Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=3[C:17]#[N:18])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.I[Si](C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[F:23][C:20]1[CH:21]=[CH:22][C:15]([O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([CH2:4][CH:3]=[O:2])[N:6]=[CH:7]3)=[C:16]([CH:19]=1)[C:17]#[N:18]
Reactant: COC(Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21)OC
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CC=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[1-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy]-5-fluorobenzonitrile (1.42 g, 4.16 mmol) in dichloromethane (62 mL) was added iodotrimethylsilane (3.33 g, 16.64 mmol) portion-wise over 3 hours. The mixture was stirred at room temperature for 2 hours. Aqueous NaHCO3 (60 mL) was added to the mixture and it was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with Na2S2O4, brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:14])([F:13])[S:9]([OH:12])(=[O:11])=[O:10].O[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=1[O:27][CH3:28].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:28][O:27][C:17]1[CH:18]=[C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:21][C:16]=1[O:10][S:9]([C:8]([F:14])([F:13])[F:7])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)Cc1ccc(O)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Yield: 99.9 %

Procedure:
Pyridine (2.10 ml, 25.9 mmol), anhydrous trifluoromethanesulfonic acid (1.61 ml, 9.53 mmol) and 4-dimethylaminopyridine (30 mg, 0.25 mmol) were added to a solution of methyl (4-hydroxy-3-methoxyphenyl)acetate (1.70 g, 8.66 mmol) in methylene chloride (20 ml) and the mixture was stirred under ice-cooling for 10 minutes and then stirred at room temperature for 20 minutes. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give methyl (3-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acetate (2.84 g, yield: 99%).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][N:6]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:10](=[O:11])[N:9]([C:18]2[C:19]([F:36])=[C:20](C(COC)C)[C:21]3[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:22]=3[CH:30]=2)[C:7]1=[O:8]>C(Cl)Cl>[F:29][C:26]([F:27])([F:28])[C:24]1[N:23]([CH:12]([CH3:13])[CH2:10][OH:11])[C:22]2[CH:30]=[C:18]([N:9]3[C:10](=[O:11])[CH:12]=[C:13]([C:14]([F:17])([F:15])[F:16])[N:6]([CH3:5])[C:7]3=[O:8])[C:19]([F:36])=[CH:20][C:21]=2[N:25]=1
Reactant: COCC(C)c1c(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)cc2nc(C(F)(F)F)[nH]c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(CO)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Temperature: -40 °C
Reaction time: 1 h
Yield: 189.3 %

Procedure:
One hundred mL of methylene chloride was stirred and cooled to about -40° C. To this was added dropwise 11.0 mL (0.011 mole) of boron tribromide (1.0M in methylene chloride). Upon completion of the addition, the reaction mixture was again cooled to -40° C., and a solution of 4.5 grams (0.010 mole) of 1-methyl-3-(1-methoxymethylethyl-2-trifluoromethyl-5-fluorobenzimidazol-6-yl)-6-trifluoromethyluracil (Compound 8--prepared in a manner analogous to that of Example 3) in about 20 mL of methylene chloride was added dropwise. Upon completion of the addition, the reaction mixture was stirred for an additional one hour at -40° C. After this time the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. The reaction mixture was then poured into a flask, and ice was added. The mixture was stirred until the ice melted, and then extracted with ethyl acetate. The combined extracts were washed with an aqueous solution saturated with sodium chloride and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 4.3 grams of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl)benzimidazol-1-yl]propan-1-ol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:23])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]21OCC[O:19]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:23])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CCCCOCc2ccccc2)CCCCC12OCCO2
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC1(CCCCOCc2ccccc2)CCCCC1=O
Yield: 92.6 %

Procedure:
A mixture of the 2-(4'-benzyloxybutyl)-1,1-ethylenedioxy-2-methylcyclohexane (32.5 g, 0.10 mol), acetone (375 ml), H2O (50 ml) and 0.002 N H2SO4 (125 ml) is refluxed for 18 hours under a nitrogen atmosphere. The reaction mixture is cooled, the acetone is evaporated under reduced pressue and the aqueous layer extracted with ether (3×500 ml). The combined organic layers are washed with satd. NaHCO3 (2×300 ml), satd. NaCl (2×500 ml) and dried (MgSO4). The solvents are removed under reduced pressure and the crude product (29 g) is chromatographed on SilicAR CC-7 (500 g) in hexane. Elution with 5% ethyl acetate/hexane gives 2-(4'-benzyloxybutyl)-2-methylcyclohexanone as a colorless oil (25.4 g, 91%): ir (neat) 1705 cm-1 (CO); nmr (CDCl3) δ1.03 (s, 3H, CH3), 2.35 (m, 2H, OC-- CH2 --CH2), 3.5 (t, 2H, O--CH2 --CH2), 4.44 (s, 2H, O--CH2 --Ph), 7.3 (s, 5H, aromatic).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:36])[CH:24](I)[CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].OP([O-])(O)=O.[K+]>CN(C=O)C>[CH3:21][O:22][C:23](=[O:36])[CH:24]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10][CH2:11]1)[CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30]
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1
Reactant: COC(=O)C(I)CCO[Si](C)(C)C(C)(C)C
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 217.3 %

