Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])#[N:2].[NH2:20][NH2:21]>C(#N)C>[NH2:2][C:1]1[NH:21][N:20]=[C:4]([NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[N:3]=1
Reactant: CSC(=NC#N)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: NN
Solvent: CC#N
Product: Nc1nc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])n[nH]1
Reaction time: 216 h
Yield: 82.2 %

Procedure:
A suspension of 29.4 g (98.0 mmol) of N'-Cyano-N-(2-nitrophenylsulfonyl)-S-methylisothiourea in 100 ml of acetonitrile was treated with 6.2 ml (6.3 g, 0.20 mol) of anhydrous hydrazine. A mild exothermic reaction occurred as the reaction mixture became homogeneous. After stirring for 9 days the precipitated solid was collected by filtration and dried to afford 22.9 g of yellow solid. The crude product was recrystallized from HOAc to yield a total of 15.9 g (57 percent) of the desired product as a pale yellow solid, mp 255°-256° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][C:12](=O)[CH2:13][CH3:14].C(O)(C(F)(F)F)=O>C(OC(C)=O)(C)C>[Cl:9][C:5]1[CH:6]=[C:7]([NH:8][CH:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CCC(=O)CC
Reactant: Nc1cc(Cl)cnc1N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: CCC(CC)Nc1cc(Cl)cnc1N
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 2,3-diamino-5-chloropyridine (7.0 g, 48.6 mmol, 1.0 equiv) and 3-pentanone (6.16 mL, 58.3 mmol, 1.2 equiv) in iPrOAc (100 mL) was added TFA (7.2 mL, 97.2 mmol, 2.0 equiv) by syringe. After stirring for 10 min, NaHB(OAc)3 (20 g, 97.2 mmol, 2.0 equiv) was added as a solid in several portions over ˜5 min. The reaction was allowed to stir overnight. The reaction mixture was then washed with satd. aq. NaHCO3 and brine, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC (10%-40% EtOAc/Hexanes) provided 5-chloro-N3-(pentan-3-yl)pyridine-2,3-diamine as a beige solid (2.6 g, 25%). m/z=214.1 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10].[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10]
Reactant: Sc1ccccc1
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)nc2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1nc(-c2ccc(Sc3ccccc3)nc2)oc1C
Yield: 73.4 %

Procedure:
[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (4.8 g, 17.98 mmol) is dissolved in anhydrous dimethylformamide (100 mL) and allowed to stir under nitrogen. Benzenethiol (2.78 mL, 27 mmol) is added by syringe, followed by anhydrous cesium carbonate (12.6 g, 36 mmol). The mixture is allowed to stir under nitrogen 50° C. and monitored by HPLC. After complete consumption of strating material, the solution is quenched with 1N sodium hydroxide solution, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure (5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acid methyl ester (4.51 g, 13.2 mmol) is isolated in 74% yield after column chromatography.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[Cl:17]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[C:7]([Cl:17])[CH:6]=1
Reactant: ClCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CNC(=O)Oc1cc(Cl)cc2c1OC(C)(C)C2
Yield: 88.9 %

Procedure:
To a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (33.2 g, 0.15 mol) in 150 ml of chloroform and 300 ml of carbon tetrachloride, chlorine (10.7 g, 0.15 mol) was gradually fed at a temperature of from 10° to 15° C. under stirring. The precipitated crystals were collected by filtration and washed with hexane, whereby 34.1 g of 5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate was obtained. The melting of this product was 167°-169° C. The structure was confirmed by 1H-NMR spectrum. Then, the product was added to 100 ml of a 10% aqueous sodium hydroxide-methanol solution and heated at 80° C. for 3 hours. The reaction solution was neutralized with hydrochloric acid and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated, whereby 23.0 g of 5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranol was obtained. The melting point of this product was 65.5°-66.5° C. The phenol thus obtained, was reacted with O-ethyl-S-n-propyldithiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 18) identified in Table 1 was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22]C(C#N)=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]([OH:42])(=[O:41])[CH3:40]>Cl.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:27][CH2:28][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:30][CH2:31]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]4[CH:23]=[CH:22][C:40]([C:39]([OH:42])=[O:41])=[CH:18][CH:17]=4)=[CH:24][CH:25]=3)[C:3]=12
Reactant: CC(=O)O
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C#N)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: Cl
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C(=O)O)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (0.200 g, 0.000394 mol) was dissolved in a mxture of acetic acid (15 mL) and 6N solution of hydrochloric acid in water (15 mL) and the solution was heated at reflux for 12 hours. It was cooled to ambient temperature and concentrated under reduced pressure and the residue recrystallized from N,N-dimethylformamide to yield cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzoic acid (0.100 g, 0.00019 mol) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=1>ClCCl>[Cl:41][C:37]1[CH:36]=[C:35]([NH:34][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:20])=[CH:8][N:7]=3)=[CH:15][CH:14]=2)[CH:40]=[CH:39][N:38]=1
Reactant: O=C(O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Nc1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)Nc1ccnc(Cl)c1
Yield: 72.5 %

