Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:13]1[C:14]2[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: Fc1ccccc1Br
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccccc1-n1ccc2ccccc21
Temperature: 75 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.431 g, 10.0 mmol), and 2-bromofluorobenzene (1.75 g, 10.1 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (0.347 g, 0.30 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30.0 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.35 g (64%) of the product 4-(2-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[NH:11]C(=O)C)(=[O:3])[CH3:2].Cl.[N:16]([O-])=O.[Na+]>C1COCC1.O>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:11][N:16]=[CH:2][C:1]2=[O:3]
Reactant: CC(=O)Nc1ccc(Br)cc1C(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cn[nH]c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A solution of Example 34B (6.28 g, 24.4 mmol) in THF (75 mL) was treated with concentrated HCl (aq.) (15 mL) and water (15 mL), heated to reflux for 1 hour, and concentrated to remove the THF. The aqueous solution was treated with additional water (5 mL) and concentrated HCl (5 mL), cooled to 0° C., treated with a solution of NaNO2 (1.85 g, 26.84 mmol) in water (10 mL) in 5 portions, warmed to room temperature gradually over a 2-hour period, and stirred overnight at room temperature. The reaction was heated to reflux for 6 hours, and filtered. The solid was washed with water (50 mL) and diethyl ether (50 mL) and dried under vacuum to provide the desired product (3.0 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([Cl:6])=[O:5].[CH3:13][N:14]([CH3:28])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[N:26]=[C:25]([NH2:27])[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH2:16]1>N1C=CC=CC=1.Cl>[ClH:6].[ClH:6].[CH3:13][N:14]([CH3:28])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[N:26]=[C:25]([NH:27][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[CH:24]=[CH:23][CH:22]=2)=[CH:17][CH2:16]1
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Temperature: 55 °C
Yield: 49 %

Procedure:
Add 2,4,6-trifluorobenzoyl chloride (117 mg, 0.60 mmol) to a solution of 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 1 (preparation 10, 100 mg, 0.46 mmol) in pyridine (6 mL) and heat at 55° C. overnight. Re-add another portion of 2,4,6-trifluorobenzoyl chloride (50 mg, 0.26 mmol) and heat at 65° C. for 4 hr. Remove volatiles under reduced pressure, dissolve the residue in 1N HCl, extract twice with ethyl ether. Adjust aqueous layer to pH>11 with 5N NaOH. Extract the aqueous layer there times with DCM. Combine organic layers, dry over sodium sulfate, filter and concentrate to give a residue. Purify the residue by chromatography (silica gel, 5% 2M NH3/MeOH in DCM) to provide the free amine of the title compound as a colorless oil (84 mg, 49%): MS (ion spray): m/z=376.2 (M+H)+; 1H NMR (CDCl3): δ 8.91 (s, br, 1H), 8.20 (d, 1H), 7.73 (t, 1H), 7.14 (d, 1H), 6.71 (m, 2H), 6.61 (m, 1H), 2.65 (m, 1H), 2.44 (m, 3H), 2.35 (s, 6H), 2.12 (m, 2H), 1.53 (m, 1H). Using a salt formation method similar to that in example 1 provides the di-hydrochloride salt. Di-hydrochloride salt: Anal. cal'd for C20H20F3N3O.2HCl: C, 53.58; H, 4.95; N, 9.37. Found: C, 53.42; H, 4.91; N, 9.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.C([N:35]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:35])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (90 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg), 1-hydroxybenzotriazole ammonium salt (59 mg) and N,N-dimethylformamide (4 mL) was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was crystallized from acetonitrile and the crystals were washed with acetonitrile-diethyl ether. The crystals were recrystallized from ethanol to give the title compound (58 mg, 64%) as off-white crystals. MS 461 (MH+). mp 225-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:20]([CH3:22])[CH3:21])[NH:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:20]([CH3:21])[CH3:22])[N:11]([CH3:25])[C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)N1NC(=O)C(c2ccc(Cl)c(Cl)c2)C1c1ccncc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)N1C(c2ccncc2)C(c2ccc(Cl)c(Cl)c2)C(=O)N1C
Temperature: 0 °C

Procedure:
In a 100 mL round bottom flask, was added 0.1 g 4-(3,4-Dichloro-phenyl)-1-isopropyl-5-pyridin-4-yl-pyrazolidin-3-one and 10 mL THF, stirred at 0° C. under nitrogen. 0.43 mL 1 M LHMDS in THF was added drop wise. After stirred at 0° C. for 30 min 0.026 mL iodomethane was added drop wise. The resulted mixture was stirred from 0° C. to rt for 2 hours, quenched with 20 mL sat. NH4Cl, extracted with dichloromethane 3×25 mL. The organic phase was dried over anhydrous Na2SO4. After purification by flash chromatography, obtained the title compound 80 mg as light solid. MS (ES+): 364 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH:12]([CH3:16])[CH2:13][CH:14]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH2:32][CH3:33])[C:24]3[C:29]([C:30]=2[CH:31]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][NH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:23]([CH2:32][CH3:33])[C:24]4[C:29]([C:30]=3[CH:31]=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(CC=O)CC(=O)Nc1ccc(C#N)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc(NCCC(C)CC(=O)Nc3ccc(C#N)cc3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.2 %

Procedure:
A solution of the compound obtained in Step 2 (110 mg, 0.48 mmol) and 3-amino-N-ethylcarbazole (151 mg, 0.72 mmol) in TFA (1 mL) and toluene (1 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added sodium triacetoxyborohydride (304 mg, 1.43 mmol), and the mixture was stirred at room temperature for additional 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 80% ethyl acetate/hexane) to give the title compound (82 mg, 0.193 mmol, 40.5%) as a pale-yellow powder.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:17])[C@@H:10]([OH:24])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C@H:39]([CH3:43])[C:40](O)=[O:41]>>[C:25]1([C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:40](=[O:41])[C@H:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])[CH3:43])[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:17])[C@@H:10]([OH:24])[CH2:9]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O[C@H]1CC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]2[C@]1(O)c1ccccc1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Agent: Cl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)C[C@H](O)[C@@]2(O)c1ccccc1
Yield: 80.1 %

Procedure:
By working in accordance with Example 1, starting from 0.5 g of (3aS,4S,5S,7aS)-7,7-diphenyl-4-phenyl-perhydroisoindole-4,5-diol hydrochloride and 0.25 g of (S)-2-(2 -methoxyphenyl)-propionic acid, 0.52 g of (3aS, 4S, 5S, 7aS)-7,7-diphenyl-4-phenyl-2-[-2-(2-methoxyphenyl)-(S)-propionyl]-perhydroisoindole-4,5 diol is obtained in the form of a white solid which melts with decomposition at 158° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([NH2:17])=[C:9]([Cl:18])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:19][CH2:20]O>Cl>[NH2:1][C@H:2]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[C:10]([NH2:17])=[C:9]([Cl:18])[CH:8]=1)[C:3]([O:5][CH2:19][CH3:20])=[O:4]
Reactant: Nc1c(Cl)cc(C[C@@H](N)C(=O)O)cc1C(F)(F)F
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(C(F)(F)F)c1

Procedure:
A solution of 3.5 g (10.97 mmol) (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid in 100 mL EtOH and 70 mL ethanolic HCl (11.5 M) was stirred overnight at RT. The mixture was evaporated down i.vac., the residue was taken up in 150 mL water, combined with 30 mL of 15% K2CO3 solution, extracted with 150 mL EtOAc, the organic phase was separated off and dried over Na2SO4. After removal of the desiccant and solvent the desired product was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([NH:14][C:15](=[O:32])[CH2:16][O:17][CH2:18][CH:19]([O:30][CH3:31])C(OCC1C=CC=CC=1)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:34]([O:37]CC)(=[O:36])C>[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([NH:14][C:15](=[O:32])[CH2:16][O:17][CH2:18][CH2:19][O:30][CH2:31][C:34]([OH:37])=[O:36])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)COCC(OC)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)COCCOCC(=O)O
Temperature: 47.5 °C
Reaction time: 9 h

Procedure:
2-[2-(2-Benzyloxy carbonyl methoxy-ethoxy)-acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (5 g) was dissolved in ethyl acetate (200 ml) in a pressure vessel. Palladium on carbon (5%, 50% wet, 2 g) was added and the mixture was stirred under an atmosphere of hydrogen (6 kg) for 9 hours at a temperature of 45-50° C. The catalyst was removed by filtration and distilled off ethyl acetate and the residue was washed with Diisopropyl ether and solvents residue was removed by applying high vacuum to get pure 2-[2-(2-Carboxy methoxy-ethoxy)-acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.2 g) as light yellow syrup. The product was characterized by 1H NMR which showed the presence of some impurities and hence was purified by column chromatography.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8].[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)#[N:23]>CN(C)C=O.CC(C)([O-])C.[K+]>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1)[NH:10][C:7](=[O:9])[CH3:8])[CH3:16]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: N#Cc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To 50 ml dimethylformamide is added 5.7 g (51 mmoles) of potassium tert-butoxide and 11.1 g (51 mmoles) of diethyl acetamidomalonate and the resulting mixture stirred at 25° for 15 minutes. The solution is then cooled to 10° and a solution of 10.0 g (51 mmoles) of 4-cyanobenzyl bromide, Case, J. Am. Chem. Soc., 47, 1143, (1925) in 40 ml of dimethylformamide is added dropwise over 20 minutes. The mixture is then stirred at 25° for 1 hour after which a further 0.285 g (2.5 mmoles) of potassium tert-butoxide and 0.5 (2.5 mmoles) of diethyl acetamidomalonate are added and stirring continued for 1 hour at 25°. The reaction mixture is then poured into 300 ml of ice water, causing the product to precipitate. Filtration, washing with water and drying yields 10.3 g (31 mmoles, 61%) of N-acetyl-4-cyano-α-(ethoxycarbonyl)phenylalanine ethyl ester, m.p. 160°-163°.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=O)C.O=S(Cl)Cl.[CH3:22][N:23]1[C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][C:36]=3[NH2:38])[CH:31]=[CH:30]2)=[CH:26][N:25]=[CH:24]1>C1COCC1>[OH:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([NH:38][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:37]=2[N:29]([CH2:28][C:27]2[N:23]([CH3:22])[CH:24]=[N:25][CH:26]=2)[CH:30]=[CH:31]3)=[O:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: Cn1cncc1Cn1ccc2cccc(N)c21
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC(C)=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)Nc2cccc3ccn(Cc4cncn4C)c23)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
(E)-3-(3-Acetoxy-4-methoxyphenyl)acrylic acid (0.099 g, 0.420 mmol) was suspended in dry THF (8 ml). SOCl2 (0.037 ml, 0.504 mmol) was added and the mixture was stirred at RT for 1 h. The solvent was evaporated to dryness and the residue was dissolved in dry THF (8.00 ml). TEA (0.059 ml, 0.420 mmol) and 1-(3-methyl-3H-imidazol-4-ylmethyl)-1H-indol-7-ylamine (0.095 g, 0.420 mmol) were added. The mixture was stirred at RT for 18 hrs, heated at reflux for hrs and then at RT for 48 hrs. The solvent was removed in vacuo and the residue was partitioned between EtOAc (10 ml) and H2O (2×10 ml). Organic phase was dried over sodium sulphate and concentrated to dryness. The crude was charged onto a SCX cartridge and eluted firstly with MeOH and then with NH3/MeOH. The title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[1-(3-methyl-3H-imidazol-4-ylmethyl)-1H-indol-7-yl]-acrylamide (56 mg) was obtained after column chromatography (eluent: DCM 100% to DCM/MeOH 98:2).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14]=O>>[O:5]=[C:4]1[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:2]=2[N:1]=[CH:14][O:6]1
Reactant: C=O
Reactant: Nc1c(C(=O)O)cccc1C(=O)O
Product: O=C(O)c1cccc2c(=O)ocnc12
Temperature: 140 °C
Yield: 89 %

Procedure:
2-Aminoisophthalic acid moiety (50.0 g; 276.0 mmol) and formaldehyde (250.0 ml; 5.00 V) were combined and heated to 140° C. for 4 h. The reaction mixture was cooled to room temperature and distilled under high vacuum on the rotary evaporator. The remaining formaldehyde was removed by azeotropic distillation with toluene. The residue was slurried with ethyl ether, filtered, and the solid was dried under vacuum to provide the desired intermediate (50.3 g, 89% yield).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH:17]([C:26]#[N:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OC(=O)C)C.[ClH:34]>C(O)C>[ClH:34].[ClH:34].[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH:17]([C:26]#[N:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ccccc1C(C#N)CC1CCN(Cc2cccnc2OC)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccccc1C(C#N)CC1CCN(Cc2ccc[nH]c2=O)CC1

Procedure:
In ethanol (2 ml) was dissolved 191 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-cyano-2-(2-methoxyphenyl)ethyl]piperidine obtained in Example 86. To the mixture was added 0.3 ml of a 4N hydrogen chloride ethyl acetate solution, followed by heating under reflux for 2 hours. The solvent was evaporated, to give 199 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([N:16]([CH2:15][C:11]1[CH:10]=[C:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1)(=[O:31])[CH3:30]
Reactant: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cccc3C)c2)C(C)=O)cc1
Yield: 97.6 %

Procedure:
A solution of methyl 3-(4-{[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.598 g, 1.60 mmol) and acetic anhydride (0.226 mL, 2.40 mmol) in pyridine (3 mL) was stirred at room temperature for 20 hr. The solvent was evaporated by concentration. The obtained residue was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-60% ethyl acetate/hexane) to give the title compound (0.649 g, yield 98%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[N:2]1.[NH2:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:34]=[C:35](I)[C:28]=12.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:34]=[C:35]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[CH:16][CH:15]=3)[C:28]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Reactant: CC1(C)OB(c2ccc(Nc3noc4ccccc34)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Nc4noc5ccccc45)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C

Procedure:
A mixture of N-benzo[d]isoxazol-3-yl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.087 g, 0.000258 mol), tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.088 g, 0.000198 mol), tetrakis-(triphenylphosphine)palladium (0.014 g, 0.000012 mol) and sodium carbonate (0.053 g, 0.000495 mol) was heated in a mixture of ethylene glycol dimethyl ether (4 mL) and water (2 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure and the residue partitioned between water and dichloromethane. The organic phase was dried with magnesium sulfate and concentrated under reduced pressure to yield crude tert-butyl 4-{4-amino-3-[4-(benzo[d]isoxazol-3-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-1-piperidinecarboxylate which was used without further purification. It was dissolved in ethyl acetate (5 mL) and treated with a 4N aqueous solution of hydrochloric acid (1 mL). The resulting emulsion was vigorously stirred for 1 hour; the water layer was neutralized with saturated solution of sodium bicarbonate in water and the layers were separated. The organic phase was concentrated under reduced pressure and residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield N3-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}benzo[d]isoxazol-3-amine acetate (0.009 g, 0,0000185 mol) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:4]=2[O:3]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl>[Br:25][CH2:11][C:10]1[C:4]2[O:3][C:2]([F:1])([F:12])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc2c1OC(F)(F)O2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: FC1(F)Oc2cccc(CBr)c2O1

Procedure:
76 g of 2,2-difluoro-4-methyl-1,3-benzodioxole and 200 mg of Azobisisobutyronitrile are added to a suspension of 90 g of N-bromosuccinimide in 400 ml of methylene chloride. The mixture is then heated under reflux, with stirring, until all the undissolved material floats to the top. After cooling, the succinimide is filtered off with suction and rinsed with carbon tetrachloride and the solution is then distilled in order to separate off the carbon tetrachloride. 117 g of crude benzyl bromide remain in the residue and are employed without purification.