Procedure:
A solution of 1.60 g (1.94 mmol) of 1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one in 15 ml of DMF was treated at 0° C. with 0.33 g (7.44 mmol) of NaH (55% dispersion in oil). After 20 min at this temperature, the suspension was warmed to RT and added to a cooled solution (0° C.) of 2.33 g (6.50 mmol) of (rac)-4-(tert-butyl-dimethyl-silanyloxy)-2-iodo-butyric acid methyl ester (intermediate 1) in 15 ml of DMF. The solution was stirred 6 h at 0° C. and neutralized with cold 10% aq. KH2PO4 solution and extracted with Et2O (3×). The organic phases were washed with 10% aq. KH2PO4 solution, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2:Et2O 4:1 to 2:1) to yield 2.06 g (68%) of the title compound as light yellow oil. MS: 489.2 (MH+)
Reaction SMILES: [OH:1][C:2]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:37][CH:38]=[CH:39][N:40]=3)=[CH:32][N:31]=2)[CH2:7][CH2:6][CH:5]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:10]2)[CH2:4][CH2:3]1.C=O.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:37][CH:38]=[CH:39][N:40]=3)=[CH:32][N:31]=2)[CH2:7][CH2:6][CH:5]([N:8]([CH3:43])[C@H:9]2[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[CH2:10]2)[CH2:4][CH2:3]1
Reactant: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncco4)cn3)CC2)C1)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C1CCC(O)(c2ccc(-c3ncco3)cn2)CC1)[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
N-{2-[(3S)-3-({4-Hydroxy-4-[5-(1,3-oxazol-2-yl)pyridin-2-yl]cyclohexyl}amino)pyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide (45 mg, 0.081 mmol) and 37% aqueous formaldehyde (30 mg, 1.0 mmol) were dissolved in methylene chloride (5.6 mL). The mixture was evaporated to dryness. Then the residue was taken up in THF (1 mL) and sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to provide the title compound (27 mg). MS (M+H) 572.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[CH2:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)N=CCC2=O
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-4-quinolone (9.72 g 34.5 mmol) and phosphorus oxychloride (130 ml) was stirred at 110° C. for 3 hours. The stirred mixture was concentrated at atmospheric pressure. The residue was dissolved in chloroform (150 ml), then ice and water was added to the solution. The mixture was rendered weakly alkaline by the addition of saturated sodium carbonate solution. The two phases were separated, the aqueous layer was extracted with chloroform. The extract was washed with water, dried over sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was solidified under diisopropyl ether to give 9.82 g of product [E]. Yield: 94%.
Reaction SMILES: CC1(C)C(C)(C)OBO1.Br[C:11]1[CH:12]=[N:13][N:14]([CH3:20])[C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl[C:28]1[C:33]([CH3:34])=[CH:32][N:31]=[C:30]([CH3:35])[N:29]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.O1CCOCC1.C(N(CC)CC)C>[CH3:35][C:30]1[N:31]=[C:32]([C:11]2[CH:12]=[N:13][N:14]([CH3:20])[C:15]=2[C:16]([O:18][CH3:19])=[O:17])[C:33]([CH3:34])=[CH:28][N:29]=1
Reactant: COC(=O)c1c(Br)cnn1C
Reactant: Cc1ncc(C)c(Cl)n1
Agent: [Pd]
Agent: CC1(C)OBOC1(C)C
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2nc(C)ncc2C)cnn1C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 110 %

