Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1.C(OCC)(=O)C>O.O1CCOCC1.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>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc([N+](=O)[O-])cc3)cc12
Yield: 115.9 %

Procedure:
246 mg of 4-bromonitrobenzene, 1.2 g of sodium carbonate in 20 cm3 of water and 365 mg of tetrakis(triphenylphosphine)palladium are added to 2 g of N-[6-chloro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 100 cm3 of dioxane. The medium is then refluxed for 20 hours and the resulting mixture is then allowed to return to room temperature and 100 cm3 of ethyl acetate and 100 cm3 of water are added. The reaction medium is filtered through a sinter funnel packed with Celite and the organic phase is separated out after settling of the phases has taken place, washed with 100 cm3 of water, with 100 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60/μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (85/15 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 690 mg of N-[6-chloro-5-(4-nitrophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of yellow crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:22]3[CH2:28][CH:27]4[N:29](C(=O)C(F)(F)F)[CH:24]([CH2:25][CH2:26]4)[CH2:23]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:36]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:22]3[CH2:23][CH:24]4[NH:29][CH:27]([CH2:26][CH2:25]4)[CH2:28]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:37]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1C2=C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-methoxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]-oct-3ylidene]-9H-xanthene-3-carboxylic acid diethylamide, 5c (3.2g, 6.22 mmol) and potassium carbonate (1.89 g, 13.7 mmol) in methanol (50 mL) was stirred at rt overnight. The mixture was evaporated, and partitioned between methylene chloride (100 mL) and water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated, yielding 2.72 g of 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-5-methoxy-9H-xanthene-3-carboxylic acid diethylamide, 6c. MS m/z=419.0 (MH+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS[C:20]1[NH:21][CH:22]=[C:23]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[N:32][CH:33]=2)[C:24](=[O:26])[N:25]=1.C(O)(=O)C(C(C(O)=O)O)O>N1C=CC=CC=1.C(O)(C)C>[N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:20]3[NH:21][CH:22]=[C:23]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[N:32][CH:33]=4)[C:24](=[O:26])[N:25]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOn1cc(CN2CCCCC2)cn1
Reactant: CSc1nc(=O)c(Cc2ccc(C)nc2)c[nH]1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Cc1ccc(Cc2c[nH]c(NCCCOn3cc(CN4CCCCC4)cn3)nc2=O)cn1

Procedure:
3.5 g of 3-(4-piperidinomethylpyrazol-1-yloxy)propylamine and 3.6 g of 2-methylthio-5-(2-methylpyrid-5-ylmethyl)-1H-pyrimid-4-one in 30 ml of pyridine are refluxed for 30 hours. The pyridine is distilled off and the residue is then chromatographed over neutral Al2O3 (activity level III) using methylene chloride/3% strength methanol as the mobile phase. The oil obtained is reacted with tartaric acid in isopropanol to give an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9](Br)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1Br.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: COc1c(Br)ccc2c(OC)c(Br)ccc12
Reactant: c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1c(-c2cccs2)ccc2c(OC)c(-c3cccs3)ccc12
Yield: 95 %

Procedure:
1,5-Dimethoxy-2,6-dibromonaphthalene (1.00 g., 0.0029 mol.) and 2-tributylstannyl)thiophene (4.314 g., 0.0116 mol.) were dissolved in 100 mL dry toluene in argon atmosphere. Pd(PPh3)4 (100 mg.) was introduced into the reaction flask using a Schlénk tube under argon. The resultant mixture was subsequently refluxed for 18 hrs. The brownish black solution was cooled and poured into 300 mL of petroleum ether to afford crude yellow solid. Upon recrystallization from CH2Cl2:petroleum ether (1:5), the desired product was obtained as a light yellow solid. Yield: 95%. M.p. 225-228° C. Anal. Calcd. for C20H16O2S2: C, 68.15%; H, 4.58%; S, 18.19%. Found: C, 67.98%; H, 4.53%; S, 18.03%. Mass spectrum: 351.84 (M+). 1H-NMR (CDCl3; in ppm): 3.88 (s, 3H), 7.16 (dd, 2H), 7.43 (dd, 2H), 7.63 (dd, 2H), 7.83 (d, 2H, 9 Hz), 796 (d, 2H, 9 Hz). 13C-NMR (CDCl3; in ppm): 61.3, 119.0, 123.2, 125.7, 126.5, 126.6, 126.9, 129.2, 138.9, 152.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:27]([CH3:38])C(=O)OCC2C=CC=CC=2)[C:10]2[N:11]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:12]=[C:13]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[N:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[CH3:45][Si:46]([CH3:61])([CH3:60])[CH2:47][CH2:48][O:49][CH2:50][N:51]1[C:55]2[NH:56][CH2:57][CH2:58][CH2:59][C:54]=2[CH:53]=[N:52]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][C:16]([CH3:20])([CH2:17][CH3:18])[CH2:15][C:13]1[N:14]=[C:10]([CH:9]([NH:27][CH3:38])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([N:56]3[CH2:57][CH2:58][CH2:59][C:54]4[CH:53]=[N:52][N:51]([CH2:50][O:49][CH2:48][CH2:47][Si:46]([CH3:61])([CH3:60])[CH3:45])[C:55]3=4)=[CH:7][CH:6]=2)[N:11]([S:21]([N:24]([CH3:25])[CH3:26])(=[O:22])=[O:23])[CH:12]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c1NCCC2
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(Br)cc2)N(C)C(=O)OCc2ccccc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(N3CCCc4cnn(COCC[Si](C)(C)C)c43)cc2)NC)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Palladium (II) acetate (5 mg, 0.02 mmol) was added to a degassed, ambient temperature solution of benzyl {2-(4-bromophenyl)-1-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}methylcarbamate (267 mg, 0.44 mmol), sodium tert-butoxide (170 mg, 1.76 mmol), 1-{[2-(trimethylsilyl)ethoxy]methyl}-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine (224 mg, 0.88 mmol) and 2-(dicyclohexylphosphino)biphenyl (15 mg, 0.04 mmol) in 1,4-dioxane (5 mL). After stirring at 110° C. overnight, the reaction mixture was cooled, diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded 4-(2,2-dimethylbutyl)-N,N-dimethyl-2-{1-(methylamino)-2-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]ethyl}-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](B2OCC(C)(C)CO2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].Cl[C:48]1[N:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([C:48]2[N:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(B2OCC(C)(C)CO2)cc1C)C(=O)OC(C)(C)C
Reactant: COc1ccc(Cl)nn1
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(-c2ccc(OC)nn2)cc1C)C(=O)OC(C)(C)C
Yield: 49.3 %

