Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[N:18]([CH2:22][CH:23]([O:25]C(=O)C)[CH3:24])[N:17]=2)=[O:14])[C:9](=[O:11])[CH:10]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[N:18]([CH2:22][CH:23]([OH:25])[CH3:24])[N:17]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: CC(=O)OC(C)Cn1nc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)nn1CC(C)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 70.4 %

Procedure:
A solution of acetic acid 2-{3-[2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-5-methyl-pyrazol-1-yl}-1-methyl-ethyl ester (Example 131, 170 mg, 0.31 mmol) in tetrahydrofuran (10 mL) and water (2 mL) at 25° C. was treated with lithium hydroxide monohydrate (40 mg, 0.93 mmol). The reaction was stirred at 25° C. for 4.5 h. At this time, the reaction was concentrated in vacuo. Silica gel column chromatography (0 to 60% tetrahydrofuran/hexanes) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as a white solid (113 mg, 70%); ES+-HRMS m/e calcd for C25H29N5O5F2 [M+H+] 518.2210 found 518.2207. 1H NMR (300 MHz, CDCl3) δ ppm 1.21 (d, J=6.0 Hz, 3H), 1.28-1.51 (m, 3H), 1.54-1.74 (m, 2H), 1.86 (br. s., 1H), 2.14-2.22 (m, 2H), 2.25 (s, 3H), 3.34 (q, J=10.8 Hz, 2H), 3.72-3.84 (m, 1H), 3.88-4.01 (m, 3H), 4.14 (br. s., 1H), 5.64-5.75 (m, 1H), 6.01 (br. s., 1H), 6.49 (s, 1H), 7.09 (t, J=8.5 Hz, 2H), 7.29-7.36 (m, 1H), 8.02 (br. s., 1H), 8.67 (br. s., 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH2:25]Br.[CH3:27][C:28]([O-:30])=[O:29].[Na+]>CC(O)=O>[C:28]([O:30][CH2:25][C:3]1[CH:4]=[C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:29])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c(CBr)c2)=NO1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3-(4-bromo-3-(bromomethyl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (36 mg, 0.068 mmol) and NaOAc (6 mg, 0.074 mmol) in AcOH (1 mL) was refluxed for 16 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in EA, washed with H2O, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-bromo-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl acetate (29 mg; yield 85%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Br.[CH3:12][N:13]([CH2:15][C:16]1[C:17]([S:23][CH3:24])=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:13]([CH3:12])[CH3:14])[C:17]=2[S:23][CH3:24])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CSc1c(O)cccc1CN(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Yield: 57.6 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.974 g, 6.26 mmol), 3-dimethylaminomethyl-2-methylsulfanyl-phenol hydrobromide (1.74 g, 6.26 mmol) and cesium carbonate (4.08 g, 12.5 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 17 h. The reaction was complete by LC/MS analysis. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-dimethylaminomethyl-2-methylsulfanyl-phenoxy)-benzonitrile (1.2 g, 58%) as a yellow oil. Fumaric acid (92 mg, 0.3 mmol) in methanol (5 mL) was added to 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (91 mg, 0.26 mmol). The solvent was removed in vacuo and diethyl ether (20 mL) was added with stirring. After 17 h, 4-chloro-2-(3-dimethylaminomethyl-2-methysulfanyl-phenoxy)-benzonitrile fumarate (63.2 mg, 47%) was filtered off as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:32]=[C:20]1[CH2:21][C:22]([C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[C:30]#[N:31])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)=[CH:10][C:9]=2[NH:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-pyrrol-1-yl-phenyl}-carbamic acid tert-butyl ester (Example M5) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (1.51 g).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[S:28][C:27]([C:29](O)=O)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:54](=[N:57][OH:58])([NH2:56])[CH3:55].O>CN(C=O)C>[CH3:3][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[S:28][C:27]([C:29]5[O:58][N:57]=[C:54]([CH3:55])[N:56]=5)=[N:26][C:25]=4[C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:36][CH:37]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: CC(N)=NO
