Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:6]=1)=[O:4].[H-].[Na+].[CH2:26](I)[CH2:27][CH3:28]>C1COCC1.C(OCC)(=O)C>[CH2:26]([O:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[N:6]=1)=[O:4])[CH2:27][CH3:28]
Reactant: CCCI
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCONC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
0.6 g (0.0018 mol) of N-hydroxy-4-methoxy-6-{3-(trifluoromethyl)phenoxy)-2-pyridine carboxamide was dissolved in THF, and the obtained solution was mixed with 0.08 g (ca. 60% in mineral oil; 0.0018×1.1 mol) of NaH and then with 0.62 g (0.0018×2.0 mol) of n-propyl iodide, followed by treating the solution under reflux for about 2 hours. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water and then washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH:15](O)([CH3:17])[CH3:16]>>[CH:15]([O:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[I:1])([CH3:17])[CH3:16]
Reactant: O=C(O)CCCOc1ccccc1I
Reactant: CC(C)O
Product: CC(C)OC(=O)CCCOc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(2-iodophenoxy)-butyric acid in 10 ml of isopropanol is mixed with 0.5 g of Amberlyst 15, stirred overnight at room temperature and then refluxed for 2 hours. Then, it is filtered from the Amberlyst 15, the filtrate is concentrated by evaporation, the residue is taken up in diethyl ether, washed with diluted sodium carbonate solution, dried and concentrated by evaporation. 920 mg of 4-(2-iodophenoxy)butyric acid isopropylester is obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1>CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:22]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
1-Bromo-4-chloro-2-nitro-benzene (7.00 g, 29.60 mmol) was dissolved in DMF to which K2CO3 (5.11 g, 37.01 mmol) and 3-Hydroxy-benzoic acid methyl ester (4.95 g, 32.57 mmol) were added. The reaction mixture was then heated to 100° C. for 2 h the reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate. Solvent dried over Na2SO4, filtered and concentrated under vacuum giving the title compound. (7.2 g, 79%)
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([S:8][CH3:9])=[N:5][C:4]=1[N:10]=[CH:11][N:12](C)C)#[N:2].N[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=1.NC1C=C(OCC2C=CC=C(Br)C=2)C=CC=1SC1C=CC(O)=CC=1>>[CH3:22][C:20]1[CH:21]=[CH:16][C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)=[C:18]([NH:2][C:1]2[C:3]3[S:7][C:6]([S:8][CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:19]=1
Reactant: CSc1nc(N=CN(C)C)c(C#N)s1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Agent: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Product: CSc1nc2ncnc(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)c2s1
Yield: 83 %

Procedure:
A solution of the product from Example 167A and the product from Example 7b were reacted according to the procedure from Example 167B substituting the product from Example 7b for the product from Example 15A to provide the crude material which was purified by trituration with methanol to provide the title compound (110 mg, 83%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.03 (s, 3H), 2.29 (s, 3H), 2.76 (s, 3H), 6.96 (d, J=8.09 Hz, 1H), 7.14 (d, J=8.09 Hz, 1H), 7.18-7.26 (m, J=8.82 Hz, 3H), 7.54 (d, J=8.46 Hz, 2H), 8.45 (s, 1H), 9.74 (s, 1H), 10.04 (s, 1H); MS (ESI)+ m/z 454 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17](S(C)(=O)=O)=[CH:16][CH:15]=3)[S:13][C:6]=12.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41](C2C=CC(B(O)O)=CC=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([N:41]4[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:43][CH2:42]4)=[CH:18][CH:19]=3)[S:13][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cc2)CC1
Yield: 70 %

