Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2.N#N>CS(C)=O.[Cu](I)I>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:33](=[O:37])[CH:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: I[Cu]I
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 110 °C
Yield: 51.1 %

Procedure:
tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (7.0 g, 19 mmol), 4-benzyloxypyridone (3.85 g, 19.2 mmol), K2CO3 (2.91 g, 21.1 mmol) and 8-hydroxyquinoline (418 mg, 2.88 mmol) were suspended in DMSO (50 mL) and the air removed under vacuum for 15 min. The system was then flushed with N2. This process was repeated and then copper iodide (547 mg, 2.88 mmol) was added. The evacuation/N2 flushing process was repeated twice more, and the reaction mixture was heated to 100-120° C. for 18 h. The mixture was cooled, partitioned between EtOAc and sat. NH4Cl and the organic phase removed, dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 100:0 to 98:2 to 95:5 to 92:8 then 90:10) gave the title compound (4.71 g, 51%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=8.2 Hz, 1H), 7.43-7.35 (m, 5H), 7.32-7.29 (m, 2H), 7.01 (d, J=7.9 Hz, 1H), 6.10-6.03 (m, 2H), 5.06 (s, 2H), 4.64 (s, 2H), 3.89 (br t, 2H), 3.63 (s, 3H), 2.82 (br t, 2H), 1.50 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].CO>O.[Ni]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1
Reactant: Cn1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(C(=O)O)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 26 h

Procedure:
12 g 6-nitro-1-methyl-1H-indole-3-carboxylic acid are dissolved in 500 ml of water, 60 ml 1 N sodium hydroxide solution and 30 ml of methanol. 1.2 g Raney nickel are added and the mixture is hydrogenated for 26 hours at 1.5 bar. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is suspended in 100 ml of pyridine. 16.3 g 3,5-dichlorophenylsulphonyl chloride are added and the mixture is stirred overnight at ambient temperature. The pyridine is eliminated in vacuo. The residue is divided between water and ethyl acetate and the pH is adjusted to 5 by the addition of citric acid. The aqueous phase is extracted 3 times with ethyl acetate and the combined organic phases are dried on magnesium sulphate. After elimination of the solvents the residue is chromatographed on silica gel (dichloromethane/methanol/acetic acid 95:5:1 to 89:10:1)
Reaction SMILES: [C:1]1([N:7]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[C:8]2[CH:20]=[CH:19][C:11]3[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:37]1[CH:38]=[CH:39][C:40]2[NH:41][C:42]3[C:47]([C:48]=2[CH:49]=1)=[CH:46][CH:45]=[CH:44][CH:43]=3.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:39]1[C:40]2[NH:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:48]=2[CH:49]=[C:37]([C:24]2[CH:23]=[CH:22][C:21]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]3[CH:20]=[CH:19][C:11]4[O:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[C:10]=4[CH:9]=3)=[CH:26][CH:25]=2)[CH:38]=1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccc4oc5ccccc5c4c3)cc2)OC1(C)C
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(N(c2ccc(-c3ccc4[nH]c5ccccc5c4c3)cc2)c2ccc3oc4ccccc4c3c2)cc1
Yield: 85.6 %

Procedure:
N-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)dibenzo[b,d]furan-2-amine (3.25 g, 7.0 mol), and 3-bromo-9H-carbazole (1.73 g, 7.0 mmol) were mixed in 45 mL of toluene and 15 ml of ethanol. To the solution was bubbled with nitrogen for 15 min. Pd2(dba)3 (0.16 g, 0.18 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.29 g, 7.0 mmol) and K3PO4 (4.49 g, 21.1 mmol) were added. The mixture was refluxed overnight under nitrogen. After cooling, aqueous layer was removed from the reaction mixture and dry over magnesium sulfate, and was filtered through filter paper and the filtrate was then evaporated. The residue was then purified by column chromatography using THF:hexane (1:3, v/v) as eluent 3.0 g (85%) of a white solid was obtained as the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)=O.[CH:10]1[C:23]2[C:22]3([CH2:25][CH2:26][CH:27]=O)[CH2:24][CH:15]([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=[CH:12][CH:11]=1>O>[O:4]1[CH2:5][CH2:6][N:1]([CH2:27][CH2:26][CH2:25][C:22]23[CH2:24][CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=42)[C:14]2[C:23]3=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: O=CCCC12CC(c3ccccc31)c1ccccc12
Reactant: C1COCCN1
Solvent: O
Solvent: O=CO
Product: c1ccc2c(c1)C1CC2(CCCN2CCOCC2)c2ccccc21
Temperature: 60 °C

