Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][C:10](=[O:21])[CH:11]([CH:16]([CH3:20])[C:17]([CH3:19])=O)[C:12](OC)=O.C(I)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C.O>[CH2:12]([CH:11]1[C:10](=[O:21])[C:9]([O:8][CH3:7])=[C:17]([CH3:19])[CH:16]1[CH3:20])[CH3:1]
Reactant: COCC(=O)C(C(=O)OC)C(C)C(C)=O
Reactant: O=C([O-])[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CCI
Solvent: O
Solvent: CC#N
Product: CCC1C(=O)C(OC)=C(C)C1C
Temperature: 60 °C
Reaction time: 1.67 h
Yield: 14.3 %

Procedure:
22.80 g (165 mmol) of potassium carbonate and 0.69 g (3 mmol) of benzyltriethylammonium chloride are suspended in 150 ml of acetonitrile. While stirring 32.42 g (150 mmol) of methyl 4-methoxy-2-(1-methylacetonyl)-acetoacetate are added thereto and the mixture is heated to 60° C. 28.08 g (180 mmol) of ethyl iodide are added thereto within 100 minutes and the mixture is stirred at 60° C. for a further 90 hours. The suspension is then poured into a solution of 10.35 g (75 mmol) of potassium carbonate in 450 ml of water and heated at reflux temperature for 30 hours. The cooled reaction solution is extracted 3 times with 300 ml of CH2Cl2. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product is distilled at 20 mbar/97°-99° C. and gives 3.61 g (14.3%) of 5-ethyl-2-methoxy-3,4-dimethyl-2-cyclopenten-1-one.
Reaction SMILES: O[C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([OH:13])=[O:12])[C:7]1([CH3:15])[CH3:14])([C:4]#[CH:5])[CH3:3].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:3]=[C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([OH:13])=[O:12])[C:7]1([CH3:15])[CH3:14])[C:4]#[CH:5]
Reactant: C#CC(C)(O)C1CC(CC(=O)O)C1(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CC(=C)C1CC(CC(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of Example 29A (253 mg, 1.2 mmol) in 5 mL of CH2Cl2 was added triethylsilane (250 μL, 1.6 mmol), followed by trifluoroacetic acid (116 μL, 1.6 mmol). The resulting mixture was stirred at room temperature for overnight. Volatile organics were removed in vacuuo and the residue was evaporated with toluene (2×10 mL). The resulting title compound was used without further purification.
Reaction SMILES: CS(C)=O.[NH2:5][C@@:6]1([C:26]#[N:27])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([NH2:24])=[O:23].C(=O)([O-])[O-:29].[K+].[K+].OO>O>[NH2:5][C@@:6]1([C:26]([NH2:27])=[O:29])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([NH2:24])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: N#C[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Reaction time: 0.5 h
Yield: 324.1 %

Procedure:
To a dimethyl sulfoxide (1.2 mL) solution containing 303.0 mg of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a), 35.5 mg of potassium carbonate was added under cooling in water bath (13° C. approximately). Subsequently, 0.2 mL of 30 wt % hydrogen peroxide was added thereto and stirred for 30 min. After stirring for 67.5 hrs at room temperature, 3 mL of water was added to the reaction solution and the precipitated solids were filtered and washed with 1.2 mL of water. The resulting solids were dried under reduced pressure at room temperature to obtain 313.2 mg of (1R, 2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxamide (7a) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8]Br)#[N:2].[CH3:12][NH:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][N:13]([CH3:12])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])#[N:2]
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 5-cyano-2-fluorobenzylbromide (CARBOCORE; CO-0137; 1.50 g; 7.01 mmol; 1 eq.), tert-butyl N-methyl-beta-alaninate (1.34 g; 8.41 mmol; 1.20 eq.) (prepared as described by Howard N., I. et al. in Bioorg. Med. Chem. 11 (2003), 3083-3099) and potassium carbonate (1.94 g; 14.02 mmol; 2 eq.) in CH3CN (25 mL) was stirred at 60° C. for 6 hours then at RT for 16 hours. The acetonitrile was evaporated in vacuo and the resulting mixture diluted with water. Extraction with EtOAc, washing with NaCl sat. solution, drying over sodium sulfate and concentration in vacuo gave title compound as a slightly yellow oil (1.9 g; 92%). 1H NMR (CDCl3) δ 7.79 (dd, J=6.7, 2.1 Hz, 1H), 7.57-7.52 (m, 1H), 7.11 (t, J=8.9 Hz, 1H), 3.57 (s, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H). LC/MS (Method B): 293.2 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 86.4%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([O:15]C)[CH:14]=1)[O:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].C1C=CC=CC=1.O>CO>[OH:15][C:13]1[CH:12]=[C:5]([CH:4]=[C:3]([OH:2])[CH:14]=1)[O:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1
Reactant: COc1cc(OC)cc(Oc2nnn[nH]2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: Oc1cc(O)cc(Oc2nnn[nH]2)c1

