Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH2:24]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])O)[CH3:25].CO>C(OCC)(=O)C>[CH2:24]([O:26][C:27](=[O:31])[C@H:28]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:30])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Reactant: CCOC(=O)[C@H](C)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the procedure of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 and ethyl-L-lactate were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (R)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionic acid ethyl ester as a yellow (315 mg, 66%). LCMS: RT=3.44 min, [M+H]+=412
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([O:17]CC1C=CC=CC=1)=[O:16])[C:6]([CH3:29])([CH3:28])[CH2:5]2.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([OH:17])=[O:16])[C:6]([CH3:29])([CH3:28])[CH2:5]2
Reactant: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc(C(=O)OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc(C(=O)O)c1
Yield: 75.9 %

Procedure:
A mixture of benzyl 3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoate (914 mg, 2.25 mmol) in methanol (30 mL) and aqueous sodium hydroxide solution (2 M, 17 mL, 34 mmol) was heated to reflux for 2 h. Solvent was removed under vacuum and the residue was acidified with 2N hydrochloric acid solution to pH=2. The precipitated white solid was collected to afford 539 mg of 3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (yield: 76%) as a white powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.Cl>O.[Fe].C(O)C>[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(I)cnc1Cl
Yield: 92.3 %

Procedure:
5-iodo-3-nitro-2-chloropyridine (230 mg, 0.809 mmol), ethanol (1 mL), water (6 drops), and concentrated HCl (0.020 mL) were stirred at room temperature for 10 min. Iron (500 mg, 8.95 mmol) was then added in small portions and the reaction round bottom flask was placed into a 100° C. oil bath for 20 min. The iron was removed by filtration, washed with ethanol, then the combined ethanol layers were concentrated under reduced pressure. The crude residue was purified by flash chromatography using 9:1 hexane:ethyl acetate to give 5-iodo-3-amino-2-chloropyridine (190 mg, 92%) as a colorless solid.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[K+].[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14]1>CO.O>[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=[C:3]2[C:4](=[O:10])[CH:5]3[CH2:8][CH2:9][N:2]2[CH2:7][CH2:6]3)=[CH:14]1
Reactant: O=Cc1ccoc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccoc2)N2CCC1CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Furan-3-carboxaldehyde (2.83 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (2.1 g, 100 mmol) was dissolved in methanol (100 ml) and 10% palladium on charcoal (0.2 g) was carefully added under nitrogen. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 8 hrs followed by quenching of the catalyst with a small amount of chloroform. The entire slurry was filtered through a pad of Celite filter aid followed by additional washing of the pad with methanol. Rotary evaporation of the pooled solvents gave the desired product, 2-((3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octan-3-one, as a clear oil that solidified upon cooling (2.05 g, 96.7%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:34])[C@@H:6]([NH:14][C:15](=[O:33])[C@@H:16]([N:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[N:27]=[C:28]([CH3:31])[S:29][CH:30]=2)[C:21]1=[O:32])[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH2:4][C@@H:5]([OH:34])[C@@H:6]([NH:14][C:15](=[O:33])[C@@H:16]([N:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[N:27]=[C:28]([CH3:31])[S:29][CH:30]=2)[C:21]1=[O:32])[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN=[N+]=[N-])C(C)C)C2=O)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN)C(C)C)C2=O)cs1
Temperature: 70 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A solution of the product of Example 274B (1.3 g) in tetrahydrofuran:water (25 mL, 4:1) was treated with triphenylphosphine (1.4 g, 2 equivalents), stirred at 70° C. for 2 hours and concentrated. The residue was partitioned between 1N HCl and dichloromethane. The aqueous layer was separated and made basic using 1N NaOH, extracted with dichloromethane and the organic extract was concentrated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid):acetonitrile (95:5) to acetonitrile (100%) to give 0.76 g (62%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[I:19]N1C(=O)CCC1=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]3)=[N:9][C:10]=2[I:19])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: OC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1

