Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[NH:34][CH2:35][CH2:36][N:37]=2)[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:21][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]5[NH:34][CH2:35][CH2:36][N:37]=5)[CH:28]=4)=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:22]([F:23])([F:24])[F:25]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1CCc2ccc(O)cc2C1
Reactant: Clc1ccnc(C2=NCCN2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1CCc2ccc(Oc3ccnc(C4=NCCN4)c3)cc2C1
Yield: 67.4 %

Procedure:
To a solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide (64 mg, 0.17 mmol) and 4-chloro-2-(4,5-dihydro-1H-imidazol-2-yl)pyridine (35 mg, 0.19 mmol) in DMF (1.70 mL) was added Cs2CO3 (170 mg, 0.52 mmol). The mixture was irradiated in a microwave for 200 sec at 200° C. Water was added, and the mixture was extracted with EtOAc. The organic solution was washed with water (3×) and brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography. The product was dissolved in MeOH, and 2.0M HCl in Et2O was added. The solvents were evaporated to give I-36 as a white solid (59 mg, 58%). 1H NMR (300 MHz, CD3OD): δ 8.62 (d, 1H), 8.17 (d, 1H), 7.82-7.78 (m, 1H), 7.63 (d, 1H), 7.53 (d, 1H), 7.25 (d, 1H), 7.21-7.18 (m, 1H), 6.96-6.91 (m, 2H), 4.11 (s, 4H), 3.14-2.82 (m, 5H), 2.24-2.16 (m, 1H), and 2.01-2.90 (m, 1H). LCMS: (FA) ES+ 516.2, ES− 513.2.
Reaction SMILES: [CH2:1]([C@H:8]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C@@H:9]([O:36][Si](C(C)(C)C)(C)C)[CH2:10][C@@H:11]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([C@H:8]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[C@@H:9]([OH:36])[CH2:10][C@@H:11]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(-c2cccnc2)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2cccnc2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.6 %

Procedure:
To the product from Example 148A (0.365 g, 0.51 mmol) was added tetrabutyl ammonium fluoride solution in tetrahydrofuran (2.0 mL, 1N) and the mixture was stirred at room temperature for 18 hours. The tetrahydrofuran was evaporated and the mixture was partitioned between ethyl acetate and water. The organic was washed with brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 80% ethyl acetate in chloroform to give the title compound (0.172 g, 41% over two steps).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[O:20]=[S:19]1(=[O:21])[CH2:18][CH2:17][CH2:16][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)cc1[N+](=O)[O-]
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1[N+](=O)[O-]

Procedure:
Using methyl 4-amino-2-nitrobenzoate (750 mg) and 3-chloropropane-1-sulfonyl chloride (0.61 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (967 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:38])=O>>[Cl:38][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OCCCN1CCOCC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Temperature: 80 °C
Yield: 58 %

Procedure:
A solution of 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (990 mg, 3.1 mmol) in thionyl chloride (10 ml) containing DMF (0.1 ml) was heated at 80° C. for 1.5 hours. After cooling, toluene was added and the solvent was removed by evaporation. The residue was triturated with ether, and the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 2M sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/methanol (1/9 followed by 95/5). The solid was triturated with hexane, collected by filtration and washed with ether to give 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (614 mg, 58%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1)C.Cl.CO>CO>[CH3:14][N:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=1)[CH3:13]
Reactant: CCOC(OCC)c1ccc(CN(C)C)cc1
Agent: Cl
Solvent: CO
Product: CN(C)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.2 %

Procedure:
To a solution of 1-(4-(diethoxymethyl)phenyl)-N,N-dimethylmethanamine (1.0 g, 4 mmol) in methanol (5 mL), a hydrochloric acid-methanol solution (10 mL) was added dropwise at 0° C. The reaction solution was stirred at room temperature overnight. Then methanol was removed in vacuo to give 4-((dimethylamino)methyl)benzaldehyde (0.68 g, yield 99%) as a light yellow oil. 1H-NMR (400 MHz, CDCl3): δ 2.26 (s, 6H), 3.50 (s, 2H), 7.49 (d, J=6.4 Hz, 2H), 7.84 (d, J=6.4 Hz, 2H), 10 (s, 1H). LC-MS (ESI) m/z: 164 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([I:22])=[N:20][NH:21][C:15]=2[CH:14]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.CS(O)(=O)=O>C(Cl)Cl.O1CCCC1>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([I:22])=[N:20][N:21]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[C:15]=2[CH:14]=1
Reactant: C1=COCCC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.45 g, 1.0 mmol) (Example 28, Step 4), dihydropyran (270 μL, 3.0 mmol) and methanesulfonic acid (13 μL, 0.20 mmol) in methylene chloride (9 mL) and tetrahydrofuran (3 mL) in reaction flask was stirred at r.t. overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.34 g, 64%). LC/MS (M+H)+=534.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(O)CCC>[Cl:18][C:13]1[N:12]=[C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:16]=[C:15]([NH:26][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:14]=1
Reactant: COc1ccc(Nc2nc(Cl)cc(Cl)n2)cc1Cl
Reactant: NC1CCCCCC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1ccc(Nc2nc(Cl)cc(NC3CCCCCC3)n2)cc1Cl
Yield: 60 %

