Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:24])[NH:7][CH2:8][CH:9]1[S:13](=[O:15])(=[O:14])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2([C:48]([F:51])([F:50])[F:49])[O:37][N:36]=[C:35]([C:38]3[CH:46]=[CH:45][C:41](C(O)=O)=[C:40]([CH3:47])[CH:39]=3)[CH2:34]2)[CH:29]=[C:30]([Cl:32])[CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2([C:48]([F:50])([F:49])[F:51])[O:37][N:36]=[C:35]([C:38]3[CH:46]=[CH:45][C:41]([C:6]([NH:7][CH2:8][CH:9]4[S:13](=[O:14])(=[O:15])[N:12]([C:16]5[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=5)[CH2:11][CH2:10]4)=[O:24])=[C:40]([CH3:47])[CH:39]=3)[CH2:34]2)[CH:29]=[C:30]([Cl:32])[CH:31]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: COc1ccc(N2CCC(CNC(=O)OC(C)(C)C)S2(=O)=O)cc1
Product: COc1ccc(N2CCC(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)cc3C)S2(=O)=O)cc1
Yield: 37.5 %

Procedure:
The compound obtained in Step C (94 mg) was deprotected and coupled with 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.125 g) (prepared according to WO 2009/080250) as described in Example 4, Steps B and C to afford the title compound as a brown solid (65 mg). LCMS (Method F) 2.02 min, M−H 654/655.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[CH:9]=[N:8]1.CC[N:21]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:40]1[CH2:44][CH2:43][O:42][CH:41]1[C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=1>CN(C=O)C>[O:40]1[CH2:44][CH2:43][O:42][CH:41]1[C:45]1[CH:52]=[CH:51][C:48]([C:49]2[N:21]=[C:16]([C:10]3[CH:9]=[N:8][N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11]=3[C:12]([F:13])([F:14])[F:15])[O:18][N:50]=2)=[CH:47][CH:46]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1ccc(C2OCCO2)cc1
Reactant: O=C(O)c1cnn(-c2ccccn2)c1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: FC(F)(F)c1c(-c2nc(-c3ccc(C4OCCO4)cc3)no2)cnn1-c1ccccn1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (31.46 g, 122 mmol) in DMF (200 mL) was added EDCI (23.34 g, 134 mmol) and HOBt (16.53 g, 122 mmol). After the reaction was stirred for 30 min. at room temperature 4-(1,3-dioxolan-2-yl)benzonitrile, Int.6-A, (16.53 g, 122 mmol) was added. The reaction mixture was stirred at 140° C. for 4 hr. The reaction mixture was concentrated under reduced pressure to remove the volatiles. The residue was partitioned between water and ethyl acetate and the organic layer was washed with aq. HCl solution, NaHCO3 solution, water, and brine before being dried over Na2SO4 and concentrated to provide 3-(4-(1,3-dioxolan-2-yl)phenyl)-5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazole (25 g, 58 mmol). The compound had an HPLC retention time=6.15 min. −Column: HYPERSIL® BDS C18 (4.6×50 mm) Flow rate=0.8 mL/min. Solvent A=, 0.1% TFA in water; Solvent B=acetonitrile. 5%-100% B (0-6 min), 100% B (6-9 min), 100%-5% B (9-11 min). LC/MS M+1=430.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[C:11]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([O:42]C)=[O:41])[CH:35]=2)=[N:10]1.O.[OH-].[Li+].CO.Cl>C1COCC1.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:25][CH:26]=3)=[N:19][C:12]=2[C:11]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([OH:42])=[O:41])[CH:35]=2)=[N:10]1
Reactant: COC(=O)c1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc23)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)n(-c5c(Cl)cccc5Cl)nc(-c5ccnc(C(=O)O)c5)c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 222 (0.36 g, 0.583 mmol) in THF (8 mL) was added lithium hydroxide monohydrate (0.049 g, 1.166 mmol) in water (8 mL). Methanol was added until a transparent solution formed (8 mL). This mixture was stirred at room temperature for 2 hours and acidified to pH 5 with 2N aqueous HCl solution. The mixture was concentrated and the formed solid was collected by filtration, washed with water and dried to give the title compound. MS (DCI/NH3) m/z 604 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH2:4][CH2:3]1.[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=3)[CH2:4][CH2:3]2)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCOC(=O)c1sc(N2CCC(N)CC2)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3nc(Cl)c(CC)[nH]3)CC2)nc1C
Yield: 92.6 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-(4-aminopiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (239a) (139 mg, 0.52 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (90 mg, 0.52 mmol), WSC hydrochloride (296 mg, 1.55 mmol), 1-hydroxybenzotriazole (70 mg, 0.52 mmol) and N-methylmorpholine (0.11 mL, 1.03 mmol), to obtain 205 mg of the title compound as a white solid (94%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:21]([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[CH3:21][CH:9]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)=[O:10]
Reactant: CNCCN1CCCCC1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(F)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(NCCN1CCCCC1)C(=O)c1ccccc1
Reaction time: 72 h
