Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-methoxy-2-methylaniline (26 mg, 0.193 mmol) similar to Example 13 and isolated as a tan solid (8 mg, 12%). 1H NMR (CDCl3): 9.72 (d, J=0.6 Hz, 1H), 8.74-8.68 (m, 2H), 7.70 (s, 1H), 7.44-7.40 (m, 1H), 7.27(s, 1H), 7.25 (s, 1H), 6.99 (s, 1H), 6.85 (dd, J=2.7, 8.7 Hz, 1H), 6.64 (s, 1H), 3.83 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:9]([CH:7]=[O:8])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])[N:23]=1
Reactant: COC(=O)c1c(O)cccc1C=O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C=O)cccc1Oc1nc(OC)cc(OC)n1
Temperature: 0 °C
Yield: 56.1 %

Procedure:
13.8 g of potassium carbonate and 50 ml of DMF were placed in a 200 ml eggplant type flask, and 11.1 g of methyl 2-formyl-6-hydroxybenzoate and 14.6 g of 4,6-dimethoxy-2-methanesulfonylpyrimidine were added thereto with stirring. The mixture was stirred at 80° C. for 1 hour, and the resultant liquor was poured into an ice water after cooling. An oily product thus precipitated was extracted with ethyl acetate, and was dried with magnesium sulfate anhydride. Ethyl acetate was distilled off under reduced pressure, and the residue thus obtained was purified by column chromatography to obtain 11.0 g of the aimed compound (melting point=91° to 93° C.) at a yield of 52%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][CH3:31])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:40]2[CH:52]=[CH:51][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:40]2[CH:41]=[CH:42][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:51][CH:52]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][CH3:31])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: O
Solvent: C1COCCO1
Product: CCCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(propyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.2 g, 0.412 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.148 g, 0.488 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.108 g, 1.01 mmol) was added and reaction mixture purged with argon for 15 min. Pd (PPh3)4 (0.048 g, 0.042 mmol) was then added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford the title compound (0.20 g, 83.68%). LCMS: 587.40 (M+1)+; HPLC: 98.68% (@254 nm) (Rt; 4.257; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H, J=4.8 Hz), 7.56 (d, 2H, J=8 Hz), 7.38 (t, 3H, J=8 Hz), 7.19 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.82-3.85 (m, 2H), 3.57 (m, 4H), 3.48 (s, 2H), 3.23 (t, 2H, J=10.8 Hz), 2.94-3.02 (m, 3H), 2.36 (bs, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.56-1.65 (m, 4H), 1.20-1.25 (m, 2H), 0.76 (t, 3H, J=6.8 Hz).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:6]1.O[Li].O.Cl>C1COCC1.CO.O.CCOC(C)=O>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8]([C:7]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])=[CH:6][N:5]2[CH2:4][C:3]([OH:21])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To as stirred solution of 2 g (6.3 mmol) of [6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic acid methyl ester in 45 ml of THF/MeOH/H2O 1/1/1, at 40° C., were added 0.79 g (18.9 mmol, 3 eq.) of LiOH.H2O. After 1 hour, the reaction mixture was diluted in EtOAc, acidified with aq.HCl 1M. The organic phase were dried over Na2SO4, and concentrated under vacuo to afford 1.9 g (99%) of [6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic acid as a white solid.
