Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCO[C:24]([CH3:26])=[O:25]>[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:24](=[O:25])[C:26]2[CH:12]=[CH:13][CH:14]=[CH:15][N:18]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cc2ccccc2Cl)cc1
Agent: [Pd]
Product: O=C(Nc1ccc(S(=O)(=O)Cc2ccccc2Cl)cc1)c1ccccn1
Reaction time: 12 h

Procedure:
To a solution of 2-chlorobenzyl)(4-nitrophenyl)sulfane (1.0 equivalent) in DCM at 0° C. was added m-CPBA (3.0 equivalents). After 30 min, the ice bath was removed. The reaction was followed by thin liquid chromatography (TLC). The reaction was added to DCM:NaHCO3 (sat'd) (1:1) and the organic layer was separated. After washing the organic layer with water (2×) and brine, it was dried (MgSO4), filtered and concentrated to provide 1-chloro-2-(((4-nitrophenyl)sulfonyl)methyl)benzene. Analytical: Rf=0.72 (50% EtOAc/hexanes); LCMS (Method 2): RT=1.41 min, >90% @ 254 nM, m/z=333.8 [M+Na]+. Step 3: To a solution of 1-chloro-2-(((4-nitrophenyl)sulfonyl)methyl)benzene in EtOAc (0.3 M) was added 5% Pd/C (˜0.1 equivalent). An H2 atmosphere (1 atm) was applied to the rxn mixture. After 12 h, TLC confirmed loss of starting material, so rxn was filtered through Celite and concentrated. The crude residue, 4-(((2-chlorobenzyl)sulfonyl)aniline, was carried through without further purification (85-95% yield over 2 steps). Analytical: Rf=0.40 (50% EtOAc/hexanes); LCMS (Method 2): RT=1.25 min, >98% @ 254 nM, m/z=281.9 [M+H]+. Step 4: To a solution of the 4-(((2-chlorobenzyl)sulfonyl)aniline in DMF:DIEA (4:1) (0.1 M). The appropriate acid chloride (1.0 equivalent) was added and after 12 h at 85° C., N-(4-(((2-chlorobenzyl)sulfonyl)phenyl)picolinamide was directly purified by mass-guided preparative HPLC.
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:20]1.C[Si](C=[N+]=[N-])(C)C>CO>[CH:1](=[N:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:20])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1NN=Cc1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccccc1NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
2-(N′-Benzylidene-hydrazino)-benzoic acid (5.0 g, 20.81 mmol) in 1:1 tetrahydrofuran and methanol (50 mL) was reacted with a solution of trimethylsilyl diazomethane in hexanes (2.0M, 12 mL, 25.0 mmol) at 0° C. for 1 hour then stirred at 25° C. for 48 hours. The solvent was removed under vacuum to give methyl 2-[2-benzylidenehydrazino]benzoate as a solid (6.00 g, 100%). 1H NMR (300 MHz, DMSO-d6) ppm 3.87 (s, 3 H) 6.84 (td, J=7.54, 1.10 Hz, 1 H) 7.41 (m, 3 H) 7.54 (m, 1 H) 7.74 (m, 3 H) 7.86 (dd, J=8.09, 1.47 Hz, 1 H) 8.21 (s, 1 H) 11.02 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[C:5]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH3:12])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=2[CH:3]=1
Reactant: CCCCCCBr
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1-2
Product: CCCCCCC1(CCCCCC)c2cc(Cl)ccc2-c2ccc(Cl)cc21
Yield: 91 %

Procedure:
2,7-Dichloro-9,9-di(1-hexyl)fluorene is prepared from 2,7-dichlorofluorene and 1-bromohexane following the procedure of Example 1 as colorless crystals (recrystallized from hexane) in 91 percent yield, melting point 66° C. to 67° C. HPLC analysis shows that the sample is 99 percent or greater pure and the spectral data confirms the title structure.
