Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].[CH2:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH:8]=[CH2:9].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH:8]=[CH2:9]
Reactant: Nc1ccccc1
Reactant: C=CCc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Product: C=CCc1ccc(Nc2ccccc2)cc1
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3, 0.2623 g, 2.864×10−4 mol] and tri-tert-butylphosphine (0.11 g, 5.437×10−4 mol) were weighed out in a glove box, transferred to a Schlenk line, and stirred for about 5 min in hexanes before adding sodium tert-butoxide (2.000 g, 2.081×10−2 mol) as a slurry in hexanes, Compound 1 (2.810 g, 1.426×10−2 mol), and 80 mL hexanes. Next, distilled aniline (1.43 mL, 1.57×10−2 mol) was added over a period of about 3 min with stirring. A brown precipitate formed after about 5 min at room temperature, and stirring was halted after 2 h. The mixture was then filtered through Celite, and the hexanes were removed in vacuo at ≦45° C. so as to minimize allyl group isomerization. The resulting oil was then placed in a freezer at −23° C. for 1 h to solidify. The resulting solid was then recrystallized from pentane to yield light tan crystals of Compound 2 (2.43 g, 82% yield) that were collected by filtration and rinsed 3× with cold pentane. GC/MS: single peak; m/z (rel. intensity) 210 (M+ +H, 17), 209 (M+, 100), 208 (M+ −H, 29), 182 (38) 117 (33). 1H NMR (CDCl3): δ7.24 (m, 2H), 7.09 (d, J=8.5 Hz, 2H), 7.04 (d, J=6.5 Hz, 2H), 7.03 (d, J=6.5 Hz, 2H), 6.89 (t, J=7 Hz, 1 H), 5.94 (m, 1H), 5.64 (s, 1H), 5.06 (m, 2H), 3.34 (d, J=6.5 Hz, 2H). 13C NMR (CD2Cl2): δ144.0, 141.4, 138.4, 133.3, 129.7, 129.6, 120.7, 118.7, 117.3, 115.5, 39.8. EA for C15H15N: Calc. %: C, 86.08; H, 7.22; N, 6.69; Found %: C, 85.95; H, 7.11; N, 6.82.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([OH:30])=[C:25]([Br:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36]C)=[O:35]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([O:30][CH2:33][C:34]([OH:36])=[O:35])=[C:25]([Br:31])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Reactant: COC(=O)CBr
Product: O=C(O)COc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3,5-dibromo-biphenyl-4-ol, and methyl bromoacetate, in substantially the same manner, as described in Example 2 step g , and was obtained as an off-white solid, mp 183-185° C.; MS m/e 606 (M+);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][NH2:28]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:27]([CH3:26])[N:28]=[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Solvent: CO
Product: Cn1nc(Cc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
4-(3-Oxo-4-phenyl-butyryl)-piperidine-1-carboxylic acid tert-butyl ester (0.118 g) was dissolved in MeOH (4 mL) and added to a refluxing solution of methyl hydrazine (0.019 g) in methanol (2 mL). After 45 minutes at reflux the reaction mixture was cooled to room temperature and solvents evaporated under reduced pressure to give the crude product as a clear oil which was purified by column chromatography on silica using Et2O as eluent to give 4-(5-benzyl-2-methyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.032 g) as a clear oil; NMR (CDCl3): 1.46 (s, 9H), 1.46-1.54 (m, 2H), 1.82 (br d, 2H), 2.64 (tt, 1H), 2.78 (br t, 2H), 3.77 (s, 3H), 3.90 (s, 2H), 4.18 (br d, 2H), 5.72 (s, 1H), 7.16-7.29 (m, 5H); MS: 356 (MH+).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:27]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:28])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(NC(=O)C2CCCCC2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (328 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (529 mg, 84%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12](Cl)=[O:13].C(N(CC)CC)C.[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCCC(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12](=[O:13])[S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Reactant: Sc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCC(C)C
Product: O=C(Cc1ccc2ccccc2c1)Sc1ccccc1
Yield: 90 %

Procedure:
2-(2-Naphthyl)acetyl chloride (308 mg, 1.5 mmol) in 4.5 mL toluene was added to a solution of triethylamine (0.21 mL, 1.5 mmol) and thiophenol (153 μL, 1.5 mmol) in 3 mL toluene. Reaction monitoring was accomplished by TLC: iso-hexane/ethyl acetate 25:1, Rf=0.33. Workup yielded 376 mg (90%) S-phenyl 2-(2-naphthyl)ethanethioate 9 as yellow solid.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: Fc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3ccccc3c(NCc3cccc(F)c3)c21
Temperature: 0 °C

