH:53][N:52]=2)[CH:50]=1.[F:68][C:69]1[C:74]([F:75])=[C:73]([F:76])[C:72]([F:77])=[C:71]([F:78])[C:70]=1[OH:79].C(N(CC)CC)C>CCOC(C)=O.C(Cl)Cl.O.C(O)(=O)C.C(#N)C>[Cl:44][C:45]1[CH:46]=[CH:47][C:48]([O:66][CH3:67])=[C:49]([C:51]2[C:60]3[C:55](=[CH:56][C:57]([S:61]([O:79][C:70]4[C:71]([F:78])=[C:72]([F:77])[C:73]([F:76])=[C:74]([F:75])[C:69]=4[F:68])(=[O:63])=[O:62])=[CH:58][CH:59]=3)[C:54](=[O:65])[NH:53][N:52]=2)[CH:50]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Agent: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: COc1ccccc1-c1n[nH]c(=O)c2cc(SCc3ccccc3)ccc12
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A round-bottom flask was charged with 7-(benzylthio)-4-(2-methoxyphenyl)phthalazin-1(2H)-one (150 mg, 0.401 mmol), acetonitrile (3770 μl), acetic Acid (141 μl), and water (94 μl) to give a yellow suspension. The mixture was sonicated to give a yellow suspension. The flask was cooled in an ice-bath for 30 min, then 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (158 mg, 0.801 mmol) was added in one portion. After 20 min, LCMS showed SM (m/z=375), sulfoxide (m/z=391), sulfonyl chloride (m/z=352), Cl-sulfonyl chloride (m/z=385,387). DCM (0.5 mL) was added to give a yellow solution. After 1.5 h, an orange suspension was formed. LCMS showed mainly 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonyl chloride. Then, 2,3,4,5,6-pentafluorophenol (147 mg, 0.801 mmol) was added at 0° C., followed by drop wise addition of triethylamine (223 μl, 1.602 mmol) via an addition funnel. After 15 min, LCMS showed mainly PFP sulfonate product. The mixture was diluted with EtOAc (20 mL) and washed with water (2×10 mL), washed with brine, and dried over sodium sulfate. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in hexanes, to provide perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (128 mg, 60.0% yield) as white solid. HMBC connectivities and ROESY cross-peaks confirmed the structure of perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (128 mg, 60% yield). Specifically, the chlorine was para to the methoxy substitutent. m/z (ESI) 533.0 (M+H)+.
Reaction SMILES: C1(N2C(C(F)(F)F)=C(C3[O:20]N=C4C5C(CCC=34)=CC(C=O)=CC=5)C=N2)C=CC=CC=1.[F:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[C:42]([C:43]([F:46])([F:45])[F:44])=[C:41]([C:47]3[O:51][N:50]=[C:49]4[C:52]5[C:57]([CH2:58][CH2:59][C:48]=34)=[CH:56][C:55]([CH:60]=C)=[CH:54][CH:53]=5)[CH:40]=[N:39]2)=[N:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[C:42]([C:43]([F:46])([F:45])[F:44])=[C:41]([C:47]3[O:51][N:50]=[C:49]4[C:52]5[C:57]([CH2:58][CH2:59][C:48]=34)=[CH:56][C:55]([CH:60]=[O:20])=[CH:54][CH:53]=5)[CH:40]=[N:39]2)=[N:36][CH:37]=1
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccc(F)cn2)c1C(F)(F)F
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccc(F)cn2)c1C(F)(F)F

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89B employing 3-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (122B) as a starting material. The compound had an HPLC retention time=3.56 min. (condition C); LC/MS M+1=428.9.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:10]2[C:22](=[O:23])[C:21]3[S:20][C:19]4[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=4[C:13]=3[CH2:12][CH2:11]2)[C:7]=1[CH:8]=[O:9].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.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]>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N:10]3[C:22](=[O:23])[C:21]4[S:20][C:19]5[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=5[C:13]=4[CH2:12][CH2:11]3)[C:7]=2[CH:8]=[O:9])=[CH:30]1
Reactant: O=Cc1c(Br)cncc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2cncc(N3CCc4c(sc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 40 %

