Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:18][CH:17]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:18][CH:17]=2)=[N:13][CH:14]=1
Reactant: [H][H]
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCc3ccccc3)cn2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)cn2)cc1

Procedure:
N-{3-[4-(5-Benzyloxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide (344 mg, 881 μmol) were dissolved in 20 ml of ethanol. Addition of 93 mg of palladium/carbon was followed by hydrogenation under a pressure of 5 bar of hydrogen at room temperature for 16 h. The catalyst was filtered off and the filtrate was concentrated. Yield: 220 mg (83%), M+H+: 301.13.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:2].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:19][CH:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ncsc1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COC(=O)c1scnc1C(C)Br

Procedure:
Following the procedure of Example 28, methyl 4-ethyl-5-thiazolecarboxylate is reacted with NBS and AIBN to give methyl 4-(1-bromoethyl)-5-thiazolecarboxylate, which is then reacted with sodium bicarbonate, or alternatively with potassium carbonate, and DMSO and the resulting methyl 4-acetyl-5-thiazolecarboxylate is treated with lithium hydroxide monohydrate to yield 4-acetyl-5-thiazolecarboxylic acid.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3\[O:11][C:12]([CH3:14])([CH3:13])[C:8]([C:30]4[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=4)=[CH:9]\3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: OB(O)c1ccc(F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(F)nc1
Temperature: 88 °C

Procedure:
To 10 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (200 mg, 0.62 mmol), 6-fluoropyridin-3-ylboronic acid (104 mg, 0.74 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 1M Na2CO3 aqueous solution (2.5 mL, 2.5 mmol). The mixture was heated at 88° C. under N2 for 2 hours, cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product. Purification of the crude product through silica gel column with 1-5% MeOH/CHCl3 afforded (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 100 mg, 47%.
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:23][CH:22]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:9]=1.[I:42]N1C(=O)CCC1=O>CC#N.C(Cl)Cl>[CH3:39][Si:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][O:33][CH2:32][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:40])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:42])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:23][CH:22]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)C2
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the “anti” tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.04 g, 10 mmol) in CH3CN (40 mL) and DCM (40 mL) was added N-iodosuccinimide (2.5 g, 11 mmol) portionwise and the resulting mixture was stirred at room temperature for 1.5 h, at which time LC/MS confirmed full conversion of starting material to product. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: C(Cl)(Cl)=O.[NH2:5][C:6]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:7]=1[C:8](O)=[O:9].CC1C=C(C)C2[NH:26]C(=O)OC(=O)C=2C=1.C12C(=CC=CC=1)NC(=O)OC2=O.[NH4+].[OH-]>O1CCOCC1>[NH2:5][C:6]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:7]=1[C:8]([NH2:26])=[O:9]
Reactant: Cc1cc(C)c2[nH]c(=O)oc(=O)c2c1
Reactant: Cc1cc(C)c(N)c(C(=O)O)c1
Agent: O=C(Cl)Cl
Agent: O=c1[nH]c2ccccc2c(=O)o1
Agent: [NH4+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Liquid phosgene (55 g.) is added to a stirred solution of 30.1 g. (0.182 mol.) of 2-amino-3,5-dimethylbenzoic acid in 300 ml. of dioxane. The temperature is raised to 40°-45° C. and held for 2 hr. The mixture is stirred overnight at room temperature and filtered. The filter cake is washed with diethyl ether, giving 33 g. (95%) of 6,8-dimethyl-2H-3, 1-benzoxazine-2,4(1H)-dione; m.p.>300° C. The isatoic anhydride is then added to 435 ml. of 1 M. NH4OH. The mixture is stirred overnight at room temperature, brought to reflux for 2 hr. cooled, filtered, and crystallized (EtOH), giving 13.4 g. (47%) of product, m.p. 162°-167° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=O)[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:20]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9](=[O:11])[C:8]2=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CN
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O
Temperature: 75 °C

