Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N:16]1[N+:20]([O-])=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O.CC(O)CC>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:11])[CH3:9])=[CH:6][C:5]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1
Reactant: CC(C)(C)c1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: Cc1ccccc1
Solvent: CCC(C)O
Solvent: O
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 84.9 %

Procedure:
37.4 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole-N-oxide, 0.125 g of palladium carbon, 300 ml of a solvent mixture comprising toluene, 2-butanol and water (ratio by volume of 10:7:10) and 5 g of 50% dimethylamine were charged into a 500- ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature of the resultant mixture was increased to 60° C. under agitation, and reaction was been effected while agitation being continued until no more hydrogen was absorbed by the mixture. After the reaction had been completed, the autoclave was cooled, and the catalyst was filtered off. After most part of the solvent had been distilled off from the filtrate, the residual solid was washed with ethanol and dried to obtain 30.4 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole as a target substance (yield, 85.0%; melting point, 153° to 155° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH2:18])([CH:14]([CH3:17])[CH2:15]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.Cl[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45].C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([N:18]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH2:15][CH:14]2[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CO)C1(N)CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)OCc2ccccc2)C12CCCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of an optically-active compound of 3-amino-3-(2-hydroxy-1-methylethyl)piperidine-1-carboxylic acid tert-butyl ester (12.9 g), triphenylphosphine (20.3 g) and triethylamine (21.6 ml) in dichloromethane (400 ml) cooled to 0° C. was added carbon tetrabromide (25.9 g) in small batches. The reaction mixture was stirred at room temperature for 1 hour, and the mixture was cooled to 4° C. Then, thereto were added triethylamine (10.8 ml) and benzyl chloroformate (10.3 ml), and the mixture was stirred at room temperature for 40 minutes. To the mixture was added 5% aqueous sodium bicarbonate solution (125 ml), and the mixture was extracted with chloroform (125 ml). The separated aqueous layer was extracted with chloroform (125 ml) again. The combined organic layer was washed with water (125 ml), 10% aqueous sodium chloride solution (125 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 7/3) to give the titled compound (12.4 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.FC1C=CC=C(F)C=1C(NC1C=NC(N2C3C=CC(OC)=CC=3N=C2C(F)(F)F)=CN=1)=O.[CH3:55][C:56]1[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=1[CH2:58][NH2:59].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I.CCOC(C)=O>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:5]3[N:6]=[CH:7][C:2]([NH:59][CH2:58][C:57]4[CH:60]=[CH:61][CH:62]=[CH:63][C:56]=4[CH3:55])=[N:3][CH:4]=3)[C:9]([C:19]([F:22])([F:21])[F:20])=[N:10][C:11]=2[CH:16]=1
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Reactant: Cc1ccccc1CN
Agent: [Cu]I
Agent: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NCc2ccccc2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (50 mg, 0.13 mmol) in DMSO (5 mL) (1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) was prepared as described for Compound 1 above). To this was added 2-methyl-benzylamine (40 mg, 0.33 mmol) followed by CuI (10 mg, 0.05 mmol). To the mixture was added L-proline (20 mg, 0.17 mmol). The resulting solution was held at 50° C. for 1 hr while the reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the reaction mixture was allowed to cool to room temperature, then washed twice with H2O (30 mL each). After removal of the volatile components under vacuum, the residue was purified by eluting through a silica gel column with a 1:10 EtOAc/PE solvent system. This resulted in 25 mg (44%) of the product [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)-amine (Compound 46) as a white solid.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]([NH:12][NH:13][C:14](=[O:30])[C@H:15]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[C:21]=1[CH3:29])[C@@H:16]([OH:18])[CH3:17])(=O)[CH3:10].N1C=CN=C1.II.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.C(Cl)Cl.O>[Si:5]([O:18][C@@H:16]([CH3:17])[C@@H:15]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[C:21]=1[CH3:29])[C:14]1[O:30][C:9]([CH3:10])=[N:12][N:13]=1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(=O)NNC(=O)[C@H](Nc1ccc(C#N)c(Cl)c1C)[C@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnc([C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O[Si](C)(C)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
TBDMS-Cl (3.20 g, 21.25 mmol) was added to a pre-cooled (0° C.) solution of (2R,3S)—N′-acetyl-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutane hydrazide (2.30 g, 7.08 mmol) and imidazole (2.41 g, 35.41 mmol) in DMF (47 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight, whereupon it was poured into H2O (300 mL) and diluted with EtOAc (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to provide crude title compound. Step 2: In a separate flask, I2 (2.70 g, 10.63 mmol) and Et3N (3.98 mL, 28.34 mmol) were added sequentially to a solution of PS-Ph3P (3.54 g, 3.0 mmol/g loading) in CH2Cl2 (25 mL) at 0° C. To this solution was added crude hydrazide in CH2Cl2 (51 mL). After 30 min, the reaction mixture was filtered and the mother liquid washed with 10% Na2S2O3 (200 mL), separated and the aqueous layer extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to provide a yellow oil, which was purified by flash chromatography over SiO2 (30% EtOAc in hexanes) yielding the title compound (2.9 g, 97%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 7.49 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 5.66-5.63 (m, 1H), 4.98 (dd, J=6.8, 8.8 Hz, 1H), 4.58-4.52 (m, 1H), 2.46 (s, 3H), 2.32 (s, 3H), 1.38 (d, J=6.0 Hz, 3H), 0.83 (s, 9H), 0.09 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([O:46][CH3:47])([CH3:45])[CH2:10][C@@H:9]([CH3:48])[C:7](=[O:8])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].[CH:53]([OH:55])=[O:54]>CC(C)=O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([O:46][CH3:47])([CH3:45])[CH2:10][C@@H:9]([CH3:48])[C:7](=[O:8])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].[CH:53]([O-:55])=[O:54]
Reactant: O=CO
Agent: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: CC(C)=O
Product: O=C[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.48 g of clarithromycin (purity: 95.4%) was suspended in 70 ml of acetone, and 0.49 ml of formic acid was added thereto and refluxed for 30 minutes. The suspension was cooled to 0° C. and stirred for 2 hours. Then, the resulting crystals were filtered, washed with cold acetone and dried to give 7.42 g of clarithromycin formate (purity: 97.9%, yield: 94%).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[CH:3]=1.[ClH:26]>ClCCl.CO.O1CCOCC1>[ClH:26].[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(4-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (˜12.3 mmol, 4.3 g) (D4a) was dissolved in dichloromethane/methanol (50 ml/20 ml) and was treated with HCl (10 eq., 0.123 mol, ˜30 ml of a 4M solution in 1,4-dioxane) at room temperature; the mixture was stirred at room temperature for one overnight. Solvent was evaporated and the solid obtained was triturated with diethyl ether to afford the title compound (3.5 g, about 12.3 mmol brown solid) as the mono hydrochloride salt, M++H=250.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Li+].CC([N-]C(C)C)C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].CCCCCC>C1COCC1>[C:1]([C:3]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 39.7 %

