Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([S:8][CH3:9])[CH:7]=1.Cl[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C([N:26](C(C)C)CC)(C)C.C(#N)C>C(Cl)Cl.CC(O)C.C(Cl)Cl>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[CH2:13][C:2]1[C:3](=[O:11])[N:4]([NH2:26])[C:5]([CH3:10])=[C:6]([S:8][CH3:9])[CH:7]=1
Reactant: CSc1cc(N)c(=O)[nH]c1C
Reactant: CCN(C(C)C)C(C)C
Reactant: ClCc1nc2ccccc2o1
Solvent: ClCCl
Solvent: CC#N
Solvent: CC(C)O
Product: CSc1cc(Cc2nc3ccccc3o2)c(=O)n(N)c1C

Procedure:
A mixture of 3-amino-5-methylthio-6-methylpyridin-2(1H)-one (0.201 g, 0.0013 mol), 2-chloromethylbenzoxazole (0.239 g, 0.0014 mol), diisopropylethylamine (0.181 g, 0.0014 mol), and acetonitrile (6 mL) was heated at reflux under nitrogen for 35 hours. The dark solids which had formed were removed by filtration (0.089 g), and the filtrate evaporated to dryness. The two fractions were combined and chromatographed on a 30 mm column containing 230-400 mesh silica gel (6 inches). The column was prepared with methylene chloride and the crude product applied in methylene chloride. Development of the column was with 2% 2-propanol/methylene chloride (500 mL), 5% 2-propanol/methylene chloride (500 mL), and 10% 2-propanol/methylene chloride (1000 mL). Concentration of the fractions containing the desired product gave 0.133 g (33.5% yield) of 3-[(2-Benzoxazolyl)methyl]amino-5-methylthio-6-methylpyridin-2(1H)-one m.p. 180°-181° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3ccc(F)cc3)C(C)(C)C2=O)cn1
Yield: 40 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-4-fluorobenzene. Yield 40%, white solid. 1H NMR (DMSO-d6, 400 MHz): s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 4.53 (s, 2H), 5.18 (s, 2H), 7.13 (m, 2H) 7.43 (m, 2H), 7.81 (s, H), 8.18 (s, 1H). MS 412 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]3[N:14]=[C:15]4[C:21]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:20][N:19](COCC[Si](C)(C)C)[C:16]4=[N:17][CH:18]=3)=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]3[N:14]=[C:15]4[C:21]([C:22]([NH:24][CH:25]([CH3:26])[CH3:27])=[O:23])=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)C)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)C)c3n2)c2ccc(Cl)cc21
Reaction time: 4 h
Yield: 90.8 %

Procedure:
2-(6-Chloro-1-ethyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 152 μmol) was dissolved in dichloromethane and to this was added trifluoroacetic acid (1.73 g, 1.17 mL, 15.2 mmol). The mixture was stirred for 4 h then concentrated en vacuo. The residue was diluted in dichloromethane and re-concentrated, and finally diluted again in dichloromethane and to this was added ethylenediamine (685 mg, 770 μL, 11.4 mmol). After 15 h the mixture was concentrated in vacuo, triturated with water and the collected solid was filtered and dried. The solid was purified by chromatography (Silica, SiliCycle 25 g cartridge, 0-5% methanol in dichloromethane, 15 min gradient) to give 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (53 mg, 138 μmol, 91.1%) as a pale yellow powder. MS (M+H)+=383; 1H NMR (CDCl3) δ: 11.74 (br. s., 1H), 9.11-9.15 (m, 1H), 8.41 (d, J=8.7 Hz, 1H), 8.20 (d, J=3.0 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 7.44 (s, 1H), 7.15 (dd, J=8.5, 1.3 Hz, 1H), 4.28-4.48 (m, 3H), 1.53 (t, J=7.2 Hz, 3H), 1.33 (d, J=6.4 Hz, 6H)
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C@H:4]([N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[CH:53][CH:52]=1>CN(C=O)C.C(OCC)C>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH:57]([C:54]2[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=2)[N:58]2[CH2:59][CH2:60][N:61]([C:5](=[O:7])[C@@H:4]([N:8]([CH3:15])[CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH2:3][CH:2]([CH3:1])[CH3:16])[CH2:62][CH2:63]2)=[CH:69][CH:68]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCOCC1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)N(C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid (0.200 g, 0.873 mmol, Example 27, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N,-diisopropylethylamine (0.304 mL, 1.75 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.331 g, 0.873 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.252 g, 0.873 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane) to provide 0.326 g (75%) of the pure titled compound as a white foam: mp 56-65° C. APCI-MS m/z 500.3 (MH+).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][OH:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>ClCCl>[C:25]([O:7][CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCC(CO)NC(C)=O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC=CCCCCCCCC(=O)OCC(CCCCCCCCCC)NC(C)=O
Yield: 82.8 %

