Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:1][CH:2]2[CH2:3][O:21]2)=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCNC(=O)c1ccc(Cl)s1
Solvent: ClCCl
Product: O=C(NCC1CO1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An ice-cooled solution of 2.0 g (9.92 mmol) of N-allyl-5-chloro-2-thiophenecarboxamide in 10 ml of dichloromethane is admixed with metachloroperbenzoic acid (183 g, about 60% strength). The mixture is stirred overnight, during which it is allowed to warm to room temperature, and is then washed with 10% sodium hydrogen sulphate solution (three times). The organic phase is washed with saturated sodium bicarbonate solution (twice) and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The product is purified by silica gel chromatography (cyclohexane/ethyl acetate 1:1).
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+].[C:24]([O:28][C:29]([NH:31][CH:32]([CH:36]1[CH2:38][CH2:37]1)[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[C:24]([O:28][C:29](=[O:30])[NH:31][CH:32]([CH:36]1[CH2:38][CH2:37]1)[C:33]([NH2:3])=[O:34])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C(N)=O)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
H2O (353 mg), WSC.HCl (460 mg), diisopropylethylamine (986 mg), and ammonium chloride (500 mg) were added to a DMF (5 ml) solution containing 2-((tert-butoxycarbonyl)amino)-2-cyclopropyl acetic acid (500 mg) at room temperature, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant was dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, and a white solid of tert-butyl(2-amino-1-cyclopropyl-2-oxoethyl)carbamate (500 mg) was thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[NH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([CH3:32])[N:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([CH3:32])[N:26]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(N)nc(C)n1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cc(C)nc(C)n1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 4-amino-2,6-dimethylpyrimidine. After completion, the reaction mixture was extracted with 1M HCl and washed with a saturated NaHCO3 solution. The organic was dried (Na2SO4), filtered and concentrated. The product was used without further purification. tR: 0.82 min (LC-MS 2); ESI-MS: 506.0/508.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=[CH:19][C:18]=1[O:29][CH3:30])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:21]1[CH:20]=[CH:19][C:18]([O:29][CH3:30])=[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:9]([C:10](=[O:11])[NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:7]=2[CH2:6][S:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH:22]=1)[CH3:28]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)O)cc2CSC(C)(C)C)c1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)NC(C)(C)C)cc2CSC(C)(C)C)c1
Reaction time: 8 h

Procedure:
3-tert-Butylsulfanylmethyl-4-(5-ethoxycarbonylmethyl-2-methoxy-phenoxy)-benzoic acid (0.2 g, 0.46 mmol), tert-butylamine (0.15 mL, 13.9 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.11 g, 0.55 mmol), and N-hydroxybenzotriazole (0.074 g, 0.55 mmol) were combined in CH2Cl2 (8 mL) and stirred overnight. The mixture was concentrated and purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:25])=[C:7]([C:16]([I:24])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:18]=1[I:19])[C:8]([N:10]([CH2:12][C:13]([OH:15])=[O:14])[CH3:11])=[O:9])(=[O:3])[CH3:2].[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1O)([O-:28])=[O:27].O1CCCC1>CN(C)C=O>[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:14][C:13](=[O:15])[CH2:12][N:10]([C:8](=[O:9])[C:7]1[C:6]([I:25])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([I:19])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:16]=1[I:24])[CH3:11])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N(C)CC(=O)O)c1I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N(C)CC(=O)Oc2ccccc2[N+](=O)[O-])c1I
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6.85 g (10 mMol) N-(3,5-diacetamido-2,4,6-triiodobenzoyl)-sarcosine and 1.7 g (12.2 mMol) o-nitrophenol are dissolved in 15 ml N,N-dimethylformamide. 60 ml tetrahydrofuran is added to this solution which is then cooled down to 0° C. 2,5 g (12 mMol) N,N-dicyclohexylcarbodiimide is added. The reaction runs for 2 hours at 0° C. and overnight at room temperature. The precipitate (N,N'-dicyclohexylurea) is filtered off, washed with 10 ml N,N-dimethylformamide, the tetrahydrofuran is distilled, the solution kept in the refrigerator overnight and then the dicyclohexylurea is again filtered off. The organic solution is added dropwise to 250 ml ether, the precipitate is decantered, dissolved with 25 ml N,N-dimethylformamide and added to water dropwise. The precipitate is filtered, washed with saturated sodium bicarbonate solution and water and dried. Yield: 5.4 g (67%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[C:10]([O:9][C:8]([NH:7][C:2]1[C:3]([B:20]([OH:25])[OH:21])=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ncccc1B(O)O
Temperature: -6 °C