Procedure:
4-tert-Butyl-N-isobutylphthalimide is prepared as described in Example 2, starting with 10 g of 4-tert-butylphthalic anhydride and 4.9 cm3 of isobutylamine in 100 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 75° C. for 10 minutes, followed by addition of a catalytic amount of para-toluenesulfonic acid and the mixture is heated at a temperature in the region of 140° C. for 3 hours. After cooling to a temperature in the region of 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2 kPa). The residue is taken up in a mixture of 50 cm3 of water and 30 cm3 of saturated aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 200 cm3 of dichloromethane. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 10.4 g of 4-tert-butyl-N-isobutylphthalimide are thus obtained in the form of a viscous yellow oil. (Rf=0.75, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:13](=O)[C:12]2[C:7](=[C:8]([CH3:15])[CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:18])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:15]
Reactant: Cc1cccc2c(=O)c(CCCl)n[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c(Cl)c(CCCl)nnc12

Procedure:
3-(2-Chloroethyl)-8-methyl-4-oxo-(1H)-cinnoline (9 g, 0.04 mol) and phosphorus oxychloride (100 ml) were heated under reflux for 2 hours. The excess phosphorus oxychloride was evaporated under reduced pressure and the residue was poured onto ice, basified with concentrated ammonia solution and extracted with chloroform (3×200 ml). The chloroform extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a dark brown solid. Recrystallization from diethyl ether/petroleum ether (b.p. 40-60°) gave an analytically pure sample, m.p. 102-104°
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Li]CCCC.[CH:14]([Si:17]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:18][C@@H:19]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23][C:22](=[O:30])[CH2:21][CH2:20]1)([CH3:16])[CH3:15]>O1CCCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[C@:22]1([OH:30])[CH2:21][CH2:20][C@H:19]([O:18][Si:17]([CH:31]([CH3:33])[CH3:32])([CH:34]([CH3:36])[CH3:35])[CH:14]([CH3:15])[CH3:16])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23]1
Reactant: CC(C)[Si](O[C@H]1CCC(=O)Cc2cccnc21)(C(C)C)C(C)C
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](O[C@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21)(C(C)C)C(C)C
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
In an oven-dried 250 mL round-bottom flask was dissolved 1,2-difluorobenzene (0.680 mL, 6.90 mmol) in tetrahydrofuran (12 mL) under nitrogen. After cooling to −65° C., n-BuLi (1M in hexanes, 2.208 mL, 5.52 mmol) was added dropwise via syringe. After the mixture was stirred between −65 and −60° C. for 30 min, it was cooled down to −78° C. A solution of (S)-9-(triisopropylsilyloxy)-8,9-dihydro-5H-cyclohepta[b]pyridin-6(7H)-one (920.5 mg, 2.76 mmol) (80304-043) in tetrahydrofuran (4 mL plus 4 mL rinse) was added via syringe (turned to yellow) and the reaction was stirred at −78° C. for 1 h (yellow color), and at room temperature for 30 min (red color). LCMS indicated good conversion. The reaction was quenched by saturated NH4Cl solution. Tetrahydrofuran was removed and the residue was partitioned between water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 80% ethyl acetate/hexane afforded the recovered SM (197 mg, 21%) as a yellow oil as well as the desired products (977 mg, 79%) as a colorless oil. MS(ESI)[M+H+]=448.33; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.26 (d, J=3.53 Hz, 1H) 7.42 (t, J=6.42 Hz, 1H) 7.35 (d, J=7.30 Hz, 1H) 6.99-7.13 (m, 3H) 5.16 (br. s., 1H) 4.63 (d, J=13.85 Hz, 1H) 3.02-3.28 (m, 1H) 2.71 (d, J=14.10 Hz, 1H) 2.34 (d, J=4.03 Hz, 1H) 2.02-2.15 (m, 2H) 1.75 (d, J=13.85 Hz, 1H) 1.06-1.19 (m, J=14.67, 7.27, 7.27, 7.05 Hz, 3H) 0.97-1.07 (m, 9H) 0.84-0.97 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN1C(=O)CCC1>[C:32]([O:31][C:30](=[O:36])[NH:29][C@@H:27]([CH3:28])[CH2:26][NH:25][C:9]1[N:8]=[C:7]([C:6]2[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:3][C:2]=2[Br:1])[CH:12]=[CH:11][N:10]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: C[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](CNc1nccc(-c2c(Br)nc(C3CC3)n2COCC[Si](C)(C)C)n1)NC(=O)OC(C)(C)C
Temperature: 110 °C