Procedure:
To a solution of compound (3-chloro-4-methoxy-phenyl)-(4,6-dichloro-pyrimidin-2-yl)-amine (0.08 g, 0.26 mmol) in butanol (3 mL) was added to cycloheptylamine (0.03 g, 0.26 mmol) at 25° C. with stirring. To this was added triethylamine (0.14 mL, 1.04 mmol), and the mixture was stirred for 30 minutes at 25° C. and then heated and refluxed for 12 hours under nitrogen atmosphere. The mixture was concentrated under vacuum, diluted with cold water, and extracted with ethyl acetate. The organic layers were collected, combined, washed with brine, dried over anhydrous sodium sulphate, and concentrated under vacuum to give the desired compound. Yield: 60%.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCOC(=O)c1nc(Br)c2sccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2sccc2c1O
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
A mixture of 7-bromo-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (example 43a, 165 mg, 0.5 mmol), ethynyl-trimethyl-silane (87 μl, 0.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.015 mmol), CuI (5 mg, 0.025 mmol), and triethylamine (1.5 ml) was heated in a microwave oven at 100° C. with stirring for 15 min. After cooling to ambient temperature water (20 ml) was added and the mixture was extracted with diethylether (1×30 ml). The organic phase was dried over MgSO4. Then silica gel was added and the mixture concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with ethyl acetate:hexanes=9:1 and in vacuo concentration gave the title compound as a dark oil (75 mg); MS-(+)-ion: MS-(+)-ion: M+1=348.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([CH2:12][CH2:13][CH2:14]3)=[C:10]([C:16](OCC)=[O:17])[C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.C1COCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([CH2:12][CH2:13][CH2:14]3)=[C:10]([CH2:16][OH:17])[C:9]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccncc2)c(-c2ccc(F)cc2)n2c1CCC2
Solvent: O
Solvent: C1CCOC1
Product: OCc1c(-c2ccncc2)c(-c2ccc(F)cc2)n2c1CCC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Ethyl 3-(4-fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate (example 1A, 4.56 g, 13 mmol) is dissolved in abs. THF (100 ml) under argon and Na bismethoxyethoxyaluminum hydride (VitrideR) is added dropwise through a septum via the cannula of a syringe (20 min). The mixture is stirred at 50° C. for 2 h, whereupon starting material is no longer detectable by tlc (Al2O3—ethyl acetate/n-hexane 3:7), then it is allowed to cool. H2O (25 ml) is cautiously added dropwise to the reaction solution, then it is concentrated in vacuo (THF evaporates), and the aqueous organic residue is treated with ethyl acetate (100 ml). The phases are separated. The organic phase is washed 2 times with water (40 ml), dried over Na2SO4 sicc. and concentrated in vacuo (5.0 g). The reddish brown-colored, resinous residue is crystallized from diethyl ether (10 ml). The crystals are washed with ethyl acetate (5 ml) and ether (5 ml) and dried. 3.67 g of the compound sought remain
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[C:13]([NH2:21])[N:12]=3)[N:9]=[C:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:5]2=[N:6][CH:7]=1.[H][H]>N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:21])[N:12]=3)[N:9]=[C:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:5]2=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccncc1
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1N

Procedure:
196 mg (0.492 mmol) of the compound from example 7A were initially charged in pyridine (22 ml), 74 mg of palladium on carbon (10% by weight) were then added and the mixture was hydrogenated at standard hydrogen pressure overnight. The reaction mixture was then filtered through kieselguhr, the filter cake was washed with ethanol and the filtrate was concentrated. The residue was triturated with ethanol at 50° C., and the solid was filtered off and dried under high vacuum. This gave 107 mg (58% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].O1CCC[CH2:23]1.C([Li])CCC.CI>CCCCCC>[CH3:23][N:5]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:21]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Product: COC(=O)N(C)c1cn2cc(Sc3ccccc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g. (0.0033 moles) of 2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine in 35 ml. of tetrahydrofuran under a argon atmosphere is treated dropwise with 1.35 ml. of a 2.45 molar solution of butyllithium in hexane at -20° C. The resultant solution is stirred for 5 minutes and 0.469 g. (0.0033 moles) of methyliodide is added. The reaction mixture is allowed to warm to room temperature and stirred for 30 minutes. The solution is diluted with ice water and the solids are collected by filtration, washed with water and dried. The solid materials is chromatographed on silica gel and eluted with 1:99 methanol in methylene chloride affording 2-[methyl-N-(methoxycarbonyl)amino]-6-(phenylthio) imidazo [1,2-a] pyridine m.p. 147°-149° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]=[O:13].[Mn]([O-])(=O)(=O)=[O:15].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([OH:15])=[O:13]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cn1cc(C=O)c2cc(F)ccc21
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1cc(C(=O)O)c2cc(F)ccc21
Temperature: 0 °C
Yield: 64.1 %