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl N-(2-pyridyl)carbamate (15.71 g, 80.9 mmol) and N,N,N′N′-tetramethylethylenediamine (TMEDA, 25.3 g, 218 mmol) in THF (400 mL) was cooled to −78° C. n-Butyllithium (81 mL of a 2.5 M solution in hexanes) was added dropwise over a period of 20 minutes. The solution was stirred for ten minutes, and then the addition funnel was rinsed with additional THF (20 mL). The solution was warmed to −6° C., stirred for two hours, and cooled again to −78° C. Triisopropyl borate (57.7 g, 307 mmol) was added over a period of ten minutes. The resulting solution was warmed to 0° C. and then poured into saturated aqueous ammonium chloride (500 mL). A yellow solid formed and was stirred with diethyl ether (300 mL), isolated by filtration, washed with diethyl ether and water, and air-dried overnight to provide 2-tert-butoxycarbonylamino-3-pyridylboronic acid as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29](OS(C(F)(F)F)(=O)=O)[C:30]([F:33])([F:32])[F:31])=[N:27][CH:28]=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH:29]([C:26]3[CH:25]=[CH:24][C:23]([Br:22])=[CH:28][N:27]=3)[C:30]([F:33])([F:32])[F:31])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OC(c1ccc(Br)cn1)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(c3ccc(Br)cn3)C(F)(F)F)cc2)C1
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
To a stirred solution of (RS)-3-(4-amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, CAS 908334-28-1) in dry THF (0.1 ml) under an argon atmosphere was added sodium hydride (14 mg, 60% dispersion in mineral oil) and stirring was continued for 15 minutes. Trifluoro-methanesulfonic acid 1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (74 mg) was then added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and with saturared brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by flash column chromatography (silical gel; gradient: heptane/EtOAc) to give (RS)-3-{4-[(RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethylamino]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (34 mg, 36%) as a yellow oil. MS (ISP): 501.9 ([{81Br}M+H]+), 500.2 ([{79Br}M+H]+), 446.2 ([{81Br}M+H—C4H8]+), 444.1 ([{79Br}M+H—C4H8]+).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.N1C=CC=CC=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([NH:21][C:5](=[O:7])[CH3:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 10.3 %

Procedure:
To a suspension of P-HOBT 1 (0.212 g, 0.125 mmol) in CH2Cl2 (5 mL) was added acetic anhydride (0.216 g, 0.200 mL, 2.12 mmol, 17 equiv.) and pyridine (0.234 g, 0.240 mL, 2.96 mmol, 24 equiv.). The suspension was subsequently rocked for 60 minutes at 25° C. The polymer was then filtered and washed with CH2Cl2 (3×5 mL), NMP (3×5 mL), CH2Cl2 (3×5 mL), and anhydrous Et2O (3×5 mL). The polymer was re-suspended in CH2Cl2 (5 mL) and benzylamine (0.0098 g, 0.010 mL, 0.91 mmol, 0.73 equiv. based on P-HOBT) was added. The suspension was rocked at 25° C. for 4 h. The polymer was then filtered and washed with CH2Cl2 (4×5 mL). The filtrate and washings were combined and concentrated to yield 0.014 g (100%) of N-benzylacetamide as a white solid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.I[CH:14]([CH3:16])[CH3:15]>CN(C=O)C>[I:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ncc2ccc(I)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (85 mg, 60%, 2.12 mmol) was added to an ice-cooled solution of 6-iodo-1H-indazole (249.5 mg, 1.02 mmol) in DMF (2.5 mL). After stirring this mixture for 1 h at 0° C., 2-iodopropane (0.32 mL, 3.2 mmol) was added and the mixture stirred at 100° C. for 16 h. After the reaction mixture was partitioned between water and ethyl acetate, the organic layer was washed sequentially with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Flash chromatography (silica gel, 5-20% ethyl acetate in hexane) yielded two products, the less polar 1-substituted-1H-indazole (105 mg) and the more polar 2-substituted indazolium (107.7 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([C:9]2[CH:18]=[C:17]3[C:12]([C:13](O)=[N:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([C:4]3[C:3]([C:2]([F:21])([F:20])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2cc(-c3ncccc3C(F)(F)F)ccc12
Product: FC(F)(F)c1cccnc1-c1ccc2c(Cl)ncnc2c1

