Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8]C([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[NH2:12][CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>O1CCOCC1.[OH-].[Na+]>[C:4]([O:3][C:1]([NH:12][CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:8])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NCCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl dicarbonate (1.64 g; 7.5 mmol) is dissolved in 1,4-dioxane (5 mL) and the solution is added to a well-stirred solution of 4-(2-aminoethyl)benzoic acid (1.0 g; 5 mmol) in 1M aqueous sodium hydroxide solution (25 mL) and 1,4-dioxane (10 mL), and the mixture is then stirred at ambient temperature for 3 hours. The 1,4-dioxane is removed by evaporation in vacuo, and then ethyl acetate (200 mL) is added to the residue. The pH of the aqueous phase is adjusted to 1.5 with 2M aqueous HCl solution. The organic phase is separated off and the aqueous phase is then extracted with ethyl acetate (100 mL). The combined organic extracts are washed with water, dried over Na2SO4 and evaporated to a volume of 10 mL. Heptane is added to the residue and then the solid precipitate is filtered off to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1I.CCCCCC.C([Li])CCC.FC(F)(F)S(O[Si:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O>C(OCC)C>[CH3:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[Si:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1cc(Br)cc(C)c1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(Br)cc(C)c1[Si](C)(C)C
Reaction time: 0.75 h
Yield: 84.9 %

Procedure:
2,6-Dimethyl-4-bromoiodobenzene (5.04 g, 16.2 mmol) was dissolved in diethyl ether (50 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (2.6 M, 6.5 ml) at −50° C. The mixture was then stirred at the same temperature for 45 minutes. To the mixture was then added dropwise trimethylsilyl trifluoromethanesulfonate (3.7 ml, 19.4 mmol). The mixture was then stirred at −30° C. for 30 minutes and at room temperature overnight. After the quenching of the reaction with water, the product was then extracted with diethyl ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off. The crude product thus obtained was then distilled under reduced pressure using a glass tube oven so that it was purified to obtain 3,5-dimethyl-4-trimethylsilylbromobenzene (3.54 g; yield: 85%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][CH2:6][CH:7]1[O:20][C:10]2=[C:11]3[C:16](=[CH:17][CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]3>O>[OH:5][CH2:6][C:7]1([N+:1]([O-:4])=[O:2])[O:20][C:10]2=[C:11]3[C:16](=[CH:17][CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]3
Reactant: O=c1ccc2c3c(ccc2[nH]1)CC(CO)O3
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=c1ccc2c3c(ccc2[nH]1)CC(CO)([N+](=O)[O-])O3
Reaction time: 0.33 h
Yield: 75.3 %

