Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(O)(C)(C)C.O.C(OCC)(=O)C>[CH:3]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)Cc1cccc(OCC2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1cccc(OCC2CCCCC2)c1
Temperature: 23 °C

Procedure:
A solution of aqueous sodium hydroxide (1N, 14 mL, 14.0 mmol, 10 equiv) was added to a solution of ethyl 3-cyclohexylmethyloxy-phenylacetate 29-3 (384 mg, 1.39 mmol, 1 equiv) in a mixture of t-butanol (8 mL) and water (4 mL) at 23° C. The reaction mixture was heated at reflux for 2 h. The solution was cooled to 23° C. and was diluted with ethyl acetate (50 mL). The organic layer was washed with an aqueous 10% potassium hydrogen sulfate solution (2×25 mL), then was dried over magnesium sulfate and was concentrated to afford the product 29-4 as a white solid, which was used without further purification.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].[CH3:17][I:18]>CC(C)=O>[IH:18].[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[NH:10])[S:9][CH3:17]
Reactant: CI
Reactant: NC(=S)Nc1ccccc1-c1ccccc1
Solvent: CC(C)=O
Product: CSC(=N)Nc1ccccc1-c1ccccc1
Product: I
Temperature: 55 °C

Procedure:
A mixture of N-(2-biphenylyl)thiourea (9.6 g), methyl iodide (2.9 ml) and acetone (100 ml) was heated at 55° C. for 3 hours to yield 1-(2-biphenylyl)-2-methyl-2-thiopseudourea hydriodide.
Reaction SMILES: N12CCCN=C1CCCCC2.F[C:13]1[C:31]([I:32])=[C:30]([CH3:33])[CH:29]=[CH:28][C:14]=1[C:15](=[N:26][OH:27])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.O>O1CCCC1>[I:32][C:31]1[C:13]2[O:27][N:26]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:14]=2[CH:28]=[CH:29][C:30]=1[CH3:33]
Reactant: COc1ccc(CNC(=NO)c2ccc(C)c(I)c2F)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CNc2noc3c(I)c(C)ccc23)cc1
Yield: 38.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.31 mL, 2.0 mmol) was added dropwise to a solution of 2-fluoro-N′-hydroxy-3-iodo-N-(4-methoxybenzyl)-4-methylbenzimidamide (preparation 23a, 0.80 g, 1.9 mmol) in tetrahydrofuran (10 mL). The mixture was then heated under microwave conditions (“Initiator sixty” from Biotage®) at 150° C. for 4 hours under an argon atmosphere. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (10:1 to 4:1 hexanes/ethyl acetate) to give the title compound (0.29 g, 38%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](C)[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH:11](=O)C1C=CC=CC=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[NH:10][CH:11]=[N:9]2
Reactant: Cc1nc(N)c(N)c(Cl)n1
Reactant: O=Cc1ccccc1
Product: Clc1ncnc2nc[nH]c12

Procedure:
In Step 1, 6-chloro-2-methyl-4,5-pyrimidinediamine is reacted with a benzaldehyde (3) to provide a 6-chloropurine (6), essentially as described in Scheme 1, Step 2, above. In Step 2, a 6-chloropurine (6) is reacted with a piperazine (5) to provide a piperazinyl purine (7) essentially as described in Scheme 1, Step 3, above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[ClH:16].[CH:17]1([NH:23][CH:24](O)[CH3:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[ClH:16].[CH3:25][CH2:24][N:23]([C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7])[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(O)NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: CCN(c1c(C(=O)O)cc(OC)c(OC)c1OC)C1CCCCC1

Procedure:
2.0 g of 3,4,5-trimethoxy-benzoic acid, 1.8 g. of cyclohexylamino-ethanol-hydrochloride and 4.0 g. of p-toluene-sulphonic acid are refluxed in 40 ml. of benzene for 12 hours. After cooling the reaction mixture is extracted with a 15% sodium carbonate solution and 10% hydrochloric acid. White crystals precipitate from the hydrochloric acid solution. Thus N-2-ethyl-cyclohexylamino-3,4,5-trimethoxy-benzoate-hydrochloride is obtained. Mp.: 207°-208° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl.[Mg].Br[CH2:16]CBr.[NH4+].[Cl-].[CH2:21]1[CH2:25][O:24]CC1>CC(C)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:25]([OH:24])([CH3:21])[CH3:16]
Reactant: C1CCOC1
Reactant: BrCCBr
Reactant: ClCCCCCOC1CCCCO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CC(C)(O)CCCCCOC1CCCCO1
Reaction time: 16 h

