Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10]([Sn:22]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:36]1[O:37][C:38]([C:51]([CH3:59])([CH3:58])[O:52][SiH2:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:39][C:40](=[O:50])[C:41]=1[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH:18]=[C:19]([CH3:20])[CH3:21])[C:10]([Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2].[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10]([C:36]2[O:37][C:38]([C:51]([CH3:59])([CH3:58])[O:52][SiH2:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:39][C:40](=[O:50])[C:41]=2[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(=O)c(O[Si](C)(C)C(C)(C)C)c(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cn(C(=O)OC(C)(C)C)c2c(CC=C(C)C)cccc12
Solvent: Cc1ccccc1
Product: CC(C)=CCc1cccc2c(-c3oc(C(C)(C)O[SiH2]C(C)(C)C)cc(=O)c3O[Si](C)(C)C(C)(C)C)cn(C(=O)OC(C)(C)C)c12
Temperature: 90 °C
Reaction time: 20 h

Procedure:
7-(3-Methyl-but-2-enyl)-3-tributylstannanyl-indole-1-carboxylic acid tert-butyl ester (203) was prepared according to the procedure developed by our group.23 Stannane 203 (1.146 g, 1.995 mmol) and 2-bromo-3-(tert-butyl-dimethyl-silanyloxy)-6-(tert-butyl-dimethyl-silanyloxymethyl)-pyran-4-one (600 mg, 1.33 mmol) were dissolved in toluene (10 mL). Tetrakis(triphenylphosphine)palladium (77 mg, 0.067 mmol) was added. Argon was bubbled through the resulting solution for 15 min to remove oxygen. The mixture was heated to 90° C. and stirred for 20 h. The mixture was cooled to room temperature, diluted with ether and washed with saturated aqueous KF solution several times. The organic layer was dried over Na2SO4 then solvent removed under vacuum. After flash column chromatography, the desired product was obtained as a light yellow oil (532 mg, 61%). 1H NMR (CDCl3): δ 0.15 (6H, s), 0.29 (6H, s), 0.92 (9H, s), 0.96 (9H, s), 1.65 (9H, s), 1.70 (3H, s), 3.77 (2H, d, J=6.6 Hz), 4.60 (2H, s), 5.24 (1H, m), 6.48 (1H, s), 7.2-7.3 (2H, m), 7.86 (1H, m), 8.24 (1H, s). 13C NMR (CDCl3): δ −5.2, −2.8, 18.2, 18.5, 19.2, 22.5, 26.0, 26.5, 28.2, 31.6, 33.6, 61.8, 84.7, 111.0, 119.5, 123.0, 124.1, 126.3, 127.2, 129.2, 129.6, 130.9, 133.4, 134.2, 137.6, 141.5, 149.2, 149.6, 165.0, 175.3. IR (KBr): 3150, 2895, 1576, 1269, 1151 cm−1. HRMS (EI): m/z Caled. for C36H55NO6Si2 [M+] 653.3568, found 653.3577.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>CO.[Pd]>[NH2:12][C:5]1[C:4]([CH3:15])=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)cc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(F)cc(C)c1N
Reaction time: 24 h
Yield: 94.2 %

Procedure:
A solution of methyl 5-fluoro-3-methyl-2-nitrobenzoate (8.4 g, 39.4 mmol) from Step B above in methanol (150 mL) was purged with nitrogen. Palladium on charcoal was added to the solution and hydrogenation was carried out for 24 h at 1 atm. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated in vacuo to afford methyl 2-amino-5-fluoro-3-methylbenzoate (6.8 g, 94%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.32 (dd, J=10.0, 3.0 Hz, 1H), 7.17 (dd, J=9.0, 3.0 Hz, 1H), 6.40 (s, 2H), 3.80 (s, 3H), 2.13 (s, 3H); MS (ESI+) m/z 184 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cccc1OCc1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c(F)cccc1OCc1ccccc1

