Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH:9]([CH:14]([CH:16]1[CH2:18][CH2:17]1)[CH3:15])[C:10]([O:12][CH3:13])=[O:11])C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[OH:8][CH:9]([CH:14]([CH:16]1[CH2:18][CH2:17]1)[CH3:15])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(OCc1ccccc1)C(C)C1CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(O)C(C)C1CC1
Reaction time: 6 h

Procedure:
To a stirred solution of methyl 2-benzyloxy-3-cyclopropylbutanoate (1.0 g, 4.0 mmol) and acetic acid (1 mL) in MeOH (25 mL) was added 10% palladium on charcoal (100 mg). Hydrogen gas was bubbled though the stirred solution for several minutes, and the reaction mixture was stirred under an atmosphere of hydrogen for 6 h. Nitrogen gas was bubbled through the solution to purge all of the hydrogen and the catalyst was removed by filtration. The filtrate solvents were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give methyl 2-hydroxy-3-cyclopropylbutanoate as a colorless oil. HPLC RT=2.47 min (Method A); LC-MS m/z=159; 1H NMR 400 MHz, CDCl3, 4.25 ppm (dd, J=3.3, 6.5 Hz, 1H), 3.77 ppm (s, 3H), 2.72 ppm (d, J=6.6 Hz, 1H), 1.05 ppm (m, 1h) 0.95 ppm (d, J=7 Hz, 3H), 0.84 ppm (m, 1H), 0.50 ppm (m, 2H), 0.19 ppm (m, 1H), 0.10 ppm (m, 1H)
Reaction SMILES: CO[C:3](=[O:22])[C@@H:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.I[CH2:24][Cl:25].[Li+].CC([N-]C(C)C)C.C(O)(=O)C>C(OC)(C)(C)C.O.C1COCC1>[Cl:25][CH2:24][C:3](=[O:22])[C@@H:4]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reactant: ClCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
To a 1-L 3-neck round bottom flask equipped with a magnetic stirrer, nitrogen inlet, thermocouple and additional funnel is added (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester (II, Step 1, 10.0 g, 0.0317 moles, 1 equivalent) followed by THF (175 mL) then cooled to −78°. Once the mixture is cooled, iodochloromethane (9.25 mL, 0.127 moles, 4 equivalents) is added in one portion via syringe. The addition funnel is charged with LDA (79 mL, 0.158 moles, 5 equivalents, 2.0 M in heptane/THF) and is subsequently added dropwise to the mixture keeping the internal temperature below −70°. Once the addition is complete, the contents are stirred for 15 min at which time acetic acid (47.2 mL, 0.824 moles, 26 equivalents) is added dropwise via the addition funnel keeping the internal temperature below −65°. Once this addition is complete, the mixture is stirred for 15 min then warmed to 0° and poured into water (500 mL), saline (500 mL) and methyl t-butyl ether (500 mL) then transferred to a separatory funnel. The phases are separated and the aqueous phase is extracted with methyl t-butyl ether (2×250 mL). The combined organic phases are washed with saturated sodium bicarbonate (500 mL), sodium sulfite (500 mL) and water (500 mL). The organic phase is then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a solid. The solid is recrystallized from heptane/i-propyl alcohol (10/1)to give the title compound, NMR (DMSO-d6) δ 7.47, 7.06–7.14, 4.78, 4.49, 3.20, 2.82 and 1.40; CMR (DMSO-d6) δ 200.87, 163.74, 161.20, 142.74, 112.80, 102.13, 79.04, 58.97, 47.72, 34.95 and 28.30.