Procedure:
A mixture of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (5.50 g, 12.8 mmol), (S)-tert-butyl 1-aminopropan-2-ylcarbamate (SM-1, 2.68 g, 15.4 mmol), diisopropylethylamine (2.68 mL, 15.4 mmol) and sodium carbonate (2.71 g, 25.6 mmol) in NMP (8 mL) was heated with 110° C. oil bath for 3.5 hours and LCMS analysis of an aliquot indicated reaction completion with desired product. The reaction was allowed to cool to ambient temperature, then partitioned between EtOAc (20 mL) and water (60 mL). The EtOAc layer was washed with water (60 mL), dried (Na2SO4), and concentrated to a light yellow foam (6.89 g, 12.1 mmol). A small portion of material was further purified by flash chromatography (SiO2, EtOAc in heptane): LCMS (m/z) 567.3 (MH+), tR=1.03 minutes; 1H NMR (CDCl3, 300 MHz) δ −0.09 (s, 9H), 0.80 (t, J=8.2 Hz, 2H), 0.98-1.07 (m, 2H), 1.10-1.18 (m, 2H), 1.21 (t, J=6.5 Hz, 3H), 1.40 (s, 9H), 1.91-2.08 (m, 1H), 3.41 (t, J=8.2 Hz, 2H), 3.44-3.59 (m, 2H), 3.82-4.01 (m, 1H), 4.65-4.87 (m, 1H), 5.41-5.61 (m, 1H), 5.78-5.99 (m, 2H), 7.10 (d, J=5.0 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:14][C:13](=[O:15])[CH2:12]2)=O)=[C:4]([NH:16][CH3:17])[CH:3]=1.CC(O)=O>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH:11]3[CH2:14][C:13](=[O:15])[CH2:12]3)[N:16]([CH3:17])[C:4]=2[CH:3]=1
Reactant: CNc1cc(Br)ccc1NC(=O)C1CC(=O)C1
Solvent: CC#N
Solvent: CC(=O)O
Product: Cn1c(C2CC(=O)C2)nc2ccc(Br)cc21
Temperature: 25 °C
Yield: 78.9 %

Procedure:
To a stirred solution of N-(4-bromo-2-(methylamino)phenyl)-3-oxocyclobutanecarboxamide (2.7 g) in CH3CN (20 ml) was added glacial AcOH (2 ml) at room temperature, and then mixture was heated at reflux for 3 h. The mixture was then cooled to room temperature, concentrated in vacuo, and poured into ice-cold saturated NaHCO3 (100 ml). The mixture was extracted with EtOAc, and the extract was washed with water (100 ml) and brine (100 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.0 g) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[N+:14]([CH3:17])([O-:16])=[O:15].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: COC(=O)C=Cc1ccc(Cl)cc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
A mixture of 290 g of p-chlorocinnamic acid methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir for 72 hours. The solution is diluted with ethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-chlorophenyl)butanoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:5]([NH:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][C:13]2[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[C:16]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:15][N:14]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:5]([NH:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][C:13]2[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[C:16]([CH2:22][C:23]([OH:25])=[O:24])=[CH:15][N:14]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)n2ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cnc(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)n2ccnc12
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of methyl (5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-c]pyrimidin-8-yl)-acetate (25 mg, 0.05 mmol) in methanol (1 mL) was added 1M NaOH aqueous solution (0.2 mL) at room temperature, and the mixture was stirred for 1 hour. After the removal of methanol under reduced pressure, water was added to the residue. The solution was washed with diethyl ether and neutralized by aqueous hydrochloric acid. The resulting precipitates were collected by filtration and dried under reduced pressure to give (5-{4-[(3,4-dichlorobenzoyl)amino]benzyl}imidazo[1,2-c]pyrimidin-8-yl)acetic acid (17.2 mg, 71%) as slightly yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.CN(C=O)C.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27]>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:5]1[CH:4]=[C:3]([F:12])[C:2]([Cl:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9])[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cc(F)c(Cl)cc1[N+](=O)[O-]
Yield: 7.3 %