Procedure:
Reflux 7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol (0.38 mmol) for 18 hours in POCl3 (5 mL). Evaporate the solvent in vacuo, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum to obtain 4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6]([C:8]1[N:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:20]=2)[N:11]=[C:10]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)[CH:9]=1)=O>CO>[NH2:2][NH:3][C:6]([C:8]1[N:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:20]=2)[N:11]=[C:10]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)[CH:9]=1)=[O:5]
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2cc(C(=O)NN)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Yield: 68.2 %

Procedure:
Hydrazine mono-hydrate (1.6 ml, 20.6 mmol) was added to a mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (1.54 g, 3.45 mmol) in methanol (20.0 ml) at ambient temperature. The resulting reaction mixture was heated at reflux for 1 hour then allowed to cool. The resulting solid was collected by filtration and washed with methanol to give the title compound (1.05 g, 68.3%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Br:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.C(ON)(=O)C=C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[Br:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CC(C)(C)Nc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Agent: C=CC(=O)ON
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Br)c1F
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Reaction time: 0.25 h

Procedure:
To a chloroform solution (5 mL) in which ethyl 3-ethoxy-2-(3-bromo-2,4,5-trifluorobenzoyl)acrylate prepared from ethyl 3-bromo-2,4,5-trifluorobenzoylacetate (1.32 g) in a manner known per se in the art was dissolved, 2-amino-6-(t-butylamino) -3,5-difluoropyridine was added under TLC monitoring of the reaction until conversion into an amino acrylate derivative was completed. The reaction mixture was concentrated under reduced pressure to obtain a yellow solid residue. To the residue, anhydrous potassium carbonate (1.2 g) and N,N-dimethylformamide (2 mL) were added, and the mixture was stirred at 90° for 15 minutes. The mixture was allowed to cool down. Chloroform (30 mL) and distilled water (300 mL) were added, and the mixture was allowed to separate into layers. The chloroform layer was washed twice with distilled water (300 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then left over. The precipitate was collected by filtration, and washed successively with ethanol and diisopropyl ether in this order to obtain the title compound (1.41 g) as a colorless powder.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]1[N:19]([CH3:37])[C:20](=[O:36])[C:21]([OH:35])=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[O:25])[N:23]=1)=O)C1C=CC=CC=1>CO.[Pd]>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:24]([C:22]2[N:23]=[C:18]([C@@H:12]3[CH2:13][C@@H:14]([O:16][CH3:17])[CH2:15][NH:11]3)[N:19]([CH3:37])[C:20](=[O:36])[C:21]=2[OH:35])=[O:25])=[CH:33][CH:32]=1
Reactant: CO[C@@H]1C[C@@H](c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1CN[C@H](c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)C1
Temperature: 25 °C

Procedure:
Benzyl-(2S,4R)-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methoxypyrrolidine-1-carboxylate was dissolved in methanol and Pd/C 10% wt (14% w/w) was added. The mixture was stirred under H2 atmosphere at room temperature. After 2 hours the reaction mixture was filtered and methanol was removed in vacuo to give title compound.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[CH3:28])[NH:24][N:23]=[CH:22]2>C(Cl)Cl>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][C:27]=3[CH3:28])[NH:24][N:23]=[CH:22]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc2[nH]ncc2cc1N
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Solvent: ClCCl
Product: Cc1cc2[nH]ncc2cc1NC(=O)c1cc(N(C)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 5-amino-6-methylindazole (Bionet), the title compound was obtained as a beige solid after trituration in DCM.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])(=O)[CH3:2].Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO>[OH:17][N:16]=[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])[CH3:2]
Reactant: NO
Reactant: COC(=O)c1ccc(C(C)=O)c(C)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(C)=NO)c(C)c1
Temperature: 40 °C
Yield: 100.1 %