Procedure:
To a mixture of morpholine (870 mg) and formic acid (460 mg) heated at 60° C. was added β-(9,10-dihydro-9,10-methano-9-anthryl)propionaldehyde (50 mg). The resultant mixture was stirred at 60° C. for 30 minutes and at 80° C. for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-γ-morpholinopropyl-9,10-dihydro-9,10-methanoanthracene, which was converted into its hydrochloride. M.P. 173°-176.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]3[CH:12]=[C:11]([CH:13]([CH:15]4[CH2:17][CH2:16]4)[OH:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1.C(OCC)C.CCO>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]3[CH:12]=[C:11]([C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)sc1nc(C(O)C3CC3)cn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc2c(c1)sc1nc(C(=O)C3CC3)cn12
Yield: 85.9 %

Procedure:
A mixture of 1.63 g (0.0062 mole) of (7-methoxy-imidazo [2,1-b]benzothiazol-2-yl)-cyclopropyl methanol and 4.8 g (0.055 mole) of manganese dioxide was stirred under reflux in 300 ml of chloroform for 1 hour. The mixture was filtered hot and evaporated to dryness. Trituration with diethyl ether yielded 1.45 g (89% yield) of (7-methoxy-imidazo[2,1-b]benzothiazol-2-yl)-cyclopropyl methanone as a colorless solid melting at 213° as 214° C. (EtOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]([S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH2:14]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:19][CH2:18][S:15](=[O:17])(=[O:16])[CH2:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CS(=O)(=O)C=C
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N2CCS(=O)(=O)CC2)C1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a refluxing solution of 3-aminoazetidine-1-carboxylic acid tert-butyl ester (10.0 g, 58.1 mmol) in EtOH (50 mL) was added drop wise a solution of divinyl sulfone (5.9 mL, 6.86 g, 58.1 mmol) in EtOH (50 mL) The resulting mixture was stirred at reflux for 15.5 h, cooled to room temperature and concentrated in vacuo. The resulting beige solid was triturated with Et2O, affording the title compound as a white solid (10.8 g, 64%). 1H NMR (CDCl3, 300 MHz): δ 3.97 (dd, J=8.8, 7.1 Hz, 2H); 3.76 (dd, J=8.8, 7.1 Hz, 2H); 3.36-3.26 (m, 1H); 3.13-3.05 (m, 4H); 2.90-2.83 (m, 4H); 1.44 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[N:6]=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Br)cn2)o1
Reactant: C1COCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCOCC3)cn2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
A mixture of 5-bromo-2-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.52 mmol), morpholine (455 μL, 5.22 mmol) and tetrabutylammonium iodide (41 mg, 0.10 mmol) was irradiated in the microwave for 1.5 h at 160° C. After cooling to ambient temperature the resulting suspension was diluted with ethyl acetate (15 mL) and stirred for 15 min at this temperature. Filtering off and washing with water (2 mL) and with ethyl acetate (1 mL) afforded the title compound (95 mg, 47%) which was obtained as a light brown solid. MS: m/e=390.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([C:12]([F:15])([F:14])[F:13])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH3:11])[C:3]([NH2:5])=[O:4].[H][H]>CO.[C].[Pd]>[F:1][C:2]([C:12]([F:13])([F:15])[F:14])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([NH2:5])=[O:4]
Reactant: [H][H]
Reactant: CCCC=CCC(F)(C(N)=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(F)(C(N)=O)C(F)(F)F
Reaction time: 24 h
Yield: 76.2 %

