Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:20][C:21]1([CH3:30])[CH2:26]C(O)[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22]1>C(O[Sn](CCCC)(CCCC)O[Sn](OC(=O)C)(CCCC)CCCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]1[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22][C:21]([CH3:30])([CH3:26])[CH2:20]1)=[O:17])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)NCCCCCC(=O)OC
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: CCCC[Sn](CCCC)(OC(C)=O)O[Sn](CCCC)(CCCC)OC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)NCCCCCC(=O)OC1CC(C)(C)NC(C)(C)C1
Temperature: 110 °C
Yield: 89.6 %

Procedure:
A 250 mL single-necked reaction flask was equipped with a magnetic stirrer and a Dean-Stark trap fitted with a condenser and nitrogen inlet/outlet. To this flask was charged 6.1 g (22.5 mmol) of compound D, 5.29 g (33.7 mmol) of 2,2,6,6-tetramethyl-4-piperidinol, and 150 mL of toluene. Under a slow nitrogen flow, 8 mL of toluene was distilled off and the trap drained. After lowering the heat source and allowing the mixture to cool to 110° C., 0.17 g (0.28 mmol) of 1,3-diacetoxy-1,1,3,3-tetrabutyldistannoxane was added and the heat source raised. Another 100 mL of toluene was slowly distilled off over 16 hours and the resulting mixture was cooled to room temperature and diluted with methylene chloride. The organic solution was washed with water to remove excess amino alcohol and dried over anhydrous sodium carbonate. Filtration and removal of solvent under reduced pressure followed by further solvent removal in vacuo (<1 mm) at 60° C. gave 8.0 g (90%) of Compound VI as a light brown wax. The structure of the material was confirmed by 1H NMR analysis. 1H NMR (CDCl3): δ5.60 (m, 1H, NHCO—); 5.18 (m, 1H, R2CHOCO—); 3.25 (dt, 2H, —CH2—NH—); 2.28 (t, 2H, —CH2COO—); 2.16 (t, 2H, —CH2CONH—); 1.95-1.10 (m, 20H, CH2(CH2)3CH2, CH2(CH2)5, CH2CH2C(CH3)2); 1.20 (d, 12H, CH2C(CH3)2; 0.88 (t, 3H, —CH2CH3).
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[C:7]([C:10]12[CH2:17][CH:16]3[CH2:18][C:12]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH2:13][CH:14]1[CH2:15]3)[CH2:11]2)(=[O:9])C.C(O)(=[O:29])C>O1CCOCC1.O>[C:22]([O:21][C:20]([NH:19][C:12]12[CH2:18][CH:16]3[CH2:15][CH:14]([CH2:13]1)[C:10]([C:7]([OH:9])=[O:29])([CH2:17]3)[CH2:11]2)=[O:26])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(=O)C12CC3CC1CC(NC(=O)OC(C)(C)C)(C3)C2
Reactant: CC(=O)O
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)C(C(=O)O)(C3)C2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
To a mixture of NaOH (1.32 g, 33.0 mmol), H2O (8.8 mL), and 1,4 dioxane (2 mL) at ice bath temperature was added Br2 (0.6 mL, 12.3 mmol) and stirred for 5 minutes. The resulting hypobromite solution was added dropwise to a stirred solution of the compound obtained in step II (0.6 g, 2.2 mmol) in 1,4-dioxane (2.4 mL) at around 10° C. The reaction mixture was gradually warmed to r.t, stirred for 1 h, then cooled to 0° C. and quenched by adding acetic acid (2 mL, 36.3 mmol). The mixture was diluted with water and extracted in EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure to obtain 1-[(tert-butoxycarbonyl)amino]tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (0.54 g) as a viscous liquid in 87% yield. m/z (M−1) 280; 1H NMR (CDCl3) 300 MHz δ 4.75 (s (br), 1H), 2.78-2.60 (m, 1H), 2.47-2.40 (m, 1H), 2.33-2.22 (m, 1H), 2.18-1.72 (m, 8H), 1.62-1.53 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][C:18]1[N:22]=[C:21]([CH3:23])[NH:20][N:19]=1>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:19]2[C:18]([CH3:17])=[N:22][C:21]([CH3:23])=[N:20]2)[N:3]=[C:4]([S:9][CH3:10])[N:5]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1n[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 4,6-dichloro-2-(methylthio)pyrimidine (1-1) (1.00 g, 5.13 mmol, 1.0 eq.) and cesium carbonate (2.70 g, 7.67 mmol, 1.5 eq.) in DMF (40 mL) at 0° C. under nitrogen was added a solution of 3,5-dimethyl-1H-1,2,4-triazole (498 mg, 5.13 mmol, 1.0 eq.) in DMF (20 mL) via a dropping funnel over 1 hour. The reaction was then warmed to room temperature. The reaction was monitored by TLC and was complete after 1 hour. The reaction was quenched by addition of water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to afford 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidine (1-2) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 2.90 (s, 3H), 2.60 (s, 3H), 2.41 (s, 3H). LRMS m/z (M+H) 256 found, 256 required.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[N+]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=1)([O-])=O.C(O)(=O)C>CN(C=O)C>[CH2:1]([S:3][C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=1)[CH3:2]
