Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH2:18]3)=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].Cl.[H][H]>C(O)(C)C.C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH2:18]3)=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: [H][H]
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1C#N
Agent: O=[Pt]
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1CN

Procedure:
A mixture of 1-(3-cyano-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.54 g, 1.0 mmol), platinum oxide (0.1 g), and 5-6M HCl in isopropanol (2 mL) in acetic acid (15 mL) is hydrogenated under 50 psi hydrogen for 48 hrs. The mixture is filtered through Celite, the filtrate is evaporated under vacuum, and the residue is purified by preparative HPLC to provide the product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:34](Br)=[C:22]4[N:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:43]B(O)O>O1CCOCC1.C(Cl)Cl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:34]([CH3:43])=[C:22]4[N:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(-c3nc4c(Br)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)nn2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CC(C)(O)C4)cc3)nc12
Temperature: 100 °C
Yield: 41 %

Procedure:
A mixture of compound 10-3 (62 mg, 0.1 mmol), Methyl boronic acid (60 mg, 1 mmol), aq.Na2 CO3 (2M, 0.25 mmol, 0.12 mL) and Pd(DPPF)Cl2 (10 mg) in dioxane (2 mL) was heated at 100° C. in microwave system under N2 atmosphere for 30 min. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 23 mg of 10-5.
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:22]([O:31][CH2:32][CH3:33])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.[CH3:37][C:38]1[C:39]([NH:44][NH2:45])=[N:40][CH:41]=[CH:42][CH:43]=1.C[O:47]C(=O)N=C(SC)C(C1C=C(OC)C2OCOCC=2C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1.N(C1N=CC=CN=1)N>>[C:32]([OH:47])(=[O:31])[CH3:33].[CH2:32]([O:31][C:22]1[CH:21]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:18])=[NH:15])=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:2])[N:44]([C:39]3[C:38]([CH3:37])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:45]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][CH2:28][O:29][CH3:30])[CH3:33]
Reactant: Cc1cccnc1NN
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OCCOC
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Agent: NNc1ncccn1
Product: CC(=O)O
Product: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3C)c(=O)[nH]2)ccc1OCCOC