Reaction SMILES: I[C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:15]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20][C:19]=2[C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[O-][Si]([O-])=O.[Mg+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(O)C.C1(C)C=CC=CC=1>[C:5]1([C:15]2[C:23]3[C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[CH:2]=[CH:3][CH:4]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: Ic1cccc2c1sc1ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)sc1cccc(-c3cccc4sc5ccccc5c34)c12
Yield: 89.1 %

Procedure:
Into a 500-mL three-neck flask were put 4.7 g (15 mmol) of 4-iododibenzothiophene, 3.6 g (16 mmol) of dibenzothiophene-4-boronic acid, and 91 mg (0.30 mmol) of tris(2-methylphenyl)phosphine, and the air in the flask was replaced with nitrogen. To this mixture were added 50 mL of toluene, 25 mL of ethanol, and 15 mL of an aqueous solution of potassium carbonate (2.0 mol/L). This mixture was degassed by being stirred while the pressure was reduced. To this mixture, 34 mg (0.15 mmol) of palladium(II) acetate was added. This mixture was stirred at 80° C. under a nitrogen stream for 3 hours to precipitate a solid. The precipitated solid was collected by suction filtration. The aqueous layer of the obtained filtrate was subjected to extraction with toluene, and the extracted solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate, and this mixture was gravity-filtered. A solid obtained by concentrating the resulting filtrate and the solid collected by suction filtration were dissolved in approximately 100 mL of toluene. This solution was suction-filtered through Celite (Catalog No. 531-16855, produced by Wako Pure Chemical Industries, Ltd.), alumina, and Florisil (Catalog No. 540-00135, produced by Wako Pure Chemical Industries, Ltd). A solid obtained by concentrating the resulting filtrate was recrystallized from toluene/hexane to give 4.9 g of a white solid, which was an objective substance, in 90% yield. Synthesis Scheme (a-1) of Step 1 is shown below.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([CH2:28][C:29]([OH:31])=O)[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.C(OCC)C>[C:1]([O:5][C:6](=[O:32])[CH:7]([CH2:28][C:29]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:31])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CC(=O)O)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CC(=O)N3CCOCC3)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
2-(Carboxymethyl)-3-{1-[(cis-4-ethoxycarbonyl-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid t-butyl ester (1.0 g, 2.21 mmole) was added to a solution of morpholine (230 mg, 2.65 mmole), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt (845 mg, 4.41 mmole), 1-hydroxybenzotriazole hydrate (675 mg, 4.41 mmole) and triethylamine (893 mg, 8.84 mmole) in dry dichloromethane (50 ml) at room temperature. After 4 days the solvent was evaporated and the residue taken up in ethyl acetate (50 ml) and washed with 1N hydrochloric acid (50 ml), water (50 ml) and saturated sodium hydrogen carbonate solution (50 ml). The organic layer was separated, dried over magnesium sulphate and evaporated to give an orange oil. Chromatography on silica gel eluting with diethyl ether followed by ethyl acetate gave the title product as a yellow foam (790 mg, 68%). Found: C,64.63; H,9.09; N,5.23. C28H46N2O7 requires C,64.34; H,8.87; N,5.36%.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[O:17])=[CH:12][CH:11]=2)[N:8]=[N:7][C:6]=1[C:24]([NH:26][CH:27]1[CH2:29][CH2:28]1)=[O:25].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH:27]1([NH:26][C:24]([C:6]2[N:7]=[N:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[O:17])=[CH:12][CH:11]=3)[C:5]=2/[CH:4]=[CH:3]/[CH3:2])=[O:25])[CH2:29][CH2:28]1
Reactant: O=C(NCC(F)(F)F)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C/C=C/c1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
5-(3-Bromopropyl)-N-cyclopropyl-1-(4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxamide (212 mg, 0.45 mmol) obtained in Example 399a) was dissolved in acetonitrile (5.0 ml), tetrabutylammonium fluoride monohydrate (140 mg, 0.54 mmol) was added, and the mixture was stirred at 80° C. for 16 hr. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/9 to 7/3) and recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (27.7 mg, 16%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[C:1]([NH:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([O:13][CH2:22][CH3:23])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OC(C)C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)Oc1ccc(NC(C)=O)cc1