Procedure:
Starting from the nitro-bromo compound 42, following the procedure described above for the synthesis of compound 48 (scheme 10, example 55) but substituting 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane for 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid, title compound 156 was obtained in 70% yield. LRMS (M+1) 550.6 (100%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][S:12](Cl)(=[O:14])=[O:13])#[N:10].O>CCOCC>[CH2:1]([NH:8][S:12]([CH2:11][C:9]#[N:10])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: N#CCS(=O)(=O)Cl
Solvent: O
Solvent: CCOCC
Product: N#CCS(=O)(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 2.14 g of benzylamine in 10 ml of ether at 5° C. was slowly added a solution of 1.37 g of cyanomethylsulfonylchloride [Sammes, et al., J. Chem. Soc. (C), 2151, 1971] in 5 ml of ether. The resulting mixture was then stirred for another 30 minutes, poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The organic layer was then washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude sulfonamide was then purified on a silica gel column (1:1 hexane/ethyl acetate) to provide 1.52 g of N-benzyl cyanomethylsulfonamide.
Reaction SMILES: O.[C:2]([OH:6])(=O)[CH:3]=O.Br.[NH2:8][C:9]1[S:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=2)=[N:13][N:14]=1>O.C(O)(=O)C.Cl>[C:26]([C:17]1[CH:16]=[C:15]([C:12]2[N:14]3[N:13]=[CH:3][C:2](=[O:6])[N:8]=[C:9]3[S:10][CH:11]=2)[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[C:18]=1[OH:25])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)c1cc(C2=NN=C(N)SC2)cc(C(C)(C)C)c1O
Agent: Br
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2csc3nc(=O)cnn23)cc(C(C)(C)C)c1O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
4.8 g (0.05 mol) of glyoxylic acid monohydrate in 75 ml of water were added dropwise to a solution of 10.0 g (0.025 mol) of 2-amino-5-(3,5-di-tert.butyl-4-hydroxyphenyl)-6H-1,3,4-thiadiazine hydrobromide from step (c1) in 250 ml of glacial acetic acid and 25 ml of 4N hydrochloric acid at 80° C. After the mixture had been stirred at 80° C. for 20 hours, it was evaporated under reduced pressure. It was advantageously possible to purify the solid residue by column chromatography on silica gel using methylene chloride/methanol (25:1) as the eluent and subsequent recrystallization from ethanol, and, from analytical and spectroscopic investigations, the product proved to be identical to that prepared by procedures (a) and (b).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]#[N:21])=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26]Br.O>CCCCCC>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2([C:20]#[N:21])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCCCCBr
Reactant: N#CCc1cn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: N#CC1(c2cn(Cc3ccccc3)c3ccccc23)CCCC1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60%, 2.26 g, 56 mmol) was added a solution of 1-benzyl-1H-indol-3-ylacetonitrile (5.7g, 22 mmol) and 1,4-dibrombutane (2.6 ml) in DMSO-ether (10 ml: 80 mL) dropwise and the mixture was stirred for 5 hours at 20° C. Water and hexane were added. Solid was collected by filtration and washed with water and hexane to give 1-(1-benzyl-1H-indol-3-yl)cyclopentanecarbonitrile (5.3 g). MS (ES): 301 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1c(F)cc(C=O)cc1OC
Yield: 78.3 %

Procedure:
The compound was prepared according to general procedure E with 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (1.8 mmol) in dry acetone (20 ml), anhydrous K2CO3 (2.4 mmol), and ethylbromoacetate (2.7 mmol) at reflux for 1 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 395 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 361 mg of purified compound were obtained (79% yield). 1H NMR (500 MHz, CD3COCD3): δ 1.25 (t, J=, 3H), 3.98 (s, 3H), 4.21 (q, J=, 2H), 4.89 (s, 2H), 7.34 (dd, J=10.3 and 1.6 Hz, 1H), 7.40 (t, J=1.6 Hz, 1H), 9.88 (d, J=1.6 Hz, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.0, 57.6, 62.1, 70.3, 110.0, 111.8 (d, J=20.6 Hz), 133.1 (d, J=7.2 Hz), 141.8 (d, J=12.7 Hz), 154.5 (d, J=4.5 Hz), 156.0 (d, J=246 Hz), 169.7, 191.3. MS (ESI): m/z 256.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]([NH2:16])=O)=[C:7]2[N:6]=[N:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14](=[S:18])[NH2:16])=[C:7]2[N:6]=[N:5]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COCn1nnc2c(C(N)=O)ncn2c1=O
Solvent: ClCCl
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: COCn1nnc2c(C(N)=S)ncn2c1=O
Reaction time: 24 h
Yield: 67 %