Procedure:
A sealed tube was charged with 105f (200 mg, 0.53 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (240 mg, 0.51 mmol), PdCl2(dppf) (42 mg, 0.05 mmol), K3PO4 (230 mg, 1 mmol), and NaOAc (80 mg, 1 mmol) in CH3CN (5 mL) and H2O (1.5 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 10:1 of DCM/MeOH to afford 105g in 40% yield (138 mg) as a pale yellow solid. MS: [M+H]+ 638.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:13])[CH3:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:3][C:2]([NH:10][C:11](=[O:13])[CH3:12])([C:4]1[CH:5]=[CH:6][C:7]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(=O)NC(C)(C)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)NC(C)(C)c1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of N-(1-methyl-1-phenylethyl)acetamide (21.3 g, 121 mmol), phenylacetyl chloride (19.5 g, 126 mmol) and aluminum trichloride (19 g, 142 mmol) in methylene chloride (140 mL) was stirred overnight at room temperature under an atmosphere of nitrogen. The reaction was poured onto ice and stirred until the ice melted, then the layers were separated and the organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography gave the title compound. MS (M+H+): calculated=295.38, observed=296.1
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(OCC)(=O)C.CO>[NH2:19][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1ccccc1Oc1ccc([N+](=O)[O-])c(C)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1ccc(N)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
Under a hydrogen atmosphere at atmospheric pressure, a solution of methyl 2-(3-methyl-4-nitrophenoxy)-benzoate (1.85 g, 6.44 mmol) in a mixture of ethyl acetate (15 ml) and methanol (8 ml) was stirred at room temperature for 5 hours. The solution was filtered and the filtrate was concentrated to obtain methyl 2-(4-amino-3-methylphenoxy)-benzoate (1.52 g, 92%).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[CH:9]([CH3:11])[CH3:10].Br[CH2:17][CH2:18][Cl:19].[Cl-].[NH4+]>O1CCCC1>[Cl:19][CH2:18][CH2:17][C:9]([CH3:11])([CH3:10])[C:8]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)C
Reactant: ClCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 22.2 ml of diisopropylamine in 150 ml of tetrahydrofuran was added 93.6 ml of 1.6M n-butyllithium-hexane with stirring at -5° to 0° C. and the mixture was stirred for 30 minutes. The reaction mixture was cooled to -78° C. and 19.0 ml of ethyl isobutyrate was added dropwise. The mixture was then further stirred for 45 minutes, after which a solution of 11.9 ml of 1-bromo-2-chloroethane in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78° C. for 1 hour and, then, at room temperature for 2 hours. After an excess amount of an aqueous solution of ammonium chloride was added, the mixture was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. Finally, the residue was distilled under reduced pressure to provide 24.7 g of the title compound as colorless oil. b.p. 54°-56° C./0.25 mmHg
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[Br:12][C:13]1[CH:14]=[C:15]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[CH:20]([NH2:26])[CH2:19][CH2:18][CH2:17][C:16]2=1>>[Br:12][C:13]1[CH:14]=[C:15]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[CH:20]([NH:26][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:9])[CH2:19][CH2:18][CH2:17][C:16]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: O=S(=O)(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1F

Procedure:
N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamide was prepared from 2-fluorobenzenesulfonylchloride and 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid: 1H-NMR (CDCl3): δ 8.56 (s, 1H), 8.00 (m, 1H), 7.65 (m, 1H), 7.58 (m, 1H), 7.2-7.4 (m, 3H), 5.04 (d, 1H), 4.60 (m, 1H), 2.65 (m, 2H), 1.6-2.1 (m, 4H); MS m/z 421 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1>O=[Pt]=O.CCO.CO>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=2)=[C:2]([F:1])[CH:23]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(N)cc2F)ncn1
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of tert-butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl(methyl)carbamate in 1:1 EtOH/MeOH (2 mL) was treated with PtO2 (10 mg) and the reaction mixture was stirred under a blanket of H2 (from a latex balloon) for 2 h. The reaction mixture was filtered and concentrated to give the desired product (30 mg, 75%) as a light brown solid. MS(ESI+) m/z 365.13 (M+H)+.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[CH:27]1[CH:32]=[CH:31][C:30]([C:33]([Cl:47])([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[CH:37]1[CH:36]=[CH:35][C:34]([C:33]([Cl:47])([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[CH:39][CH:38]=1
Reactant: CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Product: CCCC[C@H](N)C(=O)O

Procedure:
The resin was prepared using similar methodology to that described in Example 2 step 2.3 from FmocNleOH (4.37 g) and 2-chlorotrityl chloride resin (7.45 g, 0.83 mmol/g, Novabiochem) to yield 7.77 g HNle-2-chlorotrityl resin (loading: 0.50 mmol/g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CN(C=O)C.Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20]>CCCCC>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH:5]=1
Reactant: N#CCCCBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: N#CCCCOc1cccnc1
Yield: 56 %

