Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19].[N:20]([O-])=O.[Na+].Cl[Sn]Cl>CO.O.Cl>[F:19][C:3]1[CH:4]=[C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:6]=[CH:7][C:2]=1[NH:1][NH2:20]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(NN)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 70 %

Procedure:
3 g (11.22 mmol) of (S)—N-((3-(4-amino-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide (7) was dissolved in a blend of 6 mL methanol, 12 mL water and 3 mL concentrated hydrochloric acid. The resultant mixture was stirred for 10 minutes in an ice-salt bath to maintain the internal temperature below −5° C. Then, a NaNO2 solution prepared in advance was slowly dropped into the mixture. After completion of the addition, the mixture was stirred in the ice-salt bath for another 30 minutes to prepare a reaction solution of diazonium salt. Meanwhile, 6.08 g of SnCl2 was dissolved in a concentrated hydrochloric acid under vigorous stirring in an ice-salt bath. The reaction solution of diazonium salt prepared above was slowly dropped into the SnCl2 solution in hydrochloric acid, and then the mixture was warmed naturally to room temperature and stirred for another 2 hours. After completion of the reaction, the reactant was buffered to a pH between 7 and 8 with 1 ON NaOH solution. After the solvent was evaporated in a rotary evaporator, the resultant material was repeatedly grinded with methanol. After the solvent methanol was rotary evaporated, the residue was recrystallized with ethanol and then filtered to afford a light yellow crystalline solid weighed 2.2 g, with a yield of 70%. The product was kept under low temperature and in a dry place.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:32])[CH:20]([NH2:31])[CH2:21][C:22]1[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[S:25][CH:26]=1>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]([C@@H:20]1[NH:31][C@H:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=2)[C:26]2[S:25][C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[C:22]=2[CH2:21]1)=[O:32]
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)C(N)Cc1csc2ccccc12
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1Cc2c(sc3ccccc23)[C@@H](c2cccc(O)c2)N1
Temperature: 40 °C
Yield: 122.3 %

Procedure:
1.45 g (11.9 mmol) of 3-hydroxy benzaldehyde and 4.2 ml (54.6 mmol) of trifluoro acetic acid are added to a solution of 2.04 g (8.7 mmol) of 2-amino-3-benzo[b]thiophen-3-yl-propionic acid methyl ester (compound B1) in 20 ml of toluene. The solution is stirred at 40° C. over night. The mixture is washed with a saturated solution of sodium hydrogen carbonate. The aqueous layer is washed with ethyl acetate and the combined organic layers are washed with 5 M hydrochloric acid and dried with magnesium sulfate. 3.61 g of a brown oil are obtained as the crude product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:14].[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC.[Li+].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1.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>[CH:15]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:14])=[CH2:16]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2c1ccc(Br)c2CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1CCO)COC2=O
Temperature: 105 °C

Procedure:
A mixture of 5-bromo-4-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (0.460 g, 1.78 mmol), tributyl(vinyl)tin (0.676 g, 2.13 mmol), LiCl (0.224 g, 5.33 mmol) and Pd (PPh3)4 (0.10 g, 0.087 mmol) in toluene (50 mL) was heated at 100-110° C. under N2 overnight after which TLC indicated that the reaction had gone to completion. Next, EtOAc (100 mL) was poured into the solution and it was washed with brine, then water, then dried over Na2SO4, filtered and concentrated to dryness. The residue was then absorbed onto silica gel and separated over silica column to give the title compound.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2C=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29](=O)CCC.C[C@H]1CC[C@H](N)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:21]([N:7]([C@H:1]1[CH2:6][CH2:5][C@H:4]([CH3:29])[CH2:3][CH2:2]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC=O
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: C[C@H]1CC[C@H](N)CC1
Product: CCCCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using butyraldehyde, trans-4-methyl-cyclohexylamine and (2-aminothiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[O:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOCC>[Cl:26][C:4]1[O:5][C:6]([C:7]2[O:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ncoc1-c1ccc(C(F)(F)F)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of Example 31A (0.62 g, 2.8 mmol) in THF (20 mL) at −78° C. was added LiHMDS (1 M in THF, 3.4 mL, 3.4 mmol) dropwise over a period of 6-8 min. After 30 min hexachloroethane (1.35 g, 5.68 mmol) was added at once as a solid and the mixture was left to stir overnight warming to ambient temperature. The mixture was diluted with Et2O and washed with aqueous NH4Cl solution and water. The organic layer was separated and concentrated in vacuo, and the residue chromatographed on silica gel with EtOAc/hexanes (0%-20%) to yield 0.6 g (84%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.46 (m, 1H), 7.04 (d, J=3.4, 1H), 2.33 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]([CH3:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][CH:11]([F:17])[C:12](OCC)=[O:13].C[O-].[Na+].Cl>COCCOC.O.CCOC(C)=O>[F:10][CH:11]([F:17])[C:12](=[O:13])[CH2:9][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)C1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(CC(=O)C1CCCCC1)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cyclohexylmethylketone (2.52 g, 20 mmol) in DME (50 mL) at −20° C. was added ethyl difluoroacetate (7.44 g, 60 mmol) and sodium methoxide (6.48 g, 120 mmol), and the resulting reaction mixture was then stirred at room temperature for 1 hour. EtOAc (500 ml) and water (50 ml) were added, and the pH of the aqueous layer was adjusted to 6 by addition of 1 N HCl solution. The organic layer was washed with brine (50 ml), dried over Na2SO4, and concentrated in vacuo to give the title (3.8 g, 93%). This was used for the next coupling step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1.[OH:18]CC1C=CC2CCC3C=CC=CC=3SC=2C=1>>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:18])[C:7]=2[CH:17]=1
Reactant: OCc1ccc2c(c1)Sc1ccccc1C=C2
Reactant: OCc1ccc2c(c1)Sc1ccccc1CC2
Product: O=S1c2ccccc2C=Cc2ccc(CO)cc21