Reaction SMILES: C(O)(=O)C.O[C@@H]([C@H]1C(=O)N2C(C([O-])=O)=C(C3SC4=C(C(=O)CC)N=CN4C=3)[C@H](C)[C@H]12)C.[Na+].[Si]([O:40][CH2:41][CH2:42][N:43]([CH3:80])[S:44]([C:47]1[N:48]=[CH:49][N:50]2[CH:54]=[C:53]([C:55]3[C@H:56]([CH3:79])[C@@H:57]4[C@@H:74]([C@H:75]([OH:77])[CH3:76])[C:73](=[O:78])[N:58]4[C:59]=3[C:60]([O:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([N+:70]([O-:72])=[O:71])=[CH:66][CH:65]=3)=[O:61])[S:52][C:51]=12)(=[O:46])=[O:45])(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C1COCC1>[OH:77][C@@H:75]([C@H:74]1[C:73](=[O:78])[N:58]2[C:59]([C:60]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][C:67]([N+:70]([O-:72])=[O:71])=[CH:68][CH:69]=3)=[O:61])=[C:55]([C:53]3[S:52][C:51]4=[C:47]([S:44](=[O:45])(=[O:46])[N:43]([CH2:42][CH2:41][OH:40])[CH3:80])[N:48]=[CH:49][N:50]4[CH:54]=3)[C@H:56]([CH3:79])[C@H:57]12)[CH3:76]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(=O)(=O)N(C)CCO[Si](C)(C)C(C)(C)C)c4s3)[C@H](C)[C@H]12
Agent: CCC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(=O)(=O)N(C)CCO)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetic acid (0.36 ml) and 2.0 ml of a 1 M-tetra-n-butylammonium fluoride/THF solution were added under ice cooling to a solution of 273 mg, of 4-nitrobenzyl (1S,5R,6S)-2-[7-[N-(2-t-butyldimethylsilyloxyethyl)-N-methylsulfamoyl]imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 8 ml of THF. The mixture was stirred at room temperature for 6 hr. The reaction mixture was added to a dilute aqueous sodium hydrogencarbonate solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1) to give 175 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[N-(2-hydroxyethyl)-N-methyl-sulfamoyl]imidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[CH2:14]([CH:17]([C:20]#[N:21])[C:18]#[N:19])[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([C:17]([CH2:8][N:6]1[CH:7]=[C:3]([Br:2])[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5]1)([C:20]#[N:21])[C:18]#[N:19])[CH:15]=[CH2:16]
Reactant: C=CCC(C#N)C#N
Reactant: CC(C)(C)c1nn(CCl)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cn1cc(Br)c(C(C)(C)C)n1
Yield: 40.9 %

Procedure:
1.84 g of 4-bromo-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.77 g of allyl malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 2.02 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.84 g of allyl [(4-bromo-3-t-butyl-1H-pyrazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (14), hereinafter) shown by below formula.
Reaction SMILES: C(C1C=C(NC2N=C(NC3C=CC=C(C(O)=O)C=3)C(F)=CN=2)C=CC=1)(O)=O.[OH:28][C:29]1[CH:30]=[C:31]([NH:39][C:40]2[N:45]=[C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]([O:55]C)=[O:54])=[C:49]([OH:57])[CH:48]=3)[C:43]([F:58])=[CH:42][N:41]=2)[CH:32]=[CH:33][C:34]=1[C:35]([O:37]C)=[O:36].[OH-].[Na+]>>[OH:28][C:29]1[CH:30]=[C:31]([NH:39][C:40]2[N:45]=[C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]([OH:55])=[O:54])=[C:49]([OH:57])[CH:48]=3)[C:43]([F:58])=[CH:42][N:41]=2)[CH:32]=[CH:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)c(O)c3)n2)cc1O
Agent: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)O)c(O)c3)n2)cc1O
Yield: 78.1 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of N2,N4-bis[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine (70 mg, 0.16 mmol) and NaOH (100 mg, 2.5 mmol) gave N2,N4-bis(3-hydroxy-4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (50 mg, 77%) as a white solid. 1H NMR (DMSO-d6): δ 7.21 (dd, J=1.5 and 8.7 Hz, 1H), 7.46-7.52 (m, 3H), 7.63 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 8.28 (d, J=3.3 Hz, 1H), 9.71 (s, 1H, NH), 9.79 (s, 1H, NH), 11.34 (br, 2H); 19F NMR (282 MHz, DMSO-d6): δ−161.10; LCMS: ret. time: 20.76 min.; purity: 84.65%; MS (m/e): 400.95 (MH+).
