Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[CH:3]1[OH:10].C1C=C[NH+]=CC=1.[O-:18][Cr](Cl)(=O)=O.CCOCC>ClC(Cl)C>[Cl:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][C:4]([Cl:9])([F:8])[C:3]1([OH:18])[OH:10]
Reactant: OC1C(F)(Cl)CCCC1(Cl)Cl
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: OC1(O)C(F)(Cl)CCCC1(Cl)Cl
Yield: 73.9 %

Procedure:
0.96 g (4.33 mmol) of trichlorofluoro alcohol 1b in solution in 10 cm3 of dichloroethane were introduced into a 25-cm3 round bottom flask fitted with a condenser and with magnetic stirring. 2.33 g (2.5 eq.) of PCC were added with a spatula and the mixture was heated to reflux under argon atmosphere for 7 h. The reaction mixture was allowed to cool and was then taken up with 100 cm3 of ether, the whole being filtered on florisil. The solvents were evaporated off, the residue was incorporated on silica and purified by flash chromatography (eluent: ether/petroleum ether=15/85 then 20/80). 0.03 g of starting alcohol 1b, that was approximately 3%, and 0.05 g of a mixture of alcohol 1b, diol 3a and 0.76 g of pure diol 3a were isolated. The yield of compound was therefore higher than 74%.
Reaction SMILES: [O:1]=[C:2]1[CH:8](C)[O:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Cl)[C:5]2[CH:17]=[C:18](Cl)[CH:19]=[CH:20][C:4]=2[NH:3]1.C(=O)([O-])O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.O>O1CCCC1>[O:1]=[C:2]1[CH2:8][O:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: CC1OC(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Agent: O=C([O-])O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1COC(c2ccccc2)c2ccccc2N1

Procedure:
To a solution of Compound 4 prepared in Example 1-(1) (3.45 g) and sodium hydrogencarbonate (5.5 g) in tetrahydrofuran (50 ml) is added phosphorus pentasulfide (5.5 g) at 50° C., and the mixture is refluxed for 1 hour, poured into water, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium salfate, and concentrated under reduced pressure. The residue is purified on column chromatography (silica gel/methylene chloride). The resulting light yellow crystals are washed with n-hexane to give crystalline Compound 5 (3.1 g), which is recrystallized from ethyl acetate-n-hexane to give the title compound as pure crystals, mp. 193°-195° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[C:7]([NH:9][C:10]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:11]=1[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[O:8])(=[O:3])[CH3:2]>C(OCC)C>[C:1]([O:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[C:7]([NH:9][C:10]1[CH:22]=[C:21]([NH:23][C:7](=[O:8])[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[O:4][C:1](=[O:3])[CH3:2])[CH:20]=[CH:19][C:11]=1[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CCCCOC(=O)c1ccc(N)cc1NC(=O)c1ccccc1OC(C)=O
Solvent: CCOCC
Product: CCCCOC(=O)c1ccc(NC(=O)c2ccccc2OC(C)=O)cc1NC(=O)c1ccccc1OC(C)=O