Procedure:
Into a solution of 1.30 g of 2-fluoro-2-trifluoromethyl-4-octenamide in 13 ml of methanol, palladium-carbon (13 mg) was added under nitrogen. After the atmosphere was replaced with hydrogen, the mixture was stirred for 24 hours. To remove the catalyst, the resulting mixture was filtered with celite and the filtrate was concentrated. The raw product was purified by silica gel column chromatography to obtain 1.0 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19]N=C[CH:16]=2)[C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7].CC1C=C(C)C=C(C2C=C[N:37]=[CH:36]C=2)C=1OCC([O-])=O.O.NN>CCO>[CH3:1][C:2]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]2[CH:16]=[N:37][CH:36]=[CH:19][CH:20]=2)[C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7]
Reactant: Cc1cc(C)c(OCC(=O)[O-])c(-c2ccncc2)c1
Reactant: Cc1cc(C)c(OCC(=O)NN)c(-c2ccncc2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(OCC(=O)NN)c(-c2cccnc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Synthesis of 2-(2,4-dimethyl-6-(pyridin-4-yl)phenoxy)acetohydrazide: 2-(2,4-dimethyl-6-(pyridin-4-yl)phenoxy)acetate (0.1 g, 0.37 mmol) was dissolved in EtOH. Hydrazine monohydrate (0.13 g, 2.63 mmol) was added thereto, followed by stirring at 100° C. for 16 hours under reflux. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography to obtain 2-(2,4-dimethyl-6-(pyridin-3-yl)phenoxy)acetohydrazide (0.1 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14]C1N=CC=CC=1C#N.C(O)(=O)C(C)(C)C.OS(O)(=O)=O>[N+]([O-])([O-])=O.[Ag+]>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:14][CH3:13])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1C#N
Reactant: CC(C)(C)c1ccc(C#N)cn1
Agent: [Ag+]
Agent: CC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Product: COc1nc(C(C)(C)C)ccc1C#N

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 6-tert-butylnicotinonitrile starting from 2-methoxynicotinonitrile (8.02 g, 5.98 mmol), pivalic acid (3.05 g, 39.9 mmol), AgNO3 (0.13 g, 0.78 mmol), (NH4)2S2O8 (1.78 g, 7.78 mmol) and 6 ml 10% H2SO4. Purified by normal phase chromatography using 95/5 to 90/10 heptane/ethyl acetate. (Yield: 80 mg, 7%). 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 9 H), 4.04 (s, 3 H), 6.97 (d, J=7.81 Hz, 2 H), 7.78 (d, J=7.81 Hz, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:31]([C:32]([NH:34][CH3:35])=[O:33])=[C:11]3[CH:12]=[C:13](B4OC(C)(C)C(C)(C)O4)[C:14]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl[C:37]1[CH:46]=[CH:45][C:44]2[CH2:43][CH2:42][N:41]3[C:47]4[CH:48]=[CH:49][CH:50]=[C:51]([F:54])[C:52]=4[CH:53]=[C:40]3[C:39]=2[N:38]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:54][C:51]1[C:52]2[CH:53]=[C:40]3[C:39]4[N:38]=[C:37]([C:13]5[C:14]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][N:10]6[N:9]=[C:8]([C:5]7[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=7)[C:31]([C:32]([NH:34][CH3:35])=[O:33])=[C:11]6[CH:12]=5)[CH:46]=[CH:45][C:44]=4[CH2:43][CH2:42][N:41]3[C:47]=2[CH:48]=[CH:49][CH:50]=1
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 45.3 %

Procedure:
To a solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (110 mg, 0.22 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and K2CO3 (50 mg, 0.366 mmol) in 1,4-dioxane (2 mL) were added X-Phos (10 mg) and Pd2(dba)3 (10 mg) under N2. The reaction mixture was stirred at 100° C. for 5 hours and concentrated in vacuo to remove 1,4-dioxane. The reaction mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and evaporated concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product (50 mg, yield: 44%). 1H-NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 8.51 (s, 1H), 7.70˜7.73 (m, 3H), 7.52 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 7.14˜7.20 (m, 3H), 6.80 (t, J=8.0 Hz, 1H), 5.56 (br s, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.51 (s, 3H), 3.34 (t, J=6.4 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 2.63 (s, 3H). MS (M+H)+: 613.
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+].ClC1C=CC(C2C(C3C=CC(Cl)=CC=3Cl)=CN3C(CC4C=NC(C(F)(F)F)=CC=4)=NN=C3C=2)=CC=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:2]([C:32]3[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=3[CH3:30])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:24][CH:25]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cn3c(Cc4ccc(C(F)(F)F)nc4C)nnc3cc2-c2ccc(Cl)cc2)c(C)c1
Yield: 64.1 %