Procedure:
70% Nitric acid (10 ml, d=1.42) was added dropwise to 2-hydroxymethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one while cooling on ice, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice and water (200 ml), and precipitated crystals were collected by filtration. After drying with air, recrystallization was performed using methanol to obtain 3.0 g of 2-hydroxymethyl-nitro-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as yellowish brown prisms (75.3%, mp. 215°-218° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[C:29]([BH3-])#N.[Na+].C=O.C(O)(=O)C>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH3:29])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (50 mg, 0.13 mmol) in methanol (3 mL) was treated with sodium cyanoborohydride (20 mg, 0.31 mmol) followed by formaldehyde (37% in water) (37 μL, 0.50 mmol) and stirred at room temperature for 20 min. The reaction mixture was quenched with acetic acid (170 μL, 2.9 mmol), diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (30 mg, 58%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.46 (s, 1H), 7.37 (br s, 2H), 6.23 (q, J=7.0 Hz, 1H), 4.10-3.96 (m, 1H), 3.95-3.85 (m, 2H), 3.63 (s, 3H), 3.05-2.94 (m, 2H), 2.55 (s, 3H), 2.18 (s, 3H), 1.72 (d, J=7.1 Hz, 3H). LCMS for C20H23ClN7O (M+H)+: m/z=412.2; Found: 412.1.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[C:26]([O:27][CH3:28])=[CH:25][C:15]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][OH:24])=[O:17])=[C:14]([NH:29][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])[C:13]=1[O:38][CH3:39]>C(Cl)Cl.O>[CH3:11][C:12]1[C:26]([O:27][CH3:28])=[CH:25][C:15]2[C:16](=[O:17])[N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C@H:23]([OH:24])[N:29]([C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])[C:14]=2[C:13]=1[O:38][CH3:39]
Reactant: COc1cc(C(=O)N2CCCC2CO)c(NC(=O)OCC(Cl)(Cl)Cl)c(OC)c1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(c(OC)c1C)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
Anhydrous DMSO (1.006 g, 12.87 mmol) in dry DCM (10 mL) was added dropwise over 5 minutes to a stirred solution of oxalyl chloride (3.19 mL of a 2 N solution in DCM, 6.373 mmol) under a nitrogen atmosphere at −50° C. After stirring for 5 minutes, a solution of 192 (2.13 g, 4.53 mmol) in dry DCM (10 mL) was added dropwise over 45 minutes to the reaction mixture, which was then stirred for a further 45 minutes at −50°=0 C. TEA (1.83 g; 18.13 mmol) was added dropwise to the mixture over 0.5 hours and stirred for a further 15 minutes. The reaction mixture was left to warm to room temperature, diluted with H2O (100 mL)and the phases allowed to separate. The organic phase was washed with 1 N HCl (2×50 mL), water (2×50 mL), brine (2×50 mL) and dried over MgSO4. The solvent was evaporated to afford the product (193) as an off-white glass (1.84 g, 3.93 mmol; 87%). 1H NMR (270 MHz, CDCl3) δ7.05 (s, 1H) (minor rotamer 1:4, visible at d 7.06), 5.58 (dd, J=3.84 Hz, J=9.89, 1H) (minor rotamer 1:4, visible at d 5.68, J=4.21 Hz, J=9.53), 4.71 (d, J=11.72 Hz, 1H), 4.56 (d, J=11.73 Hz, 1H), 4.11 (d, J=3.85 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 3.79-3.47 (m, 2H), 2.21-1.99 (m, 4H), 2.16 (s, 3H); 13C NMR (67.8 MHz, CDCl3) rotamers δ166.82, 158.31, 157.92, 155.65, 155.43, 131.52, 124.17, 123.99, 121.62, 105.90, 105.64, 105.38, 94.53, 86.17, 85.93, 75.80, 75.23, 61.77, 61.65, 59.98, 59.58, 59.40, 55.88, 55.79, 46.56, 46.38, 28.70, 28.62, 22.94, 10.14, 9.75.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[N:32]=[CH:31][NH:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[NH:29][N:30]=[CH:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1nc[nH]n1
Product: O=C(Nc1ncn[nH]1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-amino-1,2,4-triazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1H-1,2,4-triazol-5-yl)terephthalamide. MS (Q1) 453 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccc(OC)cc1
Reactant: Nc1ccccc1
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccc(OC)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (0.54 g, 1.58 mmol) (from Example 1d supra) and aniline (0.67 g, 7.11 mmol) (Aldrich) was heated at 110° C. for 30 minutes. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude products was purified by flash column chromatography (silica gel) to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester as a white amorphous solid. (Yield 0.49 g, 68.1%).
Reaction SMILES: [C:1]([C@@H:3]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[NH:23][C:24]([C:26]1[N:27]([CH3:35])[C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)#[N:2].C(O)(=O)C>C(OCC)(=O)C>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C@H:3]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[NH:23][C:24]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[O:16])[C:1]#[N:2])=[CH:10][CH:9]=1
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc([N+](=O)[O-])cc2)cc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc(N)cc2)cc2ccccc21
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To 120 mg (0.25 mmol) of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-cyano-(4-nitro-benzyl)-methyl]-carbamoyl}-cyclohexyl)-amide dissolved in 5 mL ethyl acetate was added 20 mg activated carbon on charcoal (10% Wt.) and 0.7 mL glacial acetic acid. The reaction mixture was hydrogenated under normal atmosphere (H2 balloon) for two hours, filtered through a cake of celite, washed with water and 10% NaOH aqueous solution, dried over magnesium sulfate, and concentrated to provide 80 mg of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-(4-amino-benzyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-amide. HPLC: 92% pure, yield: 71%, MS: 444 (M+H+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:41][C:42]([F:45])([F:44])[F:43])[C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:41][C:42]([F:43])([F:44])[F:45])[C:38]=1[O:39][CH3:40])[C:33]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:34]
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1OC(F)(F)F
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (278 mg) and 37% formalin (0.18 mL) in the same manner as in Example 1 was dissolved in dichloromethane (6.5 mL), and diisopropylethylamine (0.50 mL) and 3-chloro-4-methoxy-5-trifluoromethoxybenzoyl chloride (436 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (k).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1)=[O:7].Cl>O.CO.O1CCCC1>[CH:13]([N:11]1[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[CH:10]1)([CH3:15])[CH3:14]
Reactant: COC(=O)c1cn(C(C)C)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1cnc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 161.8 %

