Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-:12]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CC#N
Product: O=S(=O)(F)c1ccc(Br)cc1
Reaction time: 5 h

Procedure:
To a solution of 4-bromophenylsulfonyl chloride (2 g, 7.83 mmol) in acetonitrile (10 mL), was added fluoride on Amberlyst A-26 (Aldrich Chemical Company, 7.5 g, 21.6 mmol F−). After agitation for 5 hours at room temperature, the mixture was filtered. The solvent was removed under reduced pressure to give 4-bromophenylsulfonyl fluoride (1.5 g) (confirmed by IR spectroscopy).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[OH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:28]
Reactant: CC(C)(O)CC(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 16.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), 3-hydroxy-3-methylbutanoic acid (57 mg, 0.485 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol), triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL), and by a reaction in the same manner as in Example 187, the title compound (22 mg, 16%) was obtained as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH:20]1OCC[O:21]1)([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH:20]=[O:21])([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Yield: 102 %

Procedure:
A solution of 2-(4-chloro-2-[1,3]dioxolan-2-yl-phenoxy)-2-propyl-pentanoic acid ethyl ester (15 g, 42 mmol) in TFA (30 mL) was stirred at room temperature overnight. Then the mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was washed with NaOH solution (1 N), water, dried over anhydrous Na2SO4 and concentrated to give the title compound (14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13](CC4C=CC(OC)=CC=4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[C:28](=[O:40])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[C:28](=[O:40])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:37])([F:38])[F:39])[CH:30]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2c(=O)c3c(nc(C(=O)c4cccc(OC(F)(F)F)c4)n3Cc3ccc(Cl)cc3)n(C)c2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)[nH]c(=O)c2c1nc(C(=O)c1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.5 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione (15 mg, 0.025 mmol) in DCM (1 ml) was added TFA (1 ml) dropwise followed by trifluoromethanesulfonic acid (0.25 ml), both at 0° C. The reaction was stirred at 0° C. for 10 min, then stirred at room temperature for 16 h. The reaction was quenched with aqueous saturated sodium bicarbonate and extracted with DCM. The organic phase was washed with water dried over sodium sulfate, filtered and concentrated to give 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione (10 mg, 83.7%) as yellow oil. LCMS retention time 1.821 min; LCMS MH+ 479.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[F:21])=[O:4].[Br:22]N1C(=O)CCC1=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:22])[C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[F:21])=[O:4]
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72.9 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.390 g, 1.34 mmol) in DMF (10 mL) was added N-bromosuccinimide (0.263, 1.48 mmol). The reaction mixture was stirred at room temperature for 25 minutes and then quenched with saturated sodium bisulfite. The reaction mixture was diluted with H2O and partitioned between EtOAc/diethyl ether and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.424 g (85%) pure desired product as a lavender foamy solid.
Reaction SMILES: S(=O)(=O)(O)O.CO[CH:8](OC)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])=[O:10].[OH-].[Na+]>>[F:20][C:19]([F:22])([F:21])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[N:11][C:9]([OH:10])=[CH:8]2
Reactant: COC(OC)C(=O)NCc1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc2cccc(C(F)(F)F)c2cn1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Sulfuric acid (18 M; 3.57 mL, 65.6 mmol) was added to 2,2-dimethoxy-N-(2-trifluoromethylbenzyl)-acetamide (1.33 g, 4.69 mmol) at rt. The solution was stirred at 40° C. overnight. The mixture was poured into ice, basified with NaOH (10 N) until pH>13, extracted with Et2O (3×30 ml), and the extracts were back-washed with water (20 ml). The combined aqueous layers were neutralized with HCl until pH=7-8 and extracted with EtOAc (3×30 ml). The EtOAc extract was washed with water (2×20 ml), brine (20 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as yellow solid. The material was used in the next step without further purification; a small quantity (15 mg) was purified using the Gilson HPLC for characterization by NMR. 1H NMR (400 MHz, DMSO-d6): δ=7.13 (s, 1H), 7.70 (t, 1H, J=8.0 Hz), 7.78 (d, 1H, J=7.2 Hz), 8.06 (d, 1H, J=8.4 Hz), 9.03 (t, 1H, J=1.0 Hz), 11.23 (brs, 1H). MS(ES+): m/z=213.38 (82) [MH+]. HPLC: tR=2.55 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:15][C:16]1[CH:43]=[CH:42][C:19]([CH2:20][NH:21][C:22]([C:24]2([CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22]([C:24]2([CH2:37][CH2:38][CH2:39][CH2:40][N:12]3[CH2:13][CH2:14][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)[CH2:10][CH2:11]3)[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:42][CH:43]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1cccc(N2CCNCC2)n1
Product: COc1cccc(N2CCN(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)CC2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluorobenzyl-amide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][C:10]=1[F:33])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A solution of [4-(t-butyl-diphenyl-silanyloxy)-2-fluoro-benzyl]-carbamic acid tert-butyl ester (2.1 g, 4.38 mmol) in 5 mL of THF was treated with tetrabutylammonium fluoride (4.5 ml of a 1M solution) and stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo and purified by flash chromatography (chloroform-methanol, 5:1) to give 0.46 g of the phenol.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:31]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:30]2=[O:57])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:31]([NH:49][C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[C:30]2=[O:57])=[O:27])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3S(=O)C2)cc1