Procedure:
By the procedure similar to that described in Example 21, n-butyl 2-(2'-acetoxybenzamido)-4-aminobenzoate and 2'-acetoxybenzoylchloride were reacted and treated to obtain a sticky mass. The mass was dissolved in diethyl ether and a physical stimulus was given to the solution to obtain crystals which precipitated. Recrystallization from ethanol gave n-butyl 2,4-bis(2'-acetoxybenzamido)-benzoate having a melting point between 149° - 152°C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K].[O-]CCCC.C(Cl)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[C:1]1([S:7][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCl
Reactant: Sc1ccccc1
Agent: CCCC[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: c1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
A soltuion of 3 g(19.4 mmol) of 5-chlorovaleryl chloride in 15 ml of anhydrous THF was added dropwise with vigorous stirring over 15 min. under nitrogen, to a solution of ethylmagnesium bromide (15 mL of 3M in ether) in 15 mL of anhydrous THF at -5° C. The reaction was allowed to warm up to room temperature and stirred for 2 hours. After cooling the mixture to 0° C. it was quenched with diluted hydrochloric acid. The mixture was extracted with ether, washed with water, dried over anh. MgSO4, filtered and evaporated. The residue was flash chromatographed through silicagel in CH2Cl2 to give 2.7 g (84%) of the chloroalcohol as a colorless liquid (5-hydroxy-5-ethyl-heptyl chloride). To a stirred solution of 1.32 g (10 mmol) of thiophenol and 1.32 g (11.3 mmol) of potassium tret.-butoxide was added 1.5 g (10 mmol) of the heptyl chloride as prepared above in 5 ml of anhydrous dimethyl formamide. The reaction mixture was stirred at room temperature overnight and extracted with dichloromethane. The organic layer was washed with 10% sodium carbonate solution and water and dried (MgSO4). Solvents were removed in vacuo and the crude oil was purified by silica gel chromatography with hexane-ethyl acetate to give the corresponding phenyl-sulfide (1.9 g) as a colorless oil. This sulfide was then dissolved in 30 mL of dry dichloromethane and 3.0 g (80-85%) of 3-chloroperbenzoic acid was added in portions with stirring and occasional cooling. The reaction mixture was stirred for 2 hrs, and quenched with 10% sodium bicarbonate. The combined organic extracts were washed with aqueous sodium sulfite and brine and dried (MgSO4). The solvents was removed in vacuo and the crude oil was purified by silica gel flash chromatography using hexane-ethyl acetate to afford the pure sulfone (1.4 g) as a colorless liquid. Calcd for C15H24O3S C, 63.34; H, 8.51; S, 11.27; Found: C,63.36; H, 8.61; S, 11.23. 1.0 g N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) containing 1% trimethylchlorosilane was added to 560 mg of the above hydroxysulfone in 1 mL of anhydrous pyridine and the mixture stirred under nitrogen at 60° C. for 3 h. After evaporation of the pyridine under reduced pressure the crude product was flash chromatographed on a silica gel column with hexane followed by 9:1 hexane-ethyl acetate to give the pure hydroxy-protected sulfone (0.62 g). Calcd for C18H32O3SSI C, 60.62; H, 9.05; S 8.99 Found C, 60.73, H, 9.22; S, 8.88%, 1H NMR (CDCl3) δ 0.058 (9H,s,Si--(CH3)3) 3.07-3.12 (2H,m, 7-H) 7.57 (2H, t, J=6.8 Hz, Ar H metal) 7.65 (1 H,t, J=6.8 Hz, Ar H para) 7.92 (2H,d J=6.8 Hz,Ar H, Ortho).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)Cc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)Cc1ccccc1
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of 1-phenylpropan-2-ol (2.72 g, 20 mmol) in CH2Cl2 (20 mL) was added pyridinium chlorochromate (PCC, 5.4 g, 25 mmol) at 0° C. and the mixture was stirred for 3 h. The mixture was concentrated and purified by flash column chromatography (PE/EtOAc=20:1) to give the title compound (2.3 g, 84%) as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([O-])(=O)C.[Na+].CO[CH:16]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH:18](OC)O1>O.C(O)(=O)C>[C:21]1([C:20]2[CH:19]=[CH:18][N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[CH:16]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC1CC(c2ccccc2)C(OC)O1
Reactant: CCOC(=O)CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cn1ccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Glycine ethyl ester hydrochloride (0.44 g, 3.17 mmol), sodium acetate (0.47 g, 5.76 mmol) were dissolved in minimum amount of water (5 mL) and added to glacial acetic acid (5 mL). The mixture was heated to 80° C. and then added to a solution of 2,5-dimethoxy-3-phenyl-tetrahydrofuran (0.6 g, 2.88 mmol) in glacial acetic acid (5 mL). The reaction was stirred at 80° C. for 2 h and then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with copious amount of water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford ethyl 2-(3-phenylpyrrol-1-yl)acetate (0.55 g, 83%).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1.CCN(CC)CC.C(Cl)(=O)C.[OH-].[Na+]>CN(C=O)C>[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]2[CH2:17][N:16]([C:3](=[O:4])[CH3:2])[CH2:15][C:13]=2[N:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CNC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Temperature: 20 °C
Reaction time: 0.03 h

Procedure:
To a stirring solution of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine trifluoroacetate (intermediate 20) (2.16 g, 2.0 mmol) in DMF (10 ml), was added Et3N (560 uL, 4.0 mmol). Reaction mixture was stirred at room temperature (20° C.) for 2 minutes followed by the addition of acetyl chloride (157 uL, 2.2 mmol) followed by stirring at room temperature overnight. The reaction mixture was basified (with 2M NaOH) before partitioning between water (25 ml) and DCM (50 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo, affording the title compound as a pink solid, which was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1.[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.C([Li])CCC>C1COCC1>[CH3:9][O:8][C:3]1[C:2]([B:10]([OH:15])[OH:11])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COc1ncncc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ncncc1B(O)O
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 44.4 %