Procedure:
trans-[4-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (18.00 g, 67.74 mmol) and N-iodosuccinimide (19.81 g, 88.06 mmol) in anhydrous DMF (360 mL) were stirred at 60° C. under N2 for 6 h. The reaction was diluted with DCM (˜600 mL), washed with water and brine, dried over anhydrous Na2SO4 and then concentrated in vacuo. The crude material was purified by a silica gel flash chromatography (eluted with 1:2 EtOAc/DCM to 1:1 EtOAc/DCM) to obtain the desired product as a pale yellow solid; By 1H NMR analysis, the product was contaminated with 0.35 eq. of NIS-impurity. The product was carried onto the next reaction without further purification; MS (ES+): m/z 391.92 (100) [MH+], 393.88 (50) [MH+2], 394.89 (10) [MH+3]; tR (polar-5 min/openlynx) 2.79 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([C:7](=[O:9])[CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)[C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCCC1
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](CC(C)C)C2)cc1OC1CCCC1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclopentyloxy-4-methoxy-phenyl)-3-isobutyl-piperazine (Example 33, Compound 121) as starting materials. Product as a light brown solid (11%). LC/MS (Method B) 2.69 min, [M+1]+ 441.1. Potency class A.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)c(C)n1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M43) (190 mg, 0.333 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a brown solid (97 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2.N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[Si:23]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: O=Cc1ccc2cccc(O)c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
8-Hydroxyquinoline-2-carbaldehyde (5.00 g, 28.9 mmol) and imidazole (4.32 g, 63.5 mmol) was dissolved in dichloromethane (50 mL) under an atmosphere of dry N2. The reaction mixture was then cooled to 0° C. and tert-butylchlorodimethylsilane (4.94 g, 31.8 mmol) was added. The reaction was stirred overnight at ambient temperature, and then partitioned between dichloromethane and water. The organic layer was washed with water and aqueous saturated NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification via flash chromatography (2:1 Hexanes/dichloromethane followed by 1:1 hexanes/dichloromethane) provided 6.50 g, 78% of the desired product as an oil.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][NH+:5]=1.[SH:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:23][C:17]=2[N:16]=1>C(O)C.[OH-].[Na+]>[CH3:11][O:10][C:8]1[C:7]([O:12][CH3:13])=[CH:6][N:5]=[C:4]([CH2:3][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:23][C:17]=3[N:16]=2)[CH:9]=1
Reactant: FC(F)(F)Oc1ccc2[nH]c(S)nc2c1
Reactant: COc1c[nH+]c(CCl)cc1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cnc(CSc2nc3cc(OC(F)(F)F)ccc3[nH]2)cc1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
1.57 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride are added to a solution of 1.64 g of 2-mercapto-5-trifluoromethoxy-1H-benzimidazole in 40 ml of ethanol and 20 ml of 1N sodium hydroxide solution, the mixture is stirred at 20° C. for 2 hours and then at 40° C. for a further hour, the ethanol is distilled off on a rotary evaporator (10 mbar/40° C.) and the colorless precipitate which thereby separates out is filtered off over a suction filter, rinsed with 1N sodium hydroxide solution and water and dried. 2.15 g (79% of theory) of the title compound of m.p. 92°-93° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH:29]=[CH2:30])=[O:22]>CS(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH:29]=[CH2:30])=[O:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C=CCOCCCOC(=O)CBr
Reactant: Oc1ccc(Cl)c2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOCCCOC(=O)COc1ccc(Cl)c2cccnc12
Temperature: 25 °C

Procedure:
3.78 g (0.021 mol) of 5-chloro-8-hydroxyquinoline and 2.91 g (0.021 mol) of potassium carbonate are heated at 60° C. in 100 ml of dimethylsulfoxide (DMSO) for 30 minutes. The mixture is allowed to cool again to room temperature, 5.0 g (0.021 mol) of 3-(allyloxy)propyl bromoacetate are then added dropwise and the solution is subsequently heated at 90° C. for 4 hours. The DMSO is then distilled off in vacuo, the residue is taken up in ethyl acetate and the solution is washed with water and 5 percent strength sodium hydroxide solution. The organic phase is dried over magnesium sulfate, the desiccant is filtered off and the solvent is stripped off under reduced pressure. After recrystallization of the residue from n-heptane, 5.4 g (76.3% of theory) of 3-(allyloxy)propyl
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[C:12]=1[O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:10].C([O-])([O-])=O.[K+].[K+].[CH2:36](I)[CH3:37]>CS(C)=O>[Cl:29][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:36][CH3:37])=[C:13]([O:18][CH3:19])[C:12]=1[O:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:10]
Reactant: CCI
Reactant: COc1c(O)ccc(C(=O)Cc2c(Cl)cncc2Cl)c1OCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c(OCCc2ccccc2)c1OC
Reaction time: 48 h