Procedure:
A small portion of a solution of the product from Step I (21.1 g, 0.102 mol) in THF (105 ml) was added, under nitrogen, to magnesium turnings (5.0 g, 0.204 g-atom). The mixture was warmed in an oil bath at 75°-80° and the reaction was started by the addition of 1.5 ml of a 1M solution of 1,2-dibromoethane in THF. The remaining chloroalkane solution was then added during 20 minutes. The resulting mixture was refluxed for 45 minutes, cooled in an ice bath and treated during 15 minutes with a solution of acetone (9.0 ml, 0.123 ml) in THF (95 ml). It was kept at ambient temperature for 16 hours, cooled in an ice bath and treated during 15 minutes with saturated aqueous NH4Cl (115 ml). The resulting mixture was extracted with EtO. The extract was washed with water and brine, dried (MgSO4) and concentrated to give 30.5 g of crude product. Distillation gave 16.77 g of 6-hydroxy-6-methylheptyl 2-tetrahydropyranyl ether, bp 107°-115° (0.07-0.1 mm Hg). The CI mass spectrum had m/z 231 (M+H)+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])[CH:20]=1)[C:15]([OH:17])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH3:40]>>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:33][NH:32][C:15](=[O:17])[C:14]1[CH:18]=[C:19]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])[CH:20]=[C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH:13]=1)[CH3:40]
Reactant: CC(C)=CCC/C(C)=C/COc1cc(OC/C=C(\C)CCC=C(C)C)cc(C(=O)O)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OC/C=C(\C)CCC=C(C)C)cc(OC/C=C(\C)CCC=C(C)C)c1
Yield: 82 %

Procedure:
In a manner identical to Example 15, 3,5-digeranyloxybenzoic acid(2.13 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 2.14 g(82%) of the aimed compound.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[CH3:9][O:10][C:11](=O)[CH2:12][C:13]([CH2:15][O:16]C)=O.Cl>CO>[CH3:6][C:5]1[N:8]=[C:12]([CH2:11][O:10][CH3:9])[CH:13]=[C:15]([OH:16])[N:7]=1
Reactant: CC(=N)N
Reactant: COCC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc(O)nc(C)n1
Temperature: 50 °C
Yield: 58.4 %

Procedure:
968 g (4 mol) of sodium methylate in methanol were added to a solution of 187 g (2 mol) of acetamidine hydrochloride and 292 g (2 mol) of γ-methoxyacetoacetic acid methyl ester in 1,000 ml of methanol at 5° C., the mixture was warmed for 3 hours at 50° C. and the solvent was then stripped off under reduced pressure. The residue was dissolved in 500 ml of ice-water and brought to pH ca.6 with concentrated hydrochloric acid, while cooling externally, the precipitate was filtered off, washed with ether and then dried in a desiccator over phosphorus pentoxide. 180 g (58% of theory) of 2-methyl-4-methoxymethyl-6-hydroxy-pyrimidine were obtained in the form of a white powder of melting point 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([CH2:32][CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:35])=[O:34])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)CCc1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)CCc3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 22 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-phenylethanesulfonyl chloride, the title compound (yield 22%) was obtained in the same manner as that of Example 145.
Reaction SMILES: C([NH:4][C:5]1C=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[C:11](=[O:16])[CH2:10][CH2:9][CH2:8]2)(=O)C.C(O[Cl:22])(C)(C)C.[CH:23]([Cl:26])(Cl)Cl>>[NH2:4][C:5]1[C:23]([Cl:26])=[C:7]2[C:12](=[C:13]([CH3:15])[C:14]=1[Cl:22])[C:11](=[O:16])[CH2:10][CH2:9][CH2:8]2
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OCl
Reactant: CC(=O)Nc1cc(C)c2c(c1)CCCC2=O
Product: Cc1c(Cl)c(N)c(Cl)c2c1C(=O)CCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A solution of the product from Example 130 (1.78 g) in chloroform (50 ml) at -78° C. was treated with t-butylhypochlorite (2 ml) in two portions. The reaction was stirred at -78° C. for 10 minutes. Following the procedure of Example 95 the desired product was obtained in 50% yield.
Reaction SMILES: [OH:1][CH:2]([CH3:43])[C:3]([CH3:42])([CH3:41])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]=[C:12]2[CH3:40])=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:41][C:3]([CH3:42])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]=[C:12]2[CH3:40])=[CH:9][CH:10]=1)[C:2](=[O:1])[CH3:43]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.26 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.28 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.19 g, 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:30][CH2:29][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])=[O:19])[C:9]3=[O:28])[C:6]=2[CH:7]=1.BrC1C=CC2C3(COC=2C=1)C1C(=CC=CC=1)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])C3=O>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:6]3[CH:7]=[C:2]([C:50]4[CH:51]=[N:40][CH:47]=[CH:48][CH:49]=4)[CH:3]=[CH:4][C:5]=3[O:30][CH2:29]2)[C:9]1=[O:28]
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Reactant: O=C(CN1C(=O)C2(COc3ccc(Br)cc32)c2ccccc21)Nc1ccccc1F
Product: O=C(CN1C(=O)C2(COc3ccc(-c4cccnc4)cc32)c2ccccc21)Nc1ccccc1F
Yield: 55 %