Procedure:
To a solution of 5-bromo-4-methoxypyrimidine (0.460 g, 2.43 mmol) and triisopropyl borate (0.671 mL, 2.92 mmol) in 12 mL of THF at −70° C. was added butyllithium (1.6 m in hexanes, 1.83 mL, 2.92 mmol) dropwise. The addition took 15 minutes and the reaction turned light yellow. The reaction stirred for 30 minutes at −70° C. and was then allowed to warm up to −20° C. The reaction was quenched with ammonium chloride (sat.) and extracted with ethyl acetate. The aqueous layer was concentrated and NaCl (sat.) was added. The aqueous layer was extracted with 3/2 chloroform/iPrOH (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 166 mg of 4-methoxypyrimidin-5-ylboronic acid as a light yellow solid. ES+=155.2 (M+H)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:12]=[CH:13][C:4]([Br:3])=[CH:5][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCCOCc2ccccc2)cc1

Procedure:
Sodium hydride (60% in mineral oil, 0.500 g) was added to a solution of 2-(4-bromophenoxy)ethanol (2.25 g) in N,N-dimethylformamide (15 mL) at room temperature with stirring. After being stirred for 20 minutes, benzyl bromide (1.42 mL) was added at that temperature, and the mixture was stirred for additional 13 hrs. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to afford 1-(2-benzyloxyethoxy)-4-bromobenzene (2.51 g).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][PH:10](=[O:14])[O:11][CH2:12][CH3:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:15]I.O>O1CCCC1>[CH:3]1([CH2:9][P:10]([CH3:15])(=[O:14])[O:11][CH2:12][CH3:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CI
Reactant: CCO[PH](=O)CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(C)(=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2.25 g of sodium hydride (55% dispersion in oil) in 10 ml of anhydrous tetrahydrofuran is cooled to 0° under an inert atmosphere. A solution of 8.9 g of ethyl (cyclohexylmethyl)phosphinate in 10 ml of anhydrous tetrahydrofuran is added dropwise maintaining the temperature at between 0°-5°. After the addition is complete the suspension is warmed to room temperature and stirred for 30 minutes before re-cooling to 0° C. A solution of 19.87 g of methyl iodide in 10 ml of anhydrous tetrahydrofuran is added slowly--very exothermic! After warming to room temperature, the reaction mixture is stirred for 45 minutes, re-cooled to 0° and carefully treated with water. Removal of the organic phase, drying and concentration affords a yellow oil. Chromatography on silica gel gives ethyl P-cyclohexylmethyl-P-methylphosphinate as a colourless oil; 1H-NMR (CDCl3): δ (ppm)=4.04 (2H, m, CH2OP), 1.94-1.57 (7H, m, 3×CH2 +CH), 1.45 (3H, d, J=15 Hz, P--CH3), 1.36-0.95 (9H, m, 3×CH2 +CH3).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:26][CH3:27])[C:16]=3[OH:25])[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][C:37]=1[CH3:44]>>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:26][CH3:27])[C:16]=3[O:25][CH2:40][C:39]3[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[C:37]([CH3:44])[CH:38]=3)[CH2:11]2)=[O:9])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(CCl)cc1C
Reactant: CCOC(=O)C1Cc2c(ccc(OC)c2O)CN1C(=O)C(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1Cc2c(ccc(OC)c2OCc2ccc(OC)c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
This compound is prepared from the phenol derivative of Example 31 and 4-methoxy-3-methyl benzyl chloride by a procedure similar to that in Example 32. The product is purified by silica gel chromatography; tlc (1:1 ethyl-acetate/hexane), one spot, Rf 0.7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([OH:16])=[CH:9][C:8]=1[F:17])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1.COC(=O)CC(=O)C(Br)C.ClC1C=CC(C(N)=S)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[S:30][C:31]=2[CH3:37])=[CH:9][C:8]=1[F:17])[CH3:2]
Reactant: Cc1sc(-c2ccc(Cl)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1cc(OCC)c(O)cc1F)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Agent: NC(=S)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc(OCC)c(OCCc2nc(-c3ccc(Cl)cc3)sc2C)cc1F)OCC