Procedure:
2-(3,5-Dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-2-phenethyloxy-phenyl)-ethanone obtained from example 112 (89.3 mg, 0.1 mmol) was treated with piperidine (0.8 mL) and water (0.32 mL). The yellow suspension was heated to 90° C. for 54 hours. The solvent was evaporated in vacuo. The crude mixture was treated with NH4Cl (sat., 1 mL) and the organic products were extracted with EtOAc (3×2 mL). The combined organic phases was dried over Na2SO4 and evaporated in vacuo. Purification by flash chromatography using a gradient of EtOAc in toluene as eluent provided 2-(3,5-dichloro-pyridin-4-yl)-1-(4-hydroxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone as a white solid. Yield 8.6 mg (20%). 2-(3,5-Dichloro-pyridin-4-yl)-1-(4-hydroxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone (5.5 mg, 0.013 mmol) was dissolved in DMSO (0.45 mL) and treated with K2CO3 (0.019 mL of a 1M aq. solution) followed by ethyliodide (0.019 mL of a 1M solution in DMSO). The reaction mixture was left at rt for 48 hours and purified by standard HPLC purification. 2-(3,5-Dichloro-pyridin-4-yl)-1-(4-ethoxy-3-methoxy-2-phenethyloxy-phenyl)-ethanone was obtained as a colourless solid. Yield 3.2 mg (36%).
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:12]3[C:13]4[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Clc1nc2cccc3c2n1CCC3
Product: c1ccc(CN2CCN(c3nc4cccc5c4n3CCC5)CC2)cc1
Yield: 70 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g) in 1-benzylpiperazine (10 ml) was stirred at 100° C., under nitrogen, for four hrs. The reaction mixture was quenched with dilute sodium bicarbonate solution (300 ml) and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel; 25:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate to give 3.6 g (70%) of product, mp 157°-158° C.
Reaction SMILES: [F:1][C@:2]([C:14]([F:17])([F:16])[F:15])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3](O)=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C@:2]([C:14]([F:17])([F:16])[F:15])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([Cl:19])=[O:4]
Reactant: CCCCCCCC[C@@](F)(C(=O)O)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CCCCCCCC[C@@](F)(C(=O)Cl)C(F)(F)F
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
2.0 g (7.7 mmol) of (R)-(+)-2-fluoro-2-(trifluoromethyl)-decanoic acid was cooled with ice, and 1.8 g (8.5 mmol) of phosphorus pentachloride was added to the acid. The resulting mixture was stirred for 30 minutes while being cooled with ice, and then stirred at room temperature for 8 hours. Subsequently, the resulting reaction mixture was distilled under reduced pressure, thereby obtaining 1.4 g of (S)-(+)-2-fluoro-2-(trifluoromethyl)decanoyl chloride having the physical properties as mentioned hereinbefore, in a yield of 66%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])=[O:22])[CH2:18][CH3:19]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([C:21]([NH:20][CH2:17][CH2:18][CH3:19])=[O:22])[CH:24]=2)=[N:3][CH:4]=1
Reactant: CCCNC(=O)c1cccc(N)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CCCNC(=O)c1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-propylamino)carbonyl]aniline were reacted to provide 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.00 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz), 7.69-7.59 (m, 2H), 7.44 (t, 1H, J=7.5 Hz), 7.16-7.05 (m, 3H), 6.67 (td, 1H, J=2.4 and 7.2 Hz), 3.34-3.29 (m, 2H), 1.65-1.56 (m, 2H), 0.96 (t, 3H, J=7.5 Hz); 19F NMR (282 MHz, CD3OD): −46049; LCMS: purity: 94%; MS (m/e): 382 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:18][CH2:19][CH3:20])(=[O:17])[C:8]1[CH:16]=[CH:15][C:13]([OH:14])=[C:10]([O:11][CH3:12])[CH:9]=1.CS(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O.C(OCC)C>CN(C)C=O>[F:28][C:27]([F:30])([F:29])[CH2:26][O:14][C:13]1[CH:15]=[CH:16][C:8]([C:7]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCC(F)(F)F)c(OC)c1
Temperature: 120 °C
Yield: 51.5 %