Procedure:
Add a solution of lithium hydroxide monohydrate (1.06 g, 25.1 mmol) in water (8 ml) to a solution of 1-isopropyl-1H-imidazole-4-carboxylic acid methyl ester (1.41 g, 8.38 mmol) in methanol (10 ml) and tetrahydrofuran (8 ml). Stir at room temperature for 20 hrs. Concentrate to give a solid. Dissolve the solid in a small amount of water and adjust to pH 4 with 5N hydrochloric acid. Wash the aqueous layer with ethyl acetate, and then concentrate the aqueous layer to provide the crude product as a solid (2.09 g). MS (m/z): 155 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([I:41])[CH:36]=1>CN(C)C=O.C(OCC)(=O)C.O>[I:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]2=[N:3][C:2]=3[NH2:1])=[C:15]([CH3:21])[CH:16]=1
Reactant: BrCc1cccc(I)c1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCc4cccc(I)c4)cc3C)cc12
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (B-4), 1.0 equiv. in dimethylformamide (0.10 M) at 22° C. was added cesium carbonate (1.5 equiv.) and the resulting mixture was allowed to stir for 30 minutes. At this point, 1-(bromomethyl)-3-iodobenzene (1.5 equiv.) was added to this mixture. The reaction mixture was allowed to stir at 55° C. for 18 hours, after which it was diluted with ethyl acetate and water. The biphasic layers were separated and the organic layer was washed twice with water. The organic layer was dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexanes gradient to provide 2-(4-(3-iodobenzyloxy)-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (4-1) as a solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([C:35]([CH3:37])=[CH2:36])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CCO.C1COCC1.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([C:35]([CH3:37])=[CH2:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C=C(C)[C@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C=C(C)[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 18 h
Yield: 79.5 %

Procedure:
To a stirred solution of 17.2 (0.048 g, 0.095 mmol) in EtOH (2.00 mL, 0.087 mmol) and THF (2.00 mL, 0.087 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). Stirring was continued for 18 hours. The resulting reaction was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 17 (36 mg, 79% yield) as a colorless oil. MS ESI (neg.) m/e: 475.1 (M−H)+.
Reaction SMILES: C[O:2][CH2:3][CH2:4][N:5]1[CH:17]=[C:16]2[C:7]([C:8]([NH2:18])=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1.B(Br)(Br)Br>>[NH2:18][C:8]1[C:7]2=[N:6][N:5]([CH2:4][CH2:3][OH:2])[CH:17]=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: COCCn1cc2c(n1)c(N)nc1ccccc12
Agent: BrB(Br)Br
Product: Nc1nc2ccccc2c2cn(CCO)nc12

Procedure:
2-(2-Methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine was treated with boron tribromide to give 2-(4-amino-2H-pyrazolo[3,4-c]quinolin-2-yl)ethanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH:24]([CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(Cc3ccccc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(CN2CCC(Nc3ccccc3)C2)cc1
Temperature: 160 °C
Yield: 47.8 %