Procedure:
In 300 ml of toluene and 200 ml of 30% potassium hydroxide were combined 8.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one and 1.92 g of tetrabutylammonium hydrogen sulfate catalyst. The mechanically stirred mixture was heated to reflux and a solution of 9.25 ml of 3-fluorobenzyl bromide in 40 ml of toluene was added over 0.5 hour. Then the reaction was further refluxed for 2 hours. The reaction mixture was then poured into 500 ml of ice and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organics were combined and washed with saturated NaCl solution, dried over magnesium sulfate, filtered and evaporated to a solid. The solid was purified by preparative HPLC (ethyl acetate). The product-containing fractions were combined and concentrated to a solid. The solid was recrystallized from 1:1 dichloromethane/pentane to yield 7.15 g of solid, mp 156°-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:11][O:12][CH2:13]Cl.C(OCC)C>C(Cl)Cl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:11][O:12][CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COCOc1ccc(Br)cc1
Yield: 87.5 %

Procedure:
5.2 g (30 mmol) of 4-bromophenol was dissolved in 20 ml of anhydrous methylene chloride, and 1.6 g (5.9 mmol) of tetrabutylammonium chloride and 20 ml (50 mmol) of 2.5N sodium hydroxide solution were added successively under ice cooling and stirring. Further, 3.4 ml (45 mmol) of chloromethyl methyl ether was added, and the mixture was brought back to room temperature and stirred for 30 minutes. After the reaction, diethyl ether was added to the reaction solution to carry out extraction, and the organic layer was washed successively with water, 1N sodium hydroxide solution, saturated saline, saturated ammonium chloride solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thereby, 5.7 g of 4-methoxymethoxybromobenzene was obtained as a colorless oil (yield 87%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:23])[CH:6]=[CH:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].CCCC[C@@H](O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(O)=O.C(CCO)CC/C=C\C/C=C\C/C=C\C/C=C\CCCC(O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:23])/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCC(O)C=CCC=CCC=CCC=CCCCC(=O)O
Agent: CCCC[C@@H](O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: O=C(O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCCO
Product: CCCCC(O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reaction time: 0.33 h

Procedure:
Isolated neutrophils were resuspended in M199 containing 1% BSA with a final concentration of 3×106 cells per ml. Cells suspensions (1 ml) were incubated with or without a test compound, 16(S)-HETE, 16(R)-HETE, or 20-HETE (concentrations 0.01 to 10 μM) for 10 min and then placed into gelatin-coated wells and further incubated for 20 min at 37° C. The wells were washed three times with 0.5 ml of solution M199 to remove non-adherent cells. The adherent cells were then removed by addition of 0.4 ml of 0.25% trypsin-EDTA in 0.1 M PBS to the gelatin-coated wells and incubation for 10 min at 37° C. The incubates were transferred and the wells were washed with 0.1 ml of M199 solution. The amount of cells in combined solutions was counted. In some experiments, the adhesion of neutrophils was stimulated by addition of 1 U/ml of thrombin to neutrophil suspension immediately prior to the transfer of cells to the wells. Experiments were performed in duplicates for each concentration of HETE. The inhibition of adhesion was expressed as percent of cells remaining in suspension (non-adherent) relative to control. The range of adherent PMNs in control incubations was 6 to 23%. This was increased two-fold in the presence of thrombin.
Reaction SMILES: C[N:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[C:9](Cl)[CH:8]=1)=O)C.[Na+].[Cl-]>C1N(CCO)CCN(CCS(O)(=O)=O)C1>[N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:2][CH:4]=1
Reactant: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: [Cl-]
Agent: [Na+]
Product: c1ccc2[nH]cnc2c1
Reaction time: 2 h

