Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[S:35][C:36]([CH:39]=[O:40])=[CH:37][N:38]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[S:35][C:36]([CH:39]=[O:40])=[CH:37][N:38]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=Cc1cnc(Br)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ncc(C=O)s4)cc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (500 mg, 1.1 mmol) in dioxane (12 mL) and H2O (4 mL) was added 2-bromo-1,3-thiazole-5-carbaldehyde (634 mg, 3.3 mmol), potassium carbonate (898 mg, 8.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (210 mg, 0.181 mmol). Reaction was run in the microwave at 150° C. for 20 min. Aqueous work-up performed to give crude product. The reaction was then repeated in the microwave at 150° C. for 30 min to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-1,3-thiazol-2-yl)-1H-indole-7-carboxamide.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][N:12]=[C:11]([CH2:14]O)[CH2:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][CH2:14][C:11]1[CH2:10][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[O:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1=NOC(c2ccc(C(F)(F)F)cc2)C1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2CC(CCl)=NO2)cc1
Reaction time: 15 h
Yield: 21.2 %

Procedure:
To a stirred mixture of (5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)methanol (245 mg, 1.0 mmol) in methylene chloride (15 mL) was added thionyl chloride (200 μL, 2.74 mmol) dropwise at 0° C. The resulting mixture was stirred under an atmosphere of nitrogen for 15 hours, concentrated under reduced pressure, and purified by preparative chromatography (3:7 EtOAc:hexane) to yield 3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole (56 mg, M+1=264.1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:6]=2[N:7]=1
Reactant: C1CNCCN1
Reactant: Nc1nc(Cl)c2nc(-c3ccc(F)cc3)oc2n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)oc2n1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of 5-amino-7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine X (50 mg, 0.19 mmol) in dioxane (5 ml) was added diisopropylethylamine (0.28 mmol, 47 μL) and a piperazine derivative (0.28 mmol). The reaction was stirred at 70° C. for 6 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compounds which were characterized by their mass spectra as indicated below:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:5]([CH3:14])[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCO>C(Cl)Cl.O>[C:32]1([C:31]([NH:1][C:2]2[S:3][C:4]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])=[C:5]([CH3:14])[C:6]=2[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])=[O:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)sc(N)c1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(C(=O)OCc2ccccc2)sc(NC(=O)c2ccccc2)c1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
To a solution of the compound prepared in Example 2 (2.78 g, 8.00 mmol), pyridine (1.6 ml, 20 mmol) and DCM (35 ml) was added benzoyl chloride (1.18 g, 8.40 mmol) dropwise. After 18 hours, the reaction was diluted reaction with EtOH and stirred for 1 hour. The reaction solution was diluted with DCM and H2O. The layers were separated and the aqueous layer was extracted with DCM. The combined aqueous layers were washed with H2O (2×), dried over MgSO4 and concentrated under reduced pressure. Recrystallization (hexane/EtOAc) yields 3.01 g (83%) of a tan solid. 1H-NMR(CDCl3) 1.56 (s, 9H), 2.79 (s, 3H), 5.32 (s, 2H), 7.30-7.60 (m, 8H), 8.03 (d, 2H, J=8.0 Hz); mp=134-135° C.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C@H:11]2[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]2)=[CH:15]1
Reactant: c1ccc(CN[C@H]2CC[C@H](c3c[nH]c4ccccc34)C2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Product: N[C@H]1CC[C@H](c2c[nH]c3ccccc23)C1
Yield: 87.4 %

Procedure:
This compound was prepared in the same manner as for Intermediate 20, using trans-benzyl-3-(1H-indol-3-yl)-cyclopentylamine (0.8 g, 2.8 mmol) and ammonium formate (1.1 g, 17.5 mmol) to afford 0.49 g (89%) of the desired product as a thick oil, which solidified upon standing: MS (ESI) m/z 201 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:35])C.C(O)C.[OH-].[Na+].Cl>C1COCC1>[CH:30]1([CH2:29][O:28][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH3:35])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCC3CCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(OCC3CCCC3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{[4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.40 mmol) was dissolved in THF (2 mL), ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 146 mg (78%). HPLC-MS: m/z: 472.9 (M)+; Rt: 3.03 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:12])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(=O)c1ccc(CC(=O)O)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CC(=O)OCc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To 4-acetyl-2-chlorophenylacetic acid (2.65 g, 12.5 mmol) in DMF solution (26 mL) were added triethylamine (3.5 ml, 25 mmol) and 4-nitrobenzyl bromide (5.4 g, 25mol), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to an ice cooled saturated potassium hydrogencarbonate solution, the organic layer was separated by a separatory funnel, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (silica gel 180 ml, hexane:EtOAc=2:1→1:1) to give 4-nitrobenzyl (4-acetyl-2-chlorophenyl)acetate (3.56 g, yield, 82%) as white crystals. The product was subjected to next reaction without further purification. To 4-nitrobenzyl(4-acetyl-2-chlorophenyl)acetate (3.56 g, 11.4 mmol) and triethylamine (2.0 ml, 15.9 mmol) in dichloromethane (36 ml) was dropped at 0° C. under stirring trifluoromethanesulfonic acid trimethylsilyl ether (2.4 ml, 14.8 mmol), and the mixture was stirred for 20 minutes. To the reaction mixture were added at 0° C. dichloromethane (50 mL), (2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinyl acetate (4.6 g, 15.9 mmol), and zinc iodide (2.2 g, 6.8 mmol), and then the ice bath was removed. The mixture was stirred at room temperature for 4.5 hours and then added to an ice cooled saturated potassium hydrogencarbonate solution. The organic layer was separated by a separatory funnel and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified with silica gel chromatography (silica gel 180 ml, hexane:EtOAc=4:1→0:1) to give 4-nitrobenzyl(4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}-2-chlorophenyl)acetate (5.2 g, yield 79.7%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=3)=[C:18]([CH3:30])[CH:17]=2)=[C:12]([CH:31]([CH3:33])[CH3:32])[O:11][N:10]=1.Cl.CN(C)CCCN=C=NCC.[CH3:46][S:47]([NH2:50])(=[O:49])=[O:48]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[S:26][C:25]([C:27]([NH:50][S:47]([CH3:46])(=[O:49])=[O:48])=[O:28])=[CH:24][CH:23]=3)=[C:18]([CH3:30])[CH:17]=2)=[C:12]([CH:31]([CH3:32])[CH3:33])[O:11][N:10]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc(C(=O)NS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A mixture of 5-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-thiophene-2-carboxylic acid (250 mg, 0.5 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol), N,N′-dimethylamino pyridine (122 mg, 1.0 mmol) and methanesulfonamide (57 mg, 0.6 mmol) in dichloromethane (20 mL) is stirred at ambient temperature overnight. The reaction mixture is diluted with dichloromethane and washed with 1N HCl. The organic phase is concentrated under reduced pressure and purified by column chromatography (gradient: 0 to 20% EtOAc in hexanes with 0.1% AcOH) to give the title compound (160 mg, 55%). LC-ES/MS m/e 579 (M+1), 100%.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:16])([F:15])[C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].O[CH2:18][CH:19]([CH2:21]O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.II>[F:6][C:7]([F:15])([F:16])[C:8]1[CH:9]=[C:10]2[C:12]([CH:18]=[CH:19][CH:21]=[N:11]2)=[CH:13][CH:14]=1
Reactant: OCC(O)CO
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: II
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)c1ccc2cccnc2c1
Temperature: 165 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
Conc. sulfuric acid (4.56 g; 1.5 equiv.) was added dropwise to a mixture of 3-(trifluoromethyl)aniline (5 g; 1 equiv.), glycerol (5.14 g; 1.8 equiv.) and iodine (150 mg). The resulting reaction mixture was stirred for 1 hour at 80-90° C. and for 3 hours at 160-170° C. When the conversion was complete, the reaction mixture was diluted at room temperature with 100 ml of water, neutralised with sodium carbonate and extracted 4× with 200 ml of dichloromethane. The combined organic phases were dried over sodium sulfate, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, 10% EtOAc/hexane). 7-(Trifluoromethyl)quinoline (1.35 g; 22.13%) was obtained in the form of a white crystalline solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.CCN(CC)CC.[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>C(Cl)Cl>[CH3:22][CH:21]([CH3:23])[CH2:20][C:19]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)=[O:24]
Reactant: CC(C)CC(=O)Cl
Reactant: CCOC(=O)[C@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(C(=O)CC(C)C)C1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Ethyl (S)-Piperidine-3-carboxylate (25 g, 159.02 mmol) in anhydrous DCM (500 mL) was cooled down to 0° C. and treated with Et3N. A solution of isovaleryl chloride (23.27 mL, 190.08 mmol, 1.2 eq.) in anhydrous DCM (200 mL) was added dropwise at 0° C. The resulting reaction mixture was kept on the cooling bath and allowed to warm up slowly to room temperature. After 6 hrs the reaction was washed subsequently with aqueous HCl solution (2M), saturated NaHCO3, brine, dried over Na2SO4, filtered, concentrated under vacuum and purified by filtration over a short silica gel column using EtOAc as solvent. The solvent was removed under vacuum to yield the desired product as pale yellow oil (37.4 g, 154.97 mmol, 97.5%) that was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6, 20° C.) δ0.88 (pseudo d, J=6.4 Hz, 6H), 1.13-1.23 (m, 3H), 1.26-1.45 (m, 1H), 1.47-1.75 (m, 2H), 1.82-2.03 (m, 2H), 2.10-2.28 (m, 2H), 2.28-2.39 (m, 0.5H), 2.45-2.56 (m, 0.5H), 2.84 (dd, J=10.0, 12.8 Hz, 0.5H), 2.97-3.11 (m, 1H), 3.38 (dd, J=8.8, 13.6 Hz, 0.5H), 3.63-3.83 (m, 1.5H), 4.00-4.14 (m, 2H), 4.26-4.36 (dm, 0.5H). MS 242 (MH).
Reaction SMILES: [C:1]1([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[H-].[Na+].Cl>COCCOC.O>[C:1]1([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH2:14][C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(=O)c1cccc2ccccc12
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)CC(=O)c1cccc2ccccc12

Procedure:
A solution of 1-(1-naphthalenyl)-1,3-butanedione (5.3 g) and diethyl oxalate (6.75 ml) in 1,2-dimethoxyethane (10 ml) was added dropwise to a stirred suspension of sodium hydride (3.6 g, 50% dispersion in mineral oil, washed with petrol 40°-60° C.) in 1,2-dimethoxyethane (40 ml) under nitrogen. The stirred mixture was heated under reflux for 5 minutes, cooled, acidified with 2 M hydrochloric acid (50 ml), diluted with water (50 ml) and filtered. The filtrate was extracted with ethyl acetate and the extract was dried and evaporated to yield ethyl 6-(1-naphthalenyl)-2,4,6-trioxohexanoate as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)[S:41][C:42]=3[CH3:43])=[CH:34][N:33]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([N:44]4[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]4)[S:41][C:42]=3[CH3:43])=[CH:34][N:33]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCCCC5)sc4C)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(N3CCCCC3)sc2C)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 57.7 %

Procedure:
To a mixture of ethyl [4-{4-[(2-methoxy-4-{[(4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl]acetate (0.36 g), tetrahydrofuran (9 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1.5 hrs. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give [4-{4-[(2-methoxy-4-{[(4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl]acetic acid as crystals (0.20 g, yield 58%). Recrystallization from ethyl acetate-hexane gave brown prism crystals. melting point: 146-148° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[N:24]=[C:23]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[CH:26]3)[CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CC#N>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[N:24]=[C:23]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[CH:26]3)[CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2nccc(-n3cnc4ccccc43)n2)CC1
Solvent: CC#N
Product: c1ccc2c(c1)ncn2-c1ccnc(NCC2CCNCC2)n1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 18 starting with 2-[1-(1-benzyloxycarbonylpiperidin-4-yl)methyl-amino]-4-[benzimidazol-1-yl]pyrimidine. Partial 1H NMR (500 M, CDCl3): δ 8.59 (s, 1H); 8.33 (br s, 1H); 8.16 (br s, 1H); 7.82 (d, J=7.8 Hz, 1H); 7.34 m, 2H); 6.73 (d, J=5.5 Hz, 1H); 3.37 (dd, J=6.2, 5.9 Hz, 2H); 3.09 (d, J=11.9 Hz, 2H); 2.58 (t, J=11.9 Hz, 2H); 1.79 (d, J=10.7 Hz, 3H); 1.23 (m, 2H). Mass spectrum 350.1 (ESI, M+CH3CN+1).
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][CH:13]([C:16]1[C:24]2[O:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:21][C:20]=2[CH:19]=[C:18]([OH:32])[CH:17]=1)[CH2:14]Br>C(#N)C>[Br:12][C:13]([C:16]1[C:24]2[O:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:21][C:20]=2[CH:19]=[C:18]([OH:32])[CH:17]=1)=[CH2:14]
Reactant: Oc1ccc(-c2nc3cc(O)cc(C(Br)CBr)c3o2)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(Br)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 24 h
Yield: 58 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.25 g, 1.65 mmol) was added into a solution of 7-(1,2-dibromoethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (0.4 g, 0.96 mmol) and acetonitrile (4 mL). The reaction mixture was stirred for 24 h, poured into cold (0° C.). HCl (1N, 10 mL) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (CH2Cl2/hexanes/isopropyl alcohol 15/5/1) gave a white solid (185 mg, 58% yield, m.p. 228–230° C.); MS m/e 332 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[C:17](Cl)(=[O:19])[CH3:18]>>[C:17]([N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:5][C:3]([N:2]([CH3:16])[CH3:1])=[O:4])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CN(C)C(=O)CNc1ccc([N+](=O)[O-])cc1
Product: CC(=O)N(CC(=O)N(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-[N-(dimethylaminocarbonylmethyl)-amino]-nitrobenzene and acetyl chloride
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[CH:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32](Cl)Cl)=[CH:27][CH:26]=1.O>ClCCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:32]([NH:31][C:28]3[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=3)[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Reactant: ClC(Cl)=Nc1ccccc1
Solvent: O
Solvent: ClCCCl
Product: COC(=O)CCCCCOc1ccc2nc(Nc3ccccc3)n(-c3ccccc3)c2c1

Procedure:
200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was dissolved in 1 ml of 1,2-dichloroethane, the solution was mixed with 85 μl of phenylisocyanide dichloride, and the mixture was heated for 6 hours to 65° C. After cooling, it was mixed with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 55 mg was obtained.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:30])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:29])=[C:25]([CH:27]=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH2:1]([O:8][NH:9][C:10](=[O:30])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:29])=[C:25]([CH2:27][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C=O
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1CN1CCOCC1

Procedure:
Method as for preparation 157 using (3R)-N-(benzyloxy)-6-cyclohexyl-3-(4-formyl-5-methyl-1,3-oxazol-2-yl)hexanamide (preparation 160) (300 mg, 0.73 mmol) and morpholine (64 μl, 0.73 mmol) as starting materials.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:41]1[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 51476.3 %

Procedure:
Following general procedure II, (R)-tert-butyl 1-(5-(3-acetyl-6-chloro-1,5-naphthyridin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (200 mg, 0.40 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (165 mg, 0.60 mmol) to afford the desired product (125 g, 51%) as a yellow-orange solid. ESI MS m/z 607 [M+H]+