Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
3-Methyl-2-nitrobenzoic acid 67 (30.0 g, 166 mmol, 1.0 equiv.) was suspended in CH2Cl2 (150 ml) and the suspension was cooled to 0° C. using an ice bath. Oxalyl chloride (2.0 M in CH2Cl2, 166 ml, 332 mmol, 2.0 equiv.) was added to the stirred reaction mixture through a pressure equalizing dropping funnel over 30 min. DMF (10 drops) was added dropwise. The reaction mixture was allowed to warm up to room temperature. After 30 min., the reaction was concentrated to dryness on a rotary evaporator. The solid material was re-dissolved in CH2Cl2 (200 ml) and was concentrated to dryness on a rotary evaporator to give 3-methyl-2-nitro-benzoylchloride 68 (32.9 g, 99%) as an off white solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)[CH2:3][OH:4].I[CH3:14]>C1COCC1>[I:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH:2]([NH2:1])[CH2:3][O:4][CH3:14])=[CH:11][CH:10]=1
Reactant: NC(CO)Cc1ccc(I)cc1
Reactant: CI
Solvent: C1CCOC1
Product: COCC(N)Cc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 12.0 g (43.3 mmol) 2-amino-3-(4-iodophenyl)-propan-1-ol (I41) and 350 mL THF is cooled down to 0° C. 3.81 g (95 mmol) NAH (60% in min. oil) are carefully added and the mixture is stirred at 0° C. for 30 min. 3.25 mL (52.0 mmol) iodomethane are added and cooling is removed. The reaction mixture is stirred at r.t. for 1 h. The mixture is poured onto water and extracted with EtOAc (2×). The combined organic layers are washed with brine, dried with Na2SO4 and the solvent is removed in vacuo. The compound is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:14])=[CH:11][N:10]=[C:9]([N:24]2[CH2:30][CH2:29][C:26]3([CH2:28][CH2:27]3)[CH2:25]2)[N:8]=1.[CH2:36]=O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH3:36])[CH2:22][CH2:23]2)=[O:14])=[CH:11][N:10]=[C:9]([N:24]2[CH2:30][CH2:29][C:26]3([CH2:27][CH2:28]3)[CH2:25]2)[N:8]=1
Reactant: C=O
Reactant: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)NCCN2CCNCC2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)NCCN2CCN(C)CC2)cc1Cl
Reaction time: 1 h
Yield: 65.4 %

Procedure:
In methanol (20 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-N-(2-(piperazin-1-yl)ethyl)-2-(5-azaspiro[2.4]heptan-5-yl)pyrimidine-5-formamide (250 mg, 0.5 mmol). Formalin (37%, 61 mg, 0.75 mmol) was added. The reaction was conducted at 0° C. for 1 h. Sodium borohydride (38 mg, 1.0 mmol) was added at 0° C. The reaction was continued for 2 h, then quenched with water. The reaction mixture was filtrated, dried and concentrated to give 4-((3-chloro-4-methoxybenzyl)amino)-N-(2-(4-methylpiperazin-1-yl)ethyl)-2-(5-azaspiro[2.4]heptan-5-yl)pyrimidine-5-formamide (168 mg, 65% yield). The product was dissolved in methanol (5 mL), and hydrochloric acid (0.1 mL) was added. The reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed by evaporation to give the hydrochloride salt of the compound as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]=[C:13]([CH3:15])[CH3:14]>>[CH:1]1([CH:7]([CH3:11])[C:8]([O:10][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)C
Reactant: CC(C(=O)O)C1CCCCC1
Product: CC(C(=O)OC(C)(C)C)C1CCCCC1

Procedure:
2-Cyclohexylpropionic acid is reacted with isobutene in the presence of an acid catalyst according to the following reaction scheme to obtain tert-butyl 2-cyclohexylpropionate. ##STR7##
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6]2)[CH3:2].FC(F)(F)C(O)=O.[N+:24]([O-])([O-:26])=[O:25].[K+]>O>[N+:24]([C:11]1[C:12]([CH2:13][CH3:14])=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[C:10]=1[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:26])=[O:25]
Reactant: CCc1cc2[nH]c(=O)c(=O)[nH]c2cc1CC
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1CC
Yield: 69.1 %

