Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:2]3[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: OB(O)c1ccc2[nH]ncc2c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 43.1 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL), was added 1H-indazol-5-ylboronic acid (386.0 mg, 2.38 mmol), K3PO4 (434.0 mg, 2.05 mmol), Pd(PPh3)4 (39.0 mg, 0.03 mmol) under nitrogen atmosphere and water (3 drops). After stirring for 20 min at 90° C., the reaction mixture was dissolved in water (30 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2%-10% ethyl acetate in petroleum ether to afford methyl 2-(1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (110.0 mg, 45%).
Reaction SMILES: [CH:1]12[CH:9]([N:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[Si]([C:28]#[N:29])(C)C.N>C(O)(=O)C>[CH:1]12[CH:9]([N:10]3[CH2:15][CH2:14][C:13]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([C:28]#[N:29])[CH2:12][CH2:11]3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: Nc1ccccc1
Reactant: O=C1CCN(C2C3CCCC2CCC3)CC1
Reactant: C[Si](C)(C)C#N
Agent: N
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCN(C2C3CCCC2CCC3)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.8 %

Procedure:
1-Bicyclo[3.3.1]non-9-yl-piperidin-4-one (2.99 g, 13.5 mmol) was dissolved in acetic acid (15 ml). Aniline (1.36 ml, 14.9 mmol) and trimethylsilylcyanide (1.44 ml, 13.5 mmol) were added at 0° C. and the mixture was stirred for 17 h at room temperature. The reaction mixture was poured into cold ammonia solution (water/28% ammonia, 30 ml/50 ml) and extracted with dichloromethane (2×100 ml). The combined organic phases were washed with brine (100 ml), dried (MgSO4) and concentrated. Column chromatography on silica gel (toluene/ethyl acetate 4:1) yielded the desired product (3.18 g, 73%) as a pale yellow solid, m.p. 168° C., MS: m/e=324.4 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([O-])=[O:18])[S:16][C:9]=12.[Li+]>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:17]([C:15]1[S:16][C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[Cl:7])[CH:14]=1)=[O:18]
Reactant: CN(C)CCN
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CN(C)CCNC(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-dimethylaminoethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 284/286 (MH+); HPLC Rf: 3.47 min.; HPLC purity: 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:5]=[CH:6][C:7]=1[Cl:8].O.C(OCC)C.[BrH:24]>>[Br:24][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: Br
Reactant: OCCCCCCCCc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCOCC
Product: Clc1ccc(CCCCCCCCBr)cc1Cl

Procedure:
A solution of 8-(3,4-dichlorophenyl)octan-1-ol (0.66 g) in 48% hydrobromic acid (7 ml) was stirred under reflux for 2 h. Water (20 ml) and diethyl ether (20 ml) were added. The organic layer was separated and the aqueous layer reextracted with diethyl ether (10 ml). The combined organic extracts were washed with water (10 ml), sodium hydrogen carbonate solution (10 ml) and brine (10 ml) and dried over magnesium sulfate. The solution was treated with charcoal, filtered and evaporated under reduced pressure to give 1-bromo-8-(3,4-dichlorophenyl)octane (0.74 g). 1H-NMR (CDCl3) δ 1.2-1.8 (12H, m), 2.55 (2H, t), 3.41 (2H, t), 7.00 (1H, dd), 7.25 (1H, dd) and 7.33 (1H, d).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:30])[N:6]([CH:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])C2=O.COC1[CH2:37][CH2:36][CH:35](OC)O1.[C:40]([OH:43])(=O)[CH3:41]>>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]([CH:13]([N:6]2[C:40](=[O:43])[C:41]3[C:4](=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:3][C:2]3[NH:1][CH:35]=[CH:36][CH:37]=3)[C:5]2=[O:30])[CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[CH3:29]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CN)c3C2=O)ccc1OC
Reactant: COC1CCC(OC)O1
Reactant: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(Cc4ccc[nH]4)c3C2=O)ccc1OC
Yield: 60 %

