Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=2[C:21]2[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:23]3[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=3[C:21]3[CH:41]=[CH:42][CH:43]=[CH:44][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was prepared. The reaction was monitored by tic (Rf=0.35, 3% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[CH:8][CH2:7][CH2:6][N:5]2[C:18]=1[CH3:19]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[CH:8][CH:7]=[CH:6][N:5]2[C:18]=1[CH3:19]
Reactant: Cc1nc2n(c1C)CCC=C2c1ccc(Cl)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc2c(-c3ccc(Cl)cc3Cl)cccn2c1C

Procedure:
2,3-Dimethyl-8-(2,4-dichlorophenyl)-5,6-dihydroimidazo[1,2-a]pyridine (3) (29.3 g, 0.1 mol) is dissolved in methylene chloride (1 L) and activated manganese dioxide (120 g) is added. The mixture is heated at reflux for 16 hours with stirring. The catalyst is removed by filtration of the reaction through a Celite pad and the filtrate is evaporated to a solid (4).
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]1[CH:17]=[C:16](B(O)O)[CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:11])[CH:17]=2)[C:8]([CH3:9])=[CH:7][C:5]=1[NH2:6]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: Cc1cc(N)c(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2cc(F)c(N)cc2C)ccn1
Temperature: 25 °C

Procedure:
To a round bottom flask charged with 4-bromo-2-fluoro-5-methylaniline 191-1 (2.04 g, 10 mmol), 2-methylpyridin-4-ylboronic acid 191-2 (1.37 g, 10 mmol) and Pd(PPh3)4 (0.4 g, 0.35 mmol) was added toluene (30 mL), ethanol (10 mL) and saturated sodium carbonate (10 mL). The flask was flushed with nitrogen and the reaction was heated to reflux for 10 hours. After the reaction was cooled down to room temperature, it was partitioned between ethyl acetate and saturated NaHCO3 and the organic phase was washed with brine and dried over Na2SO4. The solvent was removed by rotary evaporation and the residue was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give 2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)aniline 191-3. MS m/z 217.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCCC1.O>[N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
D-hPro-OH (5.0 g, 38.7 mmol) was dissolved in tetrahydrofuran (100 mL) and water (30 mL). The pH of the solution was adjusted to 9.5 with 2N NaOH and benzyl chloroformate (5.5 mL, 38.7 mmol) was added dropwise and the pH maintained at 9.5 with 2N NaOH. The reaction was stirred for an additional 1 hour at room temperature. The organic solvent was evaporated in vacuo, and diethyl ether (100 mL) and water (50 mL) were added to the residue. The aqueous layer was separated, the pH of the aqueous solution was adjusted to 2.8 with 3N HCl, and ethyl acetate (150 mL) was added. The organic layer was separated and dried (MgSO4) and the filtrate was concentrated in vacuo to give 9.6 g (95%) of a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>[OH-].[Na+].O>[OH:18][CH:15]([CH2:16][OH:17])[CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1c(C)cc(OCC(O)CO)cc1C
Temperature: 140 °C
Yield: 57.4 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (2.00 g, 12.2 mmol, 1.0 equiv) and 3-chloropropane-1,2-diol (1.02 mL, 12.2 mmol, 1.0 equiv) in 50% aqueous NaOH solution (20.0 mL) was heated at 140° C. for 16 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1-(4-(2,3-dihydroxypropoxy)-2,6-dimethylphenyl)ethanone (1.66 g, 7.0 mmol) as yellow oil in 57% yield: 1H NMR (CDCl3, 500 MHz) δ 6.57 (s, 2 H), 4.10-4.11 (m, 1 H), 4.08-4.09 (m, 2 H), 4.01-4.02 (m, 1 H), 3.74-3.75 (m, 1 H), 2.58-2.59 (brs, 1 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 2.05-2.10 (brs, 1 H); ESI-MS: m/z 239.9 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[K].[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.O>CN(C)C=O>[O:36]=[C:34]1[C:33]2[C:32](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:31](=[O:41])[N:35]1[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1nc(-c2ccc(CCCBr)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of N-{4-[4-(3-bromopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (82 mg) in N,N-dimethylformamide (0.82 ml) was added phthalimide potassium salt (30.8 mg), and the mixture was stirred for 2 hrs. at 50° C. The reaction mixture was cooled to 20° C., then water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated to give a crude material (92.0 mg). The crude material was purified by preparative thin-layer chromatography over silica gel to give N-{4-{4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]#[N:20])[CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]#[N:20])[CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: N#CC1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCC(C#N)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and piperidine-4-carbonitrile as starting raw materials, to produce an intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C([O-])=O)[C:5]([O:8][CH:9]([C:11]#[N:12])[CH3:10])=[CH:6][CH:7]=1.[OH-:16].[K+].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([OH:16])[C:5]([O:8][CH:9]([C:11]#[N:12])[CH3:10])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CC(C#N)Oc1ccc(Cl)cc1C(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CC(C#N)Oc1ccc(Cl)cc1O
Reaction time: 8 h