Procedure:
The title compound (6.5 mg, 65%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2,4-dimethylphenylboronic acid (5.9 mg, 0.039 mmol), K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56E). LC/MS (method B): retention time=2.00 min, [M+H]+=507.3.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([NH:10][C:11]([C:13]1[CH:22]=[C:21]([Cl:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[O:24][CH2:25][C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][CH:31]=1)=[O:12])([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>O>[Cl:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([O:24][CH2:25][C:26]2[CH:31]=[N:30][C:29]([C:32]([F:34])([F:35])[F:33])=[N:28][CH:27]=2)=[C:13]([C:11]([NH:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:36])=[O:5])=[O:12])[CH:22]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1cc(Cl)c2ccccc2c1OCc1cnc(C(F)(F)F)nc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC(=O)c1cc(Cl)c2ccccc2c1OCc1cnc(C(F)(F)F)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
0.015 g 2-{[4-chloro-1-(2-trifluoromethyl-pyrimidin-5-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid tert-butyl ester was dissolved in 5 mL of a mixture consisting of 95% trifluoroacetic acid, 2.5% triethylsilanes and 2.5% of water. This was left stirring at room temperature for 30 minutes, and then it was concentrated in vacuo. Purification was performed by flash chromatography on silica using methanol/dichloromethane to give 0.007 g (53%) of 2-{[4-Chloro-1-(2-trifluoromethyl-pyrimidin-5-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(OC)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: NCc1ccccc1
Solvent: COc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
The resulting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate (7) and benzyl amine were coupled in anisole at high temperature to afford 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide (KX2-391). An HCl solution formed by adding acetyl chloride to absolute ethanol was added to KX2-391 to form the bis-HCl salt, 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride, (KX2-di-HCl).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)([CH3:23])[CH3:22]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH:21]([CH3:23])[CH3:22])=[CH:26][CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(C)C)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-isopropoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 384.12 g/mol.
Reaction SMILES: C(=[C:4]([OH:22])[C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@H:7]([OH:20])[C@@H:6]1[OH:21])(C)C.[OH-:23].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[C@@H:8]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:5]([CH:4]([C:5]([O:9][CH2:8][CH3:7])=[O:23])[OH:22])[C@@H:6]([OH:21])[C@H:7]1[OH:20]
Reactant: CC(C)=C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: [OH-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
11.7 g. of Isopropylidene adenosine were dissolved in 3.5 liters of water and the pH was adjusted to 12.2 by the addition of 5.85 g. of potassium hydroxide. 23.7 g. of potassium permanganate in 825 ml. of water were added dropwise with stirring over a period of 33/4 hours. The solution was then allowed to sit at room temperature overnight. The excess permanganate was destroyed by the dropwise addition of 30% hydrogen peroxide and the reaction mixture was filtered through a layer of NH3 -washed celite. The yellow filtrate was concentrated in vacuo at 35°-45° to 600 ml. and the acid precipitated in an ice bath by adjusting the pH to 4.5 by the dropwise addition of 1:3 HCl. The white precipitate was washed with dilute (1:1000) acetic acid and dried at 135°C. to yield 7.93 g. of the crude isopropylidene product, m.p. 265-8°. The material was taken up in 100 ml. of dilute NH3, and recrystallized by adjusting the pH to 4.5 by the addition of 1:3 acetic acid to yield 7.7 g. of 2',3'-isopropylidene adenosine-5'-carboxylic acid, m.p. 272-3°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]2[CH2:28][C:27]([CH3:30])([CH3:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:31]#[N:32])[CH:25]=3)[NH:20]2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:31]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([C:15]1[CH:14]=[C:13]([NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:18]=[CH:17][CH:16]=1)[CH2:28][C:27]2([CH3:30])[CH3:29])#[N:32]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3CC(C)(C)c4cc(C#N)ccc4N3)c2)cc1
Reaction time: 8 h
Yield: 38.6 %

Procedure:
4-Methyl-benzenesulfonyl chloride (103 mg, 0.54 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (100 mg, 0.36 mmol) and pyridine (51 mg, 0.65 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-methyl-benzenesulfonamide as off-white solid (60 mg, yield: 38.6%). MS (ESI+APCI) M+1=432.2.