Procedure:
3-(Methoxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (0.100 g, 0.446 mmol), phosphorus pentasulfide (27 mg; 0.06 mmol), and hexamethyldisiloxane (87 mg; 0.114 mL; 0.535 mmol) were stirred in DCM under reflux for 24 hours. After 24 hours, a second portion of P2S5 (27 mg; 0.06 mmol) was added, and reflux continued for a further 24 hours, after which time the reaction mixture was filtered, and the precipitate was washed with EtOAc, Et2O and air dried to yield the title compound as an orange solid (67% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm 9.95 (1H, bs), 9.47 (1H, bs), 8.85 (1H, s), 5.74 (2H, s) and 3.40 (3H, s).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12](C(O)=O)=[C:8]3[CH:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC([O-])=O.[Na+].[I:31]Cl.O>C(O)(=O)C>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([I:31])=[C:8]3[CH:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)cc12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)n3ncc(I)c3c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (example C.28 step 6) (1.03 g, 2.97 mmol) in acetic acid (40 mL) was refluxed for 20 h. Cooled to 23° C., added NaOAc (325 mg, 3.95 mmol) and ICl (2M in HOAc, 1.85 mL, 3.7 mmol) and the mixture was stirred at 23° C. for 2 h. Poured into water, filtered precipitate off, washed with water, dissolved in TBME, washed with sat. NaHCO3-sol.+little sat. Na2SO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a light red solid (1.257 g, 99%). MS (ISP) 429.2 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16]Cl>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[C:11]([Cl:16])=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cc(-c2ccccc2)no1
Reactant: ClCl
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1onc(-c2ccccc2)c1Cl
Yield: 60.4 %

Procedure:
3-Phenyl-5-acetylaminoisoxazole (7) (2.022 g) was dissolved in tetrahydrofuran (50 ml), a solution of chlorine (850 mg) in carbon tetrachloride (8.8 ml) was added dropwise thereto, and the mixture was kept to react at room temperature and under ice-cooling for 30 minutes, respectively. After evaporation the resulting residue was subjected to column chromatography on silica gel (20 g) to give crystals (1.43 g) of 3-phenyl-4-chloro-5-acetylaminoisoxazole (8) from the ether fractions; mp. 141°-141.5° C. (recrystallized from ether-hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12]([Cl:29])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Cl)cc1OCCCCCCC
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.1 %

Procedure:
To a room temperature mixture of 5 g of product from Example 110 in 80 ml of methylene chloride and 5 drops of dimethylformamide is added 2.72 g of oxalyl chloride. The reaction is stirred at room temperature for 2.5 days and concentrated in vacuo. The residue is dissolved in diethyl ether, passed through a pad of diatomaceous earth and concentrated in vacuo to give 5.27 g of the desired product as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:29]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.[C:39]([O:43][C:44]([NH:46][CH2:47][C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCN(C(C)C)C(C)C.[Cl-].ClC1N(C)C=C[N+]=1C>C(Cl)Cl>[C:39]([O:43][C:44](=[O:45])[NH:46][CH2:47][C:48]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:29]([C:32]5[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=5)(=[O:31])=[O:30])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:3]=1)=[O:49])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
The 4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine (0.1 g, 0.177 mmol) and N-(tert-butoxycarbonyl)glycine (34 mg, 0.194 mmol) were dissolved in DCM (5 ml) and treated with Hunig's base (92 uL, 0.53 mmol) and 2-chloro-1,3-dimethyl-1H-imidazol-3-ium chloride (33 mg, 0.194 mmol). The mixture was kept at room temperature for 90 minutes then was diluted with DCM (10 ml). The organic phase was washed with water (2×10 ml) and with an aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo, giving a yellow oil. The product was purified by flash chromatography (gradient 70%-100% EtOAc/hexanes), affording the title compound as a pale yellow solid (71 mg). 400 MHz 1H NMR (DMSO-d6) δ: 9.86 (s, 1H), 8.73 (br. s, 1H), 8.11 (d, J=5.5 Hz, 1H), 7.84 (s, 1H), 7.79-7.75 (m, 2H), 7.70-7.65 (m, 3H), 7.45-7.37 (m, 2H), 7.26 (d, J=7.4 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.82 (br. s, 1H), 6.42 (d, J=6.9 Hz, 1H), 4.00-3.90 (m, 1H), 3.78-3.70 (m, 3H), 3.52-3.44 (m, 1H), 3.18 (s, 2H), 2.34 (t, J=10.2 Hz, 1H), 1.94-1.81 (m, 2H), 1.65-1.52 (m, 1H), 1.39 (s, 9H). LCMS: 723 [M+H].
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:14][C:15](=[O:32])[CH2:16][CH2:17][NH:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:32])[CH2:16][CH2:17][N:18]([C:8](=[O:10])[CH3:9])[CH:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:13]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CCNC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCN(C(C)=O)C1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.51 mg of triethylamine and 0.28 ml of acetyl chloride were added under ice-cooling to a solution of 0.77 g of N-(9-fluorenyl)-β-alanine ethyl ester in 25 ml of methylene chloride. The resultant mixture was stirred at 0° C. for 0.5 hour and, then, at room temperature for 3 hours. The reaction solution was poured into ice-cold 1N hydrochloric acid and extracted with methylene chloride. The organic layer was washed with saturated sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluting solution: chloroform-methanol) to give 0.85 g of N-acetyl-N-(9-fluorenyl)-β-alanin ethyl ester.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[CH2:13]([O:15][P:16]([O:17][CH2:18][CH3:19])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:20])[CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: C=CCCCCCCCCCI
Product: C=CCCCCCCCCCP(=O)(OCC)OCC