Procedure:
A mixture of 4-(aminomethyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione (0.34 g, 0.79 mmol) and 2,5-dimethoxytetrahydrofuran (0.10 g, 0.79 mmol) in acetic acid (5 mL) was heated to reflux for 1 hour. The reaction mixture was then concentrated in vacuo and the residue was stirred with ethyl. acetate (50 mL) and saturated sodium bicarbonate (25 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried and concentrated. The residue was purified by flash chromatography (methylene chloride:ethyl acetate, 95:5) to afford 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-(pyrrolylmethyl)isoindoline-1,3-dione (0.23 g, 60% yield): mp 80-82° C.; 1H NMR (CDCl3) δ7.71 (d, J=7.3 Hz, 1H, Ar), 7.57 (t, J=7.7 Hz, 1H, Ar), 7.26 (m, 2H, Ar), 7.15 (d, J=7.0 Hz, 2H, Ar), 6.96 (d, J=7.8 Hz, 1H, Ar), 6.71 (d, J=1.7 Hz, 1H, Ar), 6.22 (d, J=1.8 Hz, 1H, Ar), 5.94-5.88 (dd, J=4.4 and 10.3 Hz, 1H, NCH), 5.57 (s, 2H, CH2), 4.63-4.53 (dd, J=10.7, 14.4 Hz, 1H, CHH), 4.13 (q, J=7.0 Hz, 2H, CH2), 3.85 (s, 3H, CH3), 3.80-3.72 (dd, J=4.4, 14.4 Hz, 1H, CHH), 2.86 (s, 3H, CH3), 1.47 (t, J=6.9 Hz, 3H, CH3); 13C NMR (CDCl3) δ168.08, 167.69, 149.72, 148.63, 138.71, 134.74, 132.65, 131.86, 129.44, 126.92, 122.69, 121.46, 120.47, 112.49, 111.44, 109.15, 64.51, 55.95, 54.65, 48.73, 48.57, 41.58, 14.69; Anal. Calcd for C25H26N2O6S: C, 62.23; H, 5.43; N, 5.81; S, 6.64. Found: C, 62.25; H, 5.56; N, 5.63; S, 6.83.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:4][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH2:23])(=[O:24])=[O:25])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCCNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-])C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NCCCNC2CC2)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 291C (4.14 g) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred for 2 hours. The mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (300 mL) and washed with aqueous NaHCO3, water, and brine and dried over Na2SO4. Filtration and evaporation of solvent gave the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.C([O-])([O-])=O.[K+].[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>CN(C=O)C.CCOC(C)=O>[NH2:15][C:13]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:24][CH2:23][C:22]([O:26][CH3:27])=[O:25])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: C=CC(=O)OC
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCn1cnc2c(-c3ccco3)nc(N)nc21
Reaction time: 40 h
Yield: 11.4 %

Procedure:
A solution of 6-(2-furyl)-1H-purine-2-amine (0.70 g, 3.48 mmol) and K2CO3 (0.48 g, 3.48 mmol) in DMF (20 mL) was treated with methyl acrylate (3.3 g, 38.3 mmol), stirred for 40 h, diluted with EtOAc, filtered to remove polymeric acrylate, washed with water, dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2: EtOAc-heptane, (4:1)] to give the title compound (114 mg, 11%) as a white solid.
Reaction SMILES: C([O-])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Cl:11][C:12]1[CH:21]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]([OH:22])=[C:14]([C:23](=[O:26])[CH2:24][CH3:25])[CH:13]=1.[C:27](Cl)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15](=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:21]=1)[O:22][C:25]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:24]([CH3:27])[C:23]2=[O:26]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C([O-])c1ccccc1
Reactant: CCC(=O)c1cc(Cl)cc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Cl)cc2c(=O)c(C)c(-c3ccccc3)oc12
Yield: 90.1 %

Procedure:
A 23.8 g (0.165 mole) quantity of sodium benzoate was added with stirring to a mixture of 12.1 g (0.05 mole) of methyl 5-chloro-3-propionylsalicylate and 21.1 g (0.15 mole) of benzoyl chloride. The resulting mixture was heated at 180° to 190° C. in an oil bath for 8 hours to undergo reaction. After cooling, 100 ml of a 5% aqueous solution of sodium carbonate was added to the reaction mixture and the admixture was stirred. The solids formed were recrystallized from alcohol, giving 14.8 g (90.1%) of white crystal, which was repeatedly recrystallized from alcohol to obtain a compound having a melting point of 171.5° to 173.0° C. The compound was chemically analyzed with the results shown in Table 1 given below.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:33])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH:17]=2)[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13]>O1CCCC1.CO>[F:3][C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:33])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH:17]=2)[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)O)c(F)c2)c1
Yield: 81 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, 4.7 eq) of sodium hydroxide, 210 mg (0.51 mmol, 1 eq) of methyl (E)-3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate (prepared in Example 3b) in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 165 mg of (E)-3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder. (m.p.=148-149° C.). Yield=81%
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]2([CH3:25])[N:11]3[C:12](I)=[CH:13][N:14]=[C:10]3[N:9]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C([Mg]Br)(C)C.[C:33](=[O:35])=[O:34]>C1COCC1>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]2([CH3:25])[N:11]3[C:12]([C:33]([OH:35])=[O:34])=[CH:13][N:14]=[C:10]3[N:9]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1
Reactant: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(I)n21
Reactant: O=C=O
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of (R)-3-(4-bromo-benzyl)-1-(3,5-dichloro-phenyl)-5-iodo-3-methyl-1H-imidazo[1,2-a]imidazol-2-one (4.5 g, 7.8 mmol) in THF (50 mL) was cooled to −40° C. To this was slowly added isopropyl magnesium bromide (1M in THF, 15.6 mL, 15.6 mmol) over 30 min. The reaction mixture was stirred at −40° C. for 1 h and then CO2 gas passed through the solution for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with water. The mixture was acidified with 1N HCl and extracted with CH2Cl2 (3×100 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated in vacuo. The residue was dissolved in toluene (40 mL) and hexane was added (100 mL). The resulting precipitate was filtered and washed with hexane to afford 2.6 g of (R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid as a purple solid, m/z 495.5 [M+]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](=[S:10])[NH:6][C:5]=1[C:11]#[N:12])([O-:3])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:17]C(Br)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:17][S:10][C:7]1[N:6]=[C:5]([C:11]#[N:12])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: N#Cc1[nH]c(=S)ccc1[N+](=O)[O-]
Reactant: Fc1cc(F)cc(CC(Br)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc(SCc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 97.9 %