Procedure:
Methyl 4-acetyl-3-methylbenzoate (1.49 g, 7.76 mmol), hydroxylamine hydrochloride (4.18 g, 60.1 mmol), and sodium acetate (4.93 g, 60.1 mmol) were suspended in methanol (40 mL) and the reaction mixture heated at 40° C. for 2 h. Upon cooling to room temperature the solvent was removed under reduced pressure. The residue obtained was partitioned between ethyl acetate (75 mL) and water (30 mL). The organic extract was washed with water (20 mL) and brine. The washed extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (1.61 g, 100%). LC-MS: (FA) ES+ 208; 1H NMR (300 MHz, MeO D) δ 7.91-7.77 (m, 2H), 7.31 (d, J=8.0 Hz, 0.7H), 7.16 (d, J=7.9 Hz, 0.3H), 3.89 (s, 3H), 2.37 (s, 2H), 2.28 (s, 1H), 2.17 (s, 2H), 2.10 (s, 1H).
Reaction SMILES: CN1CCN([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:22]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)=[N:23][NH:24][CH:25]=4)[CH:18]=[CH:17][N:16]=3)=[CH:10][CH:9]=2)CC1.ClC1C=CC(C2C(C3C=CN=C(NC4C=CC=C([O:58][CH2:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)C=4)N=3)=CNN=2)=CC=1>>[CH3:66][N:63]1[CH2:64][CH2:65][CH:60]([CH2:59][O:58][C:13]2[CH:12]=[C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:22]([C:26]5[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=5)=[N:23][NH:24][CH:25]=4)[CH:18]=[CH:17][N:16]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:61][CH2:62]1
Reactant: CN1CCC(COc2cccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)c2)CC1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)cc1
Product: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3cccc(OCC4CCN(C)CC4)c3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using ethyl-4-methylbenzoate (see Example 25) and [3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester (see Example 27).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:20]([O:24][CH:25]([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22].C(OCC)(=O)C.CCCCCC.O>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[CH:15][N:16](/[CH:22]=[CH:21]\[C:20]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C=CC(=O)OC(C)C
Reactant: FC(F)(F)c1cc(-c2c[nH]cn2)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
In a 100 mL, 3N round-bottomed flask equipped with nitrogen inlet, thermometer pocket and stopper, 4-(3,5-bis(trifluoromethyl)phenyl)-1H-imidazole (1) (1.1 g, 1.0 eq.) was dissolved in dichloromethane (20 mL, 19V) the reaction mixture was cooled to 0° C. To this reaction mixture TEA (0.709 mL, 1.3 eq.) followed by Isopropyl acrylate (0.571 g, 1.3 eq.) was added at 0° C. and reaction mixture was stirred for 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 20% Ethyl acetate-n-Hexane as mobile phase. Reaction mixture was poured into water (50 mL). The filtrate was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to afford 1.2 g of Crude compound which was purified by column chromatography. Product elute at 4% ethyl acetate in hexane to give 1.0 g of crude product (Cis 39%+Trans 56%) (Yield 65.35%).
Reaction SMILES: [C:1]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:28][C:29](=[NH:31])[CH3:30]>CN(C=O)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1([C:12]2[O:14][N:31]=[C:29]([CH3:30])[N:28]=2)[CH2:10][CH2:11]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.8 %

Procedure:
To a solution of N-boc-amino-cyclopropanecarboxylic acid (1.01 g, 5.00 mmol) in 2 mL of DMF was added carbonyldiimidazole (0.812 g, 5.01 mmol). This reaction mixture was stirred at room temperature for 6 h. N-Hydroxy-acetamidine (0.374 g, 5.05 mmol) was added. This reaction mixture was stirred at room temperature for 2 h then heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water. The resultant precipitate was collected by filtration, washed with acetonitrile and water and air-dried to give 1.05 g of [1-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclopropyl]-carbamic acid tert-butyl ester as a white solid, m/z 240 [M+1]+.