Procedure:
In analogy to the procedure described in example 4 d], [rac]-2-ethoxy-3-(5-ethoxy-2-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester [example 68 a]] was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-chloro-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-5-ethoxy-2-fluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-5-ethoxy-2-fluoro-phenyl)-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1F)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)[C:11]([F:13])([F:14])[F:12])[O:8][C:33]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[F:25]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(c1ccc(Oc2ccc(C#N)cc2F)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 196, 100 mg) in N,N-dimethylacetamide (2 ml) were added 3,4-difluorobenzonitrile (46 mg) and cesium carbonate (272 mg). The mixture was stirred for 18 h at room temperature. EtOAc and ice water were added and the mixture was extracted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 95:5=>0:1) to give the title compound (133 mg) as a colorless solid. MS (m/e)=481.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: BrCCCBr
Reactant: Oc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(OCCCBr)c1

Procedure:
Analogously to Example 91b, 0.98 g of 3,5-difluorophenol and 15.2 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.70 (1:6 EtOAc-heptane); Rt=5.13.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=2C(O)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.C[Li]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=2[C:9](=[O:8])[CH3:10])=[CH:11][CH:10]=1)[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:17]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Agent: [Li]C
Product: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1

Procedure:
1-[2-(4-Benzyloxyphenylamino)-5-methoxyphenyl]ethanone [XIII; R=5-CH3O, OR°=4-OCH2C6H5, R"=H] was prepared by reduction of 2-(4-benzyloxyphenylamino)-5-methoxybenzoic acid (Example 1A, part a) with methyllithium according to the procedure of Example 5, part (a), and obtained in the form of a yellow-orange powder, m.p. 80°-81.5° C. when recrystallized from toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(CNC(=O)C2CC2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(CNC(=O)C2CC2)ccc1Cl
Yield: 52.6 %

Procedure:
To a solution of methyl 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoate (10.0 g, 30 mmol) in THF: methanol (10:20 mL) was added aqueous solution of NaOH (6.0 g, 140 mmol). The reaction mixture was refluxed for 3-5 h. The reaction mixture was concentrated, diluted with water and acidified with dilute HCl. The reaction mixture was extracted with 10% MeOH:DCM and concentrated to afford 4.0 g of desired product. 1H NMR (300 MHz, DMSO de): δ 0.67 (m, 4H), 1.59 (m, 1H), 4.28 (d, J=6.0 Hz, 2H), 7.37-7.50 (m, 2H), 7.65 (s, 1H), 8.64 (m, 1H), 13.40 (br s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=3[Cl:32])[CH:20]=2)=[CH:15][CH:16]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[C:36]([O:35][C:33]([N:7]1[CH2:8][CH2:9][C:10]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=4[Cl:32])[CH:20]=3)=[CH:15][CH:16]=2)=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)=C(C(=O)O)C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of compound C8 (1.00 g, 1.78 mmol) and aq. 1M LiOH (7.00 mL, 7.00 mmol) in THF (7.00 mL) was stirred overnight at 70° C. Aq. 1M HCl was added until a pH=4 was reached. The mixture was extracted with EtOAc (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the title compound mixed with 6-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′,3′-dicarboxylic acid 1′-tert-butyl ester (976 mg, quantitative yield) that was used further without purification. LC-MS: tR=1.06 min; ES+: 548.30.
Reaction SMILES: ON=CC1C=CC([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[O:12])=CC=1.C[O-].[Na+].C(Br)C=C>O>[CH:18]([O:17][C:15]([CH2:14][NH:13][C:11](=[O:12])[NH2:10])=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)CNC(=O)Nc1ccc(C=NO)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: O
Product: CC(C)OC(=O)CNC(N)=O

Procedure:
A solution of N-[4-(hydroxyiminomethyl)phenyl]-N'-isopropoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the corresponding N-[4-allyloxyiminomethyl)phenyl]-N'-isopropoxycarbonylmethylurea.
Reaction SMILES: C1COCC1.[C:6]1([CH3:14])[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>CCCCCC>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:9]2[CH:10]=[CH:11][C:6]([CH3:14])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(Cl)cc1
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C)cc2)cc1
Reaction time: 24 h
Yield: 92 %

Procedure:
Using a THF solution of p-tolylmagnesium bromide (1.18 mL, 1.02 M, 1.2 mmol) and 1-methoxy-4-chlorobenzene (142.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=15, 30 and 50% in hexane), the above compound was obtained as a white solid (0.182 g, yield=92%, purity=>99% (GC analysis)).