Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3]1.[Br:15]N1C(=O)CCC1=O>C(#N)C.[O-2].[O-2].[Mn+4]>[Br:15][C:5]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][N:2]([CH3:1])[C:6]=1[CH:7]=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nc(-c2ccccc2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: Cn1nc(-c2ccccc2)c(Br)c1C=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 63.5 %

Procedure:
A solution of (1-methyl-3-phenyl-1H-pyrazol-5-yl)methanol (1b) (340 mg, 1.81 mmol) and N-bromosuccinimide (338 mg, 1.90 mmol) in acetonitrile (30 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. Water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (2×12 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was taken in dichloromethane (5 mL) and manganese dioxide (1.57 g, 18.06 mmol) was added. The reaction mixture was stirred at room temperature for 40 hours, filtered over Celite®, and the filtrate was concentrated in vacuo. The residue was dissolved in a minimum of dichloromethane and purified thought a pad of silice, (cyclohexane/ethyl acetate 80/20), to provide 4-bromo-1-methyl-3-phenyl-1H-pyrazole-5-carbaldehyde (1c) (304 mg, 1.15 mmol, 63%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:13](OCC)(=[O:17])[C:14]([O-])=[O:15]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][C:14](=[O:15])[C:13](=[O:17])[NH:10]2
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: CCOC(=O)C(=O)[O-]
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
4-Trifluoromethyl-o-phenylenediamine (8.0 grams) was added to 80 ml. of ethyl oxalate and the resulting mixture was heated to reflux and refluxed for two hours. A precipitate formed during this period. The reaction mixture was then cooled to room temperature and filtered to separate the precipitate, m.p. 344°-346°C. (dec.) The product was identified as the expected 6-trifluoromethyl- 2(1H), 3(4H)-quinoxalinedione, by IR, TLC, NMR, and microanalysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.N>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1ncnc2c1c(I)cn2-c1ccccc1
Temperature: 25 °C
Reaction time: 288 h

Procedure:
A mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (280 mg, 1.00 mmol), phenylboronic acid (244 mg, 2.00 mmol), pyridine (165 μL, 161 mg, 2.04 mmol), and Cu(OAc)2 (272 mg, 1.50 mmol) in CH2Cl2 (5 mL) was stirred under air at ambient temperature for 12 d. Aqueous ammonia (1 M) and CH2Cl2 were added, the solids were filtered off, the layers of the filtrate were separated, the aqueous layer was extracted with CH2Cl2 (2×30 mL), the combined CH2Cl2 layers were washed with 1 M aqueous ammonia (2×), 2 M NaOH (2×), and brine and dried over MgSO4. The crude material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with CH2Cl2], yielding the title compound as off-white solid. 1H NMR (CDCl3, 400 MHz): δ=7.43-7.48 (m, 1H), 7.54-7.60 (m, 2H), 7.61-7.65 (m, 2H), 7.69 (s, 1H), 8.68 (s, 1H). MS (ES+): m/z 355.9/357.9 (100/35) [MH+]. HPLC: tR=3.8 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11](I)=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([OH:31])[C:29]#[CH:30]>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:30]#[C:29][CH2:28][OH:31])=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred slurry of 1.15 g of 1-(tert-butyl)-N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 10, 156 mg of copper (I) iodide, and 66 mg of dichlorobis(triphenylphosphine)palladium (II) in 23 mL of diethylamine, under argon, is added 0.16 mL of propargyl alcohol. The mixture is stirred for 18 hour at room temperature, then concentrated under reduced pressure. The residue is partitioned between water and chloroform-methanol, and the organic phase dried (MgSO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 2-4% methanol in dichloromethane affords 977 mg of tan solid. Recrystallization from ethanol provides 850 mg of the title compound as a beige solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23](Cl)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:8][CH:9]=2)[N:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-c3ccncc3)cc2)n1