Reactant: CC(C)(c1cc(-c2cccc(-c3sc(C(=O)O)nc3-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)c(-c3cccc(-c4cc(C(C)(C)S(C)(=O)=O)cc5cccnc45)c3)s2)n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of acid from step 1 in DMF (0.05M) was added CDI (1.1 eq) and, after 5 min, acetamidoxime (1.1 eq). The reaction mixture was stirred at rt for 1 h and 18 h at 110° C. The reaction mixture was cooled to rt and poured into water. The residue was purified by flash chromatography (toluene:EtOAc, 45:55) to afforded the title compound and decarboxylated analog EXAMPLE 73 (more polar product).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2.C([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)(OC(C)(C)C)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:30]3[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]3)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: O=[N+]([O-])c1cc(F)cc2cc(-c3ccccc3)[nH]c12
Product: Fc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
5-Fluoro-7-nitro-2-phenyl-1H-indole prepared in Preparation 25 and 1-BOC-piperidinone were reacted according to the same procedure as Example 90 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:20])[CH:6]=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc2cnccc2c1
Solvent: ClCCl
Product: [O-][n+]1ccc2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 6-fluoroisoquinoline (2.64 g, 17.9 mmol) in CH2Cl2 (70 mL) cooled at 0° C., MCPBA is added (3.4 g, 19.69 mmol). The reaction mixture is stirred at RT for 16 h. After 1 h of stirring, a yellow white precipitate forms. The solvent is evaporated under reduced pressure. To the yellow solid is added CH2Cl2 (5 mL), and the solid is isolated by vacuum filtration. Rinsing the solid with CH2Cl2 yields a white solid, which is dried under vacuum to afford 3 g (100%) of 6-fluoro-isoquinoline N-oxide.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:25]=[CH:24][C:18]([O:19][CH:20]2[CH2:23][NH:22][CH2:21]2)=[CH:17][CH:16]=1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:22]2[CH2:23][CH:20]([O:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=3)[CH2:21]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Yield: 66.7 %

Procedure:
The title compound (D78) (200 mg) was prepared according to the experimental procedure described in Description 62 starting from Methyl 2,5-dichloronicotinate (160 mg, 0.775 mmol) and 3-(4-(trifluoromethyl)phenoxy)azetidine (D52) (202.13 mg, 0.903 mmol).
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C@@H:23]([C@@H:93]([OH:111])/[CH:94]=[CH:95]/[CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108]CC)[CH2:24][O:25][C@@H:26]1[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([O:34][C@@H:35]2[O:40][C@H:39]([CH2:41][OH:42])[C@H:38]([O:43][C@@H:44]3[O:49][C@H:48]([CH2:50][OH:51])[C@H:47]([OH:52])[C@H:46]([O:53][C@@H:54]4[O:59][C@H:58]([CH2:60][OH:61])[C@H:57]([OH:62])[C@H:56]([OH:63])[C@H:55]4[OH:64])[C@H:45]3[NH:65][C:66]([CH3:68])=[O:67])[C@H:37]([O:69][C@@:70]3([C:87]([OH:89])=[O:88])[O:75][C@@H:74]([C@H:76]([OH:81])[C@H:77]([OH:80])[CH2:78][OH:79])[C@H:73]([NH:82][C:83]([CH3:85])=[O:84])[C@@H:72]([OH:86])[CH2:71]3)[C@H:36]2[OH:90])[C@H:28]([OH:91])[C@H:27]1[OH:92])=[O:21].C([O-])([O-])=O.[Na+].