Reactant: CC[S-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCSc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
Sodium ethanethiolate (1.6 g, 17.2 mmol) was added to a solution of methyl 5-nitropicolinate (2.8 g, 16 mmol) in DMF (30 mL), and the resulting mixture was stirred a room temperature. After 3 hours, acetic acid (1 mL) was added, and the mixture was evaporated to dryness. The residue was suspended in methanol (50 mL) and treated with 3N NaOH. The resulting mixture was stirred at room temperature for 16 hours and then evaporated. The residue was dissolved in water (100 mL), washed with ethyl acetate (2×100 mL), and acidified to pH 3-4 (conc. HCl), resulting in precipitation of the product. The precipitate was filtered, rinsed with water (100 mL) and dried under vacuum, providing 2.3 g of 5-(ethylthio)picolinic acid, in 79% yield; 1H NMR (DMSO-d6) δ 1.23 (t, 3H, J=7.3 Hz), 3.14 (q, 2H, J=7.3 Hz), 7.86 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.95 (dd, 1H, J=8.4 Hz, J=0.9 Hz), 8.57 (dd, 1H, J=2.4 Hz, J=0.9 Hz), 13.09 (br, 1H).
Reaction SMILES: CCOCC.[C:6](Cl)(=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]=[CH:18][CH3:19].[CH:22]1([CH2:25][CH2:26][CH2:27][OH:28])[CH2:24][CH2:23]1>N1C=CC=CC=1>[C:6]([O:28][CH2:27][CH2:26][CH2:25][CH:22]1[CH2:24][CH2:23]1)(=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]=[CH:18][CH3:19]
Reactant: OCCCC1CC1
Reactant: CC=CC=CCCCCCCCCC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC=CC=CCCCCCCCCC(=O)OCCCC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 30 ml. anhydrous ether and 0.23 g. 10,12-tetradecadien-1-oyl chloride is added 0.1 g. 3-cyclopropyl-1-propanol. The mixture is cooled to 0° and 0.5 ml. pyridine is added. The reaction mixture is stirred for 1 day at room temperature and then is worked up following the procedure of Example 3 to yield 3-cyclopropylpropyl 10,12-tetradecadienoate.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([N:18]3[CH2:24][CH:23]4[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]4)[CH2:19]3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.CC(C)([O-])C.[K+]>O1CCCC1>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([N:18]3[CH2:24][CH:23]4[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]4)[CH2:19]3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(c1ccc2c(c1)CCCN2)N1CC2CCC(CC2)C1
Reactant: CC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)N1CCCc2cc(S(=O)(=O)N3CC4CCC(CC4)C3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized by addition of acetyl chloride to the compound of Example 41. 3-(1,2,3,4-Tetrahydro-6-quinolinesulfonyl)-3-azabicyclo-[3.2.2]nonane (100 mg, 0.31 mmol) was dissolved in dry tetrahydrofuran. The solution was cooled with an ice bath. Potassium tert-butoxide (76 mg, 0.68 mmol) was added, followed by acetyl chloride (0.03 ml, 0.41 mmol). The mixture was allowed to warm slowly to room temperature as it stirred overnight. The solvent was evaporated and the residue extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate and evaporated to give an orange solid. Purification by chromatotron using chloroform/ethyl acetate (9/1) gave a yellow solid (36 mg, 32% yield): mp 177°-179° C.; 1H NMR (CDCl3): 7.56-7.52 (m, 3 H, aryl H's), 3.80 (t, J=6.3, 2 H, alkyl H's), 3.26 (d, J=4.2, 4 H, N(CH2R)2), 2.82, (t, J=6.6, 2 H, alkyl H's), 2.31 (s, 3 H, CH3), 2.10-1.97 (m, 4 H, N(CH2CHR)2 and alkyl H's), 1.78-1.65 (m, 8 H, alkyl H's).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:6])=[O:4].[CH2:17]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[N:40][C:39]([C:42](O)=[O:43])=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]([O:7][C:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:42]([C:39]2[N:40]=[CH:41][C:36]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=3)=[N:37][CH:38]=2)=[O:43])=[CH:13][CH:14]=1)=[O:16])[CH3:6])=[O:4]
Reactant: CCCCCCCCCCCCOc1ccc(-c2cnc(C(=O)O)cn2)cc1
Reactant: COC(=O)[C@@H](C)OC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(-c2cnc(C(=O)Oc3ccc(C(=O)O[C@H](C)C(=O)OC)cc3)cn2)cc1
Temperature: 25 °C
Yield: 13.4 %

Procedure:
In a 50 ml round flask were charged 86.3 mg (0.39 mmol) of (R)-4-hydroxybenzoic acid 1-(methoxycarbonyl)ethyl ester obtained in Example 1-2), 134.6 mg (0.35 mmol) of 2-(4-dodecyloxyphenyl)-5-pyrazinecarboxylic acid, 4.3 mg (0.035 mmol) of N,N-dimethyl-4-aminopyridine, and 5 ml of methylene chloride, followed by stirring at 25° C. To the mixture was added 79.4 mg (0.39 mmol) of DCC to conduct a reaction at 25° C. for 18 hours. After completion of the reaction, the reaction mixture was worked-up in the same manner as in Example 1-3) to obtain 27.6 mg (0.047 mmol) of Compound (11) in a yield of 13% based on 2-(4-dodecyloxyphenyl)-5-pyrazinecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].O1CCCC1.B.CO>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: B
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)cc(CO)c1
Temperature: 0 °C

Procedure:
3-Bromo-5-nitrobenzoic acid (3.2 g, 13.0 mmol) was suspended in tetrahydrofuran (25 mL) and cooled to 0° C. To this solution was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 26 mL, 26 mmol) cautiously over 15 min. The reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol, diluted with ethyl acetate, washed with 1 N sodium hydroxide (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 3.0 g (99%) as a white powder. 1H-NMR (CDCl3, 300 MHz) 8.24 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 4.78 (s, 2H). Mass spec.: 233.88 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[N+:4]([O-])[C:3]=1[C:10]([O:12]C)=[O:11].OS(O)(=O)=O.O=S(=O)=O.[N+:23]([O-])([OH:25])=[O:24].C(=O)(O)[O-].[Na+]>OS(O)(=O)=O.C(OCC)(=O)C>[N+:23]([C:7]1[CH:6]=[C:5]([Cl:8])[N:4]=[C:3]([C:10]([OH:12])=[O:11])[C:2]=1[Cl:1])([O-:25])=[O:24]
Reactant: COC(=O)c1c(Cl)ccc(Cl)[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1nc(Cl)cc([N+](=O)[O-])c1Cl
Temperature: 65 °C
Reaction time: 48 h

Procedure:
Methyl 3,6-dichloropyridine-2-carboxylate N-oxide (5.0 g, 22.52 mmol) was dissolved in a minimum amount of H2SO4. The mixture was cooled in an ice/water bath and to it was slowly added 30% oleum (9.6 mL) and fuming HNO3 (9.6 mL), gradually heated to 65° C. and stirred for 48 hr. The cooled reaction mixture was diluted with ethyl acetate (200 mL) and to it was carefully added saturated sodium bicarbonate. The product was extracted with ethyl acetate (2×150 mL) and the combined extracts were dried (MgSO4) and concentrated to give 0.10 g of a yellow solid; mp 192-193° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)#[N:4].[Cl:14][CH2:15][CH2:16][CH:17](OS(C)(=O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN1CCCC1=O>[Cl:14][CH2:15][CH2:16][CH:17]([N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:5]([C:3]#[N:4])[C:6]=2[CH:7]=[N:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cccc2[nH]ncc12
Reactant: CS(=O)(=O)OC(CCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1cnn2C(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Sodium hydride (0.092 g, 60% in oil) was added to a solution of 4-cyanoindazole (0.300 g) in N-methylpyrrolidinone (5 mL) and the reaction mixture was stirred at room temperature for 30 minutes. Methanesulfonic acid 3-chloro-1-phenyl-propyl ester (0.573 g) was added followed by 3 ml more of N-methylpyrrolidinone. The reaction mixture was stirred for an additional 6 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with water, then with brine, and dried (MgSO4). Evaporation to dryness gave a residue which was purified by column chromatography on silica gel using ethyl acetate-hexane (1:9) to give 1-(3-chloro-1-phenyl-propyl)-1H-indazole-4-carbonitrile (0.228 g) as a foam, (M+H=297).