Procedure:
A mixture of 3-nitro-6-thioxo-1,6-dihydropyridin-2-carbonitrile (4.42 mmol, 1.34 g), 3,5-diflurobenzylbenzylbromide (8.83 mmol, 1.828 g), and K2CO3 (11.04 mmol, 1.525 g) in 5 ml of acetone is heated at 70° C. for 10 hours and then evaporated under reduced pressure. The residue is purified by silica gel chromatography (AcOEt/heptane) to yield 1.33 g (98%) of the expected product.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([OH:21])=O)=[C:8]([C:11]3[N:12]4[CH:18]=[N:17][CH:16]=[C:13]4[S:14][CH:15]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[C:24](=[O:27])([O-:26])O.[Na+].[CH3:29][OH:30]>O>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:26][CH2:24][O:27][C:29](=[O:30])[C:4]([CH3:22])([CH3:5])[CH3:2])=[O:21])=[C:8]([C:11]3[N:12]4[CH:18]=[N:17][CH:16]=[C:13]4[S:14][CH:15]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CO
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3csc4cncn34)[C@H](C)[C@H]12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3csc4cncn34)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 32.5 mg of (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylic acid in a mixture of 10 ml of water and 8 ml of methanol was added 7.8 mg of sodium hydrogen carbonate, and the mixture was stirred at room temperature for 10 minutes to form a solution. Methanol was removed under reduced pressure, and the residue was lyophilized. The lyophilized product was dissolved in 2 ml of dry DMF, 0.03 ml of iodomethyl pivalate was added under the atmosphere of argon at −30° C., and the mixture was stirred for 2 hours during which the temperature was raised up to −10° C. Ethyl acetate was added to the reaction mixture, and the mixture was washed with semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a total volume of 3 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=30:1-10:1) to give 26.6 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].ON1C2C=CC=CC=2N=N1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(CC)CC)C.CNC(N=C=NCC)CCNC>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([N:24]([O:25][CH3:26])[CH3:23])=[O:6]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: CNOC
Agent: CCN=C=NC(CCNC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
To an ice cooled mixture of 3,5 difluoro benzoic acid (2.0 g, 0.012 mol), 1-hydroxy-benzotriazole (HOBT, 2.5 g, 0.018 mol) and N,O-dimethylhydroxylamine HCl (2.35 g, 0.025 mol) in CH2Cl2(100 mL) was added triethylamine (5.0 mL, 0.036 mol) and followed by addition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 3.8 g, 0.019 mol). The mixture was allowed to warm to room temperature and continuously stir overnight. The reaction mixture was added EtOAc (300 mL) and then washed by diluted HCl solution, NaHCO3 and NaCl solution. The organic layer was collected and dried with Mg2SO4 and evaporated. The crude product was purified by column (0-50% EtOAc/Heptane) to give the title compound, 2.6 gm colorless oil. (100%)
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[C:19]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20]>C1CCCCC1>[C:19]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[O-:34])([CH3:22])([CH3:21])[CH3:20].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCCCC1
Product: Cc1cc(C(C)(C)C)c([O-])c(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A 1 liter glass reaction vessel, fitted with a magnetic stirrer, a hose connector, and a septum was purged with nitrogen. Operating in an atmosphere of nitrogen, the vessel was charged with a cyclohexane solution (500 ml) which contained 50 grams poly(isobutylene-co-para-bromomethylstyrene) (Mv=10 k, 4.6% para-bromomethylstyrene). A cyclohexane solution of tetrabutylammonium 2,6-di(t-butyl)-4-methylphenoxide was prepared in a second flask under nitrogen by placing 100 ml cyclohexane, 30 ml tetrabutylammonium hydroxide (1 M in methanol) and 6.6 g 2,6-di(t-butyl)-4-methylphenol into the flask and concentrating this solution down to half its volume. This solution was then added to the flask containing the poly(isobutylene-co-para-bromomethylstyrene). Then 2.5 ml methacrylic acid was added to the polymer solution and the temperature of the solution was raised to 50° C. The reaction was complete in one hour and the polymer was isolated by precipitation in isopropanol. The polymer was dried in a vacuum oven at 1 mm Hg and 40° C. GPC of the recovered polymer (50 g, 100% yield) was identical to that of the starting poly(isobutylene-co-para-bromomethylstyrene). The analysis for the methacrylate content (FTIR and NMR) indicate that the modified polymer had 0.58 meq/gram which is consistent with the complete conversion of methacrylic acid to methacrylic ester.
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[C:21]([F:38])[CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)Cl.C1CCCCC1>[F:38][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[N:9]=[C:8]([CH2:7][CH2:6][C:5]3[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=3[CH2:3][C:2]([NH2:1])=[O:43])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=2)[CH:24]=[CH:23][C:22]=1[CH:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2F)CC1
Solvent: C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)c(F)c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate (A32) (0.209 g, 0.347 mmol) in DCM (4 mL) was added TFA (1.0 mL) and the resulting mixture was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (10 mL) and 2 M aqueous NaOH (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then the combined organic layers washed with water (10 mL), brine (10 mL) and dried over MgSO4. The volatiles were removed in vacuo to give a yellow solid which was suspended in DCM/cyclohexane and the resulting suspension filtered to give the title compound 7 as a white solid (0.107 g, 61%); 1H NMR (400 MHz, d4-MeOH) δ 8.59 (s, 1H), 7.66 (dd, J=13.2, 2.1 Hz, 1H), 7.39 (dd, J=8.5, 2.1 Hz, 1H), 7.28-7.15 (m, 5H), 3.68 (s, 2H), 3.23-3.14 (m, 4H), 3.10 (dd, J=10.6, 5.4 Hz, 2H), 2.99 (tt, J=11.7, 3.8 Hz, 1H), 2.80 (td, J=12.4, 2.9 Hz, 2H), 1.87-1.68 (m, 4H). LCMS-A: rt 4.851 min; m/z 502.2 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[C:23]1([CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1)[OH:24].[OH-].[Na+].Cl>C(O)CCC.O>[F:19][C:18]([F:20])([F:21])[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][O:24][C:23]1[CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CCCCC(CCOc1ccc(O)cc1)C(F)(F)F
Temperature: 130 °C
Reaction time: 5 h
Yield: 53.4 %