Procedure:
To a solution of 2.43 g of 2-ethanoylaminododecanol, 3 g of triethylamine in 50 ml of dichloromethane is added 3.2 g of oleoyl chloride. The reaction mixture is worked up as under Example 9 to give 4.2 g of product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH2:6][CH3:7].C(O)(=O)C.N([O-])=O.[Na+]>O>[CH2:5]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12]([CH3:18])=[CH:13][C:14]([N+:1]([O-:4])=[O:2])=[CH:15][C:16]=1[CH3:17])[CH2:6][CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CCCOC(=O)Nc1c(C)cccc1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCOC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Temperature: 0 °C
Yield: 42 %

Procedure:
To a solution of concentrated nitric acid (6.4 mL) in water (30 mL) was added (2,6-dimethyl-phenyl)-carbamic acid propyl ester (2.72 g), acetic acid (30 mL) and sodium nitrite (1.0 g). The reaction mixture was refluxed for 16 hours, water (200 mL) was added and the mixture was cooled to 0° C. The product was collected by filtration and dried in vacuo to furnish 1.40 g (42% yield) of the title compound as a yellow solid. The crude product was used without further purification. 1H NMR (500 MHz, DMSO-d6): 0.92 (t, 3H), 1.63 (m, 2H), 2.29 (s, 6H), 4.04 (t, 2H), 7.98 (s, 2H), 9.11 (b, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Agent: [Pd]
Solvent: CO
Product: N#CC1(c2ccc(N)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 4-(4-nitro-phenyl)-tetrahydro-pyran-4-carbonitrile (as prepared in the previous step, 223 mg, 0.960 mmol) and 10% Pd/C (112 mg, 50 wt %) in 10 mL of MeOH was stirred at RT under H2 (balloon pressure) for 1 h. The Pd catalyst was removed by filtration on Celite and the filtrate was concentrated to give 195 mg (100%) of the title compound as a faint yellow solid. Mass spectrum (ESI, m/z): Calcd. for C12H14N2O, 203.1 (M+H). found 203.2.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.CN(C1C=CC=CN=1)C.C(Cl)(=O)C1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([S:11]([N:8]3[CH2:7][CH2:6][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:10][CH2:9]3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: NCc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)phenyl]methanamine 7b (3.00 g, 10.1 mmol) was dissolved in DCM (20 ml), pyridine (976 μl, 12.1 mmol), 4-chlorobenzoyl chloride (1.41 ml, 11.1 mmol) and dimethylaminopyridine (catalytic amount) were added and the mixture was stirred at room temp overnight. Excess benzoylchloride was scavenged with aminomethyl-PS (2.0 g, 2.2 mmol) by shaking for 2 h. The resin was filtered off and washed with DCM (20 ml). The combined filtrates were washed with saturated aqueous citric acid (20 ml), dried over magnesium sulphate and evaporated to dryness to yield 2.7 g (59%) sulfonamide 4-chloro-N-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)benzyl]benzamide 7c in >90% purity (LC-MS).
Reaction SMILES: Br.Br[C:3]1[N:9]=[C:8](N)[CH2:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[CH:4]=1.[OH2:15].[OH2:16].O.C([O-])(=O)C.[Na+]>O>[CH2:4]1[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[CH2:7][C:8](=[O:15])[NH:9][C:3]1=[O:16]
Reactant: NC1=NC(Br)=Cc2ccccc2C1
Reactant: O
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C1Cc2ccccc2CC(=O)N1
Temperature: 85 °C
Yield: 89.9 %