Procedure:
Prepared in analogy to example 62 from 4-(pyridin-4-yl) aniline and 4-benzyl-2-chloro-6-methyl-pyrimidine (example 43a). The title compound was obtained as a brownish oil (Yield=31%). MS ISP (m/e): 353.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.80 (s, 1H), 8.57 (d, 2H), 7.95 (d, 2H), 7.74 (d, 2H), 7.69 (d, 2H), 7.40-7.15 (m, 5H), 6.68 (s, 1H), 3.95 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.Cl.[NH2:12][OH:13]>CO.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[N:12][OH:13]
Reactant: NO
Reactant: Cc1ccc(C=O)cc1Cl
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C=NO)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
In a solution of 5.0 g of 3-chloro-4-methylbenzaldehyde in 40 mL of methanol and 30 mL of water, 4.7 g of hydroxylamine hydrochloride was added, and stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was diluted with 70 mL of ethyl acetate, washed with water (30 mL×1), and then dehydrated with and dried over saturated sodium chloride and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 5.1 g of the aimed product as white crystal. The resulting product was used as such without purification for the next step.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[S:7][N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12>>[N:6]1[S:7][N:8]=[C:9]2[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2nsnc2c1
Product: O=S(=O)(Cl)c1cccc2nsnc12
Temperature: 25 °C

Procedure:
To a stirred solution of 100 mL of chlorosulfonic acid at 0° C. was added 10.0 g of 2,1,3-benzothiadiazole under an inert atmosphere. The resulting mixture was heated at reflux for 30 minutes and cooled to room temperature. The reaction mixture was added dropwise to 1000 mL ice. The precipitates was collected, washed with water, and air dried to give the title compound as a beige solid, m.p. 146°-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1.[CH:22]1[N:26]=[CH:25][N:24]([C:27](N2C=NC=C2)=[O:28])[CH:23]=1>C(#N)C>[CH3:19][N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=2)[CH:17]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([N:24]3[CH:23]=[CH:22][N:26]=[CH:25]3)=[O:28])[CH:3]=[CH:4][C:5]=2[CH3:21])[C:9]1=[O:20]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=O)n3ccnc3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(5-amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 15 (22 mg, 0.08 mmol) in ACN (0.5 mL) was added CDI (16 mg, 0.09 mmol). After stirring at rt for 2 h, solvent was removed and the crude N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-1H-imidazole-1-carboxamide 18 was used without further purification. MS m/z 374.3 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:11]1([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:31]([O:37]C(C)(C)C)(=O)[CH2:32][C:33]([O-:35])=O.C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>CO.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:27]([C:26]4[CH:25]=[CH:24][C:23]([N:20]5[CH2:21][CH2:22][N:17]([C:11]6[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=6)[CH2:18][CH2:19]5)=[CH:30][CH:29]=4)[C:31](=[O:37])[CH2:32][C:33]3=[O:35])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=Cc1ccc(N2CCN(c3ccccc3)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCN(c3ccccc3)CC2)cc1
Reaction time: 96 h

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (1.01 g, 8.27 mmol), 4-(4-phenylpiperazin-1-yl)benzaldehyde (2.2 g, 8.27 mmol), mono-tert-butyl malonate (1.98 g, 12.40 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (1.3 g, 8.27 mmol) in MeOH/CH2Cl2 1:1 (80 ml) with stirring for 4 days and sodium tert.-butoxide (1.0 g, 8.59 mmol) according to method 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(C)=O>[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:18]
Reactant: O=C(Nc1ccc(F)cc1F)c1ccccc1O
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(F)cc1F)c1ccccc1OCc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
To a solution of compound 3a (0.50 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and 2,4-difluorobenzyl bromide (0.56 mL, 4.4 mmole) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[NH:13]1[C:17](B(O)O)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:17]2[NH:13][N:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: OB(O)c1ccn[nH]1
Reactant: CCOC(=O)c1sc(Br)nc1C
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccn[nH]2)nc1C
Temperature: 100 °C
Yield: 79.1 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (2.0 g, 7.99 mmol) in toluene (60 mL), water (20 mL) and ethanol (20 mL) was added 1H-pyrazole-5-boronic acid (1.79 g, 15.99 mmol), Pd(PPh3)4 (0.92 g, 0.80 mmol), and potassium carbonate (3.30 g, 23.98 mmol). The resulting mixture was degassed three times and heated to 100° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (hexanes:ethyl acetate, 1:1) to provide 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid ethyl ester (1.5 g, 83% yield) as a yellow solid. MS (M+H)+=238; Rt=1.2 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[O:8])=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+].ClCCl>C(#N)C.O>[Cl:1][CH2:2][C:3]1[O:8][C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[N:6][N:5]=1
Reactant: O=C(CCl)NNC(=O)C1CCN(c2ccccn2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: ClCc1nnc(C2CCN(c3ccccn3)CC2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The hydrazide of Preparation 3 (50.0 g, 169 mmol) was suspended in acetonitrile (250 ml) and cooled using an ice bath. Trifluoromethanesulfonic anhydride (29.9 ml, 177 mmol) was added dropwise at T<15° C. The reaction was warmed to room temperature and stirred for 16 hours. The reaction was cooled using an ice bath and a solution of sodium hydrogen carbonate (29.8 g, 354 mmol) in water (250 ml) was added dropwise. Dichloromethane (250 ml) was added and the phases were separated. The organic containing product phase was used in preparation 14b.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24]([O:26]CC)=[O:25])=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7].[OH-].[Na+].Cl>C1COCC1.O.CO>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24]([OH:26])=[O:25])=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: CCOC(=O)c1n[nH]c2cc(-c3ccc(NC(=O)c4cccc(C(F)(F)F)c4)cc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(-c2ccc3c(C(=O)O)n[nH]c3c2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 127 %

Procedure:
To a stirred solution of ethyl 6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate (12 mg, 25 μmol) in THF/water/methanol (10/1/1, 2.5 Ml), was added 1N aqueous sodium hydroxide solution (1.3 Ml). The mixture was stirred at 70° C. for 12 h and cooled to room temperature. The pH of solution was adjusted to 4-5 with 1N hydrochloric acid aqueous solution. The aqueous solution was extracted with ethyl acetate and the combined organic layer was washed with water, dried over magnesium sulfated, and concentrated under reduced pressure to give 6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylic acid (13.5 mg), which was used in next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[CH:37][CH:36]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
1-[1-(4-Fluoro-benzyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]-pyrimidine was prepared according to General Procedure H by the reaction 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 4-fluorobenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.93-1.99 (m, 2H), 2.20-2.30 (m, 4H), 2.93-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.53 (s, 2H), 4.75-4.81 (m, 1H), 7.14-7.19 (m, 2H), 7.36-7.40 (m, 2H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.38 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=482.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C(O)(C)C>C1COCC1.O>[O:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH:23]([C:22]3[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[OH:24])=[CH:3][C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: COc1ccc(C=O)cc1
Reactant: Brc1ccc2c(c1)OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc3c(c2)OCCO3)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 6-bromo-2,3-dihydro-benzo[1,4]dioxine (1.66 g, 7.7 mmol) and dry THF (20 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (2.9 mL, 7.4 mmol) and stirred for 20 min. Then a mixture of 4-methoxy-benzaldehyde (0.90 g, 6.6 mmol) in dry THF (10 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.4 mL, 44 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organic phases were washed with water (2×30 mL), dried over MgSO4 and concentrated to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-methoxy-phenyl)-methanol as an oil (2.04 g, 102% crude yield). The product was used in the next step without further purification.
Reaction SMILES: C(O)(=O)C.[N:5]1([C:11]2[C:12](=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:8]1[CH2:7][CH2:6][N:5]([C:11]2[C:12](=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9]1
Reactant: O=c1cccccc1N1CCNCC1
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cccc(CN2CCN(c3cccccc3=O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatriene-1-one acetic acid salt (0.171 g, 0.680 mmol, example 2a), 3-methoxybenzyl chloride (0.118 g, 0.750 mmol) and potassium carbonate (0.276 g, 2.00 mmol) in acetonitrile (2.00 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo. The residue was triturated with dichloromethane and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to preparative thin layer chromatography using ethyl acetate:methanol (9:1) as the eluent. The title compound was obtained as a yellow oil (0.095 g, 45%); MS (FAB) 311 (M+ +1).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]([C:9](=[O:34])[CH:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]([NH:13][S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)(=[O:16])=[O:15])=[O:12])[CH2:7][CH3:8])C.O.[OH-].[Na+]>C1COCC1>[CH2:27]([CH:10]([C:11]([NH:13][S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)(=[O:16])=[O:15])=[O:12])[C:9]([N:6]([CH2:7][CH3:8])[CH2:5][C:4]([OH:35])=[O:3])=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CN(CC)C(=O)C(Cc1ccccc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC(=O)O)C(=O)C(Cc1ccccc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 2.5 h
Yield: 89.5 %