Procedure:
A mixture of 38.3 g. of 5-(3,5-dimethoxyphenoxy)-1H-tetrazole, 68 g. of anhydrous aluminum chloride, and 400 ml. of benzene was heated under reflux for about one and one-half hours. A mixture of 150 ml. of water and 30 ml. of methanol was added slowly to the aluminum chloride mixture. The solution was then stirred and allowed to cool. The aqueous layer was separated and extracted with ethyl acetate. After the ethyl acetate was evaporated, the product was crystallized from water. The weight of the product obtained was 28.2 g. and its melting point was 191°-193° C. The following elemental analysis was obtained:
Reaction SMILES: C([O:5][C:6](=[O:20])[NH:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)[CH:9](O)[CH3:10])(C)(C)C.[H-].[Na+]>O>[F:19][C:14]1[CH:13]=[C:12]([CH:8]2[CH:9]([CH3:10])[O:20][C:6](=[O:5])[NH:7]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CC(O)C(NC(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1OC(=O)NC1c1ccc(F)c(F)c1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a well stirred solution of [1-(3,4-difluorophenyl)-2hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) THF (20 mL) was added 95% NaH (0.09 g, 3.8 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over NaSO4, filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel (First isomer: 0.11 g, Rf=0.6, 3:1 hexane-EtOAc; second isomer: 0.23 g, Rf=0.5, 3:1 hexane-EtOAc). NOE experiment suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.O.C(O)(=O)C.C(N(CC)CC)C>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1
Reactant: O=Cc1ccccn1
Reactant: O[C@@H]1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O[C@@H]1CCCN(Cc2ccccn2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(3R)-3-Piperidinol hydrochloride (10.0 g) and triethylamine (10.13 ml) in dry 1,2-dichloroethane (350 ml) were stirred for 15 minutes at 50° C. 2-Pyridine carboxaldehyde (7.63 ml) and glacial acetic acid (4.16 ml) were added and the reaction mixture stirred for 1.5 hours at reflux. Sodium triacetoxyborohydride (34.65 g) was then added portionwise and the resulting mixture was cooled to room temperature and stirred for a further 1 hour. Water (350 ml) and 1M aqueous sodium hydroxide solution were then added until the mixture was pH12. The organic layer was separated and the aqueous extracted with chloroform, the combined organic layers were dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 95:5, by volume, chloroform:methanol to afford (3R)-1-(2-pyridinylmethyl)-3-piperidinol (8.10 g) as a brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2].[C-]#[N:21].[Na+]>CN(C)C=O>[C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[N:21])=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCBr)ccc(C(C)=O)c1O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC#N)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
A solution of 30.0 g. (91.1 mmoles) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl bromide and 4.91 g. (100.2 mmoles) of sodium cyanide in 225 ml. of dimethylformamide was heated to 75°-85° C. for about 17 hours. The reaction mixture was cooled to room temperature, filtered, and evaporated in vacuo at 75° C. Cold 0.1N hydrochloric acid was added to the residue, and the residue was extracted into ethyl acetate. The ethyl acetate layer was twice washed with 0.1N hydrochloric acid, dried over sodium sulfate, and evaporated in vacuo to yield 21.02 g. of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butane nitrile as a dark amber oil which crystallized as it cooled.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:19])=[O:12])[NH:6]2
Reactant: CO
Reactant: Cc1cccc2[nH]c(C(=O)O)cc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2c(C)cccc2[nH]1