Procedure:
4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.5 ml) was added to a 1,4-dioxane (19 ml) solution of methyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (1.9 g), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.15 g), Tris(dibenzylideneacetone)dipalladium(0) (0.16 g), and triethylamine (3.7 ml). The obtained mixture was stirred in a nitrogen atmosphere at 100° C. for 30 minutes. Thereafter, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 ml) was added to the reaction solution, and the obtained mixture was then stirred for 30 minutes at the same temperature as described above. Thereafter, an aqueous solution (3.9 ml) of potassium carbonate (3.6 g) and a 1,4-dioxane (4 ml) solution of 4-chloro-2,5-dimethylpyrimidine (1.0 g) were successively added to the reaction solution, and the obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, water was added to the reaction solution, and the mixed solution was extracted with ethyl acetate and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=3:1-1:1-0:1), so as to obtain the title compound (1.9 g) in the form of an orange liquid.
Reaction SMILES: [F:1][C:2]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH3:19][C:20]([S@:23]([NH:25][CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:18])([F:1])[C:14]([F:17])([F:16])[F:15])=[CH:6][CH:7]=1)[CH3:12])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (3.2 g, an off-white solid) from 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanone (3.0 g, 11.0 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: C([O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C:12]([F:17])([F:16])[C@@H:11]1[C:18]1[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:17][C:12]1([F:16])[CH2:13][CH2:14][CH2:15][C@H:10]([OH:9])[C@H:11]1[C:18]1[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=1
Reactant: Cn1nccc1[C@@H]1[C@@H](OC(=O)c2ccccc2)CCCC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cn1nccc1[C@@H]1[C@@H](O)CCCC1(F)F
Yield: 431.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 107e by using the (1S*,2R*)-3,3-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (206 mg, 0.643 mmol) prepared in Example 117c, potassium carbonate (270 mg, 1.95 mmol) and methanol (4.0 mL), to yield the title compound (600 mg, 43%) as a colorless solid.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.S(OC)(O[CH3:15])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:15][O:8][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10]
Reactant: Cc1ccccc1C(=O)O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1C
Yield: 75.3 %

Procedure:
o-Toluic acid (500 mg, 3.67 mmol), dimethyl sulfate (695 mg, 5.51 mmol), and K2CO3 (558 mg, 4.04 mmol) were placed in a round bottom flask and diluted with acetone (10 mL). After purging the resulting suspension with argon for 5 min, the mixture was heated to reflux for 2 h. The reaction mixture was cooled and concentrated under reduced pressure to remove acetone. After adding water to the mixture, the solution was extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Hex/EtOAc=9:1) to give 2-methylbenzoic acid methyl ester (Formula 4) (415 mg, 75%) as a white solid. Rf=0.5 (Hex:EtOAc=9:1); 1H NMR (300 MHz, CDCl3): δ 7.91 (dd, J=8.4 and 1.8 Hz, 1H), 7.40 (td, J=7.5 and 1.5 Hz, 1H), 7.24 (m, 2H), 3.89 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH3:15])[CH2:9][C:8]([CH3:17])([CH3:16])[O:7][C:6]=2[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[C:20]([O:24][C:25](=[O:43])[NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([F:42])[CH:28]=1)([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([O:24][C:25](=[O:43])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:12]3[C:11](=[O:13])[N:10]([CH2:14][CH3:15])[CH2:9][C:8]([CH3:17])([CH3:16])[O:7][C:6]=3[N:5]=[C:4]([S:18][CH3:19])[N:3]=2)=[C:29]([F:42])[CH:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: CCN1CC(C)(C)Oc2nc(SC)nc(Cl)c2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN1CC(C)(C)Oc2nc(SC)nc(-c3ccc(NC(=O)OC(C)(C)C)cc3F)c2C1=O
Temperature: 90 °C

Procedure:
1.77 g (5.85 mmol) of 4-chloro-6-ethyl-8,8-dimethyl-2-methylsulfanyl-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzocyclohepten-5-one, 2.27 g (6.73 mmol) of [3-fluoro-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]carbamic acid tert-butyl ester and 14.63 ml of a 2 M solution of Na2CO3 in 35 ml dioxane are mixed together, followed by degassing 5 times with argon. 339 mg (293 μmol) of tetrakis(triphenylphosphine)palladium (0) are added and the mixture is degassed a further 3 times with argon and then heated at 90° C. for 2 hours 30 minutes. The resulting mixture is allowed to cool. It is poured into water. The product is filtered off, washed with water, dissolved in DCM, dried and concentrated. It is taken up in Et2O, and the mixture is stirred, filtered and dried. 2.94 g of [4-(6-ethyl-8,8-dimethyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclo hepten-4-yl)-3-fluorophenyl]carbamic acid tert-butyl ester are recovered.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].Cl.[CH3:40]OC(=O)CNC>CCCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36])[CH3:40]
Reactant: CNCC(=O)OC
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CN(C)C(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 29, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and sarcosine methylester hydrochloride (commercially available, CAS RN 945218-53-1) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) as eluant. Light brown foam (33%). MS (ESI): m/z=569.135 [M+H]+.
Reaction SMILES: II.[I-].[K+].[OH:5][C:6]1[C:14](C(C)C=CC)=[CH:13][C:12]([CH3:20])=[C:11]2[C:7]=1[C:8]([CH3:23])([CH3:22])[C:9](=[O:21])[NH:10]2.S([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH2:14]([CH:6]([C:14]1[C:6]([OH:5])=[C:7]2[C:11](=[C:12]([CH3:20])[CH:13]=1)[NH:10][C:9](=[O:21])[C:8]2([CH3:23])[CH3:22])[CH:7]=[CH2:8])[CH3:13]
Reactant: CC=CC(C)c1cc(C)c2c(c1O)C(C)(C)C(=O)N2
Agent: II
Agent: O=S([O-])O
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CC(CC)c1cc(C)c2c(c1O)C(C)(C)C(=O)N2
Yield: 31.7 %