Procedure:
Following the procedure as described in EXAMPLE 37, and making non-critical variations using 2-(5-bromo-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide to replace 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (55% yield) was obtained as a white solid: mp 98-100° C.; 1H NMR (300 MHz, CDCl3) δ 8.60-8.53 (m, 2H), 8.14 (dd, 1H), 7.65 (dd, 1H), 7.41 (dd, 1H), 7.32-6.90 (m, 11H), 5.02 (d, 1H), 4.76 (d, 1H), 4.72 (d, 1H), 4.56 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 177.9, 164.8, 160.9, 154.2, 151.0, 147.1, 141.7, 134.2, 131.7, 131.5, 129.9, 129.4, 129.1, 125.1, 124.6, 124.5, 124.2, 124.0, 122.5, 122.2, 115.1, 114.8, 111.0, 109.1, 80.0, 58.1, 44.6; MS (ES+) m/z 466.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:33])[N:4]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=2)=O)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].CC([NH2:48])C(O)C1C=C(OC)C=CC=1OC.Cl.C([O:53][CH2:54]C)(=O)C>C(O)C>[Br:1][C:2]1[C:3](=[O:33])[N:4]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:24][CH:23]=2)=[N:48][O:53][CH3:54])[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18]
Reactant: COc1ccc(OC)c(C(O)C(C)N)c1
Reactant: CCOC(C)=O
Reactant: CCN(CC)c1ccc(C(=O)Cn2ncc(N[C@@H]3C[C@@H]4C[C@H]([C@H]3C)C4(C)C)c(Br)c2=O)cc1
Agent: Cl
Solvent: CCO
Product: CCN(CC)c1ccc(C(Cn2ncc(N[C@@H]3C[C@@H]4C[C@H]([C@H]3C)C4(C)C)c(Br)c2=O)=NOC)cc1
Yield: 100 %

Procedure:
4-Bromo-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl}-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (50 mg, 0.097 mmol) and methoxamine hydrochloride (41 mg, 0.485 mmol) in ethanol (0.5 mL) were stirred at 80° C. for 1 hour. After cooling, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the desired product (56 mg, 100% yield).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.ClCCl.[S:11]1[CH2:14][CH:13]([S:15][CH2:16][CH2:17][OH:18])[CH2:12]1.C[S:20](Cl)(=O)=O>O>[C:6]([O:18][CH2:17][CH2:16][S:15][CH:13]1[CH2:14][S:11][CH2:12]1)(=[S:20])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: OCCSC1CSC1
Solvent: ClCCl
Solvent: O
Product: CC(=S)OCCSC1CSC1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Triethylamine (Et3N) (18 g) was added to a dichloromethane (130 ml) solution of 2-(3-thietanylthio)ethanol (21 g). A dichloromethane (30 ml) solution of methanesulfonyl chloride (MsCl) (18 g) was added dropwise to the mixture under cooling (−15 degrees centigrade), and the reaction was carried out at 0 degree centigrade for 1 hour. Cold water was added to the reaction mixture for partition, and then the organic layer (dichloromethane solution) was added dropwise to a methanol (200 ml) solution of potassium thioacetate (AcSK) (21 g) under cooling (5 degrees centigrade), and the reaction was carried out for 10 hours. Ethyl acetate and water were added to the reaction mixture for carrying out extraction. The organic layer was washed with water and dried with magnesium sulfate. The resultant was filtered and then concentrated under reduced pressure to obtain a desired oily product (27 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[CH3:17])[CH:2]=[CH2:3].C1(C)C(C)=CC=CC=1.O.[CH3:27][CH2:28][CH:29]([NH2:33])[CH2:30][CH2:31][CH3:32]>>[CH3:27][CH2:28][CH:29]([NH:33][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([CH3:17])[C:6]=1[N+:14]([O-:16])=[O:15])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(N)CC
Reactant: C=CCc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: Cc1ccccc1C
Solvent: O
Product: C=CCc1cc([N+](=O)[O-])c(NC(CC)CCC)c([N+](=O)[O-])c1C