Procedure:
A solution of tert-butyl 4-cyanopiperidine-1-carboxylate (0.75 g, 3.57 mmol) in THF (25.0 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.8 M in THF, 6.0 mL, 5.35 mmol) and stirred at the same temperature (−78° C.) for 45 min followed by addition of ethyl chloroformate (0.46 g, 4.28 mmol). The temperature of the reaction was slowly raised to rt and left to stir for 6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 7% EtOAc:hexane to obtain the product as an orange viscous liquid (0.4 g, 48% yield). MS: 283.14 [M+H]+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](O)[CH2:3][CH2:2]1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH2:2]1
Reactant: OC1CCOc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C1=Cc2ccccc2OC1
Yield: 764.2 %

Procedure:
A mixture of 4-chromanol (30 g; 0.02 mole), benzene (200 ml) and 4-toluenesulfonic acid (200 mg) was refluxed, with a Dean-Stark trap, until separation of water ceased (ca. 3 hrs.). It was then washed successively with saturated NaHCO3 aqueous solution and water, dried over anhydrous MgSO4 and evaporated under reduced pressure to yield an almost colorless liquid which was distilled under vacuum to give benzopyran (20.2 g, 76.4%) b.p. 73°-78°/3 torr.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO>O>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 2 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in IPE (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in IPE was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 2 hours. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>CCCCCC>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in hexane (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in hexane was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[OH:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>>[F:13][C:12]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:19]1[CH2:20][CH2:21][CH:17]([OH:16])[CH2:18]1
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Reactant: OC1CCNC1
Product: OC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Yield: 45 %