Procedure:
A first generation FP probe, FP-biotin, possessed a linear decamethylene chain connecting its FP reactive group to 5-(biotinamido)-pentylamine through an amide bond (15). A variant of FP-biotin in which the agent's decamethylene chain was replaced by a more hydrophilic tetraethylene glycol linker was synthesized. Briefly, tetraethyleneglycol (1) was monosilyated to provide compound 2, which following conversion to alkyl iodide 3, was reacted with triethylphosphite to give phosphonate 4. Desilyation of 4 with HF-pyridine, followed by treatment with N,N-disuccinimidyl carbonate, provided NHS-carbonate 6. Compound 6 was converted to monoethoxy phosphonate acid 7 by treatment with oxalyl chloride followed by hydrolytic workup. Compound 7 was treated with DAST to give fluorophosphonate 8, which was then coupled to 5-(biotinamido)pentylamine (Pierce) to provide FP-peg-biotin (9).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[Na+].[Na+]>CO.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1c(F)cccc1Br
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(F)cccc1Br
Temperature: 80 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
2-Bromo-6-fluorobenzoic acid (1, 12.50 g, 57 mmol) was dissolved in a mixture of methanol (60 mL) and conc. sulfuric acid (65 mL). The solution was heated to 80° C. and stirred for 12 h. The reaction mixture was cooled and 20% sodium carbonate solution (500 mL) was added slowly to reach pH=8. The mixture was extracted with dichloromethane (3×180 mL), and the combined organic layers were dried over magnesium sulfate and evaporated. The title compound (11.29 g, 48.5 mmol, 85%) was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: Ic1ccccc1-c1cnccn1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1-c1cnccn1
Yield: 39 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (145 mg, 0.47 mmol) and 2-(2-iodophenyl)pyrazine (0.11 g, 0.46 mmol) according to the methods of Example 6 Step 4. Purification by flash column chromatography eluting with a 10-60% ethyl acetate/isohexane gradient gave 2-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}phenyl)pyrazine (79 mg, 38%). 1H NMR (500 MHz, CDCl3) δ 8.77 (1H, d, J=1.2 Hz), 8.51 (1H, d, J=2.4 Hz), 8.44-8.38 (1H, m), 8.28-8.23 (1H, m), 8.03 (1H, s), 7.98 (1H, s), 7.87 (2H, t, J=8.8 Hz), 7.79 (1H, dd, J=1.6, 8.5 Hz), 7.74-7.62 (4H, m), 7.56 (1H, dd, J=1.7, 8.6 Hz), 7.42-7.35 (1H, m), 7.23-7.15 (2H, m); m/z (ES+) 441 [MH+].
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].N12CCCN=C1CCCCC2>O1CCCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[O:16])[CH2:3]1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A mixture of 21.9 g (0.100 mole) 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml tetrahydrofuran, was cooled to 0° C. in an ice bath under nitrogen and 24.32 g (0.150 mole) carbonyl diimidazole was added. The reaction was stirred at 0° C. for 30 minutes, then at room temperature for 30 minutes. A solution of 13.55 g (0.100 mole) of 2,2,2-triflouroethylamine hydrochloride, 15.22 g (0.100 mole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 100 ml tetrahydrofuran was added. The reaction was stirred at room temperature overnight. The solvent was removed at reduced pressure. The residue was taken up in dichloromethane and washed with 3×150 ml saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure. The product was purified by column chromatography on silica with ethyl acetate to give 8.50 g of 5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide, mp 110°-112° C.