Procedure:
287 mg (1.13 mmol) of iodine was dissolved in a 4:1 chloroform-methanol solvent. To the solution were added 191 mg of potassium iodide and 4:1 chloroform-methanol solvent, followed by stirring to homogenize. This potassium iodide solution in 4:1 chloroform-methanol was added to a 4:1 chloroform-methanol solution of 259 mg (1 mmol) of 2,3-dihydro-4-hydroxy-5-(1-methyl-2-butenyl)-3,3,7-trimethyl-1H-indol-2-one under an argon atmosphere, and the mixture was stirred for 15 hours at room temperature. After the addition of an aqueous solution of sodium hydrogen sulfite, the reaction mixture was extracted with chloroform. The extract was washed with 1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by separation thin layer chromatography (silica gel, 2:1 mixture of n-hexane and ethyl acetate) to obtain, as a low polarity component, 122 mg (yield 31.7%) of light yellow crystals of the title compound (a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:31]([F:34])([F:33])[F:32])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:69]1[CH2:73][C:72](=[O:74])[NH:71][CH2:70]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:31]([F:34])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:69]4[CH2:73][C:72](=[O:74])[NH:71][CH2:70]4)=[O:22])=[C:19]([CH2:26][C:27]([F:28])([F:30])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: O=C1CNCN1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2CC(F)(F)F)CN1
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)benzoic acid (200 mg, 0.38 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), HATU (292 mg, 0.77 mmol, 2.00 equiv), DIEA (99 mg, 0.77 mmol, 1.94 equiv), imidazolidin-4-one hydrochloride (94 mg, 0.77 mmol, 1.98 equiv). The resulting solution was stirred for 2 h at r t. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with ethyl acetate/petroleum ether (2:1). This resulted in 150 mg (60%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)phenyl)carbonyl]imidazolidin-4-one as yellow oil.
Reaction SMILES: C([Mg]Br)C.[C:5]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[OH:17])([CH3:8])([CH3:7])[CH3:6].[CH2:18]=[O:19].C(N(CC)CC)C>C1COCC1.C1(C)C=CC=CC=1.CCOCC>[C:5]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH:18]=[O:19])[C:10]=1[OH:17])([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc(C=O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Into a 1 liter reactor thoroughly dried and purged with argon, 36.6 ml of an ether solution containing 110 mmol of ethylmagnesium bromide and 73.4 ml of ether were introduced. To the reactor, a solution containing 18.39 g (100 mmol) of 2-tert-butyl-4-methoxyphenol diluted with 90 ml of a THF was dropwise added at 0° C. over a period of 30 minutes, then the temperature of the system was slowly raised to room temperature, and the reaction solution was stirred at room temperature for 1 hour. Then, 350 ml of toluene was added, and the system was heated to 100° C. to distill off about 180 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to 50° C., 4.50 g (150 mmol) of paraformaldehyde and 21.0 ml (150 mmol) of triethylamine were added, followed by stirring at 80 to 90° C. for 1.5 hours. The reaction solution was allowed to cool to room temperature and then quenched with 10% hydrochloric acid. The organic layer was concentrated, and the solid precipitated was vacuum dried to obtain 11.66 g (yield: 56%) of 3-t-butyl-5-methoxysalicylaldehyde.
Reaction SMILES: CC(O)([C:4]#[C:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C>C1(C)C=CC=CC=1>[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[C:6][C:5]#[CH:4]
Reactant: CC(C)(O)C#CC#Cc1ccccc1
Solvent: Cc1ccccc1
Product: C#CC#Cc1ccccc1

Procedure:
A mixture of 2-methyl-6-phenyl-hexa-3,5-diyn-2-ol (3.8 g, 20.6 mmol) sodium hydride (60%, 83 mg, 2.06 mmol) and toluene (20 ml) was stirred at reflux for 1 hour. The mixture was evaporated. Chromatography on silica gel with petroleum and ethyl acetate (3:1), gave the title compound. Yield 0.54 g (21%).