Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]([CH3:30])=[N:10][N:11]2[C:16]([O:17][CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])=[CH:15][C:14]([CH:27]3[CH2:29][CH2:28]3)=[CH:13][C:12]=12)=[O:7])C.C[Si](C)(C)[O-].[K+]>CO>[CH:27]1([C:14]2[CH:15]=[C:16]([O:17][CH2:18][C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[N:11]3[N:10]=[C:9]([CH3:30])[C:8]([C:6]([OH:7])=[O:5])=[C:12]3[CH:13]=2)[CH2:28][CH2:29]1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: Cc1nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc2c1C(=O)O

Procedure:
1.8 ml (1.8 mmol) of a 1 M aqueous solution of sodium hydroxide were added to a solution of 180 mg (0.47 mmol) of 5-cyclopropyl-7-(2,6-difluorobenzyloxy)-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (Example 148A) in 18 ml of methanol. The reaction was stirred at reflux for 18 h and concentrated under reduced pressure. The residue was taken up in 4 ml of tetrahydrofuran, and 70 mg (0.55 mmol) of potassium trimethylsilanolate were added. The reaction mixture was stirred at 65° C. for 18 h and concentrated under reduced pressure, which gave the target compound, which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH:7]=1.[Se](=O)=[O:13]>O1CCOCC1.O>[CH3:9][C:4]1([CH3:10])[C:3](=[O:11])[C:2]([CH3:1])=[CH:7][C:6](=[O:8])[C:5]1=[O:13]
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CC1=CC(=O)C(=O)C(C)(C)C1=O

Procedure:
129.4 g of 2,6,6-trimethylcyclohex-2-ene-1,4-dione (from Example 1) were added to a solution of 100 g of selenium dioxide in a mixture of 800 ml of dioxane and 50 ml of water, and the mixture was refluxed for 9 hours with stirring. The precipitate of elemental selenium was then filtered off with suction, and then all the low boilers were removed in a rotary evaporator. The residue was distilled at 125° C./20 mbar. The distillate was melted, mortared with n-hexane and then extracted with 600 ml of n-hexane. The target product crystallized out in the form of yellow needles.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH2:24][C:25]([O:27][CH3:37])=[O:26])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(CC)c3ccc(SCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(CC)c3ccc(SCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[1-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylthio]acetic acid (88.8 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:28]([O:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1)[CH3:29]>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:28]([O:30][C:31](=[O:44])[C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:39][CH2:40][N:41]([C:2]3[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=4)=[CH:4][N:3]=3)[CH2:42][CH2:43]2)=[CH:36][CH:37]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Temperature: 120 °C
Yield: 65 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (50 mg, 0.13 mmol), a catalytic amount of DMAP, diisopropylethyl amine (0.07 mL, 0.41 mmol), 4-(piperazin-1-yl)-benzoic acid ethyl ester (94 mg, 0.41 mmol) in 5 mL in dioxane was heated at 120° C. in a sealed tube for about 23 h. The reaction mixture was cooled, followed addition of another portion of 4-(piperazin-1-yl)-benzoic acid ethyl ester (94 mg, 0.41 mmol) and diisopropyl ethyl amine (0.07 mL, 0.41 mmol) and the mixture was re-heated at 120° C. for 3 more days. The reaction mixture was then cooled and partitioned between EtOAc and aq. saturated Na2CO3. The organic layer was then collected, dried over Na2SO4 filtered and concentrated. The residue was chromatographed with a silica gel column and 20-40% EtOAc in hexanes to afford the product (23 mg. Yield: 65%). HRMS m/z calcd for C26H27N4O3I [M+H]: 571.1201. Found: 571.1197.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH3:28].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17]([C:33]4[CH:34]=[CH:35][C:30]([O:29][CH2:27][CH3:28])=[CH:31][CH:32]=4)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: CCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(-c2c(C)nn3c(-c4ccc(F)c(F)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 85 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
(S)-(1-(7-(3,4-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (27 mg), 4-ethoxyphenylboronic acid (16 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (8 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred at 85° C. for 6 hours under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure, concentrated and purified by column chromatography to yield the target compound (20 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:44][OH:45])=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[N:37]=[CH:36][C:35]([C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40])=[CH:34][CH:33]=4)[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C(Cl)CCl.[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([C:38]([CH3:43])([CH3:42])[C:39]([N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[O:40])=[CH:36][N:37]=4)[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C(=O)O)cn2)c1=O
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid (50 mg, 0.08 mmol), morpholine (11 mg, 0.12 mmol), EDC (23 mg, 0.12 mmol), and DMAP (15 mg, 0.12 mmol) were dissolved in 1 ml of DCM and stirred at room temperature under nitrogen overnight. Ethyl acetate and saturated aqueous ammonium chloride were added and the layers were separated. The organic layer was washed with dilute ammonium chloride, then saturated aqueous sodium bicarbonate, dried, and concentrated. The crude product was purified by flash chromatography using a gradient of 0% to 10% methanol in DCM to give 40 mg (74%) of 6-tert-butyl-2-(3-{5-[5-(1,1-dimethyl-2-morpholin-4-yl-2-oxo-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one. MS: (M+H)+=681. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 1.53 (s, 6 H) 3.45 (br. s, 7 H) 3.71 (s, 3 H) 3.76 (br. s., 1H) 4.41 (br. s., 2 H) 6.85 (d, J=8.69 Hz, 1 H) 7.31-7.43 (m, 3 H) 7.48-7.61 (m, 4 H) 7.96 (s, 1 H) 8.15 (s, 1 H) 8.30 (s, 1 H) 8.69 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.[NH:21]1[CH2:24][CH:23]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]1.CC(C)([O-])C.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C1(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].O>[C:29]([O:28][C:27](=[O:33])[NH:26][CH2:25][CH:23]1[CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)=[CH:4][CH:3]=2)[CH2:24]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C1
Yield: 21.7 %

