Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]([CH:17]([CH3:19])[CH3:18])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:8]#[N:9])C.O.O.C(O)(=O)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]([CH:17]([CH3:19])[CH3:18])([CH2:6][CH2:5][CH:4]=[O:3])[C:8]#[N:9]
Reactant: CCOC(CCC(C#N)(c1ccccc1C)C(C)C)OCC
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccccc1C(C#N)(CCC=O)C(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of 5,5-diethoxy-2-isopropyl-2-(2-methylphenyl)-valeronitrile (267 g) in acetone (2000 ml) is added under stirring a solution of oxalic acid dihydrate (121.7 g) in water (730 ml) and the mixture is warmed under continuous stirring for 4 hours at 40° C. Thereafter it is cooled and under external cooling to 520 C. adjusted by the addition of a 50% aqueous potassium carbonate solution to pH within the range of 6 to 6.5. The formed potassium oxalate precipitate is filtered off and washed with acetone (500 ml). From the filtrate the solvent is evaporated under reduced pressure (bath temperature above 30° C.). The residue is mixed with water (600 ml) and ether (500 ml), the separated aqueous phase is extracted with ether (2×300 ml), the combined organic solutions are washed with aqueous sodium hydrogencarbonate, water and staturated brine until neutral reaction, dried over anhydrous magnesium sulfate and the solvent is evaporated (bath temperature about 30° C.) under reduced pressure, finally at about 1.3 kPa, to yield 203 g of the oily crude product (claimed compound content of 93.2% as determined by gas-liquid chromatography). The obtained material is used without separate purification for the subsequent reductive alkylation.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)=[O:13].O>CS(C)=O>[C:1]1([S:7]([C:17]2[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH3:11])=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Yield: 87.3 %

Procedure:
Preparation 1 of WO 96/262,196 described the reaction of sodium benzenesulfinate (43 g, 0.26 mol) and 4-fluoroaceto phenone (30 g, 0.22 mol) at 130° C. in dimethyl sulfoxide (200 mL) for 48 hours. The mixture is then poured into 1000 mL of water. The solid formed is colled and dried to give 50 g of 1-(4-phenylsulfonyl-phenyl)-ethanone. This solid is suspended in ethanol (350 mL), heated to 60° C. and treated as described in J. Med. Chem., 34, 3295 (1991) to give 4-phenylsulfonyl benzoic acid melting at 269–271° C. A suspension of 4-phenyl sulfonylbenzoic acid (15 g, 0.57 mol) in toluene (50 mL) is treated with thionyl chloride (25 mL). A few drops of N,N-dimethylformamide are added and the suspension is heated to 70° C. for three hours. The solution is concentrated to give the title intermediate compound which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.[CH3:19]O.S(=O)(=O)(O)O>O>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)Cc1cc(C(=O)O)ccc1O2
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc2c(c1)Cc1cc(C)ccc1O2
Temperature: 40 °C

Procedure:
Twenty-six grams of 7-methylxanthene-2-carboxylic acid is added to 400 ml. of absolute methanol. To the resultant solution are added 18 ml. of concentrated sulfuric acid and the mixture is then heated at reflux for about 2 hours. The mixture is then cooled to 40°C and sufficient water is added to bring the total volume to 1400 ml. The resultant mixture is then filtered to give methyl 7-methylxanthene-2-carboxylate.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([Cl:30])[CH:18]=1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[Cl:30][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:16][NH2:15]
Reactant: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)c1ccc(CN)cc1Cl
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Add 4N hydrogen chloride in dioxane (0.9 mL, 3.6 mmol) to a solution of N-(tert-butoxycarbonyl)-3-chloro-4-(3,3-dimethyl-butyryl)-benzylamine (100 mg, 0.3 mmol) in dichloromethane (6 mL) and stir overnight. Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend the solid into saturated aqueous NaHCO3 and stir for 30 min. Extract twice with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as a yellow oil (66 mg, 92%).
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([C:13]2[O:26][C:2]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccn3)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3)oc12
Yield: 17.2 %

Procedure:
Methyl 2-hydroxy-3-(4-(pyridin-2-yl)benzamido)benzoate (1.04 g, 3 mmol) and 4-methylbenzenesulfonic acid monohydrate (1.2 g, 6 mmol) were added to toluene (20 mL) and the mixture was stirred under reflux for 2 days. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 10:1). 170 mg of solid of methyl 2-(4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate was obtained. Yield: 17%. LC-MS (ESI) m/z: 331 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[Cl:27][C:28]1[C:38]([Cl:39])=[CH:37][C:31]2[C:32](=O)[O:33][C:34](=[O:35])[C:30]=2[CH:29]=1>>[Cl:27][C:28]1[CH:29]=[C:30]2[C:31](=[CH:37][C:38]=1[Cl:39])[C:32](=[O:33])[N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[C:34]2=[O:35]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)c6cc(Cl)c(Cl)cc6C5=O)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5,6-dichloro-2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: [C:1]([CH:7]([OH:14])[CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][OH:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].N1C=CN=C1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[Si:20]([CH:11]([OH:12])[CH2:10][CH:9]([OH:13])[CH2:8][CH:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[OH:14])([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)C(=O)C(O)CC(O)CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(O)CC(O)CC(O)[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 75 %

