Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][C:14]([OH:16])=[O:15].Cl>>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCOc1ccc(Br)cc1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
To a solution of aqueous NaOH (0.5 M, 0.2 mol) was slowly added 4-bromophenol (34.4 g, 0.2 mol) at room temperature. After heating to boiling, 3-bromopropanoic acid (30.60 g 0.2 mol) in aqueous NaOH (0.5M, 0.2 mol) was added dropwise to the mixture above. The resulting mixture was then refluxed for 2 h. The mixture was cooled to 0° C. and the pH of the mixture was adjusted to 6-7 with 0.5 N HCl. The resulting mixture was filtered to give a solid cake, which was washed with water and n-pentane and dried to give 3-(4-bromophenoxy)propanoic acid (30 g, 60%). 1H-NMR (CDCl3): 2.72 (m, 2H), 4.90 (s, 1H), 5.01 (d, 1H), 5.50 (s, 1H), 6.73 (m, 1H), 7.21-7.43 (m, 6H), 7.61 (m, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:44]=[CH:45][CH:46]=1)[CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[C:25]4[CH:30]=[CH:29][C:28]([N:31]([C:37](=[O:42])[CH2:38][CH2:39][NH:40][CH3:41])[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)=[C:12]2[CH:11]=[N:10]1)[CH3:3].[Cl:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].C(N(CC)CC)C>C(Cl)Cl.C(=O)([O-])O.[Na+]>[ClH:47].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:44]=[CH:45][CH:46]=1)[CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[C:25]4[CH:26]=[CH:27][C:28]([N:31]([C:37](=[O:42])[CH2:38][CH2:39][N:40]([CH3:41])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[CH:29][CH:30]=4)[CH2:20][CH2:19]3)=[C:12]2[CH:11]=[N:10]1)[CH3:3]
Reactant: CCOC(=O)Cl
Reactant: CCOc1cccc(Cn2ncc3c(N4CCN(C(=O)c5ccc(N(CCN(C)C)C(=O)CCNC)cc5)CC4)ncnc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(C)CCC(=O)N(CCN(C)C)c1ccc(C(=O)N2CCN(c3ncnc4c3cnn4Cc3cccc(OCC)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of the compound obtained in Example 725 (50 mg) in methylene chloride (3 mL) is added ethyl chloroformate (10 μL) and triethylamine (22 μL) and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with a saturated sodium hydrogencarbonate solution and the mixture is extracted with chloroform. The organic layer is evaporated to remove solvent and the residue is purified by column chromatography on silica gel (solvent; chloroform/methanol=10:1), and the resultant product is treated in the same manner as described in Example 4 (3) to give 1-(3-ethoxybenzyl)-4-[4-[4-[N-[3-[N-methyl-N-(ethoxycarbonyl)amino]-propionyl)-N-[2-(dimethylamino)ethyl]amino]benzoyl]piperazin-1-yl]-1H-pyrazolo-[3,4-d]pyrimidine hydrochloride (17 mg, yield; 30%) as an amorphous powder. MS (APCI) m/z: 686 [M+H]+
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[Br:23]>>[Br:23][C:13]1[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][O:16][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: Nc1onc(-c2ccccc2)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1onc(-c2ccccc2)c1Br)c1ccccc1
Yield: 36 %