Procedure:
1-Benzyl-3-(p-toluenesulfonyloxy)pyrrolidine (3.3 g) and aniline (1.3 g) were mixed and stirred under heating at 160° C. for 3 hours. After the completion of the reaction, the mixture was cooled to room temperature, and an aqueous potassium carbonate solution was added thereto. The obtained mixture was extracted with chloroform, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=40:1). The obtained eluate was concentrated to give 3-anilino-1-benzylpyrrolidine (1.2 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[NH:12][C:11]=2[C:10](=[O:27])[N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:8]1=[O:36].[NH2:38][NH2:39]>CO.O1CCCC1>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:9]1[C:10](=[O:27])[C:11]2[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)=[N:14][C:15]=2[N:7]([CH2:6][CH2:5][CH2:4][C:3]([NH:38][NH2:39])=[O:2])[C:8]1=[O:36]
Reactant: COC(=O)CCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Reactant: NN
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCC(=O)NN)cc1

Procedure:
Prepared by the reaction of 4-[8-(4-acetylamino-benzyl)-1-(2-fluorobenzyl)-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-yl]-butyric acid methyl ester with hydrazine (10 equivalents) in methanol/tetrahydrofuran according to the general procedure of Kramer et al. as described in J. Heterocyclic Chem. 1994, 31, 1439. MS, m/z(M+H)=508.2111.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]([CH2:17][C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:16]>ClCCl>[N:1]1([C:15]([CH2:17][C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(C)C[C@H](CC(=O)Cl)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)N1CCCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a mixture of piperidine (0.281 g) and triethylamine (0.304 g) in dichloromethane (10 ml) was added dropwise a solution of benzyl (2R)-2-(chlorocarbonylmethyl)-4-methylvalerate (0.816 g) in dichloromethane (5 ml). The solution was stirred at room temperature for 30 minutes and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml), and washed with 7% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution successively. The organic layer was dried over magnesium sulfate, and concentrated in vacuo to give benzyl (2R)-2-(piperidinocarbonylmethyl)-4-methylvalerate (0.931 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:25][C:26]1[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:32][C:29]1[CH:30]=[N:31][C:26]([Br:25])=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(Br)nc1
Reaction time: 4 h
Yield: 90.5 %

Procedure:
20 g (59.8 mmol) of 2-(triphenylphosphoranylidene)acetic acid methyl ester were added, by portion, to a solution of 11.1 g (59.8 mmol) of 6-bromopyridine-3-carbaldehyde in anhydrous THF at 0° C. The mixture was stirred at 0° C. to room temperature for 4 h. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, cyclohexane/ethyl acetate 95:5) to give 13.1 g (90.4%) of the title compound (trans/cis ratio 95:5) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([O:10][Si](C(C)(C)C)(C)C)[CH2:4][C:5](=[CH2:9])[C:6]=1[CH2:7][CH3:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(O)(=O)C(O)=O>O1CCCC1>[CH3:1][C:2]1[CH:3]([OH:10])[CH2:4][C:5](=[CH2:9])[C:6]=1[CH2:7][CH3:8]
Reactant: C=C1CC(O[Si](C)(C)C(C)(C)C)C(C)=C1CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)C(=O)O
Agent: [F-]
Solvent: C1CCOC1
Product: C=C1CC(O)C(C)=C1CC
Temperature: 0 °C
Yield: 91.3 %

Procedure:
After 4.0 g of (RS)-2-methyl-4-methylidene-3-ethyl-1-t-butyldimethylsilyloxy-2-cyclopentene was dissolved in 35 ml of dry tetrahydrofuran, 17.5 ml of a 1M tetrabutylammonium fluoride/tetrahydrofuran solution was added under cooling and stirred at ambient temperatures for twelve hours. The reaction solution was then added to 100 ml of an ice-cooled 5% aqueous oxalic acid, and extracted with diethyl ether (300 ml×3 times). The combined ether layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was treated by silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1 (v/v)) to yield 2.0 g of (RS)-2-methyl-4-methylidene-3-ethylcyclopent-2-en-1-ol. Yield 92%