Procedure:
In acetone (50 ml) was dissolved 5-fluoro-1-methylindole-3-carbaldehyde (1.33 g, 7.52 mmol). To the resulting solution was added dropwise an 1N aqueous solution of potassium permanganate (7.15 ml, 7.15 mmol) under stirring at 0° C. After stirring at room temperature for 18 hours, another 1N aqueous solution of potassium permanganate (4.0 ml, 4.0 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through Celite. After washing with water, the filtrate was added with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 5-fluoro-1-methylindole-3-carboxylic acid (885 mg, 61%) as a white crystalline powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[CH2:19]1)=[O:17].[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:22][CH:21]([OH:23])[CH:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)[CH2:28][CH2:29]3)[CH2:19]2)=[O:17])=[C:9]([NH:8][C:38](=[O:40])[CH3:39])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reaction time: 1 h
Yield: 10.6 %

Procedure:
A mixture of (3R,4R; 3S,4S)-(2-Amino-4-chloro-phenyl)-{3-[4-(4-chloro-benzyl)-piperazin-1-yl]4-hydroxy-pyrrolidin-1-yl}-methanone trifluoroacetate (22 mg, 0.05 mmol) was dissolved in DMF and acetic anhydride (20 uL, 0.2 mmol) was added. The reaction mixture was shaken for 1 h and directly used for LC-MS purification, to yield 3.2 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 491.2 (100).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.C(O)(=O)C.[CH2:26]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48](=O)[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C@@H:48]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[O:4][CH2:3]2)[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:40][CH2:41]1)=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(=O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2 g), ethanol (10 ml), acetic acid (0.49 g), ethyl 8-(1-benzyloxycarbonyl-4-piperidyl)-2-oxooctanoate (3 g) and molecular sieves 3A (10 g) is stirred for 10 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.47 g) in ethanol (40 ml) for 3 hours at room temperature. After standing overnight at room temperature, the mixture is concentrated in vacuo and diluted with a mixture of water (100 ml) and ethyl acetate (200 ml). The resulting mixture is agitated thoroughly and filtered. The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (5:2-2:1) as an eluent. Evaporation of the first fraction affords tert-butyl 3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH2:8][CH2:7][NH:6][C:5]1=[O:21].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.ClCCCN1CCCCC1>CC(N(C)C)=O.C1(C)C=CC=CC=1>[CH3:3][CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH2:8][CH2:7][N:6]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:5]1=[O:21]
Reactant: ClCCCN1CCCCC1
Reactant: CC1C(=O)NCCN1c1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CC1C(=O)N(CCCN2CCCCC2)CCN1c1cccc(OC(F)(F)F)c1
Temperature: 75 °C
Yield: 84 %

Procedure:
NaH (55% dispersion in mineral oil, 36 mg, 0.82 mmol) was added portionwise at RT to a solution of 3-methyl-4-(3-trifluoromethoxy-phenyl)-piperazin-2-one (150 mg, 0.55 mmol) in DMA (3 mL), then after 1 h a solution of 1-(3-chloropropyl)-piperidine in toluene [prepared from commercially available 1-(3-chloropropyl)-piperidine hydrochloride (542 mg, 2.74 mmol) by partitioning between toluene (4 ml) and 1 M aq. sodium hydroxide solution (4 ml) and drying of the organic layer with MgSO4] was added. The reaction mixture was heated at 75° C. for 1 h, then partitioned between sat. aq. NaHCO3 solution and CH2Cl2. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc) afforded the title compound (184 mg, 84%). Light yellow oil, MS: 400.3 (M+H)+.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].CC1C=C(C(C)(C)C)[C:21]([OH:28])=[C:20](C(C)(C)C)C=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.Cl>C(O)(=O)C>[C:21]([C:10]1([OH:16])[CH:9]=[CH:8][C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:11]1[C:12]([OH:14])=[O:13])(=[O:28])[CH3:20]
Reactant: C=C(C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=C(C)C(=O)NC1=CC(C(=O)O)C(O)(C(C)=O)C=C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5-methacrylamidosalicylic acid (30 millimole, 6.7 g) was mixed with butylhydroxytoluene (20 mg), acetic anhydride (10.0 g), and acetic acid (15.0 g). After sealing the solution, its temperatures was raised to 60° C., and the solution was kept at 60° C. for 30 min while stirring. Then, a mixture (1.0 g) of concentrated sulfuric acid (1 part) with hydrochloric acid (10 parts) was added to the solution, followed by raising its temperature to 90° C., and kept at 90° C. for one hour to proceed the reaction. After the reaction was over, the solution was stood to cool to room temperature to give brown crystal. The crystal was filtrated, and recrystallized by a solution of 0.5% hydroquinone in methanol. Dried under a reduced pressure, 2-acetyl-5-methacrylamidosalicylic acid was obtained as pale reddish brown crystal having a needle shape: mp. 192.4° C., yield 2.54 g, 64.1%.
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: O=C(O)C(F)(F)F
Solvent: ClCCl
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.