Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([OH:30])=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH2:42][CH:43]1[CH2:45][CH2:44]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:42][CH:43]1[CH2:44][CH2:45]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[CH2:1]([O:8][C:9]1[C:10]([C:28]([OH:30])=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 120.1 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (250 mg, 0.62 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amine (8i) (170 mg, 0.74 mmol) in dimethylformamide (3 mL) were added N,N-diisopropylethylamine (0.3 mL, 1.85 mmol) and HATU (352 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 20 h. Water (75 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (304) (380 mg, 99.82%) as a light yellow sticky solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:19]([O-:21])=O)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:19](=[O:21])[N:29]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:30])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1ccccc1
Reactant: CCOC(=O)C1(C(=O)[O-])CC(=O)N(Cc2ccccc2)C1
Product: CCOC(=O)C1(C(=O)N(C)Cc2ccccc2)CC(=O)N(Cc2ccccc2)C1
Yield: 78.7 %

Procedure:
Monoethyl 1-benzyl-5-oxopyrrolidine-3,3-dicarboxylate (29.1 g) obtained in Preparative Example 1 (1) and N-benzyl-N-methylamine (12.1 g) were treated in the same manner as in Preparative Example 1 (2) to give 31 g of the object compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CN([CH:17]=[O:18])C.[H-].[Na+].[I-].[K+]>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[N:8]2[CH2:10][CH2:2][CH2:3][CH2:4][O:18][CH3:17])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC1(C)C(=O)Nc2cc(Br)ccc21
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: COCCCCN1C(=O)C(C)(C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 6-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.5 g) were added DMF (24 mL) and NaH (326 mg) under ice-cooling, and the mixture was stirred at room temperature 15 minutes. Then, to the mixture were added 4-chloromethyl butyl ether (1.54 g) and potassium iodide (208 mg), and the mixture was stirred at 100° C. for 7 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (1.87 g) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[I:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[I:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:15](=[O:17])[CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:13][CH:12]=2)=[N:23][CH:24]=1
Reactant: Nc1ccc(I)cn1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(I)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 65-1 (300 mg, 1.3 mmol), 5-iodopyridin-2-amine (344 mg, 1.6 mmol) and HATU (590 mg, 1.6 mmol) in DMF (8 mL) was added DIEA (503 mg, 3.9 mmol) at room temperature. After stirred at room temperature for 2 hours, the reaction mixture was diluted into ethyl acetate and washed with saturated NaHCO3 solution and then brine. The organic phase was dried over MgSO4. The solvent was removed and the crude product was purified by silica gel flash chromatography to afford N-(5-iodopyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 65-2 as off-white solid. MS m/z 430.1 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:13][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1
Reactant: CSc1nccc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(Oc2ccc([N+](=O)[O-])c(F)c2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
173 mg (6.85 mmol) 95% sodium hydride was given to a solution of 979 mg (6.23 mmol) 3-fluoro-4-nitrophenol in 10 ml DMF. Stirring was continued for 30 min. at room temperature. 1.00 g (6.23 mmol) 4-chloro-2-methylsulfanyl-pyrimidine was added and the mixture heated to 80° C. for 16 h. The reaction mixture was evaporated, taken up with water and extracted with ethyl acetate. The organic phase was extracted with water, dried (sodium sulphate) and evaporated. The obtained material was dissolved in ethyl acetate and purified by chromatography over silica (ethyl acetate/n-heptane 1:2) to give 570 mg 4-(3-fluoro-4-nitro-phenoxy)-2-methylsulfanyl-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:7]2[CH2:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[F:16][C:13]([F:14])([F:15])[CH2:12][N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([NH2:1])[CH:17]=[C:7]2[CH2:8]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(CC(F)(F)F)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2n(n1)CCN(CC(F)(F)F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 134a (390 mg, 1.56 mmol) in ethanol (20 mL) was added Pd/C (about 200 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE®. The filtrate was concentrated under reduced pressure to afford 134b as a yellow solid (308 mg, 90%), which was used in the next step without further purification. MS-ESI: [M+H]+ 221.1
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH:11]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[CH3:10][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[N:22]1[C:23]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COc1ccc(C)cc1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(C)cc1-n1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 47 %