Procedure:
Prepared using general procedure 24. A solution of 4-bromo-N-(thiazol-2-yl)benzenesulfonamide (2.0 g, 6.3 mmol), tert-butyl azetidin-3-ylmethylcarbamate acetate (1.71 g, 6.93 mmol), sodium tert-butoxide (2.55 g, 26.5 mmol), biphenyl-2-yldi-tert-butylphosphine (224 mg, 0.76 mmol), and Pd2(dba)3 (172 mg, 0.19 mmol) in toluene (16 mL) was stirred at 75° C. for 16 h. The reaction mixture was poured into H2O, and the pH was adjusted to 6. The aqueous layer was extracted 4 times with CH2Cl2, and the organics were combined, washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated. Purification via silica gel chromatography using 50-90% EtOAc in hexanes gave tert-butyl-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-yl)methylcarbamate (0.58 g, 22%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=425.0; tR=2.59 min.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:43]([NH:45][CH2:46][C:47]([CH2:53][NH:54][C:55]1[CH:63]=[CH:62][CH:61]=[C:60]2[C:56]=1[CH:57]=[N:58][N:59]2[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([OH:52])[C:48]([F:51])([F:50])[F:49])[CH3:44]>CN(C=O)C.CS(C)=O>[CH2:43]([N:45]([CH2:46][C:47]([OH:52])([CH2:53][NH:54][C:55]1[CH:63]=[CH:62][CH:61]=[C:60]2[C:56]=1[CH:57]=[N:58][N:59]2[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:48]([F:51])([F:50])[F:49])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:44]
Reactant: O=C(O)c1ccccc1
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1
Reaction time: 0.02 h
Yield: 61.3 %

Procedure:
To benzoic acid (11 mg, 0.09 mmol) was added a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol) in DMF (0.2 ml) followed by N,N-diisopropylethylamine (32 μL, 0.182 mmol). The mixture was shaken for 1 minute and then a solution of 3-(ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol (26 mg, 0.07 mmol) in DMF (0.2 ml) was added. The mixture was again shaken for 1 minute and then left to stand at room temperature for 18 hours. The crude reaction was diluted with dimethyl sulfoxide (0.1 ml) and purified by mass-directed autopreparation (system A) to give the title compound (20.7 mg).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[CH2:15]([C:17]1[N:21]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[N:20]=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1)[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH2:15]([C:17]1[N:21]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[N:20]=[CH:19][C:18]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1)[CH3:16]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cnn1S(=O)(=O)N(C)C
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(-c2cc3c(s2)C(=O)NC(C)(C)N3C)cnn1S(=O)(=O)N(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 5-ethyl-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-sulfonamide (329 mg, 1.00 mmol), cesium carbonate (815 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1.25 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 90° C. for 1 h. The mixture was poured into water (100 mL) and EtOAc (200 mL). The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to afford the title compound (139 mg, 70%) as a yellow solid:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C([O-])([O-])=O.[K+].[K+]>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: BrCCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(OCCCCCCBr)cc1
Reaction time: 20 h

Procedure:
An amount of 16.6 g (100 mmol) of ethyl 4-hydroxybenzoate, 122 g (500 mmol) of 1,6-dibromohexane, 10.0 g of K2CO3 (finely powdered in a mortar and dried) are heated under reflux in 75 ml of absolute acetone. After 20 hours, first the acetone and then the excess of dibromohexane are removed by distillation at 15 mmHg. The crude product is purified in a high vacuum by means of a bulb tube distillation apparatus. After recrystallization from a little ethanol and drying in vacuo over P4O10, about 10 g of analytically pure product are obtained. The melting point is in the room temperature range.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:44])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.C(O)(=O)C>[OH-].[Pd+2].[OH-].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:44])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: O=c1ccc2c([C@@H](O)CNCCc3ccc(Oc4cccc(-c5ccccc5)c4)cc3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CNCCc3ccc(Oc4cccc(-c5ccccc5)c4)cc3)ccc(O)c2[nH]1
Yield: 18 %