[Na+]>>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C@H:23]([C@H:93]([OH:111])/[CH:94]=[CH:95]/[CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH3:108])[CH2:24][O:25][C@@H:26]1[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([O:34][C@@H:35]2[O:40][C@H:39]([CH2:41][OH:42])[C@H:38]([O:43][C@@H:44]3[O:49][C@H:48]([CH2:50][OH:51])[C@H:47]([OH:52])[C@H:46]([O:53][C@@H:54]4[O:59][C@H:58]([CH2:60][OH:61])[C@H:57]([OH:62])[C@H:56]([OH:63])[C@H:55]4[OH:64])[C@H:45]3[NH:65][C:66]([CH3:68])=[O:67])[C@H:37]([O:69][C@@:70]3([C:87]([OH:89])=[O:88])[O:75][C@@H:74]([C@H:76]([OH:81])[C@H:77]([OH:80])[CH2:78][OH:79])[C@H:73]([NH:82][C:83]([CH3:85])=[O:84])[C@@H:72]([OH:86])[CH2:71]3)[C@H:36]2[OH:90])[C@H:28]([OH:91])[C@H:27]1[OH:92])=[O:21]
Reactant: CCCCCCCCCCCCCCC/C=C/[C@H](O)[C@@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC

Procedure:
IR spectroscopic examination on KBr pellets shows the typical band of the ester at 1750 cm-1. Chromatographic analysis of the product carried out in the same way as in Example 1 shows the presence of a unitary compound with an Rf of 0.77 and the absence of GM1 ganglioside and its internal ester (Rf 065 and 0.75, respectively). Hydrolysis with Na2CO3 as described in Example 1 produces the ganglioside GM1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].C([Sn](CCCC)(CCCC)/[CH:35]=[CH:36]\[CH2:37][N:38]1[CH2:42][CH2:41][C@@H:40]([O:43][C:44](=[O:46])[CH3:45])[CH2:39]1)CCC>O1CCOCC1.CS(C)=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH:12][C:13]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]3[C:16]([C:17]4[CH:29]=[CH:28][O:27][C:18]=4[CH2:19][O:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[C:2](/[CH:35]=[CH:36]\[CH2:37][N:38]2[CH2:42][CH2:41][C@@H:40]([O:43][C:44](=[O:46])[CH3:45])[CH2:39]2)[CH:7]=1
Reactant: CCCC[Sn](/C=C\CN1CC[C@@H](OC(C)=O)C1)(CCCC)CCCC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC[C@@H](OC(C)=O)C2)ccc2c1OCc1occc1-2
Temperature: 50 °C
Yield: 86.4 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 7, 0.09 g) and acetic acid (R)-1-((Z)-3-tributylstannylallyl)-pyrrolidin-3-yl ester (Intermediate 83, 0.170 g) in dioxane (4.5 mL) and DMSO (0.5 mL) was de-gassed and purged with argon for several minutes. tris-(Dibenzylideneacetone)dipalladium (0.017 g) and tri-tert-butylphosphonium tetrafluoroborate (0.011 g) were added and the solution was de-gassed, purged with argon and then heated at 50° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10% to give methyl 7-{4-fluoro-2-[(Z)-3-((R)-3-acetoxypyrrolidin-1-yl)-prop-1-enyl]-benzenesulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylate (0.092 g) as a thick yellow oil which was used without further characterisation.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH:4]([OH:9])[O:3]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH:4]([O:9][C:10](=[O:12])[CH3:11])[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1OC(O)C=CC1=O
Solvent: c1ccncc1
Product: CC(=O)OC1C=CC(=O)C(C)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 12.8 g quantity of 2-methyl-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran and 25 ml of acetic anhydride are reacted in the presence of 12.5 ml of pyridine with stirring at room temperature for 4 hours. After the reaction, the mixture is concentrated, the residue is poured into ice water, and the mixture is extracted with 100 ml of ether. The ethereal layer is washed with an aqueous solution of sodium carbonate and then dried over magnesium sulfate. After removing the magnesium sulfate, the ethereal layer is concentrated, and the residue is distilled at a reduced pressure of 0.4 mm Hg to give 12.6 g of 2-methyl-6-acetoxy-3-oxo-3,6-dihydro-2H-pyran as a colorless liquid fraction at 80° to 83° C in a yield of 80%.