Procedure:
2.3 g (7.78 mmol) of 4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetic acid was dissolved in 10 ml of dichloromethane and cooled to a temperature of from -10° to 0° C. Then, 1.94 g (10.1 mmol) of 1-ethyl3-(dimethylaminopropyl)carbodiimide hydrochloride was added thereto, and the mixture was stirred at a temperature of from -10° to 0° C. 20 minutes later, 1.0 g (7.78 mmol) of 4-amino-2-chloropyridine was added thereto, and the mixture was gradually returned to room temperature with stirring and further stirred over night at room temperature. Then, 10 ml of dichloromethane was added to the reaction solution. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 2.3 g of the desired product as a slightly yellow powder (melting point: 49 to 53° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:1][N:2]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CNc1nc(-c2ccccc2)cs1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of N-methyl-4-phenyl-1,3-thiazol-2-amine (1.67 g, 8.8 mmol) in N,N-dimethylformamide (25 mL) was added 60% sodium hydride (350 mg, 8.8 mmol), and the mixture was stirred for 30 min. Methyl 4-(bromomethyl)benzoate (2.1 g, 9.2 mmol) was added and the mixture was stirred at room temperature for 1.5 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (2.6 g, yield 86%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:68]([O:75][CH2:76][C@@H:77]([C:79]([OH:81])=[O:80])[NH2:78])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:78][C@H:77]([C:79]([OH:81])=[O:80])[CH2:76][O:75][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine, (20.3 mg, 0.038 mmol) in DMF (2 ml) was added N-methylmorpholine (15 μl, 0.14 mmol). TBTU (14.8 mg, 0.046 mmol) was added the mixture was stirred at 30° C. for 1.5 hours. O-benzyl-L-serine (8.8 mg, 0.045 mmol) was added and the mixture was stirred overnight. The formation of the ketone of the title compound was confirmed. M/z: 718.04 (M+1) and 716.02 (M−1). Methanol (3 ml) and sodium borohydride (10.3 mg, 0.27 mmol) were added and the mixture was stirred for 1.5 hours. Ammonium acetate (20 mg) was added and the methanol was removed under reduced pressure. The remaining DMF-solution was purified by preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The combined organic phases were concentrated and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (2.3 mg, 8.5%).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:10]=1)=[O:4].[CH3:38][NH2:39]>CO>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:12]3[N:13]=[C:8]4[CH:7]=[CH:6][C:5]([C:3](=[O:4])[NH:39][CH3:38])=[CH:10][N:9]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:15][CH:16]=2)[CH2:23][CH2:22][CH2:21]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CN
Reactant: COC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Solvent: CO
Product: CNC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Reaction time: 1.5 h

Procedure:
A mixture of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (100 mg) and a solution of methylamine in methanol (2M, 1.4 mL) was heated at 100° C. under microwave irradiation for 90 minutes followed by a further 90 minutes. On cooling, the reaction mixture was concentrated in vacuo to give the title compound which was used without further purification in the next step.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[N:24]([CH3:30])[C:25](=[N:28][CH3:29])[S:26][CH:27]=1>C(#N)C>[CH3:30][N:24]1[C:23]([CH2:22][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:27][S:26]/[C:25]/1=[N:28]\[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN=c1scc(CCl)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C/N=c1\scc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C
Yield: 98.1 %

Procedure:
tert-Butyl piperazine-1-carboxylate (2.5 g) was dissolved in acetonitrile (50 mL). Potassium carbonate (3.7 g) and N-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H) -ylidene)-N-methylamine hydrochloride (3.2 g) were added thereto, and the mixture was mixed under reflux for 4 hours. The solvent was distilled off, and to the residue was added an aqueous potassium bicarbonate solution. The mixture was then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (4.3 g) as a brown oily matter.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[S:12])[NH:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O>>[CH2:1]([NH:8][C:9](=[S:12])[NH:10][N:11]=[CH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=S)NCc1ccccc1
Reactant: O=Cc1ccccn1
Product: S=C(NCc1ccccc1)NN=Cc1ccccn1