Procedure:
A solution of 85% pure m-chloroperbenzoic acid (55.22 g) in methylene chloride (600 cc) is added dropwise, in the course of 2 hours, to a solution, cooled to -10° C., of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (or -3-ene) (mixture of the E and Z forms) (180.56 g) in methylene chloride (1.4 liters). The mixture is washed with a 5% strength solution of sodium bicarbonate (1.5 liters) and water (2×1.5 liters), dried over sodium sulphate and concentrated at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa) to a volume of 300 cc. This solution is chromatographed on a column of Merck silica gel (0.05-0.2) (3 kg) (diameter of the column: 9.2 cm; height: 145 cm). Elution is carried out successively with the following mixtures of cyclohexane and ethyl acetate: 80/20 (by volume) (15 liters) and 70/30 (by volume) (32 liters), 600 cc fractions being collected. Fractions 27 and 28 are collected and evaporated and this yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (5.56 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)=[O:7])[CH3:4].O.[Na+].[Cl-].C1[CH2:31][O:30][CH2:29]C1>>[CH3:23][C:18]1([CH2:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([N:8]3[CH2:4][C@H:3]([CH2:29][O:30][CH3:31])[O:5][C:6]3=[O:7])=[CH:14][CH:13]=2)[O:19][CH2:20][CH2:21][O:22]1
Reactant: C1CCOC1
Reactant: CCOC(=O)Nc1ccc(CCCC2(C)OCCO2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC[C@H]1CN(c2ccc(CCCC3(C)OCCO3)cc2)C(=O)O1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a suspension of 1.96 g (0.041 mol) of NaH (50% in oil) in 100 ml of THF, are added 5 g (0.017 mol) of compound 360274 (Method 3--Step 2), dissolved in 25 ml of THF. After 30 min. of stirring at 30° C.-40° C., are added 4.64 g (0.017 mol) of compound 360065 dissolved in 25 ml of THF and the reaction medium is heated at 50° C.-60° C. for 22 h. The reaction medium is cooled and poured on 500 ml of water. The aqueous phase is saturated with NaCl and extracted with ethyl acetate and then with methylene chloride. The organic phases are dried over Na2SO4 and concentrated. The residue is taken up in ethyl ether. After treatment by animal black, the ethereal solution is concentrated and the product is recrystallized from isopropanol alcool with a 30% yield. The obtained product has the same physical characteristics as those obtained by Method 1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>CC#N>[NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH2:3]1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NC1CCCCNC1
Solvent: CC#N
Product: NC1CCCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Yield: 92.3 %

Procedure:
A solution of 3-aminohomopiperidine (1.71 g, 15 mmol) in CH3CN (45 mL) was treated with p-chlorobenzyl chloride (463 mg, 2.9 mmol) and K2CO (828 g, 6 mmol) and heated to 70° C. for 9 h. The reaction mixture was cooled to 25° C. and concentrated to afford a yellow solid. The residue was partitioned between H2O (5 mL) and EtOAc (50 mL), and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated. The resulting yellow oil was purified by chromatography (SiO2, 5-20% CH3OH—CH2Cl2 gradient elution) to afford the desired product as a yellow oil (639 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([NH:9][CH:10]=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[N:21]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])=[N+:22]=[N-:23]>C1COCC1>[C:1]([O:5][C:6](=[O:12])[C@@H:7]([N:9]([C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[N:21]=[N+:22]=[N-:23])[CH:10]=[O:11])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)Cl
Reactant: C[C@H](NC=O)C(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)N(C=O)C(=O)c1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A stirred solution of (2S)-2-formylamino-propionic acid tert-butyl ester (3.524 g, 20.3 mmol) in anhydrous THF (50 mL) was treated at −78° C. with LDA (20.3 mmol) and the reaction was stirred for 15 min. A solution of 2-azidobenzoyl chloride (T. Okawa, T. Sugimori, S. Eguchi and A. Kakehi, Heterocycles, 1998, 47, 1, 375-382) (20.6 mmol) in anhydrous THF (20 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 1 h before being quenched with saturated aq. NH4Cl. The reaction was allowed to warm to room temperature and the organic layer was washed with saturated aq. NH4Cl, dried (MgSO4), filtered and evaporated and residue was purified by flash chromatography (20% ethyl acetate in hexane) to afford the sub-title compound as a pale yellow oil (3.437 g, 53%): 1H NMR (400 MHz CDCl3) δ 1.49 (9H, s), 1.60 (3H, d), 5.18 (1H, m), 7.27 (2H, m), 7.40 (1H, d), 7.59 (1H, t), 8.60 (1H, s).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Br[CH2:40][C:41]([N:43]1[C:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][CH2:45][C:44]1([CH3:52])[CH3:51])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[C:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][CH2:45][C:44]2([CH3:52])[CH3:51])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 28.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (20 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.5 mg) was obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:23])[O:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])(C(C)(C)C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=1F)[C:28]([N:30]1[CH2:33][CH2:32][CH2:31]1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:30]1([C:28]([C:27]2[CH:34]=[CH:35][C:36]([O:22][C:20]3[CH:19]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:23])[CH2:9][OH:8])[CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])=[C:25]([F:24])[CH:26]=2)=[O:29])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(O[C@@H](C)CO)c1
Temperature: 160 °C