Procedure:
2-Bromo-4-methylanisole (20.11 g, 100 mmol, 1 equiv) and carbazole (20.06 g, 120 mmol, 1.2 equiv) were dissolved in 1,4-dioxane (400 mL). Potassium phosphate tribasic (37.15 g, 175 mmol, 1.75 equiv), copper (I) iodide (0.95 g, 5 mmol, 0.05 equiv) and racemic trans-1,2-diaminocyclohexane (2.4 mL, 20 mmol, 0.2 equiv) were added and the reaction was refluxed for two days. The reaction was cooled to room temperature, then partitioned with ethyl acetate (200 mL) and water (300 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified over silica gel (150 g), eluting with 3% ethyl acetate in heptanes to give compound 1 (13.5 g, 45% yield) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6]([O:19]C(=O)C2C=CC=CC=2)([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[H-].[Na+].CN1CCC(=O)CC1.Cl>CN(C)C=O>[CH3:2][N:3]1[CH2:4][CH2:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)([OH:19])[CH2:7][CH2:8]1
Reactant: CN1CCC(OC(=O)c2ccccc2)(c2nccc3ccccc23)CC1
Agent: CN1CCC(=O)CC1
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: CN1CCC(O)(c2nccc3ccccc23)CC1
Reaction time: 8 h

Procedure:
346 g. of 1-methyl-4-benzoyloxy-4-(1-isoquinolyl)-piperidine hydrochloride (m.p. 269°, from isopropanol), obtainable by adding 30 g. of NaH in portions to a solution of 260 g. of 1-cyano-2-benzoyl-1,2-dihydroiosquinoline and 120 g. of 1-methylpiperidin-4-one in 950 ml. of dimethylformamide, with stirring, and allowing the mixture to stand overnight, are heated under reflux with 1,400 ml. of 25% hydrochloric acid for 40 hours. The mixture is cooled and worked up in the customary manner to give 1-methyl-4-(1-isoquinolyl)-piperidin-4-ol, m.p. 265°-266°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33][OH:34])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([N:42]=[C:43]=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.CCOCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][C:10]=1[CH2:33][O:34][C:43](=[O:44])[NH:42][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CO
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 100 mL round bottomed flask under N2 were charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxymethylphenyl]propionic acid tert-butyl ester (3.0 g, 6.11 mmol), cyclohexylisocyanate (4.7 mL, 36.7 mmol), and anhydrous CH2Cl2 (25 mL). A 1.0 M HCl solution in ether (3.06 mL, 3.06 mmol) was added, and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 16 h. The mixture was diluted with CH2Cl2 (100 mL), washed with brine, dried (Na2SO4), and concentrated to a brown oil. This crude oil was purified using the Biotage medium pressure chromatography system (EtOAc:hexanes 5:95) to a colorless oil (3.1 g, 82%). 1H NMR (400 MHz, CDCl3) 1.08-1.24 (m, 1H), 1.26-1.40 (m, 11H), 1.56-1.62 (m, 2H), 1.68-1.72 (m, 2H), 2.41 (t, J=8.3 Hz, 2H), 2.80 (t, J=7.8 Hz, 2H), 3.47 (br s, 1H), 4.56 (br s, 1H), 4.95 (s, 2H), 6.57 (dd, J=8.3, 2.7 Hz, 1H), 6.80 (s, 1H), 6.87 (d, J=8.6 Hz, 1H), 7.33-7.44 (m, 6H), 7.69-7.72 (m, 4H). MS (ES) m/e 616 (M+1).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:11]=1/[CH:18]=[CH:19]/[C:20](=[O:22])[CH3:21]>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[C@@H:18]1[CH2:2][C@H:19]1[C:20](=[O:22])[CH3:21]
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)/C=C/c1c(Cl)cc(Cl)cc1Cl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=O)[C@@H]1C[C@H]1c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask equipped with magnetic stirrer, nitrogen inlet and additional funnel was charged with trimethylsulfoxonium iodide (106 mg, 0.40 mmol), DMSO (2.5 ml) and powdered sodium hydroxide (0.18 mg, 0.44 mmol). The suspension was stirred for 1.0 hour at ambient temperature to yield a solution. So prepared solution was added drop wise at ambient temperature to a solution of (E)-4-(2,4,6-trichloro-phenyl)-but-3-en-2-one (0.10 g, 0.40 mmol) prepared as described in example P32 in DMSO (2.5 ml). The reaction mixture was stirred for 0.5 hours, poured onto ice water (10 ml) and extracted with ether (3×5 ml). Combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (25 g) (eluent: n-hexane/ethyl acetate 20:1) to afford 60 mg (57% of theory) of trans 1-[2-(2,4,6-trichloro-phenyl)-cyclopropyl]-ethyanone in form of a pale yellow liquid.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][C@:14]2([C:29]2[S:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(#N)C.I[Si](C)(C)C>[C:34]([C:31]1[S:30][C:29]([C@:14]23[CH2:16][NH:17][CH2:18][C@H:13]2[CH2:12][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:15]3)=[CH:33][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc([C@]23CN(C(=O)OCc4ccccc4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)s1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: N#Cc1ccc([C@]23CNC[C@H]2CSC(NC(=O)c2ccccc2)=N3)s1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 117.5 %