Procedure:
The same procedure was carried out as in Examples (21i)-(21j), except that {2-(3-ethoxy-4-(2-methoxyethoxy)phenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and (3-methylpyridin-2-yl)hydrazine were used instead of respectively the {2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in Example (21i) and 2-hydrazinopyrimidine in Example (21i), to give the title compound.
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14].[C-]#N>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([NH:16][C:17](=[O:18])[N:7]([OH:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(N=C=O)c1cccc(Cl)c1
Reactant: ONc1ccccc1
Agent: [C-]#N
Solvent: c1ccccc1
Product: CC(C)(NC(=O)N(O)c1ccccc1)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A solution of 2.2 g of N-phenylhydroxylamine in 10 ml of benzene was added to a solution of 0.02 mole of m-chloro-α,α-dimethylbenzyl isocyanate (prepared from the corresponding cyanide in the same way as in Synthesis Example 1) in 10 ml of benzene. The mixture was stirred well and allowed to stand overnight. The precipitated crystals were filtered off and washed with n-hexane to yield 5.7 g of 3-(m-chloro-α,α-dimethylbenzyl)-1-hydroxy-1-phenylurea. To 3.1 g of the urea was added a solution of 550 mg of sodium methoxide in 10 ml of methanol. The mixture was made homogeneous by stirring and 1.5 g of methyl iodide was added thereto. The mixture was then heated under reflux for 2 hours. The solvent was evaporated off and the residue was extracted with benzene and water was added. The benzene layer was dried over sodium sulfate and the solvent was distilled off to give crystals, which were recrystallized from a mixture of n-hexane and benzene to obtain 2.7 g of the title compound.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NCCF)c3)ccn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
After dissolving 160 mg of N1-(2-fluoroethyl)-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide in 10 ml of trifluoroacetic acid, the solution was stirred at room temperature for 10 minutes. Ethyl acetate and sodium bicarbonate water were added to alkalinity for liquid separation. The ethyl acetate layer was washed once with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 86 mg of a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:12]C(=O)C)(=O)[CH3:10].C([O-])(=O)C.[K+].[N:21](OCCC(C)C)=O>C(Cl)(Cl)Cl>[N:1]1([C:9](=[O:12])[CH3:10])[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[N:21]1
Reactant: CC(C)CCON=O
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)n1ncc2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 3-amino-2-methylpyridine (1.0 g, 9.25 mmol) in CHCl3 (24 ml) at 0° C. was slowly added acetic anhydride (2.0 ml, 21.3 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. Potassium acetate (272 mg, 2.77 mmol) was added followed by slow addition of isoamyl nitrite (2.7 ml, 19.9 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc and washed with water, sat'd NaHCO3 and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 100% EtOAc/heptane to give 973 mg (65%) of 1-pyrazolo[4,3-b]pyridin-1-yl-ethanone as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:25][C:26](=O)OC(C)(C)C)[CH2:11][N:12]([C:21](=[O:24])CBr)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:21](=[O:24])[CH2:26][NH:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)CN(Cc1ccc(F)cc1)C(=O)CBr
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNC(COCc2ccccc2)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-(benzyloxy)-1-{[(bromoacetyl)(4-fluorobenzyl)amino]methyl}ethylcarbamate (2.79 g, 5.47 mmol) in CH2Cl2 (28 mL) was added trifluoroacetic acid (10 ml). The reaction was stirred at ambient temperature under inert atmosphere for 2 h and then concentrated in vacuo, azeotroping the residual oil with CHCl3. The resulting residue was dissolved in CH2Cl2 (100 mL) and treated with Hünig's base (10 mL). The solution was stirred at ambient temperature under inert atmosphere for 18 h. The solvent was removed in vacuo, and the remaining residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (EtOAc to 10% MeOH/EtOAc) afforded the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.37-7.22 (m, 7H), 7.04-6.98 (m, 2H), 4.64 (d, J=14.8 Hz, 1H), 4.49-4.44 (m, 3H), 3.63 (dd, J=17.6, 41.2 Hz, 2H), 3.47 (dd, J=4.0, 9.6 Hz, 1H), 3.40 (dd, J=6.4, 9.2 Hz, 1H), 3.22-3.16 (m, 1H), 3.10-3.06 (m, 2H), 1.71 (br s, 1H). ES MS (M+1)=329.3.
Reaction SMILES: [NH2-].[Na+].CC1C=CC=CC=1.[C:10]1([CH2:16][C:17]#[N:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:19]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32](OCC)=[O:33])[CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1.C(O)C>[OH:33][C:32]([CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:31][CH2:30]1)=[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]#[N:18]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: N#CCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#CC(=C(O)C1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a stirred mixture of 7.8 parts of sodium amide 5% in benzene and 135 parts of methylbenzene was added dropwise a solution of 11.7 parts of benzeneacetonitrile in 45 parts of methylbenzene at 25° C. (cooling was necessary). After stirring for 30 minutes at 30° C., there was added dropwise a solution of 24.7 parts of ethyl 1-(phenylmethyl)-4-piperidinecarboxylate in 45 parts of methylbenzene at 30° C. Upon completion, stirring was continued overnight at 80° C. The reaction mixture was cooled, 12 parts of ethanol were added and the whole was poured into ice water. The layers were separated and the aqueous phase was neutralized with acetic acid. The oily product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 12 parts (38%) of α-[hydroxy[1-(phenylmethyl)-4-piperidinyl]methylidene]benzeneacetonitrile; mp. 191.9° C. (intermediate 5).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14].[CH3:17]O>[Pd]>[NH2:10][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=1[N:16]([CH3:17])[CH:13]([CH3:15])[CH3:14]
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: CC(C)N
Reactant: CO
Agent: [Pd]
Product: CC(C)N(C)c1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-2-nitro benzaldehyde (3.76 g, 25 mmol) in dry MeOH (120 ml), was added isopropyl amine (2.1 ml, 25 mmol) and the mixture stirred for 2 hours at room temperature in Argon atmosphere. Then it was then transferred into a Parr bottle containing 5% Pd on charcoal (246 mg) under Argon and hydrogenated at 30 psi for 18 hours. The suspension was filtered over a celite pad, washed with MeOH and evaporated at reduced pressure to afford (2-amino-4-fluorophenyl)-N-(1-methylethyl)-methylamine as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:10]=[CH:23]/[CH:24]=[O:25])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(2-pyridinyl)benzaldehyde (prepared as described in Reference Example 11) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].C(N(CC)CC)C.[CH3:32][S:33][CH2:34]Cl>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([O:15][CH2:34][S:33][CH3:32])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CSCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCSC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydro pyridine-3,5-dicarboxylic acid 5-methyl ester(3.32g), triethylamine(2.5ml)and chloromethyl methyl sulfide(0.9ml) in 30ml of acetonitrile was heated at 65° C. for 3 hours. The solvent was removed in vacuum, and then the residue was dissolved in ethylacetate. The ethylacetate solution was washed with water and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (ethylacetate:n-hexane=1:3). The eluent was concentrated in vacuum to afford a yellow solid which was recrystallized from methyl alcohol to give the titled compound(1.2g):
Reaction SMILES: [C:1]([C:4]1[N:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C1C=C[NH+]=CC=1.[Br:20][Br-]Br>Br.C(O)(=O)C>[Br-:20].[Br:20][CH2:2][C:1]([C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=[CH:12][NH+:13]=1)=[O:3]
Reactant: COC(=O)c1cccnc1C(C)=O
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc[nH+]c1C(=O)CBr
Product: [Br-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 157.6 %

Procedure:
To a solution of methyl 2-acetylnicotinate (750 mg, 4.19 mmol)—prepared according to H. Nagano et al.; Heterocycles 1987, 26, 1263-1270—in 2 ml of 33% HBr in acetic acid a suspension of pyridinium bromide perbromide (1.4 g, 4.38 mmol) in 5 ml of acetic acid was added, and stirred for 5 hours at room temperature. The precipitate formed was filtered off under suction, washed with n-pentane and dried to give 1.17 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:23])[CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25]>>[C:24]([C:26]1[CH:31]=[C:30]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5([OH:23])[CH2:22][CH2:21][CH2:20]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH:29]=[CH:28][CH:27]=1)#[N:25]
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCC4)n3)c2n1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2nc(N)nc3c2nnn3Cc2cccc(C3(O)CCC3)n2)c1