Procedure:
Repeat the process of Example 2, substituting an equivalent quantity of 3-hydroxymethyldibenzo[b,f]-thiepin for the 3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin, to obtain the title product (m.p., 146°-148° C.).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=C1COC(=O)C1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a stirring solution of 650 mg (6.5 mmol) of tetronic acid in 20 mL of dimethylformamide is added 1.0 mL (7.17 mmol) of triethylamine and 230 mg (1.88 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.50 g (7.81 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (7.81 mmol) of palmitic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is recrystallized from pentane to give 2.0 g (91%) of 4-hydroxy-3-[1-oxohexadecyl]-2(5H)-furanone, mp 81°-83° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+]=[N-].[Na+].C([O-])(O)=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH4+].[OH-]>CN(C=O)C.C1COCC1.O>[CH:1]([N:14]1[CH2:17][CH:16]([NH2:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (14.8 g, 47 mmol, Oakwood Products) was dissolved in anhydrous DMF (60 mL), and to this solution was added sodium azide (9.0 g, 138 mmol). The mixture was heated (80° C.) for 18 h, cooled to RT, then treated with water (20 mL) and satd. aq. NaHCO3 (20 mL). The resulting mixture was extracted with DCM (4×60 mL) and the organic layer dried over Na2SO4. Solvent removal yielded a crude oil (11 g) that was redissolved in THF (85 mL) and treated with triphenyl phosphine (15 g, 57 mmol). After stirring at RT (30 min; gas evolution and some exotherm noted), the mixture was heated to reflux (6 h), then cooled back down to RT before adding NH4OH (7 mL) and refluxing again (5 h). After cooling to RT, the solvent was removed and the residue treated with 3N HCl (35 mL) giving a pH 1. The resulting acidic solution was extracted with DCM (3×50 mL) and the organic layers were discarded. The aqueous layer was then basified with solid potassium hydroxide to pH 10 and then extracted again with DCM (3×75 mL). The aqueous layer was then satd. with solid sodium chloride and re-extracted with DCM (3×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to yield crude 1-benzhydryl-azetidin-3-ylamine (9.0 g, 37.8 mmol). MS (ESI+) for m/z (M+H)+239.
Reaction SMILES: C(C1C=CC(OC2C=C(F)C=CC=2[N+]([O-])=O)=C(OC)C=1)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][C:31]=2[F:39])=[C:25]([O:40][CH3:41])[CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[F:39])=[C:25]([O:40][CH3:41])[CH:24]=1
Reactant: COc1cc(Br)ccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: CCc1ccc(Oc2cc(F)ccc2[N+](=O)[O-])c(OC)c1
Product: COc1cc(Br)ccc1Oc1ccc(N)cc1F
Yield: 87.3 %

Procedure:
According to the procedure of example 50(b) except substituting 4-ethyl-1-(3-fluoro-4-nitrophenoxy)-2-methoxybenzene and 4-ethyl-1-(5-fluoro-2-nitrophenoxy)-2-methoxy benzene for 4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxy benzene (1.88 mmol; 644 mg), the title compound (87%, 512 mg) was obtained as a red oil, and used without further purification.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:17]([CH2:27][O:28]CC=C)[O:16][C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:6]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)C=C.O.II>O1CCCC1.C(OCC)(=O)C.[Ir]>[CH2:33]([O:32][C@@H:6]1[C@@H:5]([OH:4])[C@@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:17]([CH2:27][OH:28])[O:16][C@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C=CCOC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCC=C)[C@H]1OCc1ccccc1
Agent: [Ir]
Agent: II
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](O)[C@H]1OCc1ccccc1
Reaction time: 7 h
Yield: 98.4 %