Procedure:
Using the compound (510 mg, 0.802 mmol) of Example 295, step A and 3-chloro-6-methoxypyridazine (139 mg, 0.962 mmol), and according to the method of Example 295, step B, N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[4-(6-methoxypyridazin-3-yl)-2-methylphenyl]-N1-{2-[(tert-butoxycarbonyl)(ethyl)amino]ethyl}glycinamide (250 mg) was obtained as a brown oil. Using this oil (210 mg, 0.332 mmol), and according to the method of Example 46, step B, the title compound (92 mg, yield 53%) was obtained as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.C[Si]([O:29][Si](C)(C)C)(C)C.[K].[Si](O[K])(C)(C)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:3]2[C:2](=[O:29])[NH:7][N:6]3[C:8](=[O:11])[NH:9][N:10]=[C:5]3[C:4]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:19][CH:20]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: C[Si](C)(C)O[Si](C)(C)C
Agent: C[Si](C)(C)O[K]
Agent: [K]
Solvent: C1CCOC1
Product: O=c1[nH]n2c(=O)[nH]nc2c(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 22 %

Procedure:
To the solution of 6-chloro-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (28 mg, 0.078 mmol), prepared as described in Example 8B, in THF (3 ml) was added potassium trimethylsilyloxide, TMSOK, (36 mg, 0.28 mmol). The reaction mixture was refluxed for 1 hour. After this time, the solution was cooled to RT. The solution was concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give the title compound, 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (8 mg, 22%) as a yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[CH3:15])(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CS(C)=O.[C:58]([O:61][CH2:62]C)(=[O:60])C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Br:14][C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([C:58]([O:61][CH3:62])=[O:60])=[C:8]([CH3:15])[CH:9]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(Br)cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: COC(=O)c1c(C)cc(Br)cc1C
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-2,6-dimethylphenyl trifluoromethanesulfonate (1.439 g), palladium acetate (0.049 g), 1,3-bis(diphenylphosphino)propane (0.089 g) and triethylamine (1.336 mL) in methanol (10 mL)/dimethylsulfoxide (15 mL) was stirred at 75° C. overnight under an atmosphere of carbon monoxide. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford the title compound (0.435 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:19]([O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24])[CH3:20]>CCOC(C)=O>[CH2:19]([O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:20]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent.
Reaction SMILES: [OH:1][CH:2]([CH2:14][C@@H:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:3](=[O:13])[CH2:4][C@@H:5]([CH3:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH3:20][C:19](=[CH:18][CH2:17][CH2:16][C@H:15]([CH3:22])[CH2:14][C:2](=[O:1])[C:3](=[O:13])[CH2:4][C@@H:5]([CH3:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:21]
Reactant: CC(C)=CCC[C@H](C)CC(=O)C(O)C[C@@H](C)CCC=C(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)=CCC[C@H](C)CC(=O)C(=O)C[C@@H](C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1 (7.0 g, 22.7 mmol) in 100 mL of methylene chloride was added 7.5 g of PCC. The mixture was heated to reflux. After 16 hours, the mixture was cooled to room temperature and filtered. The solution was concentrated under reduced pressure. The crude compound was purified by flash chromatography on silica gel (hexane:ethyl acetate=20:1, v/v) to afford the product as a colorless oil. Yield: 3.5 g (50%). 1H NMR (400 MHz, CDCl3) δ 5.06 (m, 2H), 2.66-2.74 (dd, 2H, J=5.64, 16.71 Hz), 2.51-2.60 (dd, 2H, J=7.98, 16.73 Hz), 1.92-2.02 (m, 6H), 1.5-1.67 (s, 6H), 1.58 (s, 6H), 1.19-1.35 (m, 4H), 0.89 (d, 6H, J=6.66 Hz). 13C NMR (400 MHz, CDCl3) δ 200.05, 131.60, 124.07, 52.96, 36.94, 28.49, 25.66, 25.36, 19.71, 17.60.
Reaction SMILES: [CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[C:16](=[CH:21][C:22]([O:24]CC)=[O:23])[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1>Cl.C(O)(=O)C>[CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[C:16](=[CH:21][C:22]([OH:24])=[O:23])[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=C1CN(C(C(=O)C2CC2)c2ccccc2F)CCC1O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C=C1CN(C(C(=O)C2CC2)c2ccccc2F)CCC1O
Reaction time: 168 h
Yield: 57 %