Procedure:
Prepared from 7-chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 3-cyanophenylboronic acid by the method described for Example 7 to give the title compound (0.06 g) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH2:34][C:35]([F:38])([F:37])[F:36])[C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]4[CH2:31][CH2:32][CH2:33][C@H:28]([N:27]([CH3:26])[CH2:34][C:35]([F:36])([F:38])[F:37])[CH2:29]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN(CC(F)(F)F)[C@H]1CCCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@H](N(C)CC(F)(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)— N-methyl-N-(2,2,2-trifluoroethyl)piperidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.92 (m, 4H) 2.26-2.41 (m, 4H) 2.59-2.80 (m, 2H) 2.93-3.36 (m, 3H) 3.55 (br. s., 1H) 3.75-4.19 (m, 2H) 4.36-4.54 (m, 1H) 7.55-7.68 (m, 1H) 7.71-7.78 (m, 1H) 8.53 (s, 4H). ESI-MS m/z [M+H]+ 517.3.
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[C:13]1(C)C=CC(S(OC)(=O)=O)=CC=1.[CH3:25][N:26]([CH3:50])[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]2[N:42]([CH2:43][C:44]3[O:45][CH:46]=[CH:47][CH:48]=3)[C:41](=[O:49])[CH2:40][S:39]2)[CH:32]=1)=[O:29]>>[CH3:25][N:26]([CH3:50])[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]2[N:42]([CH2:43][C:44]3[O:45][CH:46]=[CH:47][CH:48]=3)[C:41](=[O:49])[C:40](=[C:2]3[N:6]([CH3:13])[C:5]4[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=4[S:3]3)[S:39]2)[CH:32]=1)=[O:29]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc2sc(S)nc2c1
Reactant: CN(C)CC(=O)Nc1cccc(N=C2SCC(=O)N2Cc2ccco2)c1
Product: COc1ccc2c(c1)N(C)C(=C1SC(=Nc3cccc(NC(=O)CN(C)C)c3)N(Cc3ccco3)C1=O)S2

Procedure:
In a manner similar to Example 45, 2-mercapto-5-methoxybenzothiazole was alkylated with methyl p-toluenesulfonate and then condensed with 2-dimethylamino-N-[3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)-phenyl]acetamide. MS(ESI): 550 (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][N:15]=[C:16]3Cl)=[CH:11][CH:10]=2)[C:4]1=[O:20].C([N:23](CC)CC)C.[S:28]1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[S:37](Cl)(=[O:39])=[O:38]>CC#N>[NH2:23][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:37]([C:29]4[S:28][C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)(=[O:39])=[O:38])[C:4]3=[O:20])[CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: CCN(CC)CC
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Reactant: O=S(=O)(Cl)c1cc2ncccc2s1
Agent: Cl
Solvent: CC#N
Product: Nc1nccc2ccc(CN3CC[C@H](NS(=O)(=O)c4cc5ncccc5s4)C3=O)cc12
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (0.15 g, 0.48 mmol) suspended in CH3CN (2.5 mL) is added triethylamine (0.23 mL, 1.6 mmol) followed by thieno[3,2-b]pyridine-2-sulfonyl chloride (0.14 g, 0.55 mmol). The mixture is stirred overnight, then concentrated. The residue is diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound (0.076 g, 0.16 mmol) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:3]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C=O)C>[Cl:26][CH2:25][CH2:24][CH2:23][N:11]1[C:10]2[CH:9]=[N:8][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: ClCCCBr
Reactant: Cc1nc(-c2cc3c(cn2)[nH]c2ccccc23)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc3c4ccccc4n(CCCCl)c3cn2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a solution of 3-(5-methyl-1,2,4-oxadiazol-3-yl)-β-carboline (0.25 g, 0.001 mol) in anhydrous DMF (30 mL) was added 50% sodium hydride in mineral oil (0.03 g, 0.0011 mol). The mixture was stirred for 1 h at room temperature, and then carefully added to a solution of 1-bromo-3-chloropropane (0.17 g, 0.0011 mol) in anhydrous DMF (20 mL). The resulting mixture was stirred at ambient temperature for 96 h. The reaction mixture was concentrated in vacuo, and the crude product was purified twice on a silica gel column 1) (Eluent: CH2Cl2 /methanol (9:1)); 2) (Eluent: ethyl acetate/toluene (1:1)) to give the title compound 0.21 g (64%). M.p. 130°-135° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:28][C:10]1([CH3:29])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 69.2 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.6 g, 14.2 mmol) in methanol (50 mL) and tetrahydrofuran (100 mL), 30% sodium hydroxide in water (30 mL) was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (3.6 g, 69%) as a white solid: LC/MS m/e calcd for C22H26N2O3 (M+H)+: 367.46, observed: 367.1.