Yield: 80 %

Procedure:
To a solution of 2-(4-acetamidophenoxy)propionic acid (0.5 g, 2.2 mmol) in ethanol (10 mL) is added a drop of concentrated sulfuric acid and refluxed for 4 hours. The reaction is concentrated to dryness to give a residue. The residue is partitioned between water and ethyl acetate. The ethyl acetate layer is collected, dried (MgSO4), and concentrated to give ethyl 2-(4-acetamidophenoxy)propanoate (0.44 g) (yield 80%): 1H NMR (CDCl3) delta 1.27 (t, J=7.0 Hz, 3H), 1.60 (d, J=7.0 Hz, 3H), 4.25 (q, J=7.0 Hz, 2H), 4.76 (q, J=7.0 Hz, 1H), 6.84 and 7.46 (dd, J=9.0 Hz, 4H), and 8.02 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:31]1([N:41]=[C:42]=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:42]([NH:41][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)=[O:43])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=Nc1cccc2ccccc12
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4cccc5ccccc45)nc3n2)CC1
Yield: 70.5 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.378 g of 1-naphthyl isocyanate according to the general procedure of Example 37. Chromatography, eluting first with ethyl acetate:methyl alcohol:triethylamine (90:10:1) then switching to ethyl acetate:ethanol:triethylamine (9:2:1) gave 0.97 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-naphthalen-1-yl-urea, ESMS (20/80 MeOH/CH3 CN+0.1% AcOH): M+ +H=615 (Base), 446; mp 186.5°-189° C.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:9]([CH:23]=[CH2:24])[C:10](N1[C@H](C(C)C)C(C)(C)OC1=O)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:27]O.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:9]([CH:23]=[CH2:24])[C:10]([OH:11])=[O:27])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H](C(=O)N1C(=O)OC(C)(C)[C@H]1C(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@@H](C(=O)O)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A cooled (0° C.) solution of (R)-3-{(R)-2-[(R)-1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-but-3-enoyl}-4-isopropyl-5,5-dimethyl-oxazolidin-2-one (400 mg, 1.04 mmol) in tetrahydrofuran/water (15 mL, 2:1) was subsequently treated with hydrogen peroxide (30% aqueous, 537 μL, 5.21 mmol) and lithium hydroxide monohydrate (87 mg, 2.09 mmol). The mixture was allowed to warm up to room temperature overnight. The reaction was quenched with sodium metabisulfite until Kl/starch paper negative. After stirring for 2 h at room temperature the volatiles were removed in vacuo. The mixture was then diluted with water and the pH was adjusted with potassium carbonate. The aqueous layer was washed with dichloromethane (2×20 mL) and acidified with hydrochloric acid (pH˜1) then extracted with ethyl acetate (3×30 mL). All ethyl acetate layers were combined and the volatiles were removed in vacuo to afford the title compound (200 mg, 79%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.09 (s, 3H), 0.11 (s, 3H), 0.89 (s, 9H), 1.22 (d, J=6.0 Hz, 3H), 3.07 (t, J=8.7 Hz, 4.11 (pentet, J=6.5 Hz, 1H), 5.20-5.35 (m, 2H), 5.70-5.90 (m, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([OH:31])=O)[C:22]=5[N:21]=4)=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:3][N:2]=1.[CH:32]([NH2:35])([CH3:34])[CH3:33].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>CS(C)=O.CO>[CH:32]([NH:35][C:29]([C:28]1[C:22]2[N:21]=[C:20]([C:19]3[C:13]4[C:14](=[N:15][CH:16]=[C:11]([C:4]5[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[CH:1]=[N:2][CH:3]=5)[CH:12]=4)[NH:17][N:18]=3)[NH:24][C:23]=2[CH:25]=[CH:26][CH:27]=1)=[O:31])([CH3:34])[CH3:33]
Reactant: O=C(O)c1cccc2[nH]c(-c3n[nH]c4ncc(-c5cncc6ccccc56)cc34)nc12
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)NC(=O)c1cccc2[nH]c(-c3n[nH]c4ncc(-c5cncc6ccccc56)cc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture of Compound 17 (25 mg, 0.06 mmol), isopropylamine (11 μl, 0.12 mmol), HATU (23.4 mg, 0.06 mmol) and DIPEA (35 μl, 0.48 mmol) in DMSO (1 mL) was stirred at room temperature overnight. The solution was diluted with MeOH (0.4 mL) and purified by Gilson HPLC (10% to 90% of 0.1% TFA in ACN/0.1% TFA in H2O) to yield Compound 18 (9 mg, 33%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 9.79 (s, 1H), 8.96 (s, 1H), 8.84 (s, 1H), 8.78 (s, 1H), 8.57 (d, 1H, J=8.4 Hz), 8.16 (m, 2H), 8.04 (m, 1H), 7.87 (d, 1H, J=7.8 Hz), 7.69 (d, 1H, J=6.9 Hz), 7.32 (t, 1H, J=7.8 Hz), 3.99 (m, 1H), 0.86 (d, 6H, J=6 Hz); MS (ESI) m/z: 448 (M+H+).