Procedure:
Sodium hydride (13.3 g., 0.32 mol, 57% oil dispersion) was washed with pentane to remove the oil and 26.1 g. (0.275 mol) of 3-hydroxypyridine in 300 ml. of anhydrous DMF was added with cooling in a cold water bath. The mixture was then stirred and heated at 60° for 1 hour. After cooling to 25°, 40.7 g. (0.275 mol) of 4-bromobutyronitrile in 40 ml. of anhydrous DMF was added dropwise over 1 hour with cooling to keep the reaction temperature below 30°. The reaction mixture was then stirred at 25° for 17 hours and the solvent was removed in vacuo. The residue was treated with 100 ml. of water and the product was extracted with CH2Cl2. After washing the extract with 1N NaOH and then with H2O, it was dried (MgSO4) and concentrated in vacuo to an oil which was distilled to yield 25.1 g., b.p. 133°-135°/0.4 mm, (56% yield), of 4-(3-pyridinyloxy)butyronitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 28 °C
Reaction time: 8 h
Yield: 795.3 %

Procedure:
To a stirred solution of 2-chloro-4-fluorotoluene (2.000 g, 1.383 mmol, Aldrich, used as received) in conc. H2SO4 (15.0 mL) at 0° C., KNO3 (1.400 g, 1.385 mmol) was added in one lot. The resulting pale yellow solution was allowed to warm to 28° C. and stirred overnight at 28° C. It was then poured into ice (100 g) and extracted with ethyl acetate (2×100 mL). Ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 2.085 g (80%) of title compound as an oil, which was used as such for the next reaction; 1H NMR (CDCl3): δ 2.422 (s, 3H), 7.325 (d, 1H, J1 =10.2 Hz), 7.973 (d, 1H, J1 =5.2 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16](Br)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4].[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.S(=O)(=O)(O)O>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:19][N:20]1[CH:24]=[C:23]([C:16]2[CH:15]=[N:14][C:9]3[NH:10][C:11]4[CH:12]=[N:13][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=4[C:8]=3[CH:17]=2)[CH:22]=[N:21]1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: Cn1cc(-c2cnc3[nH]c4cnc(C(=O)O)cc4c3c2)cn1
Temperature: 140 °C

Procedure:
A degassed mixture of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (30.4 mg, 99.3 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (31.0 mg, 0.149 mmol), and bis(triphenylphosphine)palladium(II) dichloride (3.5 mg, 5.0 μmol) in acetonitrile (2.5 mL) and 2N aqueous sodium carbonate solution (2.5 mL) was heated under microwave irradiation at 140° C. for 10 minutes. The cooled reaction mixture was acidified with 10% aqueous sulfuric acid, the solid removed by filtration and the resultant filtrate purified by preparative HPLC (0-30% MeCN over 30 min, 35 mL/min) to afford the title compound. 1H NMR (DMSO-D6, 500 MHz): 12.84 (s, 1H), 9.04 (d, J=2.1 Hz, 1H), 8.95 (s, 2H), 8.91 (d, J=2.1 Hz, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 6.48 (s, 1H), 3.92 (s, 3H). LCMS (Method D): RT=5.24 min, M+H+=294.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1)[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S-:21].[Na+].O>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([S:21][CH3:20])[CH:17]=1)[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CCCC(NC(=O)OC(C)(C)C)c1cncc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(NC(=O)OC(C)(C)C)c1cncc(SC)c1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A solution of [1-(5-bromo-pyridin-3-yl)-butyl]-carbamic acid tert-butyl ester (6.3 g, 19 mmol) and sodium thiomethoxide (2.7 g, 38 mmol) in anhydrous THF (27 mL) is heated at 70° C. After 2 hours the reaction is cooled to room temperature and water (200 mL) is added. The resultant mixture is extracted with ethyl acetate (3×200 mL). The combined organic layers are combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluted with 0 to 60% EtOAc/hexanes) to afford [1-(5-methylsulfanyl-pyridin-3-yl)-butyl]-carbamic acid tert-butyl ester (3.9 g, 68%) as a thick light yellow oil.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(=O)(=O)(O)O.[CH3:22][C:23]1[CH2:27][CH2:26][CH2:25][CH:24]=1>ClCCl>[CH3:22][C:23]1([O:15][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC1=CCCC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC1(C)CCCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a magnetically stirred solution of 22.3 g (0.1 mol) N-Cbz-D-alanine in 50 mls of dry dichloromethane containing 0.5 mls of concentrated sulfuric acid at 0° C., was added dropwise a 10 g (0.1 mol) sample of 1-methylcyclopentene in 50 mls of dichloromethane. After 5 days of stirring at room temperature, the mixture was heated to reflux for 4 hours, after which the reaction was cooled to room temperature, washed with 100 mls of saturated NaHCO3, 100 mls of water and dried over MgSO4. Filtration followed by evaporation of the solvent yielded 1.81 g of the product.