Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH:12]=[O:13])[CH2:9][F:10])[C:5]([F:21])=[CH:4][CH:3]=1.[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O.C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:14][S@@:15]([C:17]([CH3:18])([CH3:20])[CH3:19])=[O:16])([CH2:11][C@H:12]([OH:13])[C:23]([F:25])([F:24])[F:22])[CH2:9][F:10])[C:5]([F:21])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(CC=O)c1nc(Br)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1nc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 250 mL round-bottomed flask was added (R)-N-((S)-2-(6-bromo-3-fluoropyridin-2-yl)-1-fluoro-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (5.9 g, 15.39 mmol) and THF (130 mL). The mixture was cooled to −78° C. and (trifluoromethyl)trimethylsilane (Apollo Scientific Ltd.; 24.46 mL, 154 mmol) was added. After stirring for 10 min, tetrabutylammonium fluoride (Aldrich; 27.7 mL, 27.7 mmol, 1.0 M in THF) was added over 10 min. The solution was stirred at −78° C. for 2 h. To the solution was added 1 N HCl (10 mL) and the solution was allowed to warm to rt. The solution was carefully diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with water (100 mL) and brine (50 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 60% EtOAc/hexane, 120 g Silicycle HP) afforded:
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25].O>C(O)(=O)C>[C:2]1([C:1]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:25][N:24]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1C(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-c2nnc(-c3ccccc3)c3ccccc23)cc1
Yield: 100 %

Procedure:
To a cooled solution of 1,2-bis(benzoyl)benzene (286.32, 0.5 g, 1.75 mmol) in glacial acetic acid (12 ml) was added hydrazine monohydrate (3.5 mL) dropwise. The reaction mixture was refluxed for 4 hours. The resulting bright brown solution was added with water to produce pale yellow precipitate, yield 100%. This was used to the next reaction for complex without further purification. MS: m/z 283.0 (M+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[I:17])[C:5]([NH2:18])=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]2[NH:18][C:21](=[O:22])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[I:17])[C:6]=2[C:7]=1[F:8]
Reactant: COc1cc(F)c(F)c(Nc2ccc(F)cc2I)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cc(F)c(F)c2c1[nH]c(=O)n2-c1ccc(F)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the stirred solution of 5,6-difluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamine (0.17 gm, 0.43 mmol) in CH2Cl2 (2 ml), 1,1′-Carbonyldiimidazole (0.085 gm, 0.53 mmol) was added. This reaction mixture was kept stirring at room temperature for 16 hours when product precipitated out. The white solid was filtered and used further without any purification. (0.089 gm); m/z=419 [M−1]−.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH3:13])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][C:20]=1[Cl:21].[Cl-].[NH4+]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([C:4]2([OH:9])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[C:2]([CH3:1])[CH2:7][CH:6]([CH3:8])[CH2:5]2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: COC(=O)C1=C(C)CC(C)CC1=O
Reactant: Clc1ccc([Mg]Br)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)CC(C)CC1(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of racemic methyl 2,4-dimethyl-6-oxocyclohex-1-enecarboxylate (Example 1-03, Step 4; 100 mg) in THF (5 mL) was treated with 3,4-dichlorophenylmagnesium bromide (0.5 M, 1.3 mL). The mixture was stirred at rt overnight and then treated with saturated aqueous ammonium chloride. The resulting mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum to provide methyl (4RS,6SR)-6-(3,4-dichlorophenyl)-6-hydroxy-2,4,-dimethylcyclohex-1-enecarboxylate (97 mg). Mass spectrum m/z 353.32 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][C:9]([OH:11])=O)[C:3]=1[Br:12].[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:9](=[O:11])[CH2:8][O:7][C:4]1[C:3]([Br:12])=[C:2]([CH3:1])[O:6][N:5]=1)[N+:18]([O-:20])=[O:19]
Reactant: NCCO[N+](=O)[O-]
Reactant: Cc1onc(OCC(=O)O)c1Br
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: Cc1onc(OCC(=O)NCCO[N+](=O)[O-])c1Br
Yield: 40.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 472 mg of 5-methyl-4-bromo-3-isoxazolyloxyacetic acid and 338 mg of nitroxyethylamine nitrate, 265 mg of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]N1C(=O)CCC1=O>>[Br:16][C:11]1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Product: COC(=O)c1c[nH]c(Br)c1-c1ccccc1
Yield: 70.4 %