Procedure:
4-Bromo-1H-benzo[d]azepin-2-ylamine hydrobromide (41.2 g) was dissolved in 600 ml of H2O that was previously heated to 85° C. Sodium acetate trihydrate (18.5 g) was added portion wise and the solution was heated to 90° C. for 3 h. Cooling to room temperature caused the precipitation of a white solid that was filtered-off, washed with water and desiccated under reduced pressure to afford the title compound (20.4 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:24]4[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccc(C=O)cc3)cc1)cn2C1CCOC1

Procedure:
In a similar manner to Example 9, 4-[4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol was reacted with 4-fluorobenzaldehyde to give 4-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzaldehyde.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH:13]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[OH:30][C:26]1[CH:25]=[C:24]([C:13](=[O:12])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(O)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred suspension of PCC (42.3 g, 196 mmol) and Celite (43 g) in DCM (300 mL) was cooled to 0° C. To this was added carbamate 129 (35.0 g, 131 mmol), slowly over a period of 15 min. The reaction mixture was allowed to stir at room temperature for 2 h during which the transformation was found to be complete. The reaction mass was then filtered through a pad of Celite and the filter bed was washed with DCM. Concentration of the filtrate gave a black tarry mass which was purified by flash chromatography (30-50% Ethyl acetate-Hexanes gradient) to give tert-butyl 3-(3-hydroxyphenyl)-3-oxopropylcarbamate (145) as pale yellow solid. Yield (20.3 g, 58%): 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.27-7.40 (m, 2H), 7.01 (dd, J=8.0, 1.6 Hz, 1H), 6.80-6.83 (m, 1H), 3.22-3.27 (m, 2H), 3.08 (t, J=6.8 Hz, 2H), 1.36 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][C:5]1[C:6]([I:8])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Br)nc1I
Product: CC(=O)Oc1ccc(Br)nc1I
Reaction time: 0.5 h
Yield: 100 %

Procedure:
6-bromo-2-iodopyridin-3-ol (150 mg, 0.500 mmol) was added to acetic anhydride (2.4 mL, 25 mmol) at 130° C. It was allowed to stir for 30 min then concentrated and chased with toluene to give the expected product 6-bromo-2-iodopyridin-3-yl acetate (171 mg, 0.500 mmol, 100% yield) by NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (1H, d, J=8.28 Hz), 7.62 (1H, d, J=8.28 Hz), 2.36 (3H, s). LC-MS retention time: 1.66 min; m/z (MH+): 342, 344. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[C:13]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].CN1CCOCC1.Cl>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[C:13]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Hexanoylchloride (0.029 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.05 g.) and N-methylmorpholine (0.05 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (15 ml.). This mixture was extracted with ethyl acetate (2×20 ml.). The combined extracts were dried (MgSO4), and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 4:6 v/v ethyl acetate:hexane, to give a colorless oil, which was crystallized from a mixture of toluene and hexane to give the title compound (0.05 g, 65%) as a white powder: NMR: 0.86(t, 3H, CH2.CH3), 1.28(m,4H, CH2.CH2.CH3), 1.57(quintet, 2H, CH2.CH2.CON), 2.25(t,2H, CH2.CH2.CON), 3.69(s,3H, NCH3), 3.82(s,3H, CO.OCH3), 3.92(s,3H, OCH3), 3.97(s, 2H, CH 2.Ar), 7.05(s,1H), 7.13(d,1H), 7.27(d,1H), 7.28(d,1H), 7.40(dd,1H), 7.48(s,1H), 7.74(s,1H), 9.61(s,1H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1([C:17](C2C=CC=CC=2)=CC=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O.CO>[C:11]1([CH:17]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
A solution of 1.81 g (13.3 mmol) of 2'-hydroxyacetophenone, 2.75 g (13.2 mmol) of β-phenylcinnamaldehyde, 2.64 g NaOH (in 10 mL of water) and 100 mL MeOH was stirred for 24 hours before the solution was poured into 1000 mL water. The resulting mixture was neutralized with dilute HCl and the yellow precipitate was collected by filtration. Recrystallization from MeOH gave a pure intermediate chalcone product. Further oxidation of the above chalcone was carried out with excess H2O2 (30%) in basic (NaOH aq.) MeOH solution for 18 hours. This solution was poured into water, and neutralized with dilute HCl. The resulting light yellow precipitate was collected by filtration and the pure desired product was obtained by recrystallization from MeOH with 28% overall yield. MP: 215°-216° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 0.004. Extinction coefficient εmax (M-1 cm-1) 23,000. λmax (abs)=378 nm and λmax (em)=470 nm.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:18][C:8]1[N:7]=[CH:6][C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[CH:10][CH:9]=1
Reactant: [O-][n+]1cccc(Oc2ccccc2F)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccccc1Oc1ccc(Cl)nc1