Reaction SMILES: [C:1]1([CH:7](Br)[CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH3:24]
Reactant: FC(F)(F)c1ccc(OCCC(Br)c2ccccc2)cc1
Reactant: CNC
Product: CN(C)C(CCOc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
Still following the above procedure, 1-phenyl-3-(p-trifluoromethylphenoxy)propylbromide was reacted with dimethylamine in a sealed vessel at 150° C. for a period of 8 hours. N,N-dimethyl 1-phenyl-3-(p-trifluoromethylphenoxy)-propylamine thus formed was converted to the hydrochloride salt by the addition to the reaction mixture of 100 ml. of 10% aqueous HCl. The hydrochloride salt was isolated therefrom and melted at 178°-180° C. after recrystallization from an ethyl acetate-hexane solvent mixture.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(=O)(=O)(O)O.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[OH:25][C:19]1[CH:24]=[CH:23][C:22]([C:7]([C:22]2[CH:23]=[CH:24][C:19]([OH:25])=[CH:20][CH:21]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(=O)c1ccccn1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccccn1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
50 g. Ethyl 2-pyridine-glyoxylate were cautiously added dropwise to a pre-cooled mixture of 100 ml. 85% sulphuric acid and 100 g. phenol, while stirring. The reaction mixture was externally cooled with water and ice to keep it at ambient temperature and to control the exothermic reaction. After stirring for 60 hours, the reaction mixture was poured into ice-water and washed with chloroform. The gum-like precipitate which separated and the aqueous phase were rendered alkaline with ammonium hydroxide and the resulting solution was treated with activated charcoal. After filtration, the solution obtained was adjusted to about pH 7 with diluted sulphuric acid to give a high yield of a crystalline precipitate of ethyl α, α-di(4-hydroxyphenyl)-2-pyridine-acetate. After crystallisation from isopropanol or ethyl acetate, the product was obtained in the form of a colourless, crystalline solid which melted, with decomposition, at 252° - 254°C.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][O:33][CH3:34].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[S:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][O:33][CH3:34]
Reactant: COCOc1ccc(B(O)O)cc1OC
Reactant: Cc1cc(C)c(S(=O)(=O)n2ncc3ccc(I)cc32)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COCOc1ccc(-c2ccc3cnn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)cc1OC
Temperature: 90 °C

Procedure:
A mixture of 6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (5.78 g, 13.56 mmol, 1.00 equiv) and 3-methoxy-4-(methoxymethoxy)benzene-boronic acid (3.45 g, 16.27 mmol, 1.20 equiv) under argon was dissolved in dioxane (15 mL) and water (2.0 mL). To this solution was added triethylamine (2.83 mL, 20.3 mmol, 1.5 equiv), potassium carbonate (2.8 g, 20.3 mmol, 1.5 equiv) and dichlorobis(triphenylphosphine)palladium (476 mg, 0.678 mmol, 0.05 equiv). The reaction mixture was heated to 90° C. for 2 h and then was cooled to 23° C. The mixture was separated between ethyl acetate (250 mL) and saturated sodium bicarbonate (150 mL). The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure to give crude 6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole that was dried under high vacuum for 15 h and was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:13])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18]([NH:25][C:26]([C:28]2([CH3:31])[CH2:30][O:29]2)=[O:27])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]>>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:31][C:28]([OH:29])([C:26](=[O:27])[NH:25][C:18]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([CH3:15])[CH:17]=2)[CH3:30])=[CH:8][C:7]=1[F:13])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(O)cc1F
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: CCOC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1F

Procedure:
{2-Fluoro-4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]-phenyl}carbamic acid ethyl ester was prepared as described in Example 1 starting from (2-fluoro-4-hydroxyphenyl)carbamic acid ethyl ester and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.8% methanol). 1H NMR (400 MHz, DMSO-d6): 1.20 (3H, t, J=7.0 Hz), 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J=9.7 Hz), 4.07 (2H, q, J=7.0 Hz), 4.22 (1H, d, J=9.7 Hz), 6.21 (1H, s), 6.71-6.73 (1H, m), 6.83-6.87 (1H, m), 7.31-7.35 (1H, m), 7.86-8.05 (3H, m), 8.95 (1H, s), 10.12 (1H, s).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH:29]([NH2:33])[C:30]([OH:32])=[O:31])[CH:23]=1)[C:18]([OH:20])=[O:19]>>[C:12]([C:11]1[C:2]([NH:33][CH:29]([C:30]([OH:32])=[O:31])[CH2:28][C:24]2[CH:23]=[C:22]([CH2:21][CH:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])[CH:27]=[CH:26][CH:25]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:15])=[CH:6][CH:5]=2)([OH:14])=[O:13]
Reactant: NC(Cc1cccc(CC(N)C(=O)O)c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1cccc(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-[3-(2-amino-2-carboxy-ethyl)-phenyl]-propionic acid to provide the title compound in good yield.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25](=[O:48])[CH2:26][N:27]([CH2:44][CH2:45][CH2:46][CH3:47])[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25](=[O:48])[CH2:26][N:27]([CH2:44][CH2:45][CH2:46][CH3:47])[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:38][CH2:39][CH:40]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:41][CH2:42]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCCCN(CC(=O)OCc1ccccc1)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCN(CC(=O)OCc1ccccc1)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 18, (butyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino)-acetic acid benzyl ester, according to the procedure of Example 1 as a white solid; mp 59-64° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.78 (t, 3H), 1.10-1.40 (m, 6H), 1.80-1.95 (m, 2H), 2.60-3.00 (m, 5H), 2.91 (s, 3H), 3.05 (t, 2H), 3.70-3.80 (m, 2H), 4.04 (s, 2H), 4.40-4.50 (m, 1H), 5.20 (s, 2H), 6.80 (d, 1H), 6.95 (d, 2H), 7.00 (d, 2H), 7.18 (d, 1H), 7.30-7.45 (m, 5H), 7.50 (d, 2H); MS (ES) m/z: 689.1 (MH+).
Reaction SMILES: Cl.[C:2]([NH2:7])(=[NH:6])[CH:3]([CH3:5])[CH3:4].CC[O-].[Na+].[C:12]([OH:20])(=[O:19])/[C:13](=[C:15](\[CH:17]=O)/[Br:16])/Br>CCO>[Br:16][C:15]1[C:13]([C:12]([OH:20])=[O:19])=[N:6][C:2]([CH:3]([CH3:5])[CH3:4])=[N:7][CH:17]=1
Reactant: CC(C)C(=N)N
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1ncc(Br)c(C(=O)O)n1
Temperature: 50 °C
Yield: 38.6 %

Procedure:
To a stirred suspension of isobutyramidine hydrochloride (6.47 g, 47.5 mmol) at rt in EtOH (30 ml) under an argon atmosphere was added NaOEt solution (21 ml, 21% in EtOH) over min. The suspension was heated to 50° C. and a solution of mucobromic acid (5.7 g, 22.1 mmol) in EtOH (24 ml) was added dropwise over 5 min at 50° C. An additional portion of NaOEt solution (12 ml, 21% in EtOH) was added dropwise over 5 min. The mixture was then cooled to rt. The solids were filtered off, and the cake was washed with plenty of ethanol. The filtrate was concentrated to leave the crude product as a light brown solid. The crude material was triturated in 2 N HCl (100 ml). The product was collected by filtration, washed with plenty of H2O and plenty of n-heptane and dried to give the product (2.09 g, 73%) as beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)[CH3:14].C(Cl)Cl>C1COCC1.[Ni]>[CH3:14][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22])[CH2:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1]
Reactant: Cc1ccc2ccccc2c1CC(C)Oc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1CC(C)Oc1ccccc1N

Procedure:
2-Methyl-1-[2-(2-nitro-phenoxy)-propyl]-naphthalene (1.51 g, 4.70 mmol) was shaken with Rainey nickel (0.5 g) in THF (50 mL) at 49.0 psi H2 for 5.4 hours. TLC analysis (silica, CH2Cl2) indicated complete consumption of starting material. The reaction mixture was filtered and concentrated to give 2-[1-methyl-2-(2-methyl-naphthalen-1-yl)-ethoxy]-phenylamine in quantitative yield. MS (APCI) m/z 292.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:5]=[N:4][CH:3]=1.CC(C)=[O:23].OS(O)(=O)=O.O=[Cr](=O)=O>C(O)(=O)C>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13](=[O:23])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([CH3:1])=[CH:3][N:4]=[CH:5]1
Reactant: Cc1cncn1-c1ccccc1Cc1ccccc1Cl
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cncn1-c1ccccc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Preparation 44, 5-methyl-1-[α-(o-chlorophenyl)-o-tolyl]imidazole in acetic acid is heated with Jones reagent to give 2'-chloro-2-(5-methylimidazol-1-yl)benzophenone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[N:11]([O-:13])=[O:12].[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)CCO2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(c([N+](=O)[O-])c1)OCC2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A mixture of 5-methyl-2,3-dihydrobenzofuran (1b) (2.7 g, 20 mmol) in TFA (50 mL) was cooled to 0° C., NaNO2 (2.5 g, 36 mmol) was added thereto. Then it was warmed up to ambient temperature and stirred for 12 h. The mixture was concentrated, poured into water (50 mL), extracted with EtOAc (150 mL), washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1) to give the title compound (1c).
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[C:11]([F:12])=[C:10]([N:13]2C(=O)C3=CC=CC=C3C2=O)[C:9]([Cl:24])=[C:8]([F:25])[N:7]=1.N>CO>[NH2:13][C:10]1[C:9]([Cl:24])=[C:8]([F:25])[N:7]=[C:6]([Cl:5])[C:11]=1[F:12]
Reactant: O=C1c2ccccc2C(=O)N1c1c(F)c(Cl)nc(F)c1Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1c(F)c(Cl)nc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a mixed solution of 100 ml chloroform and 40 ml methanol was added 16.2 g of N-(2,5-dichloro-3,6-difluoropyridine-4-yl)phthalimide together with 20 ml of 25% aqueous solution of ammonia, and the mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and after adding 150 ml of chloroform to the residue, the mixture was washed with 20 ml of 15% aqueous solution of ammonia, and then, with 10 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4.55 g of the title compound as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:34][C:35]([NH:37][C:38]1[NH:39][C:40](=[O:51])[C:41]2[N:42]=[CH:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=2[N:46]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:44]2[CH:43]=[N:42][C:41]3[C:40](=[O:51])[NH:39][C:38]([NH:37][C:35]([O:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:36])=[N:46][C:45]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccccc3)nc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]1)OCc1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(benzyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.35 (bs, 2H), 8.34 (m, 1H), 8.25 (m, 1H), 7.81 (s, 0.6H), 7.77 (s, 0.4H), 7.71 (m, 2H), 7.45˜7.30 (m, 5H), 5.23 (s, 2H), 5.13 (s, 1.2H), 5.02 (s, 0.8H), 4.51 (s, 0.8H), 4.27 (s, 1.2H), 4.24 (t, 1.2H), 4.08 (t, 0.8H), 4.03 (t, 1.2H), 3.85 (t, 0.81H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)N.[ClH:10].N([O-])=O.[Na+]>O.[Cu]Cl>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)cc(Cl)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A total of 33.0 g of 3,5-dimethylaniline was added dropwise over 20 minutes to 200 ml of concentrated hydrochloric acid at such a rate that the temperature of the reaction was kept below 35° C. After several minutes of vigorous stirring, the reaction was cooled to -10° C. A solution of 19.7 g of sodium nitrite dissolved in 50 ml of water was added dropwise over 30 minutes at such a rate that the reaction temperature was kept between -12° C. to -16° C. Then, 3.0 g of copper (I) chloride was added and the reaction was warmed to 27° C. At this temperature foaming was noted and the reaction temperature was maintained below 35° C. with an ice water bath. After one hour, the reaction was poured onto 350 g of ice. Once the ice melted the crude product was extracted with 400 ml of hexanes, the organic phase was dried with magnesium sulfate, filtered, and concentrated to yield 20.2 g of a liquid. This material was diluted with 5 ml of hexanes and chromatographed on neutral alumina (Brockman 1, 150 mesh), eluting with 1200 ml of hexanes and collecting 200 ml fractions. The desired 95% pure intermediate, 10.1 g, was isolated cleanly in fractions 1 and 2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:11][C:10]=1[CH:24]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS([O-])(=O)=O.[CH3:33][C:34]([CH3:57])([CH3:56])[CH2:35][CH2:36][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:11][C:10]=1[CH:24]=[CH:36][CH2:35][C:34]([CH3:57])([CH3:56])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C=O)c2)c1
Reactant: CC(C)(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C=CCC(C)(C)C)c2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(benzyloxy)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (1.40 g) in THF (10 mL) was added 60% sodium hydride (240 mg) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added dropwise a solution of (3,3-dimethylbutyl) (triphenyl)phosphonium methanesulfonate (1.70 g) in THF (10 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude product. This compound was used for the net step without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:8]=2)[CH2:5][CH2:4][CH:3]=[CH:2]1.C(N(CC)CC)C.[C:30](Cl)(=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:32]([O:31][C:30]([N:20]1[CH2:19][CH2:18][N:17]([C:9]2[N:8]=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH:3]=[CH:2]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:22][CH2:21]1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C1=CC(Oc2nc(N3CCNCC3)nc3ccccc23)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2nc(OC3C=CCC3)c3ccccc3n2)CC1

Procedure:
To a solution of 4-[(cyclopent-2-en-1-yl)oxy]-2-(1-piperazinyl) quinazoline (1.47 g) in dry methylene chloride (15 ml) is added triethylamine (1.39 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (0.75 ml) in dry methylene chloride (3 ml). The mixture is stirred at 0° C. for 4 hours, and the reaction mixture is diluted with chloroform and washed with water, and then dried over anhydrous magnesium sulfate. The resulting solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(cyclopent-2-en-1-yl)oxy]quinazoline (1.85 g) as crystals.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.I[Si](C)(C)C.[ClH:37].CCOCC>C(Cl)(Cl)Cl.CO>[ClH:29].[OH:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH:22]([Cl:37])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1
Reactant: Clc1ccc(CC2CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1ccc(OCCN2CCC(C(Cl)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 1-[2-(4-benzyloxyphenoxy)ethyl]-4-(4-chlorobenzyl)piperidine (200 mg, 0.46 mmol) in 5 mL of chloroform was added 330 mg (1.65 mmol) of iodotrimethylsilane. The resulting solution was allowed to stir at rt for 30 min. and then methanol (4 mL) was added and was stirred for 20 min. Evaporation of solvent gave a residue, which was purified by flash chromatography (20% methanol in chloroform) to give an oil. This oil was dissolved into 5 mL of methanol and 1 mL of 1 M HCl in methanol was added. The resulting solution was allowed to stir for 10 min. Evaporation of methanol gave a residue, to which was added ether (30 mL). The resulting mixture was allowed to stir at rt overnight. The white solid was collected by filtration and dried in vacuo, giving 91 mg (52%) of the title compound, mp 168-170° C. 1H NMR (CD3OD) 1.536 (m, 2 H), 1.656 (d, J=12.6 Hz, 3 H), 2.615 (d, J=6.9 Hz, 2 H), 3.060 (m, 2 H), 3.499 (m, 2 H), 3.591 (m, 2 H), 4.245 (t, J=4.8 Hz, 2 H), 6.710 (m, 2 H), 6.823 (m, 2 H), 7.177 (d, J=8.4 Hz, 2 H), 7.280 (d, J=8.1 Hz, 2 H).