Procedure:
A slurry of the product of step (e) (105 mg) and palladium hydroxide (100 mg) in a solution of 1:1 acetic acid:tetrahydrofuran (10 mL) was stirred under an atmosphere of hydrogen for 24 h. The catalyst was filtered off, the filtrate evaporated and the residue purified by reverse phase HPLC to afford the title compound (16 mg) in the form of a white solid as a trifluoroacetate salt. m/z: [M+H+] calcd for C31H28N2O4, 493.2; found 493.5. 1H NMR (300 MHz, DMSO-d6): 10.40 (d, 1H, J=20 Hz), 8.60 (br s, 1H), 8.01 (d, 1H, J=8.8 Hz), 7.49 (d, 2H, J=8.2 Hz), 7.14-7.34 (m, 7H), 7.03 (d, 1H, J=7.4 Hz), 6.93 (d, 2H, J=7.4 Hz), 6.86-6.82 (m, 2H), 6.46 (d, 1H, J=9.9 Hz), 6.07 (s, 1H), 5.18 (m, 1H), 3.19-2.82 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1N.N([O-])=O.[Na+].[S-:16][C:17]#[N:18].[K+]>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[S:16][C:17]#[N:18]
Reactant: Nc1c(F)cccc1[N+](=O)[O-]
Reactant: N#C[S-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: N#CSc1c(F)cccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of 2-fluoro-6-nitroaniline (3 g, 0.02 mol) in conc. sulphuric acid (30 mL) and water (30 mL) was diazotized at 0-3° C. for 90 min with aqueous sodium nitrite (1.45 g, 0.021 mol). After addition of potassium thiocyanate (2.522 g, 0.026 mol) in water (10 mL), the diazo-liquor was stirred vigorously into a suspension of cuprous thiocyanate (6.05 g, 0.05 mol) in water (20 mL) at 5° C. After stirring at 5° C. for 2 hr, the mixture was then heated at 70° C. for 20 min, then was cooled overnight, filtered, and the cake extracted with EtOAc to get the crude product (3.96 g) which was used in the next step without further purification. LC-MS: m/z 199.2 (M+H)+
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40]Br)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][S:19][CH2:20][CH2:21][OH:22])=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1-c1ccccc1CSCCO

Procedure:
2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester (13.2 g, 41.35 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol (3.88 g, 49.62 mmol, 1.2 eq.) and potassium carbonate (17.14 g, 124.05 mmol, 3 eq.). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>ClC(Cl)C.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: NCc1cccs1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: O[C@H](CNCc1cccs1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 2-thiophenemethylamine and ethanol, essentially as described above in Example 57. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10].[C:11]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])([CH3:14])([CH3:13])[CH3:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>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].C(OCC)(=O)C.O.CN(C=O)C>[OH:10][CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1/[CH:18]=[CH:17]/[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1ccc(Br)c(CO)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(CO)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 2.64 g of (2-bromo-5-methylphenyl)methanol, 246 mg of bis(dibenzylideneacetone)palladium, 2.95 ml of tert-butylacrylate, 442 mg of tris(2-methylphenyl)phosphine, 2.5 ml of triethylamine, and 24 ml of DMF was stirred at 100° C. for 24 hours. After leaving to be cooled at room temperature, water and ethyl acetate were added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.32 g of tert-butyl (2E)-3-[2-(hydroxymethyl)-4-methylphenyl]acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH:7]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:25]2=[S:26])[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(Cl)cc1NCCCNC1CCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1N1CCCN(C2CCC2)C1=S
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.9 %

Procedure:
To an ice-cold solution of the diamine of Step A (3.6 g) and triethylamine (3.8 mL) in dry chloroform (40 mL) under nitrogen was added thiophosgene (1.7 mL). After 10 minutes at ambient temperature, the reaction was quenched with water and extracted with dichloromethane. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give a brown solid. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 11% ethyl acetate in hexane to 8:1:1 hexane-ethyl acetate-dichloromethane) provided pure material which was triturated with diethyl ether to give the title product (2.3 g, 54.9%) as a white solid, m.p. 152-154° C.
Reaction SMILES: CCN(CC)CC.I[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH2:15]([O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1)[CH3:16]>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:22][CH:21]=1)[CH3:16]
Reactant: CCOC(=O)Cc1ccc(S)cc1
Reactant: IC1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(SC2CCOCC2)cc1
Temperature: 25 °C

Procedure:
NEt3 (1.3 mL, 9.0 mmol) and 4-iodotetrahydropyran (1.93 g, 9.0 mmol) were added to a stirred solution of ethyl(4-mercaptophenyl)acetate (1.21 g, 6.0 mmol) in anhydrous DMF (10 mL) at 0° C. The mixture was allowed to warm to room temperature over 3 d, then the solvents were removed under reduced pressure. The residue was partitioned between Et2O (100 mL) and saturated aqueous NH4Cl (50 mL), the aqueous phase being extracted further with Et2O (45 mL). The combined ethereal extracts were washed with H2O (50 mL), H2O-saturated aqueous Na2CO3 (1:1, 50 mL), and brine (50 mL), before being dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (IH-Et2O, 10:1 to 2:1) afforded the title compound: RF (IH-Et2O, 2:1)=0.31.