Procedure:
A solution of 25 g of 3-(o-fluorophenoxy)pyridine N-oxide in 50 ml of chloroform is added dropwise to 77 g of refluxing phosphorous oxychloride. The mixture is refluxed for 2 hours. The mixture is concentrated at reduced pressure. The oil is dissolved in 500 ml dichloromethane, washed with 50 ml of ice cold concentrated ammonium hydroxide and dried over anhydrous MgSO4. The organic phase is separated, concentrated at reduced pressure and distilled to yield the mixture of desired chlorinated pyridines as an oil, bp 92°-105° C. at 0.1 mm. The oil is dissolved in 50 ml of toluene and chromatographed over 450 g of silica gel in toluene to yield in the first eluate 6-chloro-3-(o-fluorophenoxy)pyridine. Continued elution with toluene yields 2-chloro-3-(o-fluorophenoxy)pyridine. Finally elution with toluene-methanol (50:50) yields 4-chloro-3-(o-fluorophenoxy)pyridine.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[I:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:19]=2)[CH:16]=1>CO>[OH:3][NH:2][C:24](=[NH:25])[C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]3[CH:13]=[CH:12][C:11]([I:10])=[CH:16][N:15]3[CH:17]=2)=[CH:27][CH:26]=1
Reactant: NO
Reactant: N#Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N=C(NO)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Yield: 73.8 %

Procedure:
Hydroxylamine hydrochloride (208 mg) and potassium carbonate (415 mg) were added to a solution (10 mL) of 4-(6-iodoimidazo[1,2-a]pyridin-2-yl)benzonitrile (345 mg) in methanol, followed by refluxing for 14 hours. The mixture was left to cool, and the formed crystals were recovered through filtration. The crystals were washed with water and dried, to thereby yield the title compound (279 mg).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]([NH:26][NH:27][C:28](=O)[CH2:29][C:30]1([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]1)=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:28]([CH2:29][C:30]2([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:32][CH2:31]2)=[N:27][N:26]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 67.5 %

Procedure:
Pyridine (5.2 g, 65.6 mmol) was added to a 0° C. solution of tert-butyl 1-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclopropylcarbamate (4.0 g, 8.2 mmol) in DCM (40 mL). Tf2O (5.7 g, 20.5 mmol) was added slowly at 0° C. The reaction mixture was stirred at 0° C. for 3.5 hrs. Sat. NaHCO3 was added very slowly at 0° C. The organic layer was separated and washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (0˜70% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)cyclopropylcarbamate (2.6 g, 65%) as a yellow solid. ESI-MS (EI+, m/z): 470 [M+H]+.