Procedure:
One equivalent of 4-allyl-3-methyl-2,6-dinitrochlorobenzene is dissolved in three volumes of xylene containing two equivalents of 3-hexylamine. The mixture is refluxed for 5 hours and then poured into water. The organic phase is washed with 5% hydrochloric acid and then water, dried over calcium sulfate, and removed in vacuo to leave the above-named product.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][OH:51])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cr](O)(O)(=O)=[O:53].CC(O)C>CCOCC>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([OH:53])=[O:51])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Reactant: O=[Cr](=O)(O)O
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 89 %

Procedure:
The alcohol (40) (1.73 g, 2.41 mmol) was dissolved in ether (200 ml) at 30° C. and treated with chromic acid (4 ml of a 0.67M solution; 2.68 mmol). The resulting solution was allowed to stir and cool to room temperature over two hours during which time two further 1 ml portions of chromic acid were added. Propan-2-ol (5 ml) was then added and the ethereal solution washed with water four times, then dried, filtered and evaporated to leave the title compound (41) as a white powder (1.57 g; 89%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl[CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 24b) from 4-phenylphenol (0.916 g), ethanol (10 ml), sodium hydroxide (0.215 g), water (5 ml) and (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g; from Example 24a) above) to give a yellow oil. This was purified by column chromatography over silica eluting with dichloromethane:ethanol (95:5) to give the title compound as a pale yellow gum which solidified on standing (0.307 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4](Cl)=[CH:5][C:6]=1[CH3:7].C[O:10]C(Cl)Cl.[CH2:14]([Cl:16])Cl>Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[S:3][C:14]([Cl:16])=[C:5]([CH3:4])[C:6]=1[CH:7]=[O:10]
Reactant: Cc1cc(Cl)sc1Cl
Reactant: ClCCl
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: Cc1c(Cl)sc(Cl)c1C=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2,5-dichloro-3-methylthiophene [prepared according to the method of J. Amer. Chim. Soc., 1971, 333.] (11.8 g) in CH2Cl2 (200 mL) was added TiCl4(37.94 g) and dichloromethyl methyl ether (12.6 g) at −10° C. After stirring for 4 hours, the reaction mixture was poured into ice-water and the whole was stirred vigorously for 30 minutes. The resulting mixture was extracted with CH2Cl2 (200 ml×1), and the organic layers was washed with saturated NaHCO3 solution(100 mL×1), brine (100 mL×1), dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by distillation (bp: 140-145° C./10 mmHg) to provide the subtitle compound (11.75 g).
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:6]([N:11]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][C:13](=O)[NH:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1.P(Br)(Br)([Br:24])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Br:24][C:13]1[CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]([C:6]2[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][N:7]=2)[N:12]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Reaction time: 0.33 h
Yield: 149 %

Procedure:
To a 500 mL flask, acetonitrile (200 mL), ethyl 1-(3-chloro-2-pyridinyl)-3-oxopyrazolidine-5-carboxylate (21.28 g, 94%, 74.17 mmol) and phosphoryl bromide (14.88 g, 51.92 mmol) were added. The reaction mixture was heated to reflux for 2 hours. 150 mL solvent was distilled from the reaction mixture. The concentrated reaction mixture was added to the mixture of sodium carbonate (10.56 g, 155.7 mmol) and water (40 mL). The reaction mixture was stirred for 20 minutes until no more gas released, and then diluted with dichloromethane (100 mL), stirred for 50 minutes. The mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with water, dried over anhydrous magnesium sulfate, and concentrated by rotary evaporator to give ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (25.73 g) as a amber oil in 97% yield. HPLC area normalization method content is 93% (Analytical condition: chromatographic column: ZORBAX Eclipse XDB-C8 4.6×150 mm 5 μm, mobile phase:the ratio of acetonitrile to water is 70:30).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:10]=[C:11]([CH:45]=[CH:46][CH:47]=1)[C:12]([NH:14][C:15]1[S:16][C:17]2[CH2:44][CH2:43][CH2:42][CH2:41][C:18]=2[C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)=[O:21])=[O:13])[CH:5]1[CH2:7][CH2:6]1.Br[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:5]1([N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:45]=[CH:46][CH:47]=2)[C:12]([NH:14][C:15]2[S:16][C:17]3[CH2:44][CH2:43][CH2:42][CH2:41][C:18]=3[C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=3)=[CH:25][CH:24]=2)=[O:21])=[O:13])[CH2:3][CH2:2][NH:1][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN(CCN)C5CC5)c4)sc4c3CCCC4)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of methyl 4-(2-{4-[({2-[(3-{[(2-aminoethyl)(cyclopropyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 0.20 mL of ethyl bromoacetate, 212 mg of potassium carbonate, and 20 mL of DMF was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 140 mg of methyl 4-{2-[4-({[2-({3-[(cyclopropyl {2-[(2-ethoxy-2-oxoethyl)amino]ethyl}amino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.