Yield: 69 %

Procedure:
4′-Fluoroacetophenone (1.5 g, 10.86 mmol), N-methyl-1-piperidineethanamine (1.54 g, 10.86 mmol) and K2CO3 (1.80 g, 13.0 mmol) in dimethylacetamide (5 mL) are heated to 100° C. with vigorous stirring for 3 days. The reaction mixture is cooled, diluted with water (50 mL), and extracted with EtOAc (3×50 mL). The organic layer is dried (magnesium sulfate) and concentrated. The product is chromatographed on silica gel eluting with 0.3% NH4OH:2.7% MeOH:97% CH2Cl2 to give 1.95 g of a brown oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.C([N:21](CC)C(C)C)C.Cl[C:28]1[C:33]([C:34](Cl)=[O:35])=[C:32](Cl)[N:31]=[CH:30][N:29]=1.CCOC(C)=O>C1NC2NC(N)=NC(=O)C=2N2C1CN(C1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)C2.CCCCCCC>[NH2:21][C:28]1[C:33]2[C:34](=[O:35])[N:11]([C:12]3[CH:13]=[CH:14][C:15]([I:18])=[CH:16][CH:17]=3)[CH2:10][CH2:9][O:8][C:32]=2[N:31]=[CH:30][N:29]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNc1ccc(I)cc1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: CCN(CC)C(C)C
Agent: Nc1nc(=O)c2c([nH]1)NCC1CN(c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)CN21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1C(=O)N(c1ccc(I)cc1)CCO2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cooled (ice/water), stirred solution of N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-iodoaniline (1.34 g, 2.78 mmol) and diethylisopropylamine (0.7 mL, 4.0 mmol) in MTHF (5 mL) was added 4,6-dichloroprimidine-5-carbonyl chloride (560 mg, 2.65 mmol). After 5 minutes, the cooling bath was removed and the slurry was stirred for 5 hours. Aqueous hydrochloric acid (1N, 5 mL) was added and the mixture was allowed to stand for 72 hours. The layers were separated and the aqueous layer was washed with MTHF (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate, saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo to afford an oil. Chromatography (40 g silica gel column, 20-100% EtOAc:heptane) afforded the title compound, 542 mg. 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.62 (d, 2H), 7.17 (d, 2H), 4.07 (t, 2H), 3.91 (q, 2H). m/z=438.0 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.F[B-](F)(F)F.B(F)(F)F.CCOCC.C(C1OC1)Cl.[CH3:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=O>C(Cl)Cl>[CH3:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[N:1][CH2:2][CH2:3][S:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CN1CCCC1=O
Reactant: NCCSc1cc2ccccc2[nH]1
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: ClCC1CO1
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CCCC1=NCCSc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.9g (52 mM) of AlCl3 and 1.98g (52 mM) of lithium aluminum hydride in 257 ml of anhydrous ether is added 9.8g (52 mM) of this nitrile in 50 ml of anhydrous ether, and the whole is stirred for 2 hours at room temperature. A total of 10g of 50% NaOH and 2 ml of water is added to this reaction mixture over a period of 3 hours and the resulting solution is stirred for 16 hours. The ether is separated from the solids and dried over potassium carbonate. The dried solution is evaporated in vacuo to give 5.4g of product. Further extraction of the reaction solids with ether again after addition of 2.5 ml of water and 10g of 50% NaOH yields an organic layer which is then combined with the 5.4g of product and dried over potassium carbonate. The dried solution is filtered and the filtrate evaporated in vacuo to give 9.0 g of 2-(2-aminoethylthio)indole. This amine is converted to the hydrochloride salt with ethereal HCl and is recrystallized once from methanol/isopropanol to give 6.4g of crystalline solid. A solution of 3.0g (15 mM) of 2-(2-aminoethylthio)indole in 30 ml of dry CH2Cl2 is added to a solution of fluoroborate salt prepared from 3.42g (24 mM) of boron trifluoride etherate, 1.69g (18 mM) of epichlorohydrin, and 1.80g (18 mM) of N-methyl-2-pyrrolidinone, in 15 ml of dry CH2Cl2. The solution is stirred at room temperature under dry conditions for 4 hours, after which it is washed once with 1N NaOH and twice with brine, and dried over potassium carbonate. The dried solution is evaporated in vacuo to give 3.1g of crude product. Purification as the saccharine salt gives 2-[2-(1-methyl-2-pyrrolidinylideneamino)ethylthio]indole saccharinate as cream colored crystals; m.p. 175°-177° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[CH:11]=1)([O-])=O.Cl.C(OCC)(=O)C>[Pd].CO>[CH3:17][C:12]1([CH3:18])[C:13]([CH3:15])([CH3:16])[CH2:14][CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:11]1