Procedure:
0.39 g of the above-obtained 3-trifluorometylheptyl p-toluenesulfonate and 0.25 g of hydroquinone were dissolved in 1 ml of butanol. To the solution was added a solution of 0.07 g of sodium hydroxide in 2 ml of butanol, followed by 5 hours of stirring at 130° C. for reaction. Then, water and 1N-hydrochloric acid were added to the reaction solution, followed by extraction with diethyl ether. The ether solution was dried with sodium sulfate, and the solvent was distilled off. The product was then purified by thin layer chromatography with methylene as the developer to obtain 0.17 g (yield:54%) of p-(3trifluoromethylheptyloxy)phenol which showed: [α]D26 -2.8, [α]43526 -4.9 (c 1, methylene chloride).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17]Br)=[N:13][NH:12][C:11]=1[NH2:19].[NH2:20]C1NN=C(CCCO)C=1C1SC2C=CC=CC=2N=1.N>C(O)C>[NH2:20][CH2:17][CH2:16][CH2:15][C:14]1[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[C:11]([NH2:19])[NH:12][N:13]=1
Reactant: Nc1[nH]nc(CCCO)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCBr)c1-c1nc2ccccc2s1
Agent: N
Solvent: CCO
Product: NCCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (12 mg) was prepared using 130 mg (0.39 mmol) of 4-benzothiazol-2-yl-5-(3-bromopropyl)-2H-pyrazol-3-ylamine, which was derived from 3-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-propan-1-ol, and a saturated solution of ammonia gas in ethanol. MS (m/z, ES+): 274.2 (M+1, 100%), 257.2 (M−NH2, 70%).