Procedure:
Under an argon atmosphere 4-methyl-1H-indole-2-carboxylic acid (0.64 g, 3.65 mmol) was dissolved in 20 ml of methanol. Concentrated sulfuric acid (0.5 ml) was added and the resulting mixture was heated to reflux and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography. Some solvent was removed in vacuo and the resulting crystals were removed by filtration. The solids were taken up in diethyl ether, washed twice with saturated sodium bicarbonate, and then once with brine. The organic fraction was dried over magnesium sulfate and the solvents were removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([NH2:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:14][C:15]1[C:16]([N:20]=[C:21]=[S:22])=[CH:17][S:18][CH:19]=1>C1COCC1>[NH2:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=1[NH:12][C:21]([NH:20][C:16]1[C:15]([CH3:14])=[CH:19][S:18][CH:17]=1)=[S:22]
Reactant: Nc1cc(C(F)(F)F)cc(Cl)c1N
Reactant: Cc1cscc1N=C=S
Solvent: C1CCOC1
Product: Cc1cscc1NC(=S)Nc1cc(C(F)(F)F)cc(Cl)c1N

Procedure:
is obtained analogously to the procedure described in example 25 a) by reacting 3-chloro-5-trifluoromethyl-1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF at room temperature for 3 days. The solvent is distilled off and water is added to the residue, and the mixture is then extracted with ethyl acetate, the solvent is again distilled off and the amorphous residue is crystallized under diisopropyl ether. M.p.: >310° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[O:21][C:20]([F:19])([F:31])[F:32])=[CH:14][CH:13]=2)[CH2:8]1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)c3ccccc3OC(F)(F)F)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 2-trifluoromethoxybenzoyl chloride.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].N12CCCN=C1CCCCC2.Br[CH2:33][CH2:34][O:35][CH3:36].O>CN(C)C=O>[CH3:36][O:35][CH2:34][CH2:33][N:10]1[C:11]2[C:12](=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[N:8]([C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[CH3:1])[C:9]1=[O:20]
Reactant: COCCBr
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COCCn1c(=O)n([C@H]2CCCC[C@H]2C)c2c3cc[nH]c3ncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of rel-1-[(1S,2R)-2-Methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (20 mg) in N,N-dimethylformamide (0.5 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (33 μl) and 1-bromo-2-methoxyethane (21 μl). The mixture was stirred at ambient temperature for 2 hours, then 60° C. for 22 hours. To the mixture was added water. The mixture was extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give pale yellow solid, which was triturated and washed with diisopropyl ether to give rel-3-(2-methoxyethyl)-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (4 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:22][NH2:23])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1>CCO.C([O-])(O)=O.[Na+]>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:22]([C:16]2[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:23]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: COc1cc(NN)cc(OC)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)cc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C

Procedure:
To a solution of 4,4-dimethyl-3-oxopentanenitrile (754 mg, 6.02 mmol) and conc hydrochloric acid (12 M, 500 μL, 6.0 mmol) in EtOH (25 mL) was added 3,5-dimethoxyphenylhydrazine hydrochloride (1.12 g, 5.47 mmol) and the reaction mixture heated at reflux for 1 hr and then cooled to RT. After 23 hr the reaction mixture was diluted with saturated aq. NaHCO3 (50 mL) then extracted with DCM (4×50 mL). The combined organic extracts were dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) and then by SCX capture and release to afford the title compound, Intermediate A25, as a dark orange solid (400 mg, 26%); Rt 1.70 min (Method 2); m/z 276 (M+H)+, (ES+).
Reaction SMILES: [ClH:1].[CH:2]1([NH:5][C:6](=[O:21])[C@@H:7]([OH:20])[C@@H:8]([NH:12]C(OC(C)(C)C)=O)[CH2:9][CH2:10][CH3:11])[CH2:4][CH2:3]1>O1CCOCC1>[ClH:1].[CH:2]1([NH:5][C:6](=[O:21])[C@@H:7]([OH:20])[C@@H:8]([NH2:12])[CH2:9][CH2:10][CH3:11])[CH2:4][CH2:3]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1