Procedure:
In a mixture of 75 ml of concentrated hydrochloric acid and 180 ml of acetic acid, 9.72 g (26.9 mmol) of 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-3-ethoxycarbonylmethylidene-4-hydroxypiperidine were dissolved and the resulting solution was allowed to stand at room temperature for 7 days. The reaction mixture was concentrated to dryness under reduced pressure, followed by chromatography on a silica gel column (eluting solvent: chloroform/methanol=100/3~2/1), whereby 5.11 g (yield: 57%) of 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-3-carboxymethylidene-4-hydroxypiperidine were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5]([C:34]#[N:35])=[CH:4][N:3]=1.C(=N[OH:39])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5]([C:34]([NH2:35])=[O:39])=[CH:4][N:3]=1
Reactant: CC=NO
Reactant: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(N)ncc1C(N)=O)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile (69) (30.4 mg, 0.066 mmol) in anhydrous toluene (1 mL), acetaldoxime (10 μL, 0.13 mmol), palladium acetate (2 mg, 0.0066 mmol) and triphenyl phosphine (4 mg, 0.013 mmol) were added and the resulting mixture was stirred at 80° C. for 2 h. Additional amounts of acetaldoxime (10 μL, 0.13 mmol), palladium acetate (2 mg, 0.0066 mmol) and triphenyl phosphine (4 mg, 0.013 mmol) were added and stirring was continued at 80° C. for 2 h. The mixture was allowed to cool to RT, quenched with water (30 mL), and then extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-8.5% MeOH-DCM) to afford the desired product, (S)-2-amino-4-((1-(8-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxamide (79) as a white solid. ESI-MS m/z: 481.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:24][C:25]3([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]3)[CH:7]=[CH:6][CH:5]=2)[CH2:17]1
Reactant: NC1(C(=O)O)CC1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C(F)(F)F)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Yield: 21.2 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (384.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (85.6 mg, 23.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 405.2.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[N:16]=[N:15][C:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13][CH:12]=1.I[CH2:29][C:30]([NH2:32])=[O:31]>CN(C=O)C.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14](=[N:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:15]([CH2:29][C:30]([NH2:32])=[O:31])[N:16]=1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)nn2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Cl)nn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
N,N-Diisopropylethylamine (10.4 mL, 81 mmol) was added to a suspension of N-(6-chloropyridazin-3-yl)-4-methylbenzenesulfonamide (21 g, 74 mmol) in dry DMF (100 mL) under argon. To the resulting solution was added 2-iodoacetamide (15 g, 81 mmol, Aldrich, St. Louis, Mo.) and the mixture was stirred for 24 h at rt. The reaction mixture was diluted with water and precipitated solid was filtered off to afford the title compound (17 g, 68%). 1H NMR (DMSO-d6, 300 MHz): δ 2.4 (s, 3H), 4.8 (s, 2H), 7.3 (d, 2H), 7.6-7.8 (m, 4H), 7.95 (d, 1H).
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:19]=[C:18]([CH3:20])[C:11]([O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15])=[C:10]([CH3:21])[CH:9]=2)=[CH:4][N:3]=1.NC1N=CC(C2C=C(C)C(OCC(OC)=O)=C(C)C=2)=CN=1.O.NN>CCO>[CH3:20][C:18]1[CH:19]=[C:8]([C:5]2[CH:6]=[N:7][CH:2]=[N:3][CH:4]=2)[CH:9]=[C:10]([CH3:21])[C:11]=1[O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15]
Reactant: Cc1cc(-c2cnc(N)nc2)cc(C)c1OCC(=O)NN
Agent: COC(=O)COc1c(C)cc(-c2cnc(N)nc2)cc1C
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2cncnc2)cc(C)c1OCC(=O)NN
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Synthesis of 2-(4-(2-aminopyrimidin-5-yl)-2,6-dimethylphenoxy)acetohydrazide: methyl 2-(4-(2-aminopyrimidin-5-yl)-2,6-dimethylphenoxy)acetate (0.28 g, 1 mmol) was dissolved in EtOH. Hydrazine monohydrate (0.06 g, 1.2 mmol) was added thereto, followed by stirring at 100° C. for 8 hours under reflux. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The formed solid was filtered to obtained 2-(2,6-dimethyl-4-(pyrimidin-5-yl)phenoxy)acetohydrazide (0.31 g, 100%).