Procedure:
Under hydrogen gas atmosphere, a solution of Compound 12 (8.9 g, 16.7 mmol) in tetrahydrofuran (80 ml) was added to a solution of activated iridium complex (Ir(CoD)(PMePh2)2PF6, 287 mg, 0.34 mmol) in tetrahydrofuran (60 ml) at room temperature, and the mixture was stirred for 7 hours. Subsequently, water (100 ml) and iodine (8.5 g, 67.1 mmol) were added to the reaction mixture, and it was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized (ethanol/dichloromethane/diethyl ether) to obtain Compound 13 (7.4 g, 97%).
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].S(=O)(=O)(O)O.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH3:21])=[CH:15][CH:14]=1)([OH:12])=[O:11]>>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH3:21])=[C:17]([N+:1]([O-:3])=[O:2])[CH:18]=1)([OH:12])=[O:11]
Reactant: CC(=Cc1ccc(C(=O)O)cc1)[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=Cc1ccc(C(=O)O)cc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Fuming nitric acid (95-98% w/w, 3.7 ml) was added dropwise with stirring to concentrated sulphuric acid (98% w/w, 30 ml), whilst maintaining the temperature at 0°-10° C. 1-(4-Carboxyphenyl)-2-nitropropene (15.3 g) was then added in portions with vigorous stirring over 15 minutes, whilst maintaining the temperature at 0°-10° C. The mixture was stirred for 30 minutes at the same temperature. The viscous reaction mixture was poured onto an ice/water mixture (600 ml) and the resulting yellow solid was filtered off and washed with water to give 1-(4-carboxy-2-nitrophenyl)-2-nitropropene (17.17 g), m.p. 200°-202° C. (with decomposition).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].CCCCCCCCCCCC.[Bi].[OH-].[Na+].O=O>[Pt].CC(CC(C)C)=O>[CH2:1]([C:5]1[NH:6][C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)[nH]1
Agent: [Pt]
Agent: O=O
Agent: [Bi]
Solvent: CCCCCCCCCCCC
Solvent: CC(=O)CC(C)C
Product: CCCCc1ncc(C=O)[nH]1
Yield: 90 %

Procedure:
4.6 g of 2-n-butyl-5-hydroxymethylimidazole, 4.6 g of dodecane as internal GC standard, 0.6 g of 5 percent platinum and 5 percent bismuth on activated carbon (comprising 61.3 percent water), 42 g of isobutyl methyl ketone and 7.5 g of 1.6 percent strength NaOH solution were heated to about 80° C. with stirring. At 80° C., 3.6 liters (STP) of air/hour was introduced into the solution until the absorption of oxygen was complete (350 min!). The reaction mixture was filtered. The filtrate was transferred to a separating funnel, the H2O phase was separated off, the organic phase was concentrated and cooled, and the product crystallized out and was filtered off. The reaction was monitored using GC analysis (internal standard). The reaction yield was 90.0 percent (0.3 percent of starting material).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C(F)(F)F)nc(-c2cccc(Cl)c2)[nH]1
Product: FC(F)(F)c1cc(Cl)nc(-c2cccc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 87.5 %

Procedure:
A 250-mL round bottom flask was charged with 2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one (3.60 g, 13.1 mmol). POCl3 (14.4 mL, 157 mmol) was cautiously added at 0° C. The resulting mixture was stirred at 100° C. for 3.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and treated with aqueous sodium, bicarbonate until the pH˜8. The aqueous layer was extracted with dichloromethane (4×25 mL). The combined organic extract was washed the saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography using hexanes/dichloromethane (3:1) as eluent to afford the title compound (3.36 g, 87%) as a white solid. MW=293.07. 1H NMR (CDCl3, 500 MHz) δ 8.49 (t, J=1.5 Hz, 1H), 8.39 (dt, J=8.0, 1.5 Hz, 1H), 7.57 (s, 1H), 7.53 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[N:19]=[C:18]([O:20][CH:21]([F:23])[F:22])[CH:17]=[C:16]([CH3:24])[N:15]=1>C(Cl)Cl>[CH3:12][S:13]([C:14]1[N:19]=[C:18]([O:20][CH:21]([F:23])[F:22])[CH:17]=[C:16]([CH3:24])[N:15]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(C)cc(OC(F)F)n1
Solvent: ClCCl
Product: Cc1cc(OC(F)F)nc(S(C)=O)n1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A suspension of 20.6 g (0.1 mol) of 3-chloroperoxybenzoic acid in 100 ml of methylene chloride is cooled to a temperature of between -15° C. and -20° C., and there is then added dropwise a solution of 20.6 g (0.1 mol) of 2-methylthio-4-difluoromethoxy-6-methylpyrimidine in 50 ml of methylene chloride. After the reaction mixture has been stirred for 1 hour at the same temperature, it is diluted with methylene chloride; it is subsequently washed with a sodium hydrogen carbonate solution and water, dried over sodium sulfate and concentrated by evaporation. Crystallisation of the residue from a methylene chloride/petroleum ether mixture yields 21.6 g (97% of theory) of 2-methylsulfinyl-4-difluoromethoxy-6-methylpyrimidine, m.p. 105°-107° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([F:13])([C:9]([F:12])([F:11])[F:10])[C:4]([F:8])([F:7])[CH2:5][CH3:6].FC(F)(F)C(F)(C(F)(F)F)C(F)(F)[I:20].C=C>>[F:1][C:2]([F:14])([F:15])[C:3]([F:13])([C:9]([F:10])([F:11])[F:12])[C:4]([F:8])([F:7])[CH2:5][CH2:6][I:20]
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)I
Reactant: CCC(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Agent: C=C
Product: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)CCI