Procedure:
Membranes from CHO cells expressing the MCH receptor were prepared by lysing cells with 5 mM HEPES for 15 min at 4C. Cell lysates were centrifuged (12.5000×g, 15 min) and the pellet was resuspended in 5 mM HEPES. For each 96-well plate (Microlite, Dynex Technologies), 1 mg of cell membranes were incubated with 10 mg of wheat germ agglutinin SPA beads (Amersham) for 5 min at 4 C in a volume of 10 ml of binding buffer (25 mM HEPES, 10 mM MGCl2, 10 mM NaCl, 5 mM MnCl2, 0.1% BSA). The membrane/bead mixture was centrifuged (1500×g, 3.5 min), the supernatant was aspirated, and the pellet was resuspended in 10 ml binding buffer. The centrifugation, aspiration and resuspension were then repeated. The membrane/bead mixture (100 μl) was then added to 96-well plates containing 50 μl of 500 pM [125I]-MCH (NEN) and 50 ml of the appropriate concentration of compound (4× the desired final concentration). Nonspecific binding was determined by including 1 μM MCH in the binding reaction. The binding reaction was incubated at room temperature for 2 h. Plates were then analyzed in a TOPCOUNT microplate scintillation counter (Packard). Data was analyzed and Ki values were determined using GraphPad Prism.
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>CCN(CC)CC>[Br:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: Nc1ccccc1Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccccc1Br
Reaction time: 0.42 h

Procedure:
DCM (670 Kg) and Et3N (76.4 Kg) were added to a 1000 L glass-lined reactor at 0° C. Then, 2-bromoaniline (3a) (100 Kg, 581 moles, 1.0 equiv.) was added with stirring. The resulting mixture was cooled to 0˜10° C. and pivaloyl chloride (77.1 kg, 640 moles, 1.1 equiv.) was added dropwise (5 kg/h) while maintaining the same temperature. The mixture was stirred at this temperature for 1 h 25 min and reaction progress monitored by HPLC. When it was deemed complete, the reaction was quenched by addition of a 5% aqueous solution of Na2CO3 (120 kg) at a rate of 2 kg/min. After addition, the mixture was stirred for 1.5 h and the pH value tested to be between 7 and 8. The reaction was allowed to stand for 20-30 min and the organic phase was separated out. The aqueous layer was extracted with DCM twice (60×2 kg). During each extraction, the bi-phasic mixture was stirred for 15-20 min and then held for 15˜20° C. to allow for layer separation. All the organic layers were combined and a 3% aqueous solution of HCl (251.8 kg) was added to adjust the pH value between 5 and 6. Then the aqueous layer was separated and the organic layer was washed with saturated NaHCO3 (150 L). During the washing, the bi-phasic mixture was stirred for 30 min and held for 30 min. The organic phase was separated and dried over NaSO4 (50 kg) with stirring for 13 h. The resulting slurry was filtered under vacuum using a 50 L vacuum filter. The filtration cake was washed with DCM twice (25 kg×2). The filtrate was concentrated by evaporation at T<50° C. under atmospheric pressure until no solvent distilled out. Then it was additionally concentrated by evaporation under vacuum (P≦MPa) at 65˜70° C. After concentration, the mixture was cooled to 55˜60° C. and THF was added (993 kg). Then the mixture was concentrated by evaporation again under the same conditions as above. The content of DCM was monitored by GC using method F until <0.1%. The mixture was cooled to 20˜30° C. under N2 and then filtered though silica gel (8 kg) under vacuum in order to dry it. The silica plug was washed twice with THF (20 kg×2) to give a solution of crude (3b) which was transferred into 200 L drums for the following step. Typical retention time for starting material (3a) is 8.0 min and for product (3b) is 8.9 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]([F:45])([F:44])[F:43])=[CH:32][C:31]=2[C:46]2[CH:51]=[CH:50][N:49]=[N:48][CH:47]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]([F:43])([F:44])[F:45])=[CH:32][C:31]=2[C:46]2[CH:51]=[CH:50][N:49]=[N:48][CH:47]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4C(F)(F)F)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccccc3C(F)(F)F)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[3-pyridazin-4-yl-2′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 23, 339 mg, 0.45 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue purified by reverse phase preparative HPLC (Trilution method) to afford the title compound as a white solid (75 mg, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][S:10]([CH3:13])(=[NH:12])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=C3C=2OC2C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=2C3(C)C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:12]=[S:10]([CH3:13])([CH3:9])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)(=N)=O
Reactant: Brc1cccc(I)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CS(C)(=O)=Nc1cccc(Br)c1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
1-Bromo-3-iodo-benzene (250 μL, 1.96 mmol), (methylsulfonimidoyl)methane (219.188 mg, 2.353 mmol), cesium carbonate (894.466 mg, 2.745 mmol) and dioxane (12 mL) are purged with argon. (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (85.098, 0.147 mmol) and tris(dibenzylideneacetone)dipalladium(0) (44.89 mg, 0.049 mmol) are added, purged again with argon and stirred at 105° C. for 3 h.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])=[CH:9][CH:8]=1)(O)=[O:2].O1CCCC1.ClC(OCC(C)C)=O.[CH2:43]([N:45](CC)[CH2:46]C)C>>[CH3:43][N:45]([CH3:46])[C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])=[CH:9][CH:8]=1)=[O:2]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(CCCC(=O)O)cc23)c(OC)c1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cccc3ccc(CCCC(=O)N(C)C)cc23)c(OC)c1
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a mixture of methyl 4-[7-(3-carboxypropyl)-naphth-1-ylmethyl]-3-methoxybenzoate (2.40 g), tetrahydrofuran (70 ml) and triethylamine (0.681 g) was added isobutyl chloroformate (0.87 ml) After stirring for 30 min, dimethylamine (2.0 g) was bubbled into the solution and stirring continued for 18 h. The reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed (1N hydrochloric acid, aqueous sodium bicarbonate (5% w/w), brine) and dried (MgSO4). Evaporation and flash chromatography, eluting with ethyl acetate:methylene chloride (0:1, 1:10 and 2:10, successively), to give methyl 4-[7-(3-dimethylcarbamoylpropyl)naphth-1-ylmethyl]-3-methoxybenzoate (1.10 g, 43%) as a glassy solid; MS(CI), m/e=419(M+H).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH:25]4[CH2:34][CH2:33][C:28]5([O:32][CH2:31][CH2:30][O:29]5)[CH2:27][CH2:26]4)[N:23]=[CH:24][C:10]=13)[CH2:2]2.C(N(CC)CC)C.Cl[C:43]([O:45][CH2:46][CH2:47][F:48])=[O:44]>ClCCl>[F:48][CH2:47][CH2:46][O:45][C:43](=[O:44])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH:25]4[CH2:34][CH2:33][C:28]5([O:29][CH2:30][CH2:31][O:32]5)[CH2:27][CH2:26]4)[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)OCCF
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC5(CC4)OCCO5)c3n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC5(CC4)OCCO5)c3n2)cc1)OCCF
Reaction time: 0.5 h