Procedure:
To a stirred clear and colorless solution of the benzyl (4aR,7aR)-2-(benzoylamino)-7a-(5-cyanothiophen-2-yl)-4a,5,7,7a-tetrahydropyrrolo[3,4-d][1,3]thiazine-6(4H)-carboxylate (405 mg, 0.806 mmol) in acetonitrile (16 mL) under an atmosphere of nitrogen at room temperature is added iodotrimethylsilane (345 μL, 2.42 μmol). The resulting pale yellow solution is stirred at room temperature for 70 minutes. Methanol (391 μL, 9.67 mmol) is added and the pale yellow mixture is stirred for 5 minutes, and then concentrated under reduced pressure. The residue is partially purified by silica gel chromatography, eluting with a dichloromethane/methanol, gradient from 99:1 to 90:10, to give the title compound (349 mg, 118%) as a pale yellow solid (assume quantitative recovery and carry partially purified material into next step). MS/ES (m/z) 369.0 (M+H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[C:20]([OH:25])[CH:19]=3)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].COCCOC>[O-2].[O-2].[Mn+4]>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:19]4[N:30]=[C:26]([CH2:27][CH2:28][CH3:29])[O:25][C:20]=4[CH:21]=[CH:22][C:23]=3[CH:24]=2)=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: O=C(c1cc2ccc(O)cc2[nH]1)N1CCC(Cc2ccccc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: COCCOC
Product: CCCc1nc2c(ccc3cc(C(=O)N4CCC(Cc5ccccc5)CC4)[nH]c32)o1
Reaction time: 1 h
Yield: 124.5 %