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15]([OH:17])=[O:16].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:2]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15]([OH:17])=[O:16])(=[O:1])[CH3:3]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C(=O)O)ccc1Cl
Temperature: 0 °C

Procedure:
Tetrahydrofuran (THF) room temperature (RT), NaHCO3 solution 101.9 g (582 mmol) of 3-amino-4-chlorobenzoic acid were suspended in 700 ml of acetic acid and then admixed with 64.8 ml (687 mmol) of acetic anhydride. The mixture was heated under reflux for 15 h and, after cooling, was added to 1.5 l of ice-water. The precipitated crystals were isolated by filtration with suction, washed with water, and dried in a vacuum cabinet at 70° C. for 17 h.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:12]=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:27][C:28]([CH3:31])([O-])[CH3:29].[K+]>CN(C=O)C>[CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:12]=[CH:27][C:28]2[CH:31]=[CH:31][C:28]([CH:27]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][C:17]([N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:18][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:5][CH:6]=3)=[CH:29][CH:29]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCN(CC)c1ccc(C(=CC=O)c2ccc(N(CC)CC)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C(=CC=Cc2ccc(C=CC=C(c3ccc(N(CC)CC)cc3)c3ccc(N(CC)CC)cc3)cc2)c2ccc(N(CC)CC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
In 100 ml of DMF were dissolved 2.5 g of 3,3-bis(p-diethylaminophenyl)acrolein and 1.5 g of p-xylene-α,α'-diylbis(diethyl phosphonate), and then 0.9 g of potassium tert-butoxide was added to the solution at room temperature. Thereafter, the reaction was carried out for 4 hours at room temperature with stirring and the reaction mixture was poured into 100 ml of ice-water with stirring. Then, precipitates thus deposited were collected by filtration, dissolved in benzene, and separated and purified by silica gel column chromatography (eluent: benzene). After distilling off benzene from the effluent, the residue was recrystallized from ethyl acetate to provide 1.74 g (yield 63.0%) of red crystals having a melting point of 201.5° C. to 204.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]1[CH:59]=[C:60]([CH:63]=[CH:64][CH:65]=1)[CH2:61][NH2:62])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([NH:62][CH2:61][C:60]1[CH:63]=[CH:64][CH:65]=[C:58]([O:57][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:59]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(OCc2ccccc2)c1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCc1cccc(OCc2ccccc2)c1
Reaction time: 18 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)methionine (1.20 g, 4.8 mmol) in dry CH2Cl2 (25 mL) under argon were added PYBOP (2.90 g, 5.6 mmol), 3-benzyloxybenzylamine, as described above in Step I, (1.0 g, 4.7 mmol), and N,N-diisopropylethylamine (0.89 mL, 5.1 mmol). The reaction mixture was stirred for 18 hours, then extracted with saturated aqueous NaHCO3 (25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—25% EtOAc to yield the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24]
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Br)c(OCCOCCOC)c2s1
Yield: 39 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6, potassium carbonate and 2-(2-methoxyethoxy)ethyl bromide in DMF was reacted to give 0.026 g (39%) of the desired compound 12. 1H NMR (DMSO) δ 10.65 (br s, 1H, NH), 7.54 (d, 1H, J=8.5 Hz, ArH), 7.32 (d, 1H, J=8.6 Hz, ArH), 6.73 (br s, 1H, NH), 4.24 (d, 2H, J=4.4 Hz, CH2), 3.76 (d, 2H, J=4.8 Hz, CH2), 3.61 (dd, 2H, J=6.0, 5.2 Hz, CH2), 3.48 (dd, 2H, J=6.0, 5.2 Hz, CH2), 3.26 (s, 3H CH3), 3.19 (m, 2H, CH2), 1.09 (t, 3H, J=7.1 Hz, CH3); LC/MS 418 (MH+); RP-HPLC RT 2.95 minutes.