Procedure:
This compound was prepared from benzenesulfonyl chloride and 5-amino-4-bromo-3-phenylisoxazole according to the method in Example 40b in 36% yield. Recrystallization from methanol gave a yellow solid, m.p. 113°-115° C.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].C([O-])(=O)C.[Na+].[Br:44]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:44][C:22]1[CH:21]=[N:20][C:7]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:9]3[CH:10]=[N:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:6]=2[C:23]=1[N:24]1[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25]1
Reactant: BrBr
Reactant: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(Br)cnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A mixture of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate (125 mg, 0.23 mmol), sodium acetate (38 mg, 0.46 mmol), and bromine (36 μL, 0.7 mmol) in acetic acid (1 mL) was stirred at ambient temperature for 1 minute. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow oil, which was used in the next step without any further purification (65 mg).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([CH2:16][CH2:17][S:18][CH:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[CH:31][C:32]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][C:40]([Cl:46])=[CH:41][CH:42]=4)[N:37]=3)=[CH:33][C:20]1=2)(O)=[O:14].N.O>O1CCCC1>[C:13]([CH2:16][CH2:17][S:18][CH:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[CH:31][C:32]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][C:40]([Cl:46])=[CH:41][CH:42]=4)[N:37]=3)=[CH:33][C:20]1=2)(=[O:14])[NH2:3]
Reactant: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
0.98 g of 1,1'-carbonyldiimidazole was added to 1.99 g of 11-(2-carboxyethylthio)-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Example 2 dissolved in 33 ml of tetrahydrofuran and the mixture was stirred at room temperature for 4 hours. Then, 4 ml of conc. aqueous ammonia was added to the mixture and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was condensed under reduced pressure, water was added to the residue, crystals were collected by filtration and the crystals were dissolved in chloroform. After this chloroform solution was washed with water and dried over anhydrous sodium sulfate, solid obtained by removing the solvent was washed with an acetone-hexane mixed solution to obtain 1.99 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.C[Si](Cl)(C)C.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23].[OH-].[Na+]>ClCCl.O>[C:20]([NH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCC(N)C(=O)O
Reactant: CCCC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)NC(CC)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
25.78 g of 2-aminobutyric acid (250 mmol) and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred at room temperature for 1 hour and at 40° C. for one hour. After cooling to −10° C., 26.64 g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred at −10° C. for 2 hours and at room temperature for one hour. With ice-cooling, 125 ml of water are added dropwise, and the reaction mixture is stirred at room temperature for 15 minutes. Aqueous sodium hydroxide solution is added to the organic phase, and the organic solvent is removed under reduced pressure. The residue is acidified and the precipitated solid is triturated once with water and twice with petroleum ether and dried under reduced pressure at 45° C. 29.1 g (67%) of a colorless solid.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:10](=[O:16])OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:38](=[O:40])[CH3:39])[C@@H:33]([CH3:41])[CH2:32][NH:31]2>ClCCCl>[C:38]([N:34]1[C:35]2[C:30](=[CH:29][C:28]([Br:27])=[CH:37][CH:36]=2)[N:31]([C:10]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:16])[CH2:32][C@@H:33]1[CH3:41])(=[O:40])[CH3:39]
Reactant: OC1CCC1
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 5 h
Yield: 146.4 %

Procedure:
A solution of cyclobutanol (28.8 g, 399 mmol), 1,2-dichloroethane (450 mL), triphosgene (22.1 g, 74.41 mmol) and N,N-diisopropylethyl amine (58.0 mL, 333 mmol) was stirred at 50° C. for 2 hr. A solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethan-1-one (10.0 g, 37.2 mmol) and N,N-diisopropylethyl amine (58.0 mL, 333 mmol) in 1,2-dichloroethane (180 mL) was added dropwise. The resulting solution was stirred for 5 h at 50° C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate-petroleum ether) to afford cyclobutyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (20 g, 73%) as yellow oil. MS (ESI, pos. ion) m/z 367, 369 [M+1]+.
Reaction SMILES: C([N:3]([C:9]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([Cl:17])=[C:11]([NH2:18])[C:10]=1[Cl:19])[C:4](=[O:8])[C:5]([O-:7])=[O:6])C.C(Cl)Cl.[OH-].[Na+].[Na]>O>[NH2:18][C:11]1[C:10]([Cl:19])=[C:9]([NH:3][C:4](=[O:8])[C:5]([OH:7])=[O:6])[CH:14]=[C:13]([C:15]#[N:16])[C:12]=1[Cl:17]
Reactant: CCN(C(=O)C(=O)[O-])c1cc(C#N)c(Cl)c(N)c1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(NC(=O)C(=O)O)c(Cl)c(N)c1Cl