Procedure:
Under argon, to a solution of 0.5 g (1.49 mmol) of 1-(4-benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indole-2-yl)methanone and 0.14 g (0.2 mmol) of n-butylamine in 100 ml of ethylene glycol dimethyl ether 10 g (115 mmol) of manganese dioxide is added portion-wise at 0° C. After stirring for 1 h, the reaction mixture is filtered, the filtrate is concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and hexane:ethyl acetate=2:1 as eluent to yield 0.1 g (17.3%) of the title compound. Mp.: 195-196° C. (hexane-ethyl acetate).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([OH:15])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.O[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=N1.Cl.C(N=C=NCCCN(C)C)C.C1(N)C=CC=CC=1N>CN(C)C=O.C(OCC)(=O)C>[NH2:29][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
A solution of 2-benzamidoisonicotinic acid (0.50 g, 2.06 mmol), N,N-diisopropylethylamine (1.10 mL, 6.32 mmol), 1-hydroxybenzotriazole (0.418 g, 3.09 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.59 g, 3.09 mmol) in N,N-dimethylformamide (25 mL) was stirred for 15 minutes at ambient temperature and 1,2-phenylenediamine (0.22 g, 2.06 mmol) was added. The resulting solution was stirred for 20 hours at ambient temperature, diluted with ethyl acetate (75 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to give N-(2-aminophenyl)-2-benzamidoisonicotinamide as an off-white solid (0.37 g, 53%): MS (ES+) m/z 333.5 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:18][CH2:19][CH2:20][C:21]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:24]=[C:23]2[NH:40][N:41]=[C:42]([CH3:43])[C:22]=12)=O)C1C=CC=CC=1>ClCCl>[NH2:18][CH2:19][CH2:20][C:21]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:24]=[C:23]2[NH:40][N:41]=[C:42]([CH3:43])[C:22]=12
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2[nH]nc(C)c2c1CCNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2[nH]nc(C)c2c1CCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8 mL of trifluoroacetic acid is added to a solution of 220 mg (0.45 mmol) of ethyl 4-(2-(benzyloxycarbonylamino)ethyl)-6-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate dissolved in 5 mL of dichloromethane. The reaction medium is stirred at room temperature for 3 hours and then quenched by addition of 1M soda until pH=8 is reached. The product is extracted with ethyl acetate. The organic phases are dried on magnesium sulfate and concentrated to yield ethyl 4-(2-aminoethyl)-6-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a yellow oil. The latter is dissolved in 10 mL of anhydrous tetrahydrofurane before adding 15 mg of sodium hydride (60% dispersion in oil). The reaction medium is stirred at 25° C. for 48 hours. The product is extracted with ethyl acetate. The organic phases are dried on magnesium sulfate and concentrated to yield 123 mg (88%) of 5-(4-methoxyphenyl)-1-methyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one in the form of a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH2:29]>C(#N)C>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH:29][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(F)c1CNCCOc1cccc(-c2noc3ccsc23)c1
Reaction time: 8 h

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2,6-difluorobenzylamine and acetonitrile essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column chromatography using a solvent gradient of 5% ethyl acetate in dichloromethane to 10% methanol in ethyl acetate. Purity by LC/MS (APCI)=99%, [M+H]+=387.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>>[CH3:24][N:25]([CH3:27])[CH:26]=[C:3]([C:2](=[O:1])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Ethyl 3-oxo-3-(4-trifluoromethyl-phenyl)-propionate (130 mg, 0.5 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (151 mg) as a red oil which was used directly in the next step.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=O>>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:27]([C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=3)[N:22]=[C:16]2[CH:17]=1
Reactant: Nc1cc(Br)cc[n+]1N
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Fc1cccc(-c2nc3cc(Br)ccn3n2)c1
Yield: 70.9 %

Procedure:
The product was prepared in the same manner as described in example 1b using 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2 g, 5.15 mmol) and 3-fluorobenzoyl chloride (1.24 ml, 10.3 mmol) as starting materials. The reaction affords 7-Bromo-2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (1.067 g, 70.9%) as pink solid. mp.: 186-188° C., MS: m/z=291.9/293.9 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:18])=[C:9]([NH:11]C(=O)C(F)(F)F)[CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[NH2:11][C:9]1[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[CH3:18]
Reactant: CC(=O)Nc1ccc(C)c(NC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(C)c(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(5-Acetylamino-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (2.93 g, 11.24 mmol) was taken up in methanol (50 mL) and sodium carbonate (5.96 g, 56.20 mmol) was added. The reaction was stirred at room temp for 12 h. The reaction mixture was into water and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was utilized without further purification. Yield 1.60 g. 1H NMR (CDCl3, 300 MHz): δ2.16 (s, 3H). 2.31 (s, 3H), 7.18 (d, J=9 Hz, 1H), 7.32 (d, J 9 Hz, 1H), 7.64 (s, 1H), 7.64 (s, 1H).