Procedure:
The title compound was prepared from a mixture of 4-benzylthiosemicarbazide (100 mg, 0.552 mmol) and 2-pyridinecarboxaldehyde (52 μL, 0.552 mmol) similar to Example 3 and isolated as a pale white solid (83 mg, 59%). 1H NMR (DMSO-d6): 11.84 (s, 1H), 9.27 (t, J=5.7 Hz, 1H), 8.57 (d, J=4.8 Hz, 1H), 8.30 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.40-7.31 (m, 3H), 7.26 (d, J=4.8 Hz, 1H), 4.86 (d, J=6.0 Hz, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N+:14]([O-])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(C2CC2)c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C2CC2)c2ccccc12
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of 1-cyclopropyl-4-nitronaphthalene (5 g, 23 mmol) in ethanol (200 mL) was stirred under hydrogen in the presence of Pd/C (10% net, 10.8 g). The reaction mixture was shaken overnight, filtered over celite, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield 1-amino-4-cyclopropylnaphthalene (3.1 g, 73%).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH:7]=1.CO>>[C:14]1([NH:13][S:12]([C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=2)(=[O:25])=[O:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[3-(naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid methyl ester (14d) (0.29 g, 0.79 mmol) in methanol (3 ml) 1N NaOH solution (2.4 ml, 2.4 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.22 g, 79%).
Reaction SMILES: [F:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:38]([F:42])([F:41])([F:40])[F:39]>C(OCC)C>[F:39][B-:38]([F:42])([F:41])[F:40].[F:1][CH2:2][S+:3]([C:14]1[CH:13]=[CH:12][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)CF)cc1
Reactant: c1ccc2ccccc2c1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2ccc3ccccc3c2)cc1

Procedure:
1-((Fluoromethyl)sulfinyl)-4-methylbenzene (481 mg, 2.79 mmol) of example 5 was dissolved in dry diethyl ether (15 mL) under argon atmosphere. Naphthalene (393.8 mg, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −50° C. After stabilizing the temperature below −50° C., trifluoromethanesulfonic anhydride (0.47 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred, at the same temperature, until the reaction was complete. HBF4 in diethyl ether (54%, 0.77 mL, 2 eq) was added. The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and washed with diethyl ether at 0° C. The desired product was obtained as a yellow oily solid (1.873 g) after heating at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: OCCOCCOc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of diethyleneglycol monophenyl ether (1.56 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-ethyl acetate; 50:1) and crystallized from dichloromethane-hexane to provide 0.9 g of 4-[[2-[[2-(phenoxy)ethyl]oxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 75°-76° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([NH:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][C:36]=1[O:44][CH3:45])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:25]([NH:32][C:33](=[O:34])[C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:37][C:36]=1[O:44][CH3:45])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B(O)O)ccc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)NCc1ccccc1

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (141 mg, 0.319 mmol), 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (100 mg, 0.351 mmol), palladium tetrakistriphenyphosphine (22 mg, 0.019 mmol) and sodium carbonate (81 mg, 0.765 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-benzyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (126 mg, 71%). 1H NMR (CDCl3) δ 1.83 (m, 6H), 2.34 (s, 3H), 2.45 (m, 11H), 4.02 (s, 3H), 4.43 (d, J=5.66 Hz, 2H), 4.95 (m, 1H), 5.52 (bs, 2H), 7.37 (m, 7H), 8.18 (m, 1H), 8.41 (m, 1H); LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =555.5, Rt=2.65 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:27]C(Br)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][C:17]([Br:27])=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Reactant: CC(Br)Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(Cc1cc(F)cc2cc(Br)oc12)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of 0.50 gm (1.71 mMol) N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane in 17 mL tetrahydrofuran at −78° C. were added 2.4 mL (3.84 mMol) n-butyllithium (1.6 M in hexane) dropwise. The resulting mixture was stirred for 1.5 hour and then 0.16 mL (1.86 mMol) dibromoethane were added. After stirring for an additional hour the reaction mixture was poured into a mixture of 25 mL saturated aqueous sodium bicarbonate and 50 mL diethyl ether. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride. All aqueous phases were combined and extracted with 50 mL diethyl ether. All organic phases were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 15% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.53 gm (89%) of the desired compound.