Procedure:
A solution of 2.97 g. (0.01 mole) of ethyl(3-amino-2,4-dichloro-5-cyanophenyl)oxamate in 100 ml. of methylene chloride is placed in a separatory funnel. There is added a solution of 8 ml. of 1 N sodium hydroxide diluted to 100 ml. with water. There is added an additional 300 ml. of water to dissolve the sodium salt that forms. The phases are separated and the aqueous layer acidified with glacial acetic acid. To the solution is then added 5 ml. of concentrated hydrochloric acid. The precipitate is removed by filtration.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([OH:19])[C@@H:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH:7]([CH3:10])[CH2:8]C.CO[CH2:23][CH:24]=[CH2:25]>CN(C)C=O>[CH3:1][O:2][C:3]([CH:4]1[O:19][C:24]([CH3:25])([CH3:23])[N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C@H:5]1[CH2:6][CH:7]([CH3:8])[CH3:10])=[O:20]
Reactant: C=CCOC
Reactant: CCC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)C1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S)-3-(N-t-butoxycarbonylamino)-5-methyl-2-hydroxyheptanoic acid methyl ester (4.40 g) in N,N-dimethylformamide (16 ml) was added methyl-2-propenyl ether (4.60 ml) and further was added dl-camphor sulfonic acid (186 mg) and the mixture was stirred overnight at room temperature. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1 to 4:1) to give the title compound (3.90 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+:36]>C(O)C>[CH2:1]([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3].[Na+:36]
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)[O-])c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 90 ml of ethanol is dissolved 9.0 g of 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]-propionic acid. After adding 18.2 ml of 1 mol/L aqueous solution of sodium hydroxide, the mixture is stirred at ambient temperature for 10 minutes. The solvent is distilled off from the reaction mixture under reduced pressure, and the residue is purified by reverse phase silica gel column chromatography [eluent; acetonitrile:water=1:1] to obtain 7.6 g of sodium 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]-propionate as a colorless foaming product.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=O)C.C(OC1C(=CC=CC=1)C(O)=O)(=O)C.S(Cl)(Cl)=O.[NH2:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([OH:39])=[C:34]([Cl:40])[CH:33]=1>>[Cl:38][C:36]1[CH:37]=[C:32]([CH:33]=[C:34]([Cl:40])[C:35]=1[OH:39])[NH:31][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[OH:4]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: CC(=O)Oc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccccc1O

Procedure:
Acetylsalicyloyl chloride prepared by reaction of acetylsalicylic acid with thionyl chloride was condensed with 4-amino-2,6-dichlorophenol, and then deacetylated to give 3',5'-dichloro-2,4'-dihydroxybenzanilide. That compound (4 g.) was dissolved in cold anhydrous acetic acid (50 ml.) and with stirring there was added with 3 drops of concentrated sulfuric acid. After reaction for 1-2 hours at 5°-6° C., the solution was poured into ice-cold water (500 ml.) and the white precipitate thus formed was collected by filtration, rinsed with water, dried and recrystallized from methanol to give white needle-like crystals (3.65 g.) of 2,4'-diacetoxy-3',5'-dichlorobenzanilide. Yield: 71.1%. Melting point: 154°-156° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:15]2[O:14][CH:13]([C:16]([Cl:19])([Cl:18])[Cl:17])[O:12][CH:11]([C:20]([Cl:23])([Cl:22])[Cl:21])[C:10]=2[CH:9]=[C:8]([CH3:24])[CH:7]=1.C(O)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:24][C:8]1[CH:7]=[CH:6][C:15]2[O:14][CH:13]([C:16]([Cl:17])([Cl:19])[Cl:18])[O:12][CH:11]([C:20]([Cl:22])([Cl:23])[Cl:21])[C:10]=2[CH:9]=1
Reactant: Cc1cc(N)c2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C

Procedure:
Solid sodium nitrite (1.34 g.) was added in portions to a boiling suspension of 8-amino-6-methyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin (4.7 g.) in a mixture of absolute ethanol (20 ml.), toluene (5 ml.) and concentrated sulphuric acid (1.34 ml.). The mixture was heated under reflux for 3 hours, cooled to ambient temperature and evaporated to dryness under reduced pressure. The oily residue was triturated with petroleum ether (b.p. 60°-80° C.) and filtered, and the solid was crystallised from aqueous ethanol to give 6-methyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin m.p. 134°-135° C.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[N:14][C:15]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1.[ClH:42]>C(Cl)Cl.O1CCOCC1>[ClH:42].[ClH:42].[ClH:42].[OH:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[N:14][C:15]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:28][N:29]1[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4nc(-c5ccccc5)ccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3nc(-c4ccccc4)ccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.019 g, 0.034 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.014 g, 74%).
Reaction SMILES: [C:1]([NH:4][C:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])(=[O:3])[CH3:2].[BH4-].[Li+].O>O1CCCC1>[OH:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:5]([NH:4][C:1](=[O:3])[CH3:2])([CH3:7])[CH3:6])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(C)(C)NC(C)=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NC(C)(C)c1ccc(CO)cc1

Procedure:
To a solution of methyl 4-(1-acetamido-1-methylethyl)benzoate (37.14g) in tetrahydrofuran (370 ml) was added lithium borohydride (6.88 g) and the mixture was refluxed for 19 hr. The reaction mixture was poured into water (1000 ml) and extracted with ethyl acetate (1000 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from ethyl acetate to give the title compound (18.24 m.p.=126-129° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>CO.[Cu-]=O>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: O=[Cu-]
Solvent: CO
Product: COC(=O)c1ccc(-n2cccn2)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (2.40 g) and 1H-pyrazole (0.99 g) in methanol (54.0 mL) was added copper(I) oxide (0.10 g), and the mixture was stirred overnight at 50° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.89 g).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH:8]2[CH2:10][CH2:11][CH:5]1[CH2:6][N:7]2[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N+]=[N-].B#B.Cl>C1COCC1>[NH2:1][CH:4]1[CH2:9][CH:8]2[CH2:10][CH2:11][CH:5]1[CH2:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NC1CC2CCC1CN2C(=O)c1ccccc1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: NC1CC2CCC1CN2Cc1ccccc1
Yield: 96.9 %