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][O:30][C:31]2[CH:54]=[CH:53][C:34]([NH:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([NH:44][CH2:45][C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[O:43])[CH2:38][CH2:37]3)=[CH:33][CH:32]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][NH:44][C:42]([N:39]2[CH2:38][CH2:37][CH:36]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=4)=[CH:54][CH:53]=3)[CH2:41][CH2:40]2)=[O:43])=[CH:51][CH:50]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCOc2ccc(NC3CCN(C(=O)NCc4ccc(F)cc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 86.7 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethoxy)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.125 g, 0.15 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.075 g, 0.13 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16]O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 50 °C
Yield: 72 %

Procedure:
To a solution of 5-(4-chlorophenyl)-2-furoic acid (5.0 g, 22 mmol) in MeOH (50 mL) was added conc. H2SO4 (4 drops) and the resulting solution heated to 50° C. for 4 days. The reaction was cooloed and concentrated in vacuo. The residue was taken up in EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (2×20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash cjromatography (hexane/EtOAc 19:1) to give 3.8 g (72%) of a cream powder; MS m/z 254 (M++18, 100).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C([O-])([O-])=O.[Na+].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+].O1CCOCC1>[CH2:21]([O:20][C:18]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Glutamine (1.84 g, 12.62 mmol) was dissolved in 1 N NaOH (12.58 mL) and the solution was cooled to 0° C. and stirred for 30 min, when Na2CO3 (3.30 g) and benzyl chloroformate (4.38 mL) in dioxane (19.30 mL) were gradually added, in equal portions. Stirring continued at 0° C. for 1 h, then the solution was allowed to stir overnight at room temperature and was extracted with ethyl ether (2×20 mL). The aqueous solution was acidified with 2N HCl to pH 5 and extracted with ethyl acetate (3×50 mL), which was dried over sodium sulfate, and evaporated to give an oil which crystallized overnight. Recrystallization of the crude product gave a white crystalline material (3.07 g, 87%); FABMS 319.1 (M+K), 281.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:44])(=O)=O)=CC=1>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([F:44])=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(N3CCc4cc(S(C)(=O)=O)ccc43)c2F)CC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
4a (43 mg, 0.09 mmol) was dissolved in 1 mL of DCE with N-fluorobenzenesulfonimide (62 mg, 0.2 mmol). The mixture was stirred for 2 days at 75° C. then the solvent was evaporated under vacuum. The crude material was dissolved in 20% of DCM in methanol and purified by preparative HPLC to give 13-1; LCMS 493.1 (MH+), tR=5.21 (Method 5). EC50: 382 nM.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[CH:6][CH:5]=1.[Li]CCCC.[Cl:22]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:22][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:15])[F:16])=[CH:5][CH:6]=2)=[CH:11][N:12]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: FC(F)(F)Oc1ccc(-c2cnco2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(-c2cnc(Cl)o2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
To a round bottom flask was added 5-(4-(trifluoromethoxy)phenyl)oxazole (3.49 g, 15.23 mmol) and THF (15 mL). The reaction was cooled to −78° C. Then 2.5 M nBuLi (6.70 mL, 16.75 mmol) was added to the reaction at −78° C. The reaction turned to deep red color. After 15 min, hexachloroethane (2.59 mL, 22.84 mmol) was added at −78° C. The reaction was slowly warmed to rt over 2 hrs. The reaction was then poured onto ice and extracted with EtOAc (2×30 ml). The combined EtOAc layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 2-chloro-5-(4-(trifluoromethoxy)phenyl)oxazole, (2 g, 7.59 mmol, 49.8% yield) as a light orange liquid. Anal. Calcd. for C10H5F3NO2 m/z 263.1, found: 264.1 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.64 (s, 2 H), 7.30 (s, 4 H); 13C NMR (126 MHz, CDCl3) δ ppm 152.51, 149.41, 146.62, 125.57, 123.83, 121.41, 119.36.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:36][CH:35]=1>>[NH:2]=[C:1]([N:44]1[CH2:45][CH2:46][N:41]([CH2:40][C:37]2[CH:36]=[CH:35][N:34]=[CH:39][CH:38]=2)[CH2:42][CH2:43]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(Cc2ccncc2)CC1
Yield: 11 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of 1-(pyridin-4-ylmethyl)piperazine as secondary amine. The product was purified by preparative HPLC.