Procedure:
Using methyl 4-phenyl-1H-pyrrole-3-carboxylate (2.01 g) and N-bromosuccinimide (1.85 g), a procedure as in Reference Example 40 was performed to give the title compound as white crystals (yield 1.97 g, 70%).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][CH:18]([CH2:20][OH:21])[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:19][CH:18]([CH2:20][OH:21])[CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Reactant: OCC(O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc(SCC(O)CO)cc1

Procedure:
14.0 g (0.07 mol) of 4-chlorobenzophenone, 10.0 g (0.93 mol) of 1-thioglycerol and 28.5 g (0.21 mol) of potassium carbonate in 60 ml of dimethylacetamide are kept at 110° C. for 6 hours, under N2 gas and with stirring. After cooling, the reaction mixture is poured into 200 ml of water. The crude product, which is obtained in the form of an oil, is taken up in ethyl acetate, the solution is washed with water until neutral, dried over K2CO3 and concentrated, isopropanol is poured over the concentrate and the resulting mixture is stirred. The product, which is obtained in the form of crystals, is filtered off. 9.4 g (47%); melting point 86°-88° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C1COCC1.[Pd]>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])[CH:12]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(Sc2cccnc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(Sc2cccnc2)c1
Yield: 71.6 %

Procedure:
3-(3-nitrophenylthio)pyridine (3.2 g, 13.8 mmol) was dissolved in 200 ml of THF, 2 g of palladium on carbon was added, reacted with hydrogen gas at normal pressure and 50° C. for 8 h. Suction filtration was carried out, and the reaction solution was concentrated to obtain an object product 2 g.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.C[N:31](C=O)C>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4]([NH2:31])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-5-{2-[4-(trifluoromethyl)pyridin-3-yl]-1,3-thiazol-4-yl}benzoic acid (205 mg) was dissolved in THF (5 ml) and thionyl chloride (0.06 ml) and DMF (0.01 ml) were added. The mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated under reduced pressure and re-dissolved in THF (5 ml). 28% Aqueous ammonia (3 ml) cooled to 5° C. was gradually added. The reaction mixture was stirred at room temperature for 30 min. and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=9:1→ethyl acetate) for purification and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (130 mg) as colorless powder crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].[C:9]([O:13][C:14]([N:16]1[CH2:19][C:18](=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[CH2:4]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CN1CCNCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1=O
Yield: 69.9 %

Procedure:
A mixture of 1-methylpiperazin-2-one (128 mg, 1.12 mmol), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (231 mg, 1.35 mmol) and 4 Å powdered molecular sieves (150 mg) in DCE (4 mL) was stirred at room temperature for 1.5 h before the addition of sodium triacetoxyborohydride (475 mg, 2.24 mmol). The reaction mixture was filtered through celite, washing with DCM. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording 3-(4-Methyl-3-oxopiperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as an oil (211 mg, 70%). 1H NMR (CDCl3, 300 MHz): δ 3.99-3.92 (m, 2H); 3.81 (dd, J=8.8, 5.1 Hz, 2H); 3.36 (t, J=5.5 Hz, 2H); 3.20-3.14 (m, 1H); 3.08 (t, J=5.5 Hz, 2H); 2.97 (s, 3H); 2.70-2.56 (m, 2H); 1.44 (s, 9H).
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]2=O)[CH2:4][CH2:3][CH2:2]1.[CH3:16][NH2:17]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:16][N:17]=[C:9]1[CH:10]2[N:5]([CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]1=2
Reactant: O=C1c2ccccc2CN2CCCCC12
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CN=C1c2ccccc2CN2CCCCC12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of the ketone of example 5 (1.10 g, 5.47 mmol) in CH2Cl2 (20 mL) was added to methylamine (5 mL) followed by the addition of TiCl4 (2.74 mmol, 2.74 mL of 1.0 M solution in toluene). The mixture was stirred at room temperature for 10 h. It was filtered through a pad of diatomaceous earth (sold under the brand name CELITE) and rinsed with CH2Cl2. The filtrate was concentrated in vacuo to give a mixture of red solid and oil (1.29 g, 100%) which was directly used for the next step without purification.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc2ccncc12
Product: Clc1nccc2ccncc12
Temperature: 130 °C
Yield: 68 %