Procedure:
To a solution of 59 (8.0 g, 39.16) and imidazole (3.0 g, 43.07 mmol) in CH2Cl2 (170 mL) is added TBDPS-chloride (11.20 mL, 39.16 mmol) over a period of 1 h at room temperature. After stirring for 1 more h, the solvent is removed and the residue is purified on a silica gel column using ethyl acetate:hexanes as eluent to provide 13 g (75%) of 60, as a colorless oil: 1HNMR (DMSO-d6): 7.57-7.67 (m, 4 H), 7.36-7.47 (m, 6 H), 4.55 (d, J=5.8 Hz, 1 H), 4.06-4.11 (m, 2 H), 3.66-3.85 (m, 3 H), 1.53-1.73 (m, 4 H), 1.11 (s, 9 H) and 0.97 (s, 9 H). IR (KBr, cm−1): 3514, 2959, 2858, 1726, 1473 and 1428. HRMS Calcd for C26H38O4Si (M+H)+ 443.2617. Found 443.2598.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(Br)cc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 92 %

Procedure:
As described for Example 49, 3-(4-bromo-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (91 mg, 0.3 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (117 mg, 92%) which was obtained as a light yellow solid. MS: m/e 425.0/426.9 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:40])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:39])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:39][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
Lithium hydroxide monohydrate (0.011 g, 0.26 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.032 g, 0.06 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.027 g, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H) 8.23 (d, J=8.90 Hz, 2 H) 8.16 (d, J=8.30 Hz, 2 H) 7.97-8.05 (m, 1 H) 7.90 (s, 1 H) 7.68 (d, J=8.70 Hz, 2 H) 7.54 (d, J=8.80 Hz, 2H) 7.34-7.43 (m, 1H) 6.63 (d, J=10.90 Hz, 1 H) 3.83 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C26H17F4O5S [(M−H)−] 517, obsd. 517.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:26]1([N:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])[CH2:38][CH2:37]2)[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:46][CH2:45][CH2:44][CH2:43][CH2:42][N:39]2[CH2:40][CH2:41][N:36]([C:26]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)[CH2:37][CH2:38]2)=[O:11])[CH:2]=1
Reactant: NCCCCN1CCN(c2cccc3c2CCCC3)CC1
Reactant: O=C(O)C=Cc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCN(c2cccc3c2CCCC3)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.6 g (11.1 mmol) 3-(3-pyridyl)-acrylic acid and 6.2 ml (44.3 mmol) TEA are suspended in 80 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. 2.0 g (12.1 mmol) 81% HOBT and 2.3 g (12.1 mmol) EDC are added and the mixture is stirred for 30 min under ice cooling. 4.0 g (10.1 mmol) 4-[4-(5,6,7,8-tetrahydro-naphthalin-1-yl)-piperazin-1-yl]-butylamine are added and the mixture is stirred without cooling overnight at RT. Subsequently, the batch is washed twice with 25 ml 2M sodium hydroxide solution and 25 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically pre-purified over silica gel with CHCl3/CH3OH (95/5) and crystallized twice from acetonitrile (25 ml and 15 ml): Colorless crystals of MP. 108-109° C.; yield 2.7 g (64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[CH:21][N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[N:19]=3)[CH:16]=2)[N:11]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:10]=1.C([Li])CCC.[C:48](=[O:50])=[O:49]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[C:21]([C:48]([OH:50])=[O:49])[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:24])=[O:25])[N:19]=3)[CH:16]=2)[N:11]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccn(S(=O)(=O)c4ccc(C)cc4)n3)cc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)O)n(S(=O)(=O)c4ccc(C)cc4)n3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a cooled solution (−78° C.) of 3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-5-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (458 mg, 0.765 mmol) in dry tetrahydrofuran (7 mL) was added 2.5 M n-butyl lithium (n-BuLi) (336 μL. 0.842 mmol) over 15 min. After 2 h at −78° C., a stream of carbon dioxide gas was added to the mixture for 5 min. The reaction was allowed to warm to room temperature. After stirring 3 h, the reaction was quenched by the addition of saturated ammonium chloride and extracted into ethyl acetate. The organic layer was dried over sodium sulfate and purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford 5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(toluene-4-sulfonyl)-2H-pyrazole-3-carboxylic acid (114 mg, 23%). MS: m/z 643 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1CCN2C(=NCCC2)CC1>COCCOC>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1COc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 10.76 g (55 mmol) of N-chloromethylphthalimide in 80 ml of DME, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene was added. The mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the reaction mixture was poured into water and extracted with ethyl acetate. The precipitate was filtered off. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.67 g of the desired compound (yield: 21%, colorless crystals).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.[H-].[Na+].Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35].O>CN(C)C=O>[N+:31]([C:28]1[CH:27]=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=[CH:30][C:29]=1[S:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1)([O-:33])=[O:32]