Procedure:
A mixture of 1-benzyloxy-3-fluoro-2-nitrobenzene (1.32 g, 5.34 mmol), SnCl2 (4.96 g, 26.2 mmol), and 1N HCl (5.5 mL, 5.5 mmol) in EtOH (25 mL) is refluxed for 18 h. The mixture is concentrated and stirred with EtOAc and 1N NaOH solution. Solid NaOH is added until strongly basic. The precipitate is removed by filtration, and the organic phase is separated. It is then dried and concentrated. The residue is purified to give the title compound: MS (M+H)+=218.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][S:5][CH2:6][CH2:7][NH2:8].[CH3:25][S:26][C:27](SC)=[CH:28][N+:29]([O-:31])=[O:30]>C(#N)C>[CH3:25][S:26][C:27]([NH:8][CH2:7][CH2:6][S:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:28][N+:29]([O-:31])=[O:30]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCSCCN
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Yield: 78.7 %

Procedure:
A mixture of 2-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ylthio)ethylamine (14.0 g, 40.0 mmol, prepared as described in Example 5) and 1,1-bis(methylthio)-2-nitroethylene (6.60 g, 40.0 mmol) in 100 ml of acetonitrile was heated at reflux temperature for 5 hours. The reaction mixture was evaporated in vacuo to dryness and the remaining residue was chromatographed on silica gel, eluting with CHCl3 /MeOH (200:1) to afford 14.7 g (78.6%) of the desired compound, as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[C:32]([F:33])=[CH:31][C:30](B(O)O)=[C:29]([O:37][CH3:38])[CH:28]=1>CN(C=O)C>[F:26][C:27]1[C:32]([F:33])=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:29]([O:37][CH3:38])[CH:28]=1
Reactant: COc1cc(F)c(F)cc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4,5-difluoro-2-methoxy phenylboronic acid (CAS RN 870777-32-5) and using DMF as reaction solvent. Off-white solid (27%). MS (ESI): m/z=491.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:20]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([N:25]1[CH2:26][CH2:27][CH:28]([NH:31][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[C:2]([NH2:1])[N:3]=2)[CH2:29][CH2:30]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: COc1ccc(F)cc1C(=O)c1ccc(Cl)nc1N
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 19) and ethyl-4-amino-1-piperidine carboxylate (Aldrich 96) using the procedure described in Step B. Example 6. HRMS, observed: 417.1938, Calcd for (M+H)+: 417.1933.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:37]C1C=C2C(C(=O)C(I)=C(C3C=CC=CC=3)O2)=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([F:37])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc(F)ccc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(F)ccc4c3=O)cc2)CCC1
Yield: 95 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-fluoro-3-iodo-2-phenyl-chromen-4-one was reacted to give the title compound (46 mg, 95%) as a colourless solid. LCMS (Method A): RT=4.91 min, [M+H]+=486.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([O:22]C)[CH:20]=3)[CH2:15][CH2:14][N:13]2[CH3:25])[CH2:11][CH2:10]1.[BrH:26]>C(O)(=O)C>[BrH:26].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([OH:22])[CH:20]=3)[CH2:15][CH2:14][N:13]2[CH3:25])[CH2:10][CH2:11]1
Reactant: COc1cc2c(cc1F)CCN(C)C2C1(c2ccc(Cl)cc2Cl)CC1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCc2cc(F)c(O)cc2C1C1(c2ccc(Cl)cc2Cl)CC1