Procedure:
A pressure bottle, equipped with a magnetic stirrer, was charged with 1-hydroxy-2,7-naphthyridine (2.6 g, 17.8 mmol) and 100 mL of phosphorous oxychloride. The bottle was sealed and heated at 130° C. overnight. Upon cooling, the bottle was opened and the excess POCl3 was removed by evaporation in vacuo. The residue was treated with excess saturated Na2CO3 and extracted twice with CHCl3. The organic layer was washed with brine and dried (Na2SO4). Evaporation of the solvent afforded the product as a light brown solid (2.0 g, 68%, purity 90-95% based on NMR). The product was of suitable purity for use in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[OH:11].Cl.I[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>>[OH:9][CH2:8][C:7]1[C:2]([CH3:1])=[C:3]([O:11][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[C:4]([CH3:10])=[N:5][CH:6]=1
Reactant: N#Cc1cccc(I)c1
Reactant: Cc1ncc(CO)c(C)c1O
Agent: Cl
Product: Cc1ncc(CO)c(C)c1Oc1cccc(C#N)c1
Yield: 6.7 %

Procedure:
The coupling of 4-deoxypyridoxine hydrochloride (5.6 g, 29.5 mmol) and 3-iodobenzonitrile (10.0 g, 43.0 mmol), as described in Example 81, gave 3-(5-hydroxymethyl-2,4-dimethyl-pyridin-3-yloxy)-benzonitrile (93) (0.5 g, 7.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:32])[C:6]=2[CH:33]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:32])[C:6]=2[CH:33]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2oc3ccc(Cl)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)NCCC(=O)O)cc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl]amino}propanoate (196 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.50 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.50 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (170 mg, 92%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:27])[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:11][CH2:10][C:9]=12)=O.[NH3:28].[K+].[Br-]>CO.C(Cl)Cl>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[N:8]2[C:7]([Cl:27])=[N:6][C:5]([C:3]([NH2:28])=[O:2])=[C:9]2[CH2:10][N:11]=1
Reactant: N
Reactant: COC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 0.5 g (0.0012 mole) of 6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester and 20 ml of a 20% solution of ammonia in methanol was heated at 120°-125° in a steel bomb for 18 hrs. Evaporation of the solvent at reduced pressure gave an amorphous solid. The solid was dissolved in methylene chloride, washed with water, dried and evaporated at reduced pressure to give a tan, amorphous solid which crystallized when stirred with a small amount of boiling ether. Recrystallization from a solution of methanol and methylene chloride gave white crystals with mp 285°-288°. Uv λ 214 mμ (ε=44,300) sh 245 (26,500) sh 260 (16,400) sh 300 (600); ir (KBr) 3470, 3335 cm-1 (NH2) 1670 (CON).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]([F:32])([O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[CH:21]([F:23])[F:22].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([O:24][C:20]([F:19])([F:32])[CH:21]([F:22])[F:23])[CH:26]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC(F)(F)C(F)F)c1
Yield: 72.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 300 mg of 3-(1,1,2,2-tetrafluoroethoxy)aniline, and 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 300 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[CH2:23](O)[CH2:24][CH3:25].O>CN(C=O)C>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([O:22][CH2:23][CH2:24][CH3:25])=[O:21]
Reactant: O=C(O)c1ccccc1O
Reactant: CCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
CDI (2.34 g, 14.48 mmol) was added to a solution of salicylic acid (2.00 g, 14.48 mmol) in DMF (40 mL). The reaction mixture was stirred at 50° C. for 4 h and PrOH (2.72 mL, 36.20 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 16 h and allowed to reach r.t. It was poured into H2O (20 mL) and extracted with Et2O (2×40 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 2.05 g of propyl 2-hydroxybenzoate (colourless oil, yield: 79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][CH:17]([CH:31]([CH3:33])[CH3:32])[CH2:18][CH:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]1[CH2:22][O:21]1)[CH:12]=[CH:11]2.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(O)(C)C>[OH:21][CH:20]([CH:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:18][CH:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[CH:8][CH:9]=2)[CH:14]=1)[CH:31]([CH3:32])[CH3:33])[CH2:22][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COCCOc1cccc2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Reactant: C1CCNCC1
Solvent: CC(C)O
Product: COCCOc1cccc2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CN3CCCCC3)C(C)C)cc12