Procedure:
To a 4 M 1,4-dioxane solution (60 mL) of hydrogen chloride, (2S,3S)—N-cyclopropyl-3-(t-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (4.5 g) was added. A solid of the product aggregated to form a lump after about 5 minutes, and the flowability of the reaction liquid worsened. After the disappearance of the starting material, the solvent was evaporated away with an evaporator to obtain a concentrated product of (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (chemical purity: 89.8 area %).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([F:43])[C:41]=1[F:42]>>[CH3:9][CH:7]([CH3:8])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:38]2[CH:37]=[C:36]([F:35])[C:41]([F:42])=[C:40]([F:43])[CH:39]=2)[CH:15]=1)[C:4]([OH:3])=[O:34]
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(F)c(F)c(F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3,4,5-trifluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.92 (d, J=6.60 Hz, 6H), 1.50-1.58 (m, 1H), 1.70-1.78 (m, 1H), 2.01-2.15 (m, 1H), 3.75-3.81 (m, 1H), 7.18-7.25 (m, 2H), 7.46 (s, 1H), 7.52-7.58 (m, 2H), 7.63-7.73 (m, 4H); Calcd for C25H20F6O2 (M+Na) 489.42, Found 488.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22]([OH:29])[C:23]([O:27][CH3:28])=[C:24]([OH:26])[CH:25]=1.CCN(CC)CC.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH2:19][C:20]1[CH:25]=[C:24]([OH:26])[C:23]([O:27][CH3:28])=[C:22]([OH:29])[CH:21]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: COc1c(O)cc(CN)cc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1c(O)cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Yield: 107.3 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (89 mg, 0.32 mmol), 5-aminomethyl-2-methoxy-benzene-1,3-diol hydrochloride salt (66 mg, 0.32 mmol) and Et3N (111 μL, 0.8 mmol) in N,N-dimethylformamide (DMF) (2 mL) is stirred at 25° C. for 24 hours. H2O (10 mL) is added to the reaction mixture. The resulting precipitate is filtered, washed with H2O and dried in vacuo to give 144 mg of the title compound as a beige powder. HRMS (ESI) m/z calcd for C18H15BrN2O5 (M+H)+1 419.02371. found: 419.02294.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[C:6]([CH3:15])([CH3:14])[CH2:5]1)(=O)C.C([O-])(O)=O.[Na+]>Cl.C1(C)C=CC=CC=1>[CH3:14][C:6]1([CH3:15])[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2cc(O)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)CNc2ccc(O)cc21
Yield: 107.4 %

Procedure:
A solution of 1-acetyl-3,3-dimethylindolin-5-ol (150 mg, 0.73 mmol) in 1.5 mL of 6 M HCl was stirred at 105° C. for 17 h. After the reaction mixture was diluted with toluene, the separated aqueous layer was neutralized by saturated NaHCO3 aqueous solution, and extracted with ethyl acetate. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 3,3-dimethylindolin-5-ol (128 mg). To a solution of the above product in a 1:1 solution (2.0 mL) of acetic acid and tetrahydrofuran was added benzaldehyde (0.15 mL, 0.15 mmol) at room temperature. After being stirred at the same temperature for 1 h, sodium cyanoborohydride (10.4 mg, 0.165 mmol) was added with additional stirring for 1 h. After the reaction mixture was neutralized by saturated NaHCO3 aqueous solution, the reaction mixture was diluted with ethyl acetate. The separated organic layer was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound (108 mg, 56%).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:32])[C:28]=2[F:31])[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[C:28]([F:31])[C:27]([F:32])=[CH:26][CH:25]=3)[CH2:30][CH:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Reactant: CC1Cc2c(ccc(F)c2F)N1
Agent: [Na+]
Product: CC1Cc2c(ccc(F)c2F)N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 46.9 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 80 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 8a and 51 mg of (+)-2-methyl-4,5-difluoro-2,3-dihydro-1H-indole (reference example 2a). After silica column purification: eluent 98/02 dichloromethane/methanol, 54 mg of 5-fluoro-2-[2-((−)-4,5-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3-methyl-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4].N1C=CC=CC=1>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1coc2cc(Oc3cc(Cl)nc(N)n3)ccc12
Agent: [Pd]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1coc2cc(Oc3ccnc(N)n3)ccc12

Procedure:
A solution of 9.2 g (28.8 mMol) 6-(2-amino-6-chloro-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid methyl ester and 23.4 ml (0.29 Mol) pyridine in 1 l THF is hydrogenated in presence of 3.9 g Pd/C 10% during 5 h. The mixture is filtered through a pad of celite and char coal, the solid washed extensively with THF and MeOH and the filtrate concentrated. The residue is stirred with 400 ml EtOAc and 200 ml water. Filtration of the suspension and washing with water and EtOAc yields the title compound: m.p.: 194-196° C.; MS: [M+1]+=286. The aq. layer is separated off from the filtrate and extracted 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Trituration from ether and EtOAc yields more of the title compound.