Reactant: CC1(C)C=C(c2ccccc2[N+](=O)[O-])CC1(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccccc2N)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A mixture of 1-nitro-2-(3,3,4,4-tetramethylcyclopent-1-enyl)benzene (450 mg, 1.83 mmol) produced in Example (54b), 10% palladium on carbon (200 mg, wet) and methanol (40 mL) was stirred for 3 hours and 30 minutes at atmospheric pressure and room temperature under a hydrogen atmosphere. The reaction mixture was filtered, 10% palladium on carbon (200 mg, hydrous) and a 4N solution of hydrogen chloride in ethyl acetate (0.915 mL, 3.66 mmol) were added to the filtrate, and then stirring was continued for 13 hours and 30 minutes at room temperature and atmospheric pressure under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 295 mg of the title compound as a brown oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[CH2:52][CH:53]=[O:54]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:53]([OH:54])[CH2:52][CH:48]2[CH2:49][CH2:50][CH2:51][O:47]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: O=CCC1CCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1cnc2c(c1)cc(C(O)CC1CCCO1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
To a solution of 1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 10, 6 g, 20.8 mmol) in dry tetrahydrofuran (40 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (19.5 mL, 31.2 mmol) to a 0° C. solution of diisopropylamine (4.7 mL, 32.8 mmol) in dry tetrahydrofuran (20 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-furan-2-yl)-acetaldehyde (3.5 g, 30.7 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-furan-2-yl)-ethanol (2.5 g, 30%) as a white solid: LC/MS m/e calcd for C21H22N2O5S [M+H]+ 403.47, observed 403.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20].C(OCC)(=O)C>COC(C)C(O)=O>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: COC(C)C(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of methoxypropionic acid is heated to 100° C. The mixture is maintained and stirred at this temperature for 1 hour. After completion of the reaction, the mixture is cooled and 5 ml of ethyl acetate are added. The resulting mixture is stirred for 10 minutes, then it is filtered and the crystals are washed with ethyl acetate. After drying, 0.66 g of raw deferasirox is obtained, i.e. 60% of the theory, with an HPLC content of 99.3% and a melting temperature of 259 to 263° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Product: CC(C)NS(=O)(=O)c1[nH]c2ccccc2c1C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 79.4 %

Procedure:
Substantially the same procedure as in Example 266 was repeated using 4,4'-difluorobenzhydrol (0.99 g, 4.50 mmol) and N-isopropylindole-2-sulfonamide (1.00 g, 4.46 mmol) to give 1.56 g (yield: 80%) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:26]=[CH:25][N:24]=[C:23]5[NH:27][N:28]=[CH:29][C:22]=45)[CH2:17][CH2:16]3)[N:12](C)[CH:13]=2)=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31].[Cl:34][CH2:35]Cl>>[ClH:34].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:35])[CH:11]([CH:15]3[CH2:16][CH2:17][N:18]([C:21]4[N:26]=[CH:25][N:24]=[C:23]5[NH:27][N:28]=[CH:29][C:22]=45)[CH2:19][CH2:20]3)[NH:12][CH:13]=2)=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31]
Reactant: ClCCl
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3[nH]ncc23)CC1
Agent: Cl
Product: CN1C(c2ccc(F)c(C(F)(F)F)c2)=CNC1C1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.47 %

Procedure:
Add hydrogen chloride (1.1 equiv; 18.52 mmoles; 4.63 mL) to a suspension of 4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine (7.5 g; 1.00 equiv; 16.84 mmoles) in dichloromethane (50 mL), and stir the mixture for 1 hour at RT. Remove the solvent in vacuo, and triturate the crude in MTBE for 1 hour. Filter the solid and dry in vacuo overnight to give 4-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-3-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (7.99 g; 16.58 mmoles; 98.47% yield) as a white solid. 1H-NMR (300 MHz, DMSO): 614.01-13.99 (m, 1H), 8.57-8.54 (m, 2H), 8.26-8.19 (m, 3H), 7.72-7.63 (m, 1H), 5.23-5.20 (m, 2H), 3.89 (s, 3H), 3.41 (m, 2H), 2.15-2.07 (m, 3H), 1.10 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]4C(=O)C5=CC=CC=C5C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.O.NN.[ClH:35]>CO.O.C(O)C>[ClH:35].[ClH:35].[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: CO
Solvent: O
Product: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidinyl]-butyl]phthalimide (6.9 g, 16.4 mmol) and hydrazine monohydrate (1.64 g, 32.8 mmol) in methanol (70 ml) was heated at reflux for 3 hours. At the end of the reaction, methanol was removed to leave a crude solid. This was dissolved in water and acidified with HCl to pH 2. The insolubles were filtered. The aqueous solution was basified with 50% NaOH, and then extracted with dichloromethane. The dichloromethane solution was washed with water and brine, and then dried over MgSO4. The solvent was removed to a colorless oil: 4.48 g. This oil was treated with 2.5 equivalents of HCl in ethanol. The solid was collected. Recrystallization from ethanol (65 ml) and methanol (20 ml) gave 2.0 g of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride as white crystals, m.p.=234°-237° C.