Procedure:
To a stirred solution of (±) 5-azido-2-benzoyl-2-azabicyclo[2,2,2]octane (D3d) (3.3 g) in dry THF (100 ml) under nitrogen was added a solution of diborane in THF (50 ml, 1M solution) and the whole heated under reflux for 12 hours. On cooling, an excess of 5N HCl was added and the mixture heated on a steam bath for 2 hrs. Basification and saturation with K2CO3, extraction with CH2Cl2, drying (K2CO3), concentration and distillation afforded the (±)-5-amino-2-benzyl-2-azabicyclo[2,2,2]-octane (D4b) (2.7 g, 85%) bp 120°-140°/0.1 mm.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[CH3:11][C:12]1[C:17]([O:18][C:19]2[N:24]=[CH:23][N:22]=[C:21]3[N:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:26]=[CH:27][C:20]=23)=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(C(C)C)CC)(C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH:5]1([O:4][C:2]([N:31]2[CH2:30][CH2:29][CH:28]([N:25]3[C:21]4=[N:22][CH:23]=[N:24][C:19]([O:18][C:17]5[C:12]([CH3:11])=[N:13][CH:14]=[CH:15][CH:16]=5)=[C:20]4[CH:27]=[N:26]3)[CH2:33][CH2:32]2)=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 12.9 %

Procedure:
A solution of cyclohexyl chloroformate (Waterstone Technology, LLC, Carmel, Ind., USA; 42 mg, 0.26 mmol) in dichloromethane (150 μL) was added to a cooled (˜0° C.) solution of 4-(2-methyl-pyridin-3-yloxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 28; 52 mg, 0.17 mmol), diisopropylethylamine (77 μL, 0.80 mmol) and 4-dimethylaminopyridine (1 mg) in anhydrous dichloromethane (2 mL) over 30 sec. The mixture was stirred at 0° C. for 5 min, then warmed to room temperature and stirred for 1 h. Water (5 mL) was added. The layers were separated and the organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, and purified on an Isco 4 g column eluting with 0-4% methanol/dichloromethane. Fractions containing the product were pooled, concentrated and lyophilized to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclohexyl ester (9.6 mg, 13%). Mass spectrum (ES) MH+=437.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]#[N:14])=[CH:9][CH:10]=2)[NH:5]1.Cl[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N+:17]=1[O-].P(Cl)(Cl)Cl>C(=O)([O-])O.[Na+].CN(C)C=O>[C:13]([C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=3)=[C:4]([OH:3])[NH:5]2)=[CH:10][CH:9]=1)#[N:14]
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: CCOC(=O)c1ccc(Cl)[n+]([O-])c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2c(O)[nH]c3cc(C#N)ccc23)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
To a N,N-dimethylformamide (6 mL) suspension of sodium hydride (97%, 0.144 g, 6.0 mmol) was added 2-oxoindoline-6-carbonitrile (0.712 g, 4.5 mmol). The formed mixture was stirred for 10 min at room temperature followed by the addition of ethyl 6-chloronicotinate 1-oxide (0.605 g, 3.0 mmol). The resulting reaction mixture was set under N2 atmosphere and stirred for 2 h at room temperature. The N,N-dimethylformamide reaction solution was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform and ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The remaining N,N-dimethylformamide was removed by co-evaporation with toluene. The residue was dissolved in chloroform (10 mL) and phosphorus trichloride (1.65 g, 12.0 mmol) was added. The reaction mixture was stirred for 30 min at 60° C. and then cooled to room temperature. The mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting brown precipitate was filtered off and the mother liquor was extracted with chloroform (4×). The organic layers were concentrated in vacuo and the residue was combined with the filtrate and was washed with ethyl acetate and diethyl ether to afford 0.55 g (60% yield) of the title compound as a yellow-brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.85 (s, 1H), 8.06 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.29 (d, J=8.8 Hz, 1H), 4.33 (m, 2H), 1.35 (t, J=7.2 Hz, 3H); MS (EI) m/z 308 (M++1).