Procedure:
1,1,1,2,3,3-Hexafluoro-2-(trifluoromethyl)-pentane ((CF3)2CFCF2CH2CH3) may be prepared by the reaction of 1,1,1,2,3,3-hexafluoro-2-(trifluoromethyl)-3-iodo-propane with ethylene to give 1,1,1,2,3,3-hexafluoro-2-(trifluoromethyl)-5-iodopentane followed by zinc reduction in an acid such as HCl or acetic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[C:10]([F:16])[CH:9]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])=[C:10]([F:16])[CH:9]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N,N-Dimethylcarbamoyl chloride (101 μL, 1.1 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)methanamine (0.204 g, 1.0 mmol) and triethylamine (148.1 μL, 1.10 mmol) in methylene chloride (5 mL) at 0° C., followed by 4-dimethylaminopyridine (0.012 g, 0.1 mmol). After 10 min, the ice-water bath was removed and the mixture was stirred overnight at RT. The mixture was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:43])[CH2:6][NH:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH2:24][C:23]([C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=2)=[CH:12][CH:11]=1)=[O:9]>O1CCCC1.O>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:34]=[C:29]([C:23]2([C:25]([F:26])([F:27])[F:28])[O:22][N:21]=[C:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]([C:8]([NH:7][CH2:6][C:5]([OH:43])=[O:4])=[O:9])=[CH:11][CH:12]=3)[CH2:24]2)[CH:30]=[C:31]([C:39]([F:40])([F:42])[F:41])[CH:32]=1
Reactant: COC(=O)CNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An aqueous solution of LiOH (300 mg, in 10 mL of H2O) was added to a stirred solution of N-[[4-[5-[3,5-bis(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine methyl ester (i.e. the product of Step B, 850 mg) in tetrahydrofuran (10 mL). After stirring at room temperature for 1 h, the reaction mixture was diluted with water and extracted with hexane. The aqueous layer was acidified with 6.0 N HCl to pH 2, and a white precipitate formed. The aqueous mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound (800 mg) as a white solid. 1H NMR (CDCl3): δ 8.63 (d, 1H), 8.12 (d, 1H), 8.10 (s, 2H), 7.99 (s, 1H), 7.23-7.48 (m, 4H), 7.09 (br t, 1H), 4.20 (d, 1H), 4.19 (s, 2H), 3.83 (d, 1H).
Reaction SMILES: [CH:1]1[C:2]([CH2:19][C:20]([OH:22])=[O:21])=[CH:3][C:4]([I:18])=[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)[C:6]=1[I:7].[C:23](O)([CH3:26])([CH3:25])[CH3:24].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1.CN(C)C1C=CN=CC=1>[C:23]([O:21][C:20](=[O:22])[CH2:19][C:2]1[CH:1]=[C:6]([I:7])[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)=[C:4]([I:18])[CH:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Yield: 10 %

Procedure:
In anhydrous conditions, Tetrac (30.0 g, 40.1 mmol, 1.0 eq.) was dissolved in anhydrous dioxane (200 mL). Tert-butyl alcohol (11.4 mL, 120.3 mmol, 3.0 eq.) and 4-dimethylaminopyridine (3.9 g, 32.1 mmol, 0.8 eq.) were then added. The solution was stirred and dicyclohexylcarbodiimide (9.1 g, 44.1 mmol, 1.1 eq.) was added over a 5 minutes period. The mixture was stirred for 3 hours at room temperature. The cyclohexylurea that has precipitated was removed by filtration through a fritted Büchner funnel, and the filtrate was washed with 10% potassium bicarbonate solution (2×100 mL). During this procedure, some additional cyclohexylurea precipitated and was removed by filtration of both layers to facilitate their separation. The organic solution was then dried over magnesium sulfate, filtered and then evaporated with a rotary evaporator to obtain the crude product as a yellow powder which was purified by column chromatography (DCM/cyclohexane 90/10) to yield tert-butyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetate (3.2 g, 4.0 mmol) as a solid.