Procedure:
6,7-Diethyl-2,3-quinoxalinedione 25 (218 mg, 1.0 mmol) was added to trifluoroacetic acid (8 mL; Sigma). To this suspension was added potassium nitrate (121.2 mg, 1.2 mmol; Baker) in one portion with stirring under N2. The reaction was stirred at room temperature for 48 h. Trifluoroacetic acid was evaporated in vacuo to give a residue. Water (10 mL) was added to this residue with vigorous stirring. A yellow solid precipitated, which was collected by suction filtration and dried in vacuo to give 182 mg (69%) of the title compound 26 as a yellow solid; mp 270-272° C. (dec.); 1H NMR (DMSO-d6, 300 MHz) δ 1.137 (m, 6H), 2.622 (m, 4H), 7.088 (s, 1H), 11.762 (s, 1H), 12.028 (s, 11H). EIMS m/e 263 (100, M+). (HPLC purity 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])C(OC)=O)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])O.[Na+]>CC(O)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH2:18][S:23]([N:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)C(c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1)S(=O)(=O)N(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 100 °C

Procedure:
Methyl (3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)[(dimethylamino)sulfonyl]acetate (2.04 g, 4.85 mmol) was dissolved in a mixture of AcOH (24.24 ml) and 6M HCl (24.24 ml) and heated to 100° C. for 3 h. The solution was then cooled to room temperature, basified with saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane (3×50 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.48 (d, 1H); 8.21 (s, 1H); 7.84 (m, 2H); 7.49 (d, 1H); 7.33 (d, 1H); 4.63 (s, 2H); 2.74 (s, 6H). LRMS (APCI) calculated for C17H16ClN2O3S [M+H]+, 363.1; found 363.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[NH:21][N:20]=2)[C:15]([Cl:28])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:15]1[C:16]([NH:18][C:19]2[CH:23]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[NH:21][N:20]=2)=[N:17][C:12]([NH:10][CH:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=2)[CH3:9])=[N:13][CH:14]=1
Reactant: CC(N)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(NC(C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 160 °C
Yield: 27.3 %

Procedure:
A microwave reaction vessel was charged with 1-(5-fluoropyrimidin-2-yl)ethanamine (Method 1, 0.25 g, 1.77 mmol), 2,5-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 2, 0.50 g, 1.77 mmol), and DIPEA (0.30 g, 2.34 mmol). Anhydrous n-BuOH (2 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 10 hours. The reaction mixture was purified by silica gel chromatography twice (by ISCO Combiflash with gradient EtOAc and DCM) to afford the title compound as a white solid (0.19 g, 27%). LC-MS, 393 (M+1). 1H NMR (CDCl3) δ 8.50 (s, 2H), 7.75 (s, 1H), 5.50 (s, 1H), 5.20 (m, 1H), 4.68 (m, 1H), 1.55 (d, 3H), 1.20 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]#[N:22])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: N#Cc1ccccc1CBr
Product: N#Cc1ccccc1CNc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 20.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (140 mg, 0.66 mmol) and 2-(bromomethyl)benzonitrile (156 mg, 0.80 mmol) to provide 462 (45 mg, 21% yield) as a white powder. LC-MS (M+H=327, obsd.=327). 1H NMR (400 MHz, DMSO-D6) δ 8.56 (dd, J=1.6, 8.0, 1H), 8.47 (dd, J=1.6, 4.7, 1H), 8.06 (d, J=8.7, 1H), 7.87 (dd, J=1.2, 7.7, 1H), 7.47 (m, 1H), 7.41 (m, 1H), 7.40 (d, J=7.7, 1H), 7.36 (dd, J=4.7, 7.9, 1H), 6.98 (d, J=7.9, 1H), 6.91 (dd, J=2.0, 8.7, 1H), 6.25 (s, