Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[N:6][CH:5]=[CH:4][N:3]=1.Cl.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH:23]([NH2:25])[CH3:24])[CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH:23]([NH:25][C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][N:6]=2)=[O:10])[CH3:24])[CH2:21][CH2:22]1
Reactant: O=C(O)c1nccnc1Cl
Reactant: CC(N)C1(c2ccc(Cl)cc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(NC(=O)c1nccnc1Cl)C1(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
To a solution of 2-chloropyrazine-3-carboxylic acid (0.15 g, 1.0 mmol), 1-[1-(2,4-dichlorophenyl)cyclopropyl]ethylamine hydrochloride (0.25 g, 0.94 mmol) and 4-dimethylaminopyridine (0.29 g, 2.4 mmol) in chloroform (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g, 1.2 mmol) and the mixture was stirred at room temperature for 12 hrs. After adding water and chloroform, the mixture was separated, and the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give a desired compound (yield; 0.24 g, 69%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1>CC(=O)OCC.[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)CC1
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 4,4-dimethyl-cyclohex-2-enone (50 g, 403 mmol) in EA (230 mL), a suspension of Pd/C (2.5 g, 10% Pd) in EA is added. The suspension is stirred at it for 2 h under 1 bar H2. The catalyst is filtered off and the solvent of the filtrate is carefully evaporated to give 4,4-dimethyl-cyclohexanone (50 g) as a colourless oil which slowly crystallizes; 1H NMR (CDCl3): δ 2.34 (t, J=6.4 Hz, 4H), 1.66 (t, J=6.4 Hz, 4H), 1.09 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=1.[Cl:33][C:34]1[N:35]=[N:36][C:37](Cl)=[CH:38][CH:39]=1>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]([C:37]1[N:36]=[N:35][C:34]([Cl:33])=[CH:39][CH:38]=1)[CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(Cl)nn2)cc1)C(=O)O

Procedure:
Similarly prepared from methyl 2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3,6-dichloropyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>O1CCCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([NH:1][C:20]([CH:17]3[CH2:19][CH2:18]3)=[O:21])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cnn2c(NC3CC3)cc(NC(=O)C3CC3)nc12
Temperature: 60 °C

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (step b) (58 mg, 0.266 mmol) in 1.0 mL tetrahydrofuran was added cyclopropane carbonyl chloride (38 ul, 0.419 mmol) and DIPEA (39.0 ul). The reaction mixture was heated at 60° C. for one hour. The reaction was partitioned between ethyl acetate and water, the organic layer was dried under sodium sulfate concentrated on high vac to yield N-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)cyclopropanecarboxamide. The crude product was taken to next step without further purification. LCMS (M+1=286)
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:38])[C@:4]1([OH:37])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C[O:29]1.I(O)(=O)(=O)=O>O1CCCC1.O>[Cl:1][CH2:2][C:3](=[O:38])[C@:4]1([OH:37])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28](=[O:29])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC4(c5ccccc5)CO4)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [O-][I+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC(=O)c4ccccc4)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Yield: 51.3 %

Procedure:
A solution of 4.8 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[(2-phenyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione in 150 ml of tetrahydrofuran is stirred with a solution of 10 g of periodic acid in 40 ml of water for 4 hours. The resulting slurry is diluted with 1 liter of water and filtered. The solid is dried in vacuo and recrystallized from methanol-chloroform to give 2.4 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, melting point 266°-268°C, dec.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH2:19](I)[CH3:20]>O>[CH2:19]([NH:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:20]
Reactant: CCI
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCNc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 6.95 g of 2-amino-5-chlorobenzophenone was added portionwise 1.37 g of 63 % sodium hydride. After the mixture was stirred at room temperature for 30 minutes, 5.62 g of ethyl iodide was added dropwise thereto, and the reaction mixture was further stirred at room temperature for 2 hours. Then, the mixture was poured into 400 ml of water and extracted twice with 100 ml of methylene chloride. The extracts were combined, washed with diluted hydrochloric acid, followed by water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel using chloroform as an eluent to give 7.1 g of 2-ethylamino-5-chlorobenzophenone as red oil, which was recrystalized from ethanol-cyclohexane to give yellow prisms having a melting point of 57° - 58° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[CH:11]1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCCCCCNC(=O)c1ccccc1
Yield: 28.1 %

Procedure:
Using the general method of Example 186 1-(8-aminooctyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.85 mmol) was reacted with benzoyl choride (450 μL, 3.85 mmol) to provide 0.45 g of N-[8-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzamide as an off white powder, m.p. 133.1-136.7° C. Analysis: Calculated for C25H29N5O.0.25H2O: % C, 71.49; % H, 7.08; % N, 16.67; Found: % C, 71.37; % H, 7.05; % N, 16.62.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=1[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(NCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 111.4 %

Procedure:
A solution of 4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.57 g, 10 mmol), benzylamine (1.20 mL, 11 mmol) and p-toluenesulfonic acid hydrate (19 mg, 0.1 mmol) in toluene (40 mL) was heated at reflux under a Dean-Stark trap for 22.75 hours. The mixture was cooled to room temperature and concentrated under vacuum to provide a yellow gummy solid (3.86 g), used without further purification. 1H NMR (300 MHz, CDCl3) δ9.25 (bt, J=6 Hz, 1H), 7.4-7.1 (m, 5H), 4.42 (d, J=6 Hz, 2H), 4.11 (s, 2H), 3.71 (s, 3H), 3.49 (t, 2H), 2.38 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]([CH2:14][CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=O.C(OCC)(=O)C.O.[OH-].[Na+]>C(OCC)C>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:13])[C:6]=1[NH:5][CH2:3][CH:2]([NH2:1])[CH2:14][CH3:15]
Reactant: CCC(N)C(=O)Nc1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(N)CNc1c(C)cccc1C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
2.5 g (66 mmoles) of lithium-aluminium-hydride are added in small portions, at room temperature, to a solution of 3.6 g (17.4 mmoles) of N-(2-aminobutyryl)-2,6-dimethyl-aniline in 40 ml of dry diethyl ether, and the resulting mixture is boiled for 3 hours. The mixture is cooled with ice, and 10 ml of ethyl acetate, 10 ml of water, finally 12 ml of a 5 n aqueous sodium hydroxide solution are added dropwise. The etheral phase is decanted, and the thick, gelly aqueous phase is washed thrice with 25 ml of diethyl ether, each. The etheral solutions are combined, washed thrice with 25 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated. The yellow, oily residue is distilled under reduced pressure to obtain 1.37 g of 1-(2,6-dimethylphenyl-amino)-2-amino-butane, b.p.: 122°-124° C./66.7 Pa, and 0.62 g of unreacted starting substance, b.p.: 158°-172° C./66.7 Pa. The product is obtained with a yield of 49%, calculated for the converted starting substance.
Reaction SMILES: C(OC(=O)NCCCC[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:33])[NH:21][CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH:15]=1)=[O:13])(C)(C)C.[ClH:35]>>[Cl-:35].[C:12]([NH:21][CH2:22][CH2:23][CH2:24][NH3+:25])(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:21][CH2:22][CH2:23][CH2:24][NH3+:25])=[O:33])[CH:15]=1.[Cl-:35]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)c1cccc(C(=O)NCCCNC(=O)OC(C)(C)C)c1
Reactant: Cl
Product: [Cl-]
Product: [NH3+]CCCNC(=O)c1cccc(C(=O)NCCC[NH3+])c1
Reaction time: 2 h
Yield: 56 %

Procedure:
To the crude tert-butyl(5-(3-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)phenyl)-5-oxopentyl)carbamate from Step 1 was added methanolic HCl (150 mL, 1.0 M). The reaction mixture was stirred for 2 h and concentrated under reduced pressure. The solid was collected by vacuum filtration and washed with Et2O (30 mL) and hot MeOH (30 mL) to afford the desired product (0.388 g, 56%) as a white solid.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([O:13][C:14]1[C:15]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N+:16]([O-:24])[C:17]([O:22][CH3:23])=[C:18]([CH2:20][OH:21])[N:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClCCl.C(N(CC)CC)C>C(OCC)C>[CH2:6]([O:13][C:14]1[C:15]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N+:16]([O-:24])[C:17]([O:22][CH3:23])=[C:18]([CH2:20][O:21][S:1]([CH3:4])(=[O:3])=[O:2])[N:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(CO)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1c(COS(C)(=O)=O)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Reaction time: 0.5 h

Procedure:
At 0° C., 52 μl of mesyl chloride was added to a mixture of 210 mg of 3-benzyloxy-5-hydroxymethyl-6-methoxy-2-isobutylpyrazine 1-oxide, 2 ml of dichloromethane and 184 μl of triethylamine. The mixture was stirred for 30 minutes at the same temperature, then diethyl ether was added to the reaction mixture. The mixture was washed with water and dried over magnesium sulfate, then the solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (eluting solvent: 50% by volume of ethyl acetate-n-hexane) to obtain 260 mg of 3-benzyloxy-2-isobutyl-6-methoxy-5-mesyloxymethylpyrazine 1-oxide (Compound B-17) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3([CH3:17])[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[N+](C1C=CC(S(O[CH2:31][C:32]([F:35])([F:34])[CH3:33])(=O)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CC(N(C)C)=O.C(O)(C)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:31][C:32]([F:35])([F:34])[CH3:33])[C:7](=[O:12])[C:6]3([CH3:17])[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: CC(F)(F)COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC12COCCN1c1nc(Cl)ncc1NC2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Temperature: 60 °C
Reaction time: 22 h

Procedure:
2-Chloro-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (384 mg, 1.508 mmol), 2,2-difluoropropyl 4-nitrobenzenesulfonate (767 mg, 2.73 mmol), cesium carbonate (1240 mg, 3.81 mmol) were combined in DMA (2 mL) at ambient temperature for about 1 hour and then heated in an oil bath at 60° C. After about 22 hours, the reaction mixture was allowed to cool to ambient temperature, diluted reaction mixture with 25 mL EtOAc, transferred to a separatory funnel, and the reaction vessel rinsed twice with 10 mL 1:1 EtOAc/water. An additional 10 mL of water was then added, the layers were mixed and then separated. The organic layer was extracted with water (10 mL) and the combined aqueous layers were extracted with 10 mL of EtOAc, which was then extracted with 5 mL brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated on a rotovap to give a residue. The residue was combined with isopropanol (5 mL) and heated in an oil bath at 50° C. oil bath. An addition 1.5 mL was added and the solution was allowed to cool to ambient temperature with stirring to give a solid. Collected the solid by filtration, rinse the filter cake with 1 mL isopropanol and air dry for 2 hours, then dry under vacuum to give the title compound.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH:28]([C:34]#[N:35])[O:29][Si](C)(C)C)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1>CO.C1COCC1>[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH:28]([OH:29])[CH2:34][NH2:35])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)OC(C#N)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Solvent: C1CCOC1
Solvent: CO
Product: NCC(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reaction time: 8 h

Procedure:
Ranney-Ni (20 mg) is washed with MeOH (3×5 mL) before a solution of (±)-5-[6-(cyano-trimethylsilanyloxy-methyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (100 mg, 0.19 mmol) in MeOH (5 mL) and THF (3 mL) is added. The mixture is stirred under H2 atmosphere (ballon) overnight. The mixture is filtered through Celite® and the filtrate is concentrated. The residue is then separated by FCC (0-10% MeOH/EtOAc) to provide the title compound. MS (ESI) m/z 458.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60-8.70 (m, 1H), 8.36 (d, J=8.59 Hz, 1H), 8.06 (br. S., 1H), 7.90 (d, J=7.58 Hz, 1H), 7.95 (d, J=3.28 Hz, 2H), 7.73 (d, J=4.55 Hz, 1H), 7.57 (t, J=7.83 Hz, 1H), 7.37-7.47 (m, 3H), 7.12 (d, J=8.59 Hz, 2H), 7.04 (s, 1H), 6.75 (br. S., 1H), 4.89 (d, J=5.05 Hz, 1H), 3.67 (dd, J=12.25, 7.71 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[C:27]([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:26])[CH:3]=2)[C:31]1=[O:35])(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)c(F)c2)C1=O
Yield: 33.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (418 mg) described in Preparation Example 121 and 1-acetylimidazolidin-2-one (128 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (156 mg) was obtained.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@@H:2]([C:8]([NH:10][CH2:11][C:12]([N:14]([CH3:30])[C@H:15]([C:23]([NH:25][NH:26][C:27]([CH3:29])=[O:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[O:9])[CH2:3][CH2:4][S:5]([CH3:7])=[O:6].CC(OC(N[C@H](C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)CC1C=CC(O)=CC=1)=O)(C)C.[NH:68]([C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[C@H:69]([C:78]([NH:80][C@@H](C(NCC(O)=O)=O)CCSC)=[O:79])[CH2:70][C:71]1[CH:76]=[CH:75][C:74]([OH:77])=[CH:73][CH:72]=1>CN(C=O)C>[NH:68]([C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[C@H:69]([C:78]([NH:80][C@@H:2]([C:8]([NH:10][CH2:11][C:12]([N:14]([CH3:30])[C@H:15]([C:23]([NH:25][NH:26][C:27]([CH3:29])=[O:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[O:9])[CH2:3][CH2:4][S:5]([CH3:7])=[O:6])=[O:79])[CH2:70][C:71]1[CH:72]=[CH:73][C:74]([OH:77])=[CH:75][CH:76]=1
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)OC(C)(C)C
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
Using 0.54 g of BOC-(D)-Met(O)-Gly-MePhe-NHNH-CO-CH3 and 0.46 g of BOC-Tyr-ONB in a similar manner to (III) of Example 36 is obtained (0.46 g) of the desired product, m.p. 141°-142° C., [α]D22 -25.4° (c=0.48, DMF), Rf1 =0.22.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCNC[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C[C@@H]1C
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (S)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 186 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][NH2:19])([O-:8])=[O:7].O.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][N:19]=[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([O-:8])=[O:7]
Reactant: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=C1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(NN=C2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 95 %

Procedure:
Concentrated sulfuric acid (2 mL) and 0.4456 g of 2,4-dinitrophenylhydrazine (2,4-DNP) were combined in a 25-mL Erlenmeyer flask. Water was added (2 to 3 mL) dropwise with swirling until the 2,4-DNP dissolved. This was followed by 10 mL of 95% ethanol. This solution was added, dropwise with swirling, to a solution of cyclohexanone, 0.5725 g, dissolved in 20 mL of 95% ethanol. A precipitate formed within 5 minutes. The mixture was refrigerated overnight. The precipitate was filtered to yield a yellow-orange crystalline solid. The product was re-crystallized from approximately 30 mL of absolute ethanol to afford 0.4 g of cyclohexanone 2,4-dinitrophenylhydrazone as orange flakes. The yield was 95%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](C(CC)(CC)C([O-])([O-])[O-])[CH3:13].[CH3:23][C:24]1C=CC(S(O)(=O)=O)=CC=1>>[CH3:12][C:13]1[O:11][C:3]2[C:4]([C:5]([O:7][CH2:23][CH3:24])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: Nc1cccc(C(=O)O)c1O
Product: CCOC(=O)c1cccc2nc(C)oc12
Yield: 95 %

Procedure:
A solution of 3-amino-2-hydroxybenzoic acid (1 g, 6.53 mmol), triethylorthoacetate (4 mL), and P-toluenesulfonic acid (40 mg) was heated at 100° C. for 18 hours. The reaction was concentrated in vacuo and the crude product was purified by flash column chromatography on silica gel with hexanes and EtOAc (30%) to afford ethyl 2-methylbenzo[d]oxazole-7-carboxylate (743) (1.27 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: ClCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
1-[2-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone (compound 314) (150 mg), 1-bromo-2-chloroethane (191 mg), and potassium carbonate (307 mg) were suspended in N,N-dimethylformamide (6 ml). The mixture was stirred at room temperature overnight, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (122 mg, 68%).