Reaction SMILES: C([C:3]1([CH2:19][O:20][CH3:21])[CH2:8][C:7]([C:9]([O:11]C)=[O:10])=[CH:6][CH:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.O.[OH-].[Li+].[CH2:25]1COC[CH2:26]1>O>[CH2:25]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[CH:5]=[CH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:3]=1[CH2:19][O:20][CH3:21])[CH3:26]
Reactant: CCC1(COC)CC(C(=O)OC)=CC=C1c1ccccc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of methyl 2-ethyl-2-(methoxymethyl)-1,1′-biphenyl-4-carboxylate (12 g, 0.0422 mol) in THF (150 mL) and water (30 mL), was added lithium hydroxide monohydrate (5.31 g, 0.127 mol) in portions. After 12 h at RT, the reaction mixture was concentrated and the aqueous phase was acidified using conc. HCl and extracted with EtOAc. Then the organic layers were washed with water and brine solution. The solvents were dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a white solid (9 g, 80%). 1H NMR (DMSO-d6, 300 MHz) δ 12.9 (1H, bs), 8.08 (1H, s), 7.88-7.90 (1H, m), 7.34-7.35 (2H, m), 7.21-7.25 (2H, m), 7.03-7.05 (1H, m), 4.04-4.13 (2H, m), 3.16-3.18 (3H, s), 2.29-2.38 (1H, m), 2.19-2.24 (1H, m), 0.92-0.95 (3H, m). LC/MS (Method A): 269.0 (M−H)−. HPLC (Method B) Rt 5.06 min (Purity: 97.4%).
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[I:1][C:2]1[N:6]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(C)n[nH]c1I
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nn(C2CCCCO2)c1I
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of ethyl 5-iodo-3-methyl-1H-pyrazole-4-carboxylate (2.1 g, 7.50 mmol, 1.00 equiv), 3,4-dihydro-2H-pyran (3.15 g, 37.45 mmol, 4.99 equiv) and toluenesulfonic acid (258 mg, 1.50 mmol, 0.20 equiv) in tetrahydrofuran (100 mL) was stirred at 80° C. for 8 h. The reaction mixture was cooled to room temperature and then diluted with H2O. The pH value of the solution was adjusted to 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with 3×80 mL of ethyl acetate. The combined organic layers were washed with 1×80 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-25% of ethyl acetate in petroleum ether to give 1.5 g (55%) of (R/S) ethyl 5-iodo-3-methyl-1-(oxan-2-yl)-1H-pyrazole-4-carboxylate as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): δ 5.45 (dd, J=9.9 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.88-3.84 (m, 1H), 3.69-3.60 (m, 1H), 2.49 (s, 3H), 1.95-1.75 (m, 2H), 1.65-1.45 (m, 4H), 1.29 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.55 min, m/z=365.0 [M+H]+.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH2:32])=[O:31])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=C(C=CC=1)C(N)=O>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=3)[C:30]([NH2:32])=[O:31])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cccc(C(N)=O)c2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: NC(=O)c1cccc(Br)c1
Product: NC(=O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 96 %

Procedure:
3-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzamide. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (72 mg, 0.109 mmol) and 3-bromobenzamide following General Procedure A. Flash chromatography (10-40% EtOAc/hexanes) yielded the title compound as a white solid (52 mg, 96%): 1H NMR (CD3OD, 600 MHz) δ 8.23 (s, 1H), 8.03 (s, 1H), 7.83 (m, 1H), 7.53 (m, 1H), 7.35 (m, 1H), 7.18-7.09 (m, 5H), 3.30 (t, 1H, J=6.0 Hz), 2.53 (t, 2H, J=7.5 Hz), 1.92-1.86 (m, 2H), 1.65-1.55 (m, 2H), 1.34-1.29 (m, 6H), 0.87 (s, 9H), 0.09 (s; 3H), −0.03 (s, 3H); 13C NMR (CD3OD, 150 MHz) δ 166.2, 151.6, 143.3, 136.6, 135.4, 131.3, 130.8, 128.8, 128.7, 126.9, 126.1, 124.0, 122.9, 122.6, 69.2, 36.8, 36.3, 32.0, 29.6, 29.5, 25.7, 25.6, 18.5, −5.3, −5.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[NH2:30].[C:32](Cl)(=[O:35])[CH2:33][CH3:34].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[CH:6][C:5]=1[NH:30][C:32](=[O:35])[CH2:33][CH3:34]
Reactant: COC(=O)c1cc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)ccc1N
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acid methyl ester (55 mg, 0.12 mmol), propionyl chloride (13 mg, 0.14 mmol), and triethylamine (15 mg, 0.14 mmol) in dichloromethane (2 ml) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc (10 ml) and washed with 5% NaHCO3 (10 ml), 2M HCl (10 ml), water (10 ml) and brine (10 ml). The organic phase was dried and evaporated to give the product as a colourless glass 50 mg 85%. LC/MS: Rt=4.09[M+H] 490 (1 Cl).
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:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[O:45][CH3:46])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:25]([NH:33][C:34](=[O:35])[C:36]1[CH:41]=[CH:40][C:39]([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:38][C:37]=1[O:45][CH3:46])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(B(O)O)ccc1C(=O)NCCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)NCCc1ccccc1

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (154 mg, 0.349 mmol), 4-[(phenethylamino)carbonyl]-3-methoxyphenylboronic acid (115 mg, 0.384 mmol), palladium tetrakistriphenyphosphine (24 mg, 0.021 mmol) and sodium carbonate (89 mg, 0.839 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-phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (64 mg, 32%). 1H NMR (CDCl3-d) δ 1.62 (m, 4H), 2.16 (m, 16H), 2.87 (m, 2H), 3.57 (m, 2H), 3.90 (s, 3H), 4.83 (m, 1H), 7.31 (m, 7H), 7.95 (m, 1H), 8.22 (m, 2H); 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+ =569.3, Rt=2.50 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9](Cl)(=O)=O)=[CH:4][C:3]=1[N+:13]([O-])=O.Cl>[Zn].C(O)C>[F:1][C:2]1[C:3]([NH2:13])=[CH:4][C:5]([SH:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Cc1cc(F)c(N)cc1S
Temperature: 75 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
156.9 g (2.4 mol) of zinc, 500 ml of ethanol and then 77 g (0.3 mol) of 4-fluoro-6-methyl-3-nitrobenzenesulfonyl chloride were placed in a 2-liter eggplant-shaped flask equipped with a mechanical stirrer, a thermometer and a dropping funnel. Thereinto was dropped 500 g (5 mol) of hydrochloric acid in a water bath so that the temperature of the reaction system did not exceed 50° C., followed by stirring at 75° C. for 6 hours. Ethanol was distilled off under reduced pressure; the residue was cooled to room temperature; sodium bicarbonate was added to neutralize the reaction system; extraction was conducted twice with ethyl acetate; the ethyl acetate layer was washed with water and then with a saturated aqueous sodium chloride solution. The ethyl acetate layer was dried with anhydrous sodium sulfate and subjected to distillation under reduced pressure to distil off ethyl acetate to obtain 41 g of a title compound at a yield of 87%.