Procedure:
3-Chloro-6-(1-cyanoethoxy)-phenyl-formate (56.4 g., 0.25 mole) is added to a solution of 85% potassium hydroxide (17.1 g., 0.26 mole) in 95% alcohol (200 ml.) at ambient temperature, and the mixture then stirred overnight under nitrogen. The reaction mixture is treated with a slight excess of dilute hydrochloric acid, and most of the alcohol removed under reduced pressure. The product is extracted with ether, the ethereal extract is washed with water, then with 5% sodium carbonate solution and again with water. The ethereal extract then is dried over magnesium sulfate and then over calcium sulfate and the ether removed by evaporation yielding 3-chloro-6-(1-cyanoethoxy)-phenol, which is crystallized from chloroform-petroleum ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.O>[Zn].C(O)(=O)C>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=1[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: Brc1ccc2noc(-c3ccccc3)c2c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 80 °C
Yield: 98.2 %

Procedure:
5-Bromo-3-phenyl-2,1-benzisoxazole (7.5 g, 28.6 m mol), water (14.6 ml), and zinc dust (9.3 g, 143 m mol) were combined. Acetic acid (8.6 ml, 143 m mol) was added and the mixture was stirred and heated at 80° C. for 90 minutes. After cooling to room temperature, both the liquid and solid portion of the reaction were extracted with methylene chloride. The combined methylene chloride solutions was washed once with sodium hydroxide solution (10%) and several times with water. Drying (sodium sulfate) and evaporation yielded the desired product (7.42 g) of mp. 92°-102° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CCN3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 86.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.77 g) and 1-(2-chloroethyl)piperidine hydrochloride (0.55 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.54 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21](O)=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)O)cc2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)NCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.26 g (7 mmole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxycarbonylmethoxy-tetralin were mixed with 80 ml of DMF and 0.749 g (7 mmole) of benzylamine, 3.1 g of BOP and 1.47 ml (10.5 mmole) of triethylamine were added. The mixture was stirred at ambient temperature for 6 hours then left to stand overnight without stirring. The solvent was evaporated off; the residue was taken up in ethyl acetate and washed with a 5% sodium bicarbonate solution. The organic phase was dried and the solvent was evaporated off under reduced pressure. The compound of the heading was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[C:14]([C:13]([C:4]1[CH:3]=[C:2]([NH:1][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])[CH3:16])#[N:15]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C#N)c1cc(N)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Yield: 76.1 %

Procedure:
Using the procedure described in Example 306A, to a solution of 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (451 mg, 2 mmol) and potassium carbonate (359 mg, 2.6 mmol) in anhydrous DCM (4 ml) was added dropwise phenyl chloroformate (0.28 ml, 2.2 mmol) as a solution in DCM (2 ml) to afford phenyl 3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (527 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 1.74 (s, 6H), 6.66 (s, 1H), 7.05-7.60 (m, 11H); LC-MS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([S:11]([CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:22][OH:23].C=O>C(Cl)Cl>[OH:23][CH2:22][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=2[N:9]=[C:8]1[S:11]([CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)=[O:12]
Reactant: CO
Reactant: COc1ccnc(CS(=O)c2nc3c(F)cccc3[nH]2)c1
Agent: C=O
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3c(F)cccc3n2CO)c1
Reaction time: 0.07 h

Procedure:
4-Fluoro-2-[[(4-methoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (1.6 g, 5.2 mmol) was suspended in methylene chloride (50 ml). Methanol was added until a clear solution was obtained. The mixture was concentrated on a rotavapor under reduced pressure. The oily residue, which was not allowed to crystallize, was dissolved in methylene chloride (30 ml). A solution of formaldehyde (5 M, 10 ml, 50 mmol) was added and the mixture was stirred violently for four minutes. After separation the organic solution was dried (Na2SO4) and concentrated until 10 ml of the mixture was left. The flask was chilled for 15 minutes whereupon the formed precipitate was filtered off and washed with cold methylene chloride. In this way the title compound was obtained (1.1 g, 63%). NMR data is given below.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([O:9][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:8]
Reactant: CC(C)(Br)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Br

Procedure:
Isobutene is condensed into a solution of 2-bromo-2-methylpropanoic acid (10 mmol) and trifluoromethane sulfonic acid (0.1 mmol) in 100 mL of CH2Cl2 until the starting material is consumed, as observed by TLC. The volatile components are evaporated in vacuo, and the residue is filtered through a pad of neutral alumina using 50% ether/hexane. The filtrate is concentrated in vacuo and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[OH:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:44]4[CH2:45][CH2:46][C@@H:42]([OH:41])[CH2:43]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: O[C@H]1CCNC1
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(-c3ccc(CN4CC[C@@H](O)C4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.7 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (0.075 g, 0.14 mmol), (S)-3-hydroxypyrrolidine (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of (S)-3-hydroxypyrrolidine (0.1 mL) and sodium triacetoxyborohydride (0.084 g, 0.40 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. 1N NaOH (1 mL) was added and the reaction mixture was concentrated in vacuo. The residue was dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 16.5-18.4 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[(3R)-3-hydroxytetrahydro-1H-1-pyrrolyl]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.027 g, 0.043 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.89 (1H, s), 8.30-8.33 (2H, m), 8.13-8.14 (2H, m), 7.90-7.80 (1H, m), 7.84 (1H, d, J=10.8 Hz), 7.70 (1H, d, J=7.6 Hz), 7.35-7.59 (4H, m), 4.64 (1H, bs), 4.14-4.23 (1H, m), 3.91 (3H, s), 3.62 (2H, s), 2.61-2.62 (2H, m), 2.27-2.28 (2H, m), 2.27-2.28 (2H, m), 2.02 (1H, m), and 1.60 (1H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.41 min. MS: MH+ 622.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[ClH:31].[CH2:32](O)[CH3:33]>>[ClH:31].[ClH:31].[CH2:32]([O:22][C:21](=[O:23])[CH2:20][O:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)[CH3:33]
Reactant: CCO
Reactant: O=C(O)COC/C=C\CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: Cl
Product: CCOC(=O)COC/C=C\CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 27.5 °C
Reaction time: 4 h

Procedure:
To a stirred solution of {4-{4-[bis-(4-fluorophenyl)methyl]-piperazin-1-yl}-(Z)-but-2-enyloxy}acetic acid (1.0 g, 0.0024 mol) in ethanol (20 ml), is added a solution of anhydrous ethanolic HCl till pH is 1-2. The solution is refluxed for around 2 hrs, cooled to 25-30° C. and stirred for 4 hrs. The crystallized solid is filtered, washed with ethanol (2×5 ml), and dried in oven at 60-65° C. to get the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][C:6]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH:24]=[C:25]([CH3:27])[CH3:26])([C:12]([OH:14])=[O:13])[CH2:5]2>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][C:6]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH2:24][CH:25]([CH3:26])[CH3:27])([C:12]([OH:14])=[O:13])[CH2:5]2
Reactant: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2cc(F)c(F)cc2C1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3cc(F)c(F)cc3C2)c1CC(C)C
Temperature: 25 °C
Yield: 69.7 %

Procedure:
5,6-Difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (158) (200 mg, 0.63 mmol) is dissolved in acetic acid (15 mL) by heating. The resulting solution is cooled down to RT and then the catalyst, Pd—C (5 wt. % Pd, 134 mg, 6.3% mmol) is added under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 55 psi, 95° C., overnight. The catalyst is removed by filtration through a pre-column (10 g silica gel) and washed with EtOH. The combined organic solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (159) as white solid (170 mg, 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[O:35]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:35])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CCCCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 48.4 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and azepan-2-one (119 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (234 mg) was obtained.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1
Product: O=C(Cl)c1ccccc1
Yield: 71.2 %

Procedure:
To 12.2 g of benzoic acid, 24 g of thionyl chloride was added, and allowed to react under reflux for 2 hours. Alter the termination of the reaction, thionyl chloride was evaporated under reduced pressure, and then distilled under reduced pressure at 20 mmHg to obtain 10 g of benzoic acid chloride at a distillation temparature of 105° C. The benzoic acid chloride was dissolved in 50 ml of toluene, ant added with 8 g of 4-fluorophenol and 8 g of pyridine to react at 40 ° C. for 3 hours. After the termiration of the reaction, 100 ml of water was added, and the organic layer was separated. The organic layer was washed with dilute hydrochloric acid, dilute alkali aqueous solution and saturated sodium chloride solution successively, and then, dried by adding anhydrous sodium sulfate. Subsequently, the organic layer was filtered, and solvent was evaporated from the filtrate under reduced pressure. The reaction product was recrystallized from hexane, and then distilled under reduced pressure at 1 mmHg to collect the fractions at a distillation temperature of 160° C. Thus, 9 g of benzoic acid (4-fluorophenyl) ester represented by the following formula was obtained. The melting point of the ester was 58.0° C. The infrared absorption spectrum of the ester is shown in FIG. 1. ##STR4##