Procedure:
By using 6.32 g of 5-chloro-2,4-difluoronitrobenzene, 9.91 g of triethylamine, 60 ml of DMF, 60 ml of THF and 4.56 g of glycine ethyl ester hydrochloride, 0.66 g (7%) of N-(4-chloro-5-fluoro-2-nitrophenyl)glycine ethyl ester was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:30])[C:25]=4[CH:26]([OH:29])[C:27]#[CH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:31]([N:38]=[N+:39]=[N-:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CS(C)=O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2].CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:30])[C:25]=4[CH:26]([C:27]4[N:40]=[N:39][N:38]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:28]=4)[OH:29])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CC(O)c1c(-c2ccc(-c3ccc(C4(C(=O)OCC)CC4)cc3)cc2)cnn1C
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4C(O)c4cn(Cc5ccccc5)nn4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-{4′-[5-(1-Hydroxy-prop-2-ynyl)-1-methyl-1H-pyrazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.17 g, 0.45 mmol) and benzyl azide (0.072 g, 0.54 mmol) were combined DMSO (5 mL). Copper(II) sulfate (0.001 g, 0.005 mmol) and sodium ascorbate (0.001 g, 0.05 mmol) were combined in H2O (2 mL) and the solution was added to the DMSO mixture. The reaction was stirred at room temperature for 18 hours then submitted to EtOAc/H2O workup. Purification on silica gel (0-70% EtOAc in hexanes) provided the title compound.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:21]([CH3:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([F:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[C:18]([C:17]1[CH:20]=[C:21]([CH3:22])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:3][C:4]=3[F:25])=[O:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)#[N:19]
Reactant: O=C1NCCO1
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2F)CC1
Yield: 81.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(4-bromo-2-fluorobenzoyl)piperazin-1-yl]-5-methylnicotinonitrile (215 mg) described in Preparation Example 134 and oxazolidin-2-one (70 mg), the title compound (178 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:10]([C:13]1[S:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]([C:13]1[S:17][C:16]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:15][CH:14]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: Cn1cc(Br)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(=O)n(C)c2)s1
Temperature: 100 °C
Yield: 60.7 %

Procedure:
To a solution of 5-bromo-1-methylpyridin-2(1H)-one (0.2 g, 1.06 mmol) in 1,4-dioxane (5 mL) and water (2 mL), (5-acetylthiophen-2-yl)boronic acid (0.2 g, 1.27 mmol), tetrabutyl ammonium bromide (0.034 g, 0.16 mmol), K2CO3 (0.4 mL, 3.19 mmol) and Pd(PPh3)2Cl2 (0.18 g, 1.59 mmol) were added under argon. The mixture was purged with argon for 10 min and heated to 100° C. for 1 h. The reaction mixture was filtered through Celite® reagent, the filtrate concentrated, the residue extracted with EtOAc (2×100 mL), and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column purifier (80% ethyl acetate in hexane) and obtained as yellow viscous liquid (0.15 g, 62% yield). 1H NMR (400 MHz, CDCl3): δ 7.69-7.58 (m, 3H), 7.08 (d, 1H), 6.65 (d, 1H), 3.61 (s, 3H), 2.54 (s, 3H); LC-MS m/z calculated for [M+H]+234.05. found 234.1.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH2:19][C@:20]32[O:23][C@H:21]3[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.CC1C=C(C)N=C(C)C=1>CCCCCCC>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H]1O[C@@]12CC[C@H]1[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@@]12C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCCCCCC
Product: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 37.7 %

Procedure:
To (1S,3R,17R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-17,20-epoxypregna-5-ene (100 g) obtained in Example 1, 2,2′-azobis(isobutyronitrile) (7.98 g) and γ-collidine (82.4 mL) were added, and the resulting mixture was stirred in n-heptane (1000 mL) at 75° C. for 15 minutes. After cooling the mixture to room temperature, a precipitate was removed by filtration, and the filtrate which was a solution in n-heptane was concentrated under reduced pressure. To the obtained concentrated residue containing γ-collidine, toluene (650 mL) and aluminum isopropoxide (3.64 g) were added, and the resulting mixture was heated to reflux for 2 hours. The reaction solution was cooled, and the organic layer was sequentially washed with aqueous hydrochloric acid, aqueous sodium bicarbonate and with water, followed by concentration under reduced pressure. After suspending the obtained concentrated residue in a mixed solvent of ethyl acetate, acetonitrile and triethylamine, a precipitate was collected by filtration, washed with acetonitrile, heat-dried under reduced pressure to obtain (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-20-hydroxypregna-5,7,16-triene as slightly yellow powder (37.5 g; yield: 37.7%).