Procedure:
To a mixture of the compound (250 mg) obtained by Example 2 in THF (10 mL)/water (3 mL) was added 1 mol/L aqueous sodium hydroxide solution (1.5 mL) at room temperature, and the mixture was stirred for 2.5 hr. After concentration under reduced pressure, the residue was adjusted to pH=1-2 by the addition of 1 mol/L hydrochloric acid and extracted with ethyl acetate (50 mL×2). The organic layer was washed with saturated brine and concentrated under reduced pressure to give the title compound (211 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]([N:9]1[CH2:14][C@H:13]([CH3:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH3:24])=[O:8].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.C([O:48][C:49](=[O:56])[CH:50]([S:52](Cl)(=[O:54])=[O:53])[CH3:51])C>O1CCCC1.C(OCC)(=O)C>[Cl:29][C:27]1[CH:26]=[CH:25][C:4]([O:5][CH2:6][C:7]([N:9]2[CH2:14][C@H:13]([CH3:15])[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:11][C@H:10]2[CH3:24])=[O:8])=[C:3]([CH:28]=1)[CH2:2][NH:1][S:52]([CH:50]([CH3:51])[C:49]([OH:56])=[O:48])(=[O:54])=[O:53]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN
Reactant: CCOC(=O)C(C)S(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C(=O)O)S(=O)(=O)NCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C

Procedure:
To a solution of 2-(2-aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.05 g, 0.119 mmol) in tetrahydrofuran (1 ml) at −40° C. was added triethylamine (0.021 ml, 0.151 mmol), catalytic dimethylaminopyridine and finally a solution of 2-chlorosulfonyl-propionic acid ethyl ester (for preparation, see: Helv. Chim. Acta., (1997) 80, 671 and Bull. Soc. Chim. Fr. (1975), 807) (0.029 g, 0.145 mmol) in tetrahydrofuran (0.25 ml), added over 5 minutes. The reaction was allowed to warm to ambient temperature. After 23 hours the reaction was diluted with ethyl acetate and washed with pH 7 phosphate buffer (0.5 M). The organic layer was dried over magnesium sulfate, filtered and concentrated. The desired product was isolated via silica gel chromatography (0.047 g). This ester (0.07 mmol) was dissolved in 1:1 tetrahydrofuran:water (1 ml) and lithium hydroxide hydrate (5.8 mg, 0.138 mmol) was added. After 21 hours the reaction was concentrated and the title compound obtained after silica gel chromatography (0.039 g, LRMS: 556.1).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[N:9]=1>>[Br:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:2]([CH3:5])([CH3:3])[CH3:1])[N:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Brc1cccc(Br)n1
Agent: [K+]
Product: CC(C)(C)c1cccc(Br)n1
Yield: 69 %

Procedure:
To potassium tert-butoxide (1.0M in tert butanol, 100 ml, 100 mmol) was added 2,6-dibromopyridine (15.87 g, 67 mmol), and the resulting mixture heated at reflux for 3.5 hours. The mixture was evaporated and the residue quenched by the addition of water (150 ml). The mixture was extracted with ethyl acetate (3×80 ml) and the combined organic layers washed with brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with 2% Et2O in iso-hexanes to give the title compound (9.9 g, 69%) as a clear oil.