Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCCc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(CCCBr)cc1Cl
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Compound 38-2 (2.82 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (4.02 g) and N-bromosuccinimide (2.71 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.42 g) as a colorless oil.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.N([O-])=[O:13].[Na+]>O>[OH:13][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)cc1Cl
Temperature: 5 °C
Yield: 59.7 %

Procedure:
In a solution of 10 ml of concentrated sulforic acid in 30 ml of water was dissolved 10 g of 4-amino-2-chlorobenzoic acid, the solution was reacted under reflux for 1 hour, and the thus obtained solution was cooled to 5° C. Then, 4.6 g of sodium nitrite and 20 ml of water were added to the solution and the mixture was refluxed for 5 hours and cooled. The precipitated crystal was recovered by filtration and washed with water to obtain 6.0 g of 4-hydroxy-2-chlorobenzoic acid. Then, 3 g of this 4-hydroxy-2-chlorobenzoic acid was dissolved in an aqueous solution of sodium hydroxide, 10 g of n-dodecyl bromide was added to the solution, and reaction was carried out at 80° C. for 5 hours with stirring. The thus-obtained solution was put in ice-cooled hydrochloric acid. Precipitated 4-dodecyloxy-2-chlorobenzoic acid was recovered by filtration, washed with water, dried and dissolved in dichloromethane. Then, 2.0 g of p-benzyloxyphenol and 2.0 g of dicyclohexylcarbodi-imide were added to the solution, and reaction was carried out at room temperature with stirring overnight. The precipitate was recovered from the thus-obtained solution by filtration, concentrated and purified by the silica gel column chromatography to obtain 2.3 g of 4-benzyloxyphenyl 4-dodecyloxy-2-chlorobenzoate. This product was catalytically reduced in the presence of Pd/C as the catalyst under a hydrogen pressure of 1 kg/cm2 according to customary procedures to obtain 2.0 g of 4-hydroxyphenyl 4-dodecyloxy-2-chlorobenzoate.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([F:26])[CH:13]=1.[OH-:27].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:9]1[CH:10]=[C:2]([OH:27])[C:3]2[CH:4]=[CH:5][N:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:14]([F:26])[CH:13]=3)[C:7]=2[CH:8]=1
Reactant: Fc1cc(Br)c2ccn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1cc(F)cc2c1ccn2-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 90 °C
Yield: 46 %

Procedure:
To a solution of 4-bromo-6-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indole (D17) (980 mg, 2.366 mmol) in 1,4-dioxane (20 mL) and water (20 mL) was added potassium hydroxide (531 mg, 9.46 mmol). The reaction mixture was purged with argon and then treated with 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (60.3 mg, 0.142 mmol) and tris(dibenzylideneacetone)dipalladium(0) (43.3 mg, 0.047 mmol). The reaction mixture was heated at 90° C. for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The pH was adjusted to ˜7 by the addition of 1M hydrochloric acid. After separation of the layers, the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 5-40% ethyl acetate in hexane to yield the title compound (D18), (382 mg).
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)[CH2:16][C:17]([C:19]([OH:21])=[O:20])=[O:18].Cl>O.C1(C)C=CC=CC=1>[CH2:9]([C:10]([OH:14])([C:11]([OH:13])=[O:12])[CH2:16][C:17](=[O:18])[C:19]([OH:21])=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CC(=O)C(=O)O
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O
Yield: 37 %

Procedure:
After 16.23 g of potassium hydroxide (having a purity of 85% by weight) was dissolved in 48 ml of water, 5.0 g (30.5 mmol) of phenylpyruvic acid and 12.1 g (91.4 mmol) of oxalacetic acid were added to the resulting solution, for reaction at ambient temperature for 72 hours (about pH 13 at the start of the reaction). Using conc. hydrochloric acid, the reaction solution was adjusted to pH 2.2, and extracted in ethyl acetate. The organic layer was rinsed in aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain the residue. The residue was recrystallized in ethyl acetate and toluene, to obtain 2.8 g (11.3 mmol) of 4-benzyl-4-hydroxy-2-ketoglutaric acid in crystal form.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[C:25]1([S:31]([O-:34])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+].C(OCC)(=O)C>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:25]1([S:31]([O:34][C@@H:6]2[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S([O-])(=S)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OS(=O)(=S)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
2,3,4,6-Tetra-O-acetyl-α-galactopyranosyl bromide (2.0 g, 5 mmol) was dissolved in anhydrous acetonitrile (80 mL). To this sodium phenylthiosulfonate (2.02 g, 10.3 mmol) and tetrabutylammonium bromide (160 mg, 0.5 mmol) were added. The resulting mixture was stirred under argon at 70° C. After a 5 h period, t.l.c. (petrol:ethyl acetate, 1:1) indicated the formation of a product (Rf 0.4) with complete consumption of the starting material (Rf 0.6). The solution was concentrated in vacuo. The crude oil was partitioned between DCM (50 mL) and water (50 mL), and the aqueous layer re-extracted with DCM (2×50 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petrol:ethyl acetate, 2:1) to afford the title product (1.7 g, 65%, 2 steps) as a white crystalline solid; mp 53-54° C.; [α]D27+24.2 (c, 1.0 in CHCl3); δH (400 MHz, CDCl3) 1.98, 2.03, 2.06, 2.11 (4×3H, 4×s, 4×OAc), 3.85 (1H, dd, J5,6 8.8 Hz, J6,6′ 14.0 Hz, H-6), 3.95-4.00 (2H, m, H-5, H-6), 5.11 (1H, dd, J2,3 9.7 Hz, J3,4 3.3 Hz, H-3), 5.23 (1H, at, J10.3 Hz, H-2), 5.25 (1H, d, J1,2 10.2 Hz, H-1), 5.43 (1H, dd, J3,4 3.6 Hz, J4,5 1.0 Hz, H-4), 7.54-7.68 (3H, m, Ar—H), 7.93-7.97 (2H, m, Ar—H).
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2(O)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:13]([CH3:24])[CH2:12]2)=[CH:7][CH:6]=1.NS(F)(F)[F:28].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[F:28][C:11]1([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:13]([CH3:24])[CH2:12]1
Reactant: NS(F)(F)F
Reactant: CC1CC(O)(c2ccc(F)cc2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1CC(F)(c2ccc(F)cc2)CCN1C(=O)OC(C)(C)C
Yield: 90.1 %

Procedure:
To a dichloromethane solution (2.0 mL) of tert-butyl 4-(4-fluorophenyl)-4-hydroxy-2-methylpiperidine-1-carboxylate (60.0 mg, 0.194 mmol) synthesized in Reference Synthesis Example 279, bis(2-methoxyethyl))amino-sulfur trifluoride (46.9 mg, 0.291 mmol) was added at −78° C. and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, saturated sodium carbonate aqueous solution was added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (54.4 mg) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:13]1([NH2:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1>C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:19][C@H:16]3[CH2:17][CH2:18][C@@H:13]([NH2:20])[CH2:14][CH2:15]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NC1CCC(N)CC1
Solvent: CCO
Product: N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Temperature: 250 °C

Procedure:
A mixture of 4,7-dichloroquinoline(2 g, 10.2 mmol) and 1,4-cyclohexanediamine (2.5 g, 21.9 mmol) was heated at 250° C. for 15 hours, cooled to room temperature, diluted with ethanol, and filtered. The residue was extracted with chloroform from 50%NaOH solution. The extract was dried with Na2SO4 and MgSO4, filtered and concentrated to give the desired compound. MS (ESI(+)Q1MS m/z 276 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:34])[CH3:33])[S:7][C:6]=2[CH:35]=1.[C:36](O)(=[O:38])[CH3:37].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:36]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:33])[CH3:34])[S:7][C:6]=2[CH:35]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)O
Reactant: CC(C)c1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccccc3C(C)C)sc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (63 mg, 0.129 mmol) in DCM (2.5 mL) was added acetic acid (0.030 mL, 0.518 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (99 mg, 0.518 mmol) and 4-dimethylaminopyridine (9.49 mg, 0.078 mmol). The resulting mixture was stirred at room temperature for 16 h after which time the reaction was quenched by addition of 0.1N HCl and diluted with DCM. The phases were separated and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-40% EtOAc/Heptane) to afford (E)-tert-butyl 3-(4-((6-acetoxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (65 mg, 0.123 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (d, J=2.0 Hz, 1H), 7.40 (d, J=12.9 Hz, 1H), 7.37 (d, J=5.9 Hz, 1H), 7.28-7.22 (m, 4H), 7.22-7.18 (m, 1H), 7.11-7.02 (m, 1H), 6.98 (dd, J=8.6, 2.1 Hz, 1H), 6.81-6.72 (m, 2H), 6.12 (d, J=15.9 Hz, 1H), 3.11 (p, J=6.8 Hz, 1H), 2.28 (s, 3H), 1.44 (s, 9H), 1.09 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([NH:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([O:37]C)=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=2)=[CH:15][CH:14]=1)[CH3:12])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.O>[C:3]([O:7][C:8]([NH:10][CH:11]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([OH:37])=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=2)=[CH:17][CH:18]=1)[CH3:12])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LiOH (69.0 mg, 2.86 mmol) was added to a solution of methyl 2-(2-(2-(2-(4-(1-(tert-butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A65) (320 mg, 0.573 mmol) in THF (7.5 mL) and water (2.5 mL) and the resulting mixture stirred at room temperature overnight. The resulting mixture was evaporated in vacuo then the residue was partitioned between EtOAc (15 mL) and 1 M aqueous HCl. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried with Na2SO4 and concentrated to give the title compound A66 (310 mg, 99%); LCMS-B: rt 8.30 min; m/z 545.4 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[CH2:30](Br)[CH2:31][CH2:32][CH3:33]>>[C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[O:19])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)CNC1CCN(c2ccc(NC(=O)C3(c4ccc(O)cc4)CC3)cc2)C1
Reactant: CCCCBr
Product: CCCCOc1ccc(C2(C(=O)Nc3ccc(N4CCC(NCC(C)=O)C4)cc3)CC2)cc1

Procedure:
1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1yl]phenyl}amide was reacted with n-butyl bromide by method H. This resulted in the product with the molecular weight of 449.60, (C27H35N3O3); MS(ESI): 450 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:47]=[O:48])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:6]=1[CH2:7][CH2:8][CH3:9].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:47]=[O:48])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: CCCc1c(Cl)cc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: CCCc1c(Cl)cc(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 65 %

Procedure:
This compound was prepared using the same procedure as in Example 1.12 g of 4-chloro-5-n-propyl-1-[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]-2-pyrrolaldehyde (0.019 moles) and 24 mL of 4N HCl (0.095 moles) yield 5.0 g of product. Formula: C22H20ClN5O (m.w. 405.89). Yield 65%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3c(F)cccc3F)cc1)nn2C[C@H]1CCCN1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of tert-butyl (2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)-pyrrolidine-1-carboxylate (280 mg, 0.54 mmol, 1.00 equiv) in dichloromethane (10 mL). Trifluoroacetic acid (2 mg, 0.02 mmol, 0.03 equiv) was added dropwise with stirring at 25° C. The resulting solution was stirred for 3 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with 50 mL of dichloromethane, washed with ethyl acetate and H2O, brine and concentrated under vacuum to give 200 mg (88%) of 3-[4-(2,6-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][N:15]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH:19]=4)[CH2:16][N:15]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:14]3=[O:31])=[CH:11][CH:12]=2)=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)CCN1CC(c2cccc(O)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: Brc1ccccn1
Product: CS(=O)(=O)CCN1CC(c2cccc(Oc3ccccn3)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O

Procedure:
The title compound is prepared as described in Example 269 from Example 290 and 2-bromopyridine. HPLC-MS calculated for C29H26ClN3O5S (M+H+): 564.0, found 564.0.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+](C)C.[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>ClCCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:10][N+:11]1[CH:15]=[CH:14][N:13]([CH3:6])[CH:12]=1
Reactant: C[O+](C)C
Reactant: Cn1ccnc1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: Cn1cc[n+](C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The procedure of Example 2 was followed. 3.9 g of trimethyloxonium tetrafluoroborate in suspension in 20 ml of 1,2-dichloroethane was added to 2.1 ml (2.16 g) of N-methylimidazole in 5 ml of 1,2-dichloroethane. The mixture was stirred for 4 hours at room temperature. A salt was formed (lower phase) which was non miscible with the solvent and was separated by decanting. The remaining solvent was evaporated off under vacuum using a vane pump. A colorless liquid was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[CH2:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:26])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([O:21][CH3:22])[CH:15]=[CH:14][C:13]=2[CH2:23][C:12]1=[O:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1c2ccc(OC)cc2CCN1C(=O)OCc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C(=O)C2
Reaction time: 8 h
Yield: 28.8 %

Procedure:
To a solution of 6-methoxy-1-methylene-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (0.66 g) in 20 mL of glacial acetic acid was added lead tetraacetate (1 g). The reaction was stirred overnight, then quenched by the addition of 2 mL of glycerol. The volatile material was evaporated and the resulting residue was partitioned between 50 mL of saturated sodium chloride and 50 mL of dichloromethane. The aqueous phase was re-extracted with 50 mL more dichloromethane and the combined extracts were dried over sodium sulfate. The volatile material was evaporated and chromatography (20% ethyl acetate in hexanes) yielded 0.20 g of 7-methoxy-2-oxo-1,2,4,5-tetrahydrobenzo[d]azepine-3-carboxylic acid benzyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(OC)[C:20](=[O:29])[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH2:28].CCCCCC.C([Li])CCC>O1CCCC1.C(OCC)(=O)C.O>[NH2:28][C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[C:20]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Yield: 70.7 %

Procedure:
A solution of N-tert-butoxycarbonyl-3-bromophenethylamine (1.7 g) and N-methyl-N-methyloxy-2-amino-5-chloro-benzamide (1.9 g) in tetrahydrofuran (50 ml) was cooled to -70° C. To the solution was added dropwise, while stirring, a hexane solution of n-butyl lithium (1.6 mol/L) (18 ml). To the reaction mixture were added water (100 ml) and ethyl acetate (80 ml). The mixture was shaken. The organic layer was separated, which was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-amino-3′-(2-tert-butoxycarbonylaminoethyl)-5-chloro-benzophenone (1.5 g) as a yellow crystalline product. m.p.: 128-129° C.
Reaction SMILES: [Na:1].[CH2:2]([CH:6]([CH2:12][C:13]([O:15]CC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]([CH3:5])=[O:4]>C(O)C>[Na:1].[O:15]=[C:13]1[CH2:5][C:3](=[O:4])[CH2:2][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:12]1
Reactant: CCOC(=O)CC(CC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1CC(=O)CC(=O)C1
Temperature: 25 °C

Procedure:
To 150 ml of ethanol containing 3.4 g of sodium was added dropwise 31 g of diethyl acetonylsuccinate (or diethyl acetmethylsuccinate) over about one hour with stirring at ambient temperature. The mixture was heated under reflux for 2 hours and then cooled to room temperature, followed by distillation off of the ethanol under reduced pressure. There was thus obtained a brown viscous liquid comprising sodium salt of ethyl 3,5-dioxocyclohexanecarboxylate as formed, to which were added 100 ml of toluene, 50 ml of ice water and 0.3 g of γ-picoline and then added dropwise 15 g of n-butyryl chloride at ambient temperature under agitation over about 2 hours. The resultant reaction mixture was agitated for further 30 minutes and then the toluene layer was separated, washed with water, dried and admixed with 0.8 g of 4-N,N-dimethylaminopyridine. The admixture was heated with agitation at a temperature of 80°-90° C. for 3 hours. The toluene was then distilled off from the reaction solution under reduced pressure and the residue was chromatographed on a column of silica gel developed with benzene to give 19.5 g (55.9%) of the object compound (Compound No. 15).