Procedure:
A solution of 0.23 g of tert-butyl {3-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-4-methyl-1-oxiranylpentyl}carbamate in 4 ml of isopropanol and 0.99 ml of piperidine is stirred at 70° C. On completion of reaction (TLC monitoring), the reaction mixture is concentrated by evaporation, and the residue is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:20](=O)([O:28]C1C=CC=CC=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>C1COCC1>[C:22]1([O:21][C:20](=[O:28])[NH:17][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[N:4]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1nc(OCc2ccc(F)cc2)ncc1F)Oc1ccccc1
Yield: 21 %

Procedure:
To a stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.20 g, 0.84 mmol) in dry THF (3 mL) at ice-bath temperature was added NaH (0.034 g of 60 wt. % suspension in mineral oil, 0.84 mmol). When bubbling ceased, the resulting mixture was transferred (dropwise) via cannula to an ice-cold, stirred mixture of diphenyl carbonate (1.8 g, 8.4 mmol) in dry THF (5 mL). The mixture was stirred overnight, poured into EtOAc, and washed with saturated aq. NH4Cl solution followed by brine solution. The EtOAc layer was separated, dried over Na2SO4, filtered, and evaporated. The crude material was purified on silica gel using a gradient of EtOAc and hexanes to give 0.063 g (21%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]carbamic acid phenyl ester as a white solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.3 Hz, 1H), 7.43 (m, 5H), 7.30-7.20 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 5.38 (s, 2H); HPLC-MS (ESI) m/z 358 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K]>CN(C)C=O>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:27]3[C:26](=[O:28])[C:25]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]4[C:23]3=[O:33])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A mixture of 75 g (0.235 mol) of 1-(diphenylmethyl)-3-(methanesulphonyloxy)-azetidine, 47.1 g (0.254 mol) of potassium phthalimide and 800 ml of dimethylformamide was refluxed for 1½ hours, during which time a fine precipitate gradually settled out. After cooling the precipitate was filtered off and the solvent was evaporated off in vacuo, finally under a high vacuum. The colourless residue crystallised when left to stand. Yield: 78.0 g (90% of theoretical). Rf=0.95 (El N).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=[O:4])=[O:3]>CN(C=O)C.[Pd]>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=[O:3])=[O:4]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(2-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (I65) (1.50 g, 3.76 mmol) was taken up in DMF (30 mL) then 10% Pd/C (750 mg) was added. The resulting suspension was stirred under H2 (1 atm) for 16 hours at room temperature. The crude reaction mixture was filtered through Celite, washing with MeOH. The filtrate was evaporated under reduced pressure to give a yellow liquid which was adsorbing onto silica. The silica adsorbed material was chromatographed on silica gel (0-100% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I66) (1.38 g, 91%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J=0.7 Hz, 1H), 7.30-7.12 (m, 4H), 3.72 (s, 2H), 3.68 (s, 3H), 3.41-3.35 (m, 2H), 3.35 (s, 3H), 3.20 (dd, J=9.6, 6.3 Hz, 2H). LCMS Method C: rt 5.92 min; m/z 425.1 (M+Na), 403.1 (M+1), 401.1 (M−1), 371.1 (M-OMe), 343.1 (M-COOMe).