Procedure:
A mixture of 1 -[1-(2,4 -dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (8.5 g), 48% aqueous hydrobromic acid (100 ml) and glacial acetic acid (100 ml) was heated under reflux for 2 hours. The solvents were removed in vacuo and the residue dried by azeotropic distillation with propan-2-ol. The resulting solid was recrystallised from propan-2-ol to yield 1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (7.2 g), m.p. 235°-237° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].Cl.[CH3:20]I>>[O:18]=[C:14]([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:8][CH:9]=1)[CH3:20])[C:15]([OH:17])=[O:16]
Reactant: CI
Reactant: CC(C)Cc1ccc(CC(=O)C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Cc1ccc(C(C)C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
A 3N aqueous solution of sodium hydroxide (20 ml; 60 mmoles) was slowly added to a solution of 6.60 g (30 mmoles) of p-isobutylphenylpyruvic acid and 10 ml of methyl iodide. After the addition, the mixture was stirred at room temperature for 4 hours, acidified with 1N hydrochloric acid, and extracted with 150 ml of ether. The ether layer was dried over magnesium sulfate, and the ether was evaporated under reduced pres-sure to give pale yellowish white crystals. The NMR spectrum of the crystals led to the determination that the crystals were nearly pure 2-oxo-3-(p-isobutylphenyl)butanoic acid (4.67 g; yield 67 %).
Reaction SMILES: [C:1]([C:3]1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[C:15]([CH:17]1[C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]2[CH2:30][CH2:31][CH2:32][C:19]=2[CH:18]1[C:33]([O-:35])=[O:34])#[N:16]>C1(C)C=CC=CC=1>[C:15]([C:17]1[C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]2[CH2:30][CH2:31][CH2:32][C:19]=2[C:18]=1[C:33]([O:35][CH2:1][CH3:3])=[O:34])#[N:16]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: N#CC1c2c([nH]c3ccccc23)C2=C(CCC2)C1C(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c2c(c3[nH]c4ccccc4c3c1C#N)CCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 252 %