Reaction SMILES: [CH:1]1[NH:2][CH:3]=[CH:4][C:5]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2[C:5]=1[CH:4]=[CH:3][NH:2][CH:1]=2)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: C1=CC=C2C=CNC=C2C=C1
Product: CC(=O)OC1=C2C=CNC=C2C=CC=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclohepta[1,2-c]pyridine, N-oxide (24.00 g, 0.147 mole) was added portionwise to a stirred solution of acetic anhydride (140 ml). The resulting yellow mixture was then stirred for 2 hours at its reflux temperature and overnight at room temperature. Excess acetic anhydride was removed by evaporation at ~55° C. on a rotary evaporator and the dark brown, oily residue was distilled (170°, 0.03 mm) and chromatographed on silica gel eluting with a mixture of ethyl acetate in methylene chloride (1:4) to give the desired product.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=N)[CH2:6][C:7](OCC)=[O:8])[CH3:3].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[NH:25][NH2:26].[Na].C(O)(=O)C>CO.O>[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[N:25]1[C:7](=[O:8])[CH:6]=[C:5]([O:4][CH2:2][CH3:3])[NH:26]1
Reactant: COC(=O)c1cc(Cl)c(NN)c(Cl)c1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCOc1cc(=O)n(-c2c(Cl)cc(C(=O)OC)cc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Preparation using the method described in U.S. Pat. No. 3,615,506. A mixture of 11 g of ethyl β-ethoxy-β-iminopropionate hydrochloride and 12 g of 2,6 -dichloro-4-methoxycarbonylphenylhydrazine [Intermediate (h) used in Method (a) above] in 100 ml of methanol was stirred at room temperature for 1 hour. A solution containing 3g of metallic sodium dissolved in 50 ml of methanol was added dropwise to the mixture, and the mixture was further stirred at room temperature (about 20°-30°C) for 1 hour. After adding 15 ml of acetic acid, the reaction mixture was poured into 500 ml of water. The cyrstals formed were collected and recrystallized from methanol to obtain 11 g of 1-(2,6 -dichloro-4-methoxycarbonylphenyl)-3-ethoxy-5-pyrazolone having a melting point of 101°-102.5°C. A mixture of 8 g of the 3-ethoxy-5-pyrazolone compound and 4 g of 2,4 -dichloroaniline was heated to 140° C to form a uniform melt and after adding 1.4 g of methanesulfonic acid to the melt, the reaction was carried out at 140°-150°C for 3 hours with stirring while distilling off the ethanol formed. The reaction mixture was allowed to cool to 100°C and after adding 10 ml of methanol to dissolve the solid, the mixture was allowed to cool to room temperature to form cyrstals which were collected and recrystallized from methanol to obtain the desired compound. The melting point of the product was 132°-135°C and no lowering of the melting point was observed when it was melted together with 1-(2,6 -dichloro-4-methoxycarbonylphenyl)-3-(2,4 -dichloroanilino)-5-pyrazolone prepared by Method (a). The infrared spectra of both compounds were completely identical.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1B(O)O>>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Agent: OB(O)c1ccccc1
Product: COc1ccc(-c2ccc3c(c2)C(c2cccc(C#N)c2)=NCC(=O)N3C)c(OC)c1
Yield: 49 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2,4-dimethoxyphenyl boronic acid. The title compound (135 mg) was obtained as a yellow solid, (yield=49%).