Procedure:
was also prepared by an alternative route: 36 mg 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was dissolved in dichloromethane (0.5 mL) containing triethylamine (100 uL). 93 uL 2-fluoroethyl chloroformate was added and the mixture was stirred for 30 minutes. The mixture was concentrated and the title compound was obtained after HPLC purification. MS: 553.2 [M+H], RT 2.42.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=O)[CH2:44][CH:45]1[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46]1)=[O:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:40][C:43]([CH2:44][CH:45]2[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])[CH2:46]2)=[N:42][N:41]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
To s solution of PPh3 (2.2 g, 8.2 mmol) in dry DCM (60 mL) was added I2 (2.1 g, 8.2 mmol). After I2 was dissolved completely, TEA (1.7 g, 16.4 mmol) was added quickly at rt. The mixture was stirred for 15 mins. Tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-1-carboxylate (2.0 g, 4.1 mmol) was added. The mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (gradient elution 0˜40% EtOAc/petroleum ether) to afford tert-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-1-carboxylate (1.3 g, 66%) as a white solid. ESI-MS (EI+, m/z): 470 [M+H]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:15][N:16]=1.Cl>O.CO>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[NH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])=[N:16][CH:15]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2ccccc2OC)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1cnc(CCCCCCC(=O)O)[nH]1
Temperature: 40 °C
Yield: 76.3 %

Procedure:
Add a solution of sodium hydroxide (1.85 g, 46 mmol) in water (40 mL) to a solution of 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid methyl ester (5.84 g, 18.5 mmol) in methanol (30 mL) at room temperature under nitrogen and heat the mixture at 40° C. for 4.5 hours. Cool the mixture and treat with 1 N HCl (46 mL) and heat at reflux for 30 minutes. Collect the precipitate, wash with water (3×30 mL), and dry under reduced pressure for 12 hours. Triturate the solid with methylene chloride (50 mL) at reflux for 40 min and collect by filtration to provide 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid (4.27 g, 77%). APCI mass spectrum m/z 301 [C17H22N2O3−H]−.