Reaction SMILES: C(O)C(N)(CO)C[OH:4].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OP(O)(O)=O)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O.[CH3:73][C:74]1[S:78][CH:77]=[C:76](/[CH:79]=[C:80](/[C@H:82]2[O:99][C:97](=[O:98])[CH2:96][C@H:95]([OH:100])[C:94]([CH3:102])([CH3:101])[C:92](=[O:93])[C@H:91]([CH3:103])[C@@H:90]([OH:104])[C@@H:89]([CH3:105])[CH2:88][CH2:87][CH2:86][C:85]([CH3:106])=[CH:84][CH2:83]2)\[CH3:81])[N:75]=1>>[CH3:105][C@@H:89]1[C@H:90]([OH:104])[C@@H:91]([CH3:103])[C:92](=[O:93])[C:94]([CH3:102])([CH3:101])[C@@H:95]([OH:100])[CH2:96][C:97](=[O:98])[O:99][C@H:82](/[C:80](/[CH3:81])=[CH:79]/[C:76]2[N:75]=[C:74]([CH3:73])[S:78][CH:77]=2)[CH2:83][C@@H:84]2[O:4][C@:85]2([CH3:106])[CH2:86][CH2:87][CH2:88]1
Reactant: NC(CO)(CO)CO
Reactant: CC1=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: 90 °C
Reaction time: 1.12 h

Procedure:
The EpoK assay was performed as follows (See Betlach et a., Biochem (1998) 37:14937, incorporated herein by reference). Briefly, reactions consisted of 50 mM Tris (pH7.5), 21 μM spinach ferredoxin, 0.132 units of spinach ferredoxin: NADP+ oxidoreductase, 0.8 units of glucose-6-phosphate dehydrogenase, 1.4 mM NADP, and 7.1 mM glucose-6-phosphate, 100 μM or 200 μM epothilone D (a generous gift of S. Danishefsky), and 1.7 μM amino terminal his tagged EpoK or 1.6 μM carboxy terminal his tagged EpoK in a 100 μL volume. The reactions were incubated at 30° C. for 67 minutes and stopped by heating at 90° C. for 2 minutes. The insoluble material was removed by centrifugation, and 50 μL of the supernatant were analyzed by LC/MS. HPLC conditions: Metachem 5 μ ODS-3 Inertsil (4.6×150 mm); 80% H2O for 1 min, then to 100% MeCN over 10 min at 1 mL/min, with UV (λmax=250 nm), ELSD, and MS detection. Under these conditions, epothilone D eluted at 11.6 min and epothilone B at 9.3 min. the LC/MS spectra were obtained using an atmosphere pressure chemical ionization source with orifice and ring voltages set at 20 V and 250 V, respectively, at a mass resolution of 1 amu. Under these conditions, epothilone E shows an [M+H] at m/z 493, with observed fragments at 405 and 304. Epothilone B shows an [M+H] at m/z 509, with observed fragments at 491 and 320.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:26])([C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:5][OH:6].Cl[CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1>CN(C)C=O>[F:3][C:4]([F:26])([C:7]([F:24])([F:25])[C:8]([F:22])([F:23])[C:9]([F:20])([F:21])[C:10]([F:18])([F:19])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:5][O:6][CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1
Reactant: CC1(CCl)COC1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dispersion of 50 weight percent sodium hydride (4.0 g, 83 mmol) in mineral oil was washed with hexanes and suspended in 200 milliliters of dimethylformamide. A solution of 30 grams of 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol (75 mmol) in 50 milliliters of dimethylformamide was added over a period of 3 hours, and the resulting mixture was stirred at room temperature for one hour. Next, a solution of 9.3 grams (77 mmol) of 3-chloromethyl-3-methyloxetane in 20 milliliters of dimethylformamide was added and the resulting mixture was heated at 75° C. for 16 hours. The mixture was cooled to room temperature and slowly poured into 1 liter of ice/water and extracted with two volumes of Freon 113. The combined organic extracts were