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH2:46]([O:53][C:54](=[O:88])[NH:55][CH2:56][C:57]([N:59]1[CH2:63][CH:62]([C:64](=[O:76])[NH:65][C:66]2[C:75]3[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=3)[CH:69]=[CH:68][CH:67]=2)[CH:61]2[N:77]([C:80](=[O:87])[CH:81]([NH2:86])[C:82]([CH3:85])([CH3:84])[CH3:83])[CH2:78][CH2:79][CH:60]12)=[O:58])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN1C(=O)CCC1.CCOC(C)=O>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]([C:11](=[O:13])[NH:86][CH:81]([C:80]([N:77]1[CH2:78][CH2:79][CH:60]2[N:59]([C:57](=[O:58])[CH2:56][NH:55][C:54]([O:53][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:88])[CH2:63][CH:62]([C:64](=[O:76])[NH:65][C:66]3[C:75]4[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=4)[CH:69]=[CH:68][CH:67]=3)[CH:61]12)=[O:87])[C:82]([CH3:83])([CH3:84])[CH3:85])[CH3:10])[CH3:14])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)C(N)C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
A solution of Boc-N(Me)Ala-OH (152 mg, 0.74 mmol) in NMP (3 mL) was cooled to 0° C. and treated with HATU (313 mg, 0.83 mmol) followed by NMM (0.15 mL). After 10 min, 58 (450 mg) in NMP (2 mL) was added. The reaction mixture was allowed to warm to ambient temperature overnight. The solution was diluted with EtOAc, washed successively with 1M HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. Purification by reverse phase HPLC (2″ Dynamax® C18, 10-70% ACN in H2O with 0.1% HOAc over 30 min) afforded 59 as a white solid (430 mg). Mass spectrum, m/z [771.3] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.ClC1C(C(F)(F)F)=CC=CN=1.[Cl-:22].[Al+3].[Cl-:24].[Cl-:25]>>[Cl:1][C:2]1[C:3]([C:4]([Cl:25])([Cl:24])[Cl:22])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: [Cl-]
Reactant: O=C(O)c1cccnc1Cl
Agent: FC(F)(F)c1cccnc1Cl
Agent: [Al+3]
Product: Clc1ncccc1C(Cl)(Cl)Cl

Procedure:
The process according to claim 4 wherein 2-chloronicotinic acid is produced by reacting 2-chloro-3-trifluoromethyl pyridine with aluminum chloride to obtain 2-chloro-3-trichloromethyl pyridine and then hydrolyzing the 2-chloro-3-trichloromethyl pyridine in the presence of sulfuric acid or phosphoric acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.C([Sn](CCCC)(CCCC)[C:34]1[O:35][CH:36]=[CH:37][N:38]=1)CCC>O1CCOCC1.C([O-])(O)=O.[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:7]=[C:6]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
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: COc1cn(-c2ccc(-c3ncco3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 52.6 %

Procedure:
A mixture of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 2-(tributylstannanyl)-1,3-oxazole (0.209 mL, 1.0 mmol) and Pd (PPh3)4 (57.8 mg, 0.05 mmol) in 1,4-dioxane (3 mL) was heated to reflux for 11 h under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100 and AcOEt/MeOH=100/0 to 70/30) and recrystallized with EtOH/hexane to yield the title compound (113 mg, 53% yield) as a yellow solid: mp 223-225° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 7.02 (1H, d, J=1.9 Hz), 7.16 (1H, t, J=8.3 Hz), 7.31-7.51 (6H, m), 7.77-7.83 (2H, m), 7.96 (1H, dd, J=11.5, 1.7 Hz), 8.34 (1H, s), 8.55 (1H, d, J=2.6 Hz). Anal. Calcd for C23H16FN5O3.0.1H2O: C, 64.06; H, 3.79; N, 16.24. Found: C, 63.92; H, 3.67; N, 16.23.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH2:31][N:32]([C:11](=[O:13])[C:10]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=3)[CH:9]=2)[CH2:33][CH2:34]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: N#Cc1ccc(Oc2cc(O)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 68.5 %

Procedure:
Following the procedure of Example 9(e) 3-(4-cyano phenoxy)-5-hydroxy benzoic acid 1.6 g (6.3 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (1.43 g, 6.27 mmol) were used to afford 2.0 g of the required product. Percentage purity (LCMS): 79.6%, (M+1)=465.2+1.