Procedure:
To a portion of methyl 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-hydroxybenzoate (102 mg, 0.3 mmol) and 1-(3,4-difluorobenzoyl)azetidine (71 mg, 0.36 mmol) in DMF (2.0 mL) was added potassium carbonate (207 mg, 1.5 mmol) and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 120 minutes. The mixture was allowed to reach ambient temperature and pressure then partitioned between ethyl acetate (2×25 mL) and water (25 mL). The organic layer was separated, washed with brine, dried (MgSO4), and evaporated in vacuo to give the crude product which was used without further purification (100 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N+:13]([O-:24])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OCc2ccccc2)c[n+]1[O-]

Procedure:
A solution of 38.1 g. (0.1915 mol) of 5-benzyloxy-2-methylpyridine in 1 l. of chloroform is treated at 25°C. with 42.7 g. of 85% m-chloroperbenzoic acid. Ater one hour the solution is washed with 5% aqueous sodium carbonate, water, dried and evaporated to give 5-benzyloxy-2-methylpyridine-N-oxide, m.p. 87°-89°C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])(=O)=O.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 3,3,3-trifluoropropyl tosylate (4.057 gm; 15.12 mmol), 3-hydroxybenzaldehyde (1.85 gm; 15.12 mmol), and K2CO3 (4.15 gm; 30.0 mmol) in DMF (80 mL) and heat at 100° C. After 18 hours, cool to room temperature, dilute with water (200 mL) and extract with dichloromethane (2×200 mL). Combine organic extracts and wash sequentially with water (100 mL), 0.1 M NaOH (2×100 mL), saturated sodium bicarbonate (100 mL) and saturated brine (100 mL), dry (MgSO4), and concentrate. Chromatography on silica gel (0-20% ethyl acetate in hexane) to give the title product.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:43][N:44]1[C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=[N:45]1>>[CH3:41][C@@H:39]1[CH2:40][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([NH:50][CH2:49][C:48]4[N:44]([CH3:43])[N:45]=[CH:46][CH:47]=4)=[O:30])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:36][C@H:37]([CH3:42])[O:38]1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: Cn1nccc1CN
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)NCc4ccnn4C)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and (1-methyl-1H-pyrazol-5-yl)methanamine
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[O:17]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:15][C:14]1[C:8]2[C:9](=[N:10][N:6]([CH2:5][C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:32][CH:31]=3)([C:3]#[N:4])[CH3:16])[N:7]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(N)(C#N)Cn1nc2cccc(Cl)c2n1
Product: CC(C#N)(Cn1nc2cccc(Cl)c2n1)NC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg, described in Example 35) and 4-phenoxybenzoyl chloride (0.10 mL), the title compound was isolated as a white solid (70 mg, 38%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=432. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.43 (d, J=13.3 Hz, 1H), 5.50 (d, J=13.3 Hz, 1H), 7.04-7.10 (m, 4H), 7.22 (t, J=7.4 Hz, 1H), 7.43-7.48 (m, 3H), 7.59 (d, J=6.6 Hz, 1H), 7.84 (d, J=8.9 Hz, 2H), 7.94 (d, J=8.0 Hz, 1H) and 8.73 (s, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH:20]=[O:21])=[C:15]([N+:22]([O-])=O)[CH:14]=2)=[C:8]([O:25][CH3:26])[CH:7]=1>C(OCC)(=O)C.[Pd]>[NH2:22][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH:2]3[O:1][CH2:5][CH2:4][O:3]3)=[CH:7][C:8]=2[O:25][CH3:26])[CH:18]=[CH:17][C:16]=1[NH:19][CH:20]=[O:21]
Reactant: COc1cc(C2OCCO2)ccc1Oc1ccc(NC=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C2OCCO2)ccc1Oc1ccc(NC=O)c(N)c1

Procedure:
(4-{[4-(1,3-Dioxolan-2-yl)-2-(methyloxy)phenyl]oxy}-2-nitrophenyl)formamide (430 mg) was hydrogenated in approximately 75 mL of ethyl acetate under an atmosphere of hydrogen over 100 mg of 10% Pd on carbon (wet, degussa type) for 3 days. The catalyst was filtered away and the filtrate was concentrated to give (2-amino-4-{[4-(1,3-dioxolan-2-yl)-2-(methyloxy) phenyl]oxy}phenyl)formamide, which was used without further purification. (M+1) 330.9, 1.79 min (LC/MS method B)