Procedure:
Potassium carbonate (62.2 g, 450 mmol) was added to a solution of ethyl vanillate (58.9 g, 300 mmol) in dimethylformamide (400 ml) and the reaction heated to 120° C. 2,2,2-Trifluoroethyl methanesulphonate (63.4 g, 360 mmol) was added over 15 minutes and the reaction heated at 120° C. for 15 hours. The reaction was cooled to ambient temperature, diethyl ether (400 ml) was added and the reaction was filtered. The filtrate was evaporated in vacuo and the residue was taken up in a mixture of diethyl ether (375 ml) and isohexane (375 ml). The organic layer was concentrated in vacuo to a total volume of 250 ml and the solid which crystallised out was collected by suction filtration. Drying of the solid in vacuo yielded ethyl 4-(2,2,2-trifluoroethoxy)-3-methoxybenzoate (43.0 g, 52% yield) as a white crystalline solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:5]([NH2:7])=[O:6].Br[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[N:23][CH:22]=1>O1CCOCC1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].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>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)=[CH:35][CH:36]=2)=[N:23][CH:22]=1)[C:5]([NH2:7])=[O:6]
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2F)OC1(C)C
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
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: CN(C)C=O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4F)n4ccnc34)cc2)CC1

Procedure:
In the same way as described for Compound 127, step 4, using 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (82 mg, 0.31 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (60 mg, 0.155 mmol) and Pd(PPh3)4 (45 mg, 0.038 mmol) in dioxane (0.68 mL), DMF (1.52 mL) and 1.5M Na2CO3 (0.83 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The title compound is isolated as a solid. HPLC (254 nm): Rt 1.92 min (95.0%); m/z (APCI) 446 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: C=CCOc1ccc(C(C)=O)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Product: C=CCOc1ccc(C(=O)C=Cc2ccc(OC)cc2OC)cc1
Reaction time: 18 h
Yield: 92.2 %

Procedure:
17.6 g (0.1 mol) of 4-allyloxyacetophenone and 16.6 g (0.1 mol) of 2,4-dimethoxy-benzaldehyde were under an inert dry atmosphere (argon) dissolved in 100 ml of dry ethanol (freshly distilled from sodium under argon atmosphere). The solution was added 1 g of sodium hydroxide and left under stirring for 18 h. The reaction mixture was filtered to give 29.9 g (97%) of 2,4-dimethoxy-4′-prop-2-enyloxychalcone identical to that obtained in Example 2.22, m.p. 74.5-75° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.ClCCl.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 49.3 %

Procedure:
In a 250 ml Parr flask, 2.4 g (6.5 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide is dissolved in 50 ml of an absolute ethanol/dichloromethane mixture (1/1) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for one hour. After filtration on celite, the filtrate is concentrated under vacuum. The evaporation residue is taken up in 25 ml of a 1 M HCl solution. The precipitate formed is filtered and rinsed with 50 ml of diethyl ether followed by 50 ml of ethyl acetate. The amine is released from its salt by agitation in a mixture of 50 ml of ethyl acetate and 50 ml of 1 M NaOH. After decanting, the organic phase is washed with 25 ml of IM NaOH and 25 ml of brine. The organic solution is dried over sodium sulphate, filtered, rinsed and concentrated to dryness under reduced pressure to produce 1.09 g (49%) of a white powder. Melting point: 220-221° C.