Procedure:
DDQ (1.35 g, 5.95 mmol) was added to solution of 5-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-4-carboxylate (820 mg, 2.66 mmol) in toluene (12 mL). The solution immediately turned dark brown, and was stirred at 60° C. for 3 hr. The mixture was cooled to 20° C. overnight and filtered. The precipitate was rinsed twice with hexanes to give 2.04 g of a light green solid. This was suspended in methanol (8 mL), filtered, and the precipitate rinsed with methanol (3 mL, in portions), and ether to give 603 mg (75% yield) of product as a light green solid, mp 233–234° C. NMR (CDCl3) δ 8.80 (d, 1H), 8.20 (s, 1H), 7.52 (m, 2H), 7.38 (t, 1H), 4.52 (q, 2H), 3.42 (t, 2H), 3.19 (t, 2H), 2.31 (quintet, 2H), 1.51 (t, 3H). Anal. Calcd for C19H16N2O2-0.2H2O: C, 74.11; H, 5.37; N, 9.10. Found: C, 74.03; H, 5.06; N, 9.04.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[OH:40][C@@H:41]([C:45](C)([S:47]([CH3:50])(=[O:49])=[O:48])[CH3:46])[C:42](O)=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:42](=[O:43])[C@@H:41]([OH:40])[CH:45]([S:47]([CH3:50])(=[O:49])=[O:48])[CH3:46])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: CC(C)([C@H](O)C(=O)O)S(C)(=O)=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](O)C(C)S(C)(=O)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution containing the product from Example 2C (0.020 g, 0.038 mmol) in tetrahydrofuran (0.40 mL) were added the product from Example 156C (0.008 g, 0.041 mmol), DEPBT (0.015 g, 0.050 mmol), and N,N-diisopropylethylamine (0.020 mL, 0.115 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 50% acetone in dichloromethane to give the product (0.015 g, 56% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.81 (s, 9 H), 0.97 (s, 3 H), 1.01 (s, 3 H), 1.49-1.53 (m, 2 H), 2.53-2.60 (m, 1 H), 2.76-2.81 (m, 3 H), 2.93 (s, 3 H), 3.49 (s, 3 H), 3.64-3.70 (m, 1 H), 3.83 (d, J=9.9 Hz, 1 H), 4.21 (d, J=6.3 Hz, 1 H), 4.17-4.30 (m, 2 H), 4.98 (d, J=5.5 Hz, 1 H), 6.28 (d, J=6.3 Hz, 1 H), 6.67 (d, J=9.92 Hz, 1 H), 7.12-7.33 (m, 9 H), 7.52 (d, J=9.6 Hz, 1 H), 7.80-7.91 (m, 5 H), 8.64 (d, J=4.8 Hz, 1 H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([OH:31])[CH:25]=[CH:26][CH:27]=2)[N:22]=1.[CH2:32](O)[CH2:33][CH2:34][OH:35].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[NH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: Nc1ccc2cccc(O)c2n1
Reactant: OCCCO
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc2cccc(OCCCO)c2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 100 mL round bottom flask equipped with a stirring bar and a pressure equalized dropping funnel, under N2, was charged with 0.652 g (2 equiv) PPh3, 0.200 g (1.25 mmol) of 2-amino-8-hydroxyquinoline and 10 mL of anhydr. THF. After stirring for 10 min, 1.8 mL of 1,3-propanediol (20 equiv) was added in one portion. The reaction mixture was then cooled to 0° C. and 0.43 g (1.5 equiv) of DBAD in 15 mL THF was added dropwise over 10 minutes. The reaction was allowed to slowly warm to room temperature and stirring was maintained for 8 h. Then, 0.652 g (2 equiv) of PPh3 was added, the reaction mixture was cooled to 0° C. and 0.431 g (1.5 equiv) of DBAD in 15 mL THF was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 12 h. The solution was evaporated in vacuo, the residue was dissolved in DMA (25 mL) and MP-TsOH resin (Argonaut Technologies, Inc., 4.5 g) was added. The resulting suspension was agitated at room temperature for 12 h. The supernatant was subsequently drained and the resin was washed with DMA (2×20 mL), MeOH (2×20 mL) and DMA (20 mL). The washed resin was treated with a mixture of 2 N NH3 in MeOH (15 mL) and DMA (5 mL) at room temperature for 1 h. The solution was drained and the basic wash was repeated two more times. Filtered solutions were combined. The resin was washed with MeOH (20 mL), DMA (20 mL), MeOH (20 mL), DMA (20 mL) and MeOH (20 mL). The washes were combined with the previously collected solutions and evaporated in vacuo. The resulting crude material was purified by silica gel column chromatography (20:1 EtOAc/MeOH+2% TEA) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.87 (d, 1H), 7.29 (dd, 1H), 7.17 (t, 1H), 7.12 (dd, 1H), 6.72 (d, 1H), 4.34 (t, 2H), 3.99 (t, 2H), 2.12 (m, 2H), MS (DCI/NH3) m/z 219 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11]C(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.[N:20]1[CH:25]=[C:24]([C:26]2[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=2)[CH:23]=[N:22][CH:21]=1>>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9](=[O:11])[C:29]2[CH:28]=[CH:27][C:26]([C:24]3[CH:25]=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:34][CH:33]=2)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2cncnc2)cc1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3cncnc3)cc2)C1
Yield: 68 %

Procedure:
Following the general methods as outlined in Example 4, starting from 1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate and 4-(5-pyrimidinyl)benzoic acid, the title compound was obtained, after flash-chromatography, as a mixture of two isomers as an oil in 68% yield (93.0% purity by HPLC).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C([O-])(=O)C.[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([CH3:41])[C:21]2[N:22]([C:24]([CH2:33][CH:34]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[OH:35])=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=2)[CH:23]=1.O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH3:41])[C:21]2[N:22]([C:24]([CH2:33][C:34]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[O:35])=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:26]=2)[CH:23]=1
Reactant: Cc1cc(Cl)cn2c(CC(O)c3cccs3)c(-c3ccccc3)nc12
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Cl)cn2c(CC(=O)c3cccs3)c(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.8 %