Procedure:
The title compound (6.84 g, yield 45%) was obtained from 1-bromo-2,4-bis(trifluoromethyl)benzene and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11]C(=O)C.[I:16]I>FC(F)(F)C([O-])=O.[Ag+]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:16])[C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11]
Reactant: II
Reactant: COC(=O)c1ccc(Cl)cc1NC(C)=O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Product: COC(=O)c1cc(I)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a suspension of 2-acetylamino-4-chlorobenzoic acid methyl ester (2.0 g in 80 mL of dry chloroform) and 2.5 g silver trifluoroacetate was added iodine (2.87 g in 40 mL chloroform) and the mixture stirred at room temperature. After 5 hours, the mixture was filtered over diatomaceous earth and the filtrate concentrated in vacuo. Purification of the resulting oil by flash chromatography on silica gel (hexane:ethyl acetate, 95:5; then 90:10) gave the title compound (2.26 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClC(Cl)Cl>[Cl:3][CH:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: OC(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(C(Cl)c2ccccc2)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred mixture of 40 parts of sulfinyl chloride in 150 parts of trichloromethane is added dropwise a solution of 64 parts of α-phenyl-3-(trifluoromethyl)benzenemethanol in 375 parts of trichloromethane. Upon completion, stirring is continued for 1 hour at room temperature. The whole is heated to reflux and stirring is continued for 3 hours at reflux temperature. After stirring overnight at room temperature, the solvent is evaporated. The residue is taken up in methylbenzene and the latter is evaporated again, yielding 70 parts (100%) of 1-(chlorophenylmethyl)-3-(trifluoromethyl)benzene as an oily residue.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH3:6].[OH-].[Na+].C(O)(=O)C.Cl>O.CN1C(=O)CCC1>[F:30][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([OH:13])=[O:12])[CH3:6]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)O)c1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
To methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoate (76.3 g, 179 mmol) was added NMP (534 mL), water (305 mL) and the solution was stirred at 0° C. 2N sodium hydroxide (152 mL, 305 mmol) was charged dropwise and the reaction stirred for 4 hours. Acetic acid (41 mL, 718 mmol) was charged dropwise followed by water (1068 mL) and 1N HCl (400 mL) was added until pH 3 was reached and some material oiled out. The aqueous layer was extracted with toluene (3×988 mL) and combined with the material that oiled out which was dissolved in ethyl acetate (988 mL) and the combined organic layers were washed with water (988 mL), saturated aqueous brine (988 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 5% MeOH in dichloromethane to afford the title compound (64 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O.C(OCC)C>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(F)cccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A mixture of 3-fluorosalicylaldehyde (3.52 g, 25.12 mmol) and cesium carbonate (20.46 g, 62.81 mmol) in N,N-dimethylformamide (30 mL) is treated with iodomethane (3.13 mL, 50.2 mmol) and stirred at room temperature under nitrogen for 2 h. The reaction mixture is diluted with diethyl ether (150 mL) and washed with 0.5 M hydrochloric acid (2×150 mL). The organic portion is dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3.42 g (88%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, 1H), 7.32 (dd, 1H), 7.04 (m, 1H), 4.04 (s, 3H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[CH2:20]([C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[N:32][CH:33]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+].O>C(O)CCC>[CH2:20]([C:28]1[CH:33]=[N:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:36][CH:35]=2)=[N:30][CH:29]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCc1cnc(-c2ccc(OCC(F)CCCCC)cc2)nc1
Reaction time: 5.5 h

Procedure:
0.43 g (1.5 mmol) of the thus obtained (+)-2-fluoroheptyl p-toluenesulfonate and 0.28 g (1.0 mmol) of 5-octyl-2-(4-hydroxyphenyl)pyrimidine were mixed with 0.2 ml o±1-butanol, followed by sufficient stirring. To the solution was quickly added a previously obtained alkaline solution of 0.048 g (1.2 mmol) of sodium hydroxide in 1.0 ml of 1-butanol, followed by 5.5 hours of heat-refluxing. After the reaction, 10 ml of distilled water was added, and the mixture was extracted respectively once with 10 ml of benzene and 5 ml of benzene, followed by drying with an appropriate amount of anhydrous sodium sulfate, distilling-off of the solvent and purification by silica gel column chromatography (eluent: chloroform) to obtain 0.17 g (0.43 mmol) of objective (+)-5-octyl-2-[4-(2-fluoroheptyloxy)phenyl]pyrimidine.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=1[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:34])[N:26]([CH3:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[CH:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[N:17]=[C:16]([C:38]([NH:40][C:41]2([C:51]([OH:53])=[O:52])[CH:48]3[CH2:49][CH:44]4[CH2:45][CH:46]([CH2:50][CH:42]2[CH2:43]4)[CH2:47]3)=[O:39])[CH:15]=1.[OH-].[OH:55][CH2:56][CH2:57][N+:58]([CH3:61])([CH3:60])[CH3:59]>CO>[OH:55][CH2:56][CH2:57][N+:58]([CH3:61])([CH3:60])[CH3:59].[CH3:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH3:4])[C:7]=1[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:34])[N:26]([CH3:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])=[CH:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[N:17]=[C:16]([C:38]([NH:40][C:41]2([C:51]([O-:53])=[O:52])[CH:42]3[CH2:43][CH:44]4[CH2:45][CH:46]([CH2:47][CH:48]2[CH2:49]4)[CH2:50]3)=[O:39])[CH:15]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)[O-])C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
A solution of 1 ml of DCM containing 0.05 g of the compound obtained in EXAMPLE 1' and 0.025 ml of a 45% solution of choline hydroxide in MeOH are left stirring for 15 minutes at 35° C. and the mixture is then concentrated under vacuum. The residue is triturated in 5 ml of ether and the precipitate formed is drained. 0.03 g of the expected product is obtained, m.p.=150° C.