washed twice with water, once with 2 weight percent aqueous hydrochloric acid and once with brine, dried over magnesium sulfate, filtered, and evaporated to give 32 grams of crude product. The crude product was distilled under reduced pressure to give 26.5 grams (73%) of analytically pure 3-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctoxymethy)-3-methyloxetane (i.e., 15-FOX), an oil with a boiling point of 68 to 70° C./16 mm-Hg. The experimental analyses were: 1H NMR (CDCl3/Freon 113) δ 4.49 and 4.37 (AB, J=5.5 Hz, 4 H), 4.00 (triplet, J=13.2 Hz, 2 H), 3.70 (singlet, 2 H), and 1.32 (singlet, 3 H); 13C NMR δ 21.02, 40.33, 68.77 (triplet, J=146.2 Hz), 78.60, and 79.87 (signals from carbon bearing fluorine are not included due to complex splitting patterns and low peak intensities); 19F NMR δ −81.3 (3 F), −119.9 (2F), −122.6 (2 F), −123.3 (2 F), −123.5 (2 F), −123.9 (2 F) and −126.8 (2 F). The elemental analysis was: Calculated for C13H11F15O2: C, 32.2; H, 2.3; F, 58.9. Found: C, 32.2; H, 2.2; F, 58.3.
Reaction SMILES: [Cl-].[NH4+:2].C([O-])(=O)C.[Na+].[Cl:8][C:9]1[C:10]([CH2:27][CH:28]=O)=[C:11]([CH:25]=O)[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:13]([CH:15]([OH:17])[CH3:16])[CH:14]=1.O1CCCC1>O>[Cl:8][C:9]1[CH:14]=[C:13]([CH:15]([OH:17])[CH3:16])[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:11]2[C:10]=1[CH:27]=[CH:28][N:2]=[CH:25]2
Reactant: CC(O)c1cc(Cl)c(CC=O)c(C=O)c1-c1cccc(F)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ammonium chloride (28.5 mg, 0.533 mmol) and sodium acetate (43.7 mg, 0.533 mmol) in water (0.4 mL) was added to a solution of 4-chloro-3′-fluoro-6-(1-hydroxyethyl)-3-(2-oxoethyl)biphenyl-2-carbaldehyde (0.171 g, 0.533 mmol) in tetrahydrofuran (0.4 mL, 5 mmol). The reaction mixture was stirred at room temperature overnight and then extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, concentrated to dryness under reduced pressure. The crude product was used in the next step (0.16 g, 99%). LCMS calculated for C17H14ClFNO (M+H)+: m/z=302.1; Found: 302.1
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][N:31]=1>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:37](=[O:38])[CH2:36][C:33]2[CH:32]=[N:31][C:30]([Cl:29])=[CH:35][CH:34]=2)[CH2:26][CH3:27])[CH:13]=1)[CH3:4]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cc2ccc(Cl)nc2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and 2-chloropyridine-5-acetic acid were reacted as described in Example 8, Step 6 to provide {5-[2-({N-[2-(6-chloro-pyridin-3-yl)-acetyl]-N-ethyl-amino}-methyl)-4-trifluoromethyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]/[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]/[CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of tert-butyl (E)-4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl]piperidine-1-carboxylate (0.0313 g, 0.0807 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0118 g, 0.0807 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((E)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0308 g, 74%).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[CH:4]=[N:3]1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[CH:7]([C:5]1[CH:4]=[N:3][N:2]([O:1][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)=[O:8]
Reactant: O=Cc1cnn(O)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1cc(C=O)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-formylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (73%, oil).