Procedure:
A dry round bottom flask was charged with anhydrous CH2Cl2 (2 mL), PCC (22 mg, 0.10 mmol) and sodium acetate/4 Å MS (1:1, 22 mg, 0.10 mmol NaOAc). To the suspension was added 2-(6-chloro-8-methyl-2-phenyl-imidazo[1,2-a]pyridin-3-yl)-1-thiophen-2-yl-ethanol 44d (19 mg, 0.05 mmol) dissolved in CH2Cl2 (1 mL). The resulting brown suspension was stirred at room temperature for 5 h. Water (5 mL) was added, and the crude reaction was washed with CH2Cl2 (3×20 mL). The organic washes were combined and washed with brine (1×20 mL), then dried (Na2SO4), filtered and concentrated. Purification by preparative TLC with 5% MeOH/CH2Cl2 gave the title compound (4.0 mg, 21%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.70–7.62 (m, 4H), 7.48–7.37 (m, 3H), 7.09 (at, 1H), 7.02 (s, 1H), 4.61 (s, 2H), 2.66 (s, 3H). Mass spectrum (m/e) 367 (M+1)+
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:3]=1.[Cl:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O>[Cl:21][C:22]1[N:26]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)[N:3]=2)[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OC
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)cc(OC)c1OC
Temperature: 65 °C

Procedure:
To a suspension of (4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (2.97 g, 10 mmol) and 2-chlorobenzimidazole (1.53 g, 10 mmol) in dry AcCN (100 mL) was added ground K2CO3 (1.68 g, 12 mmol). The resulting mixture was heated at 65° C. for 4 h, cooled to RT, concentrated in vacuo and purified by column chromatography (EtOAc/n-Hexanes) to provide [4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine as a white powder. MS m/z 413=[M+H]+. Calc'd for C19H17ClN6O3: 412.11:
Reaction SMILES: C[O:2][C:3]([C@@H:5]([NH:16][C@H:17]([CH3:43])[C@H:18]([NH:23]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]([O:21]C)=[O:20])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:4]>CO.Cl>[NH2:23][C@@H:18]([C@H:17]([NH:16][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:43])[C:19]([OH:21])=[O:20]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)N[C@H](C)[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC
Agent: Cl
Solvent: CO
Product: C[C@@H](N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A solution of methyl (2S,3R)-3-[[(1S)-1-methoxycarbonyl-2-(3-indolyl)ethyl]amino]-2-tritylaminobutyrate (600 mg) in a mixture of methanol (10 ml) and 1N hydrochloric acid (2 ml) was stirred for 1 hour at room temperature and methanol was evaporated in vacuo. The residual aqueous solution was washed with chloroform and diluted with water (15 ml). To the solution was added sodium hydroxide (500 mg) and the mixture was stirred overnight at room temperature. The mixture was adjusted to pH 3 with 1N hydrochloric acid and the solution was subjected to a column of Dowex 50W x 8 (H+, 20 ml). The column was washed with water and the elution was carried out with 1.4% aqueous ammonia. The object fractions were collected and lyophilized to give (2S,3R)-2-amino-3-[[(1S)-1-carboxy-2-(3-indolyl)ethyl]amino]butyric acid (260 mg) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[NH:12][NH:11][C:10]2=[O:15])=[CH:5][CH:4]=1)#[CH:2].BrN1C(C)(C)C(=O)N(Br)C1=O>CC#N>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10](=[O:15])[N:11]=[N:12][C:13]2=[O:14])=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CC#N
Product: C#Cc1ccc(N2C(=O)N=NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound 13e (4.43 mg, 0.022 mmol) in CH3CN (44 μL) was added 1,3-dibromo-5,5-dimethylhydantoin (6.29 mg, 0.022 mmol) at room temperature. The resulting solution was stirred at room temperature for 10 minutes. The obtained material was easily degraded at temperature. Therefore, the 0.5 M CH3CN mixture reaction solution was used for next reaction without purification after confirmation of reaction color changing from clear to material specific deep red.