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCc1sc(Sc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])nc1-2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.30 g, 4.04 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% dispersion in liquid paraffin, 178 mg, 4.45 mmol) at 0° C., and the mixture was stirred at room temperature for 10 minutes. To this mixture was added 1-chloro-2,4-dinitrobenzene (900 mg, 4.45 mmol) and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was poured into water (30 mL) and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl [(2-(2,4-dinitrophenyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.17 g). To a solution of this compound (1.17 g, 2.40 mmol) in a mixture of tetrahydrofuran (16 mL) and methanol (4 mL) was added 1N-aqueous sodium hydroxide (3.0 mL) dropwise and the mixture was stirred at room temperature for 20 minutes. After the solvent was distilled off water reduced pressure, 1N-hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to provide 0.91 g of the title compound. Yield 49%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]2[NH:24][N:25]=[CH:26][C:19]=12.C(N(CC)C(C)C)(C)C>CC(O)C>[CH2:8]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[CH:26][C:19]=23)[CH2:12][CH2:11]1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@H]1CC[C@H](OCCc2ccccc2)CC1
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: c1ccc(CCOC2CCC(Nc3ncnc4[nH]ncc34)CC2)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
A mixture of 219 mg of trans-4-(2-phenyl-ethoxy)-cyclohexylamine, 154 mg of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (R. K. Robins, J. Amer. Chem. Soc., 78, 784-790 (1956)), 10 mL of 2-propanol and 0.174 mL of N,N-diisopropyl-ethylamine was heated to 80° C. for 12 hours. The mixture was cooled and concentrated under reduced pressure and purified by either preparative TLC eluting with 50:50:5 THF:diethyl ether:NH4OH or preparative reverse phase chromatography on delta Pak C (C-18 column) eluting with a gradient of 90:10 to 0:100 of 0.1% TFA in H2O: CH3CN gave 60-92% of (4-phenethyloxy-cyclohexyl)-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amine as a white crystalline solid. MS (m+1)=338.32; 1H NMR (400 MHz, CDCl3) 8.43 (s, 1H), 7.92 (s, 1H), 7.3-7.2 (m, 5H), 3.7 (t, 2H), 3.3 (m, 1H), 2.9 (t, 2H), 2.22 (d, 2H), 2.1 (d, 2H), 1.7 (m, 1H), 1.5 (dd, 2H), 1.4 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:7](O)=[O:8])[S:5][CH:6]=1.S(Cl)([Cl:13])=O>CN(C=O)C.ClCCCl>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:7]([Cl:13])=[O:8])[S:5][CH:6]=1
Reactant: Cc1c(Br)csc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1c(Br)csc1C(=O)Cl
Yield: 100.2 %

Procedure:
A slurry of 1.11 g (5 mmole) of 4-bromo-3-methyl-2-thiophenecarboxylic acid, 0.44 mL (6 mmole) of thionyl chloride, 5 drops of DMF, and 10 mL of 1,2-dichloroethane was heated at 80° C. for 1.5 h. The clear solution was cooled and concentrated on a roto-evaporator. The residue was dissolved in 5 mL of 1,2-dichloroethane and reconcentrated on a roto-evaporator to give 1.2 g of a tan solid, 97% pure (GC area). This acid chloride was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C-:12]#[N:13].[Na+].O>CN(C)C=O>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:12]#[N:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CC#N)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
To a stirred solution of 100 g of 4-isopropylbenzyl chloride in 1500 mL of N,N-dimethylformamide was added 32.0 g of sodium cyanide under ice-cooling. The mixture was stirred at 70° C. for 4 hours, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 96.5 g of (4-isopropylphenyl)acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]([CH2:29][CH2:30][C:31](O)=[O:32])=[CH:27][O:26][N:25]=2)=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:28]2[C:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)=[N:25][O:26][CH:27]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2conc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.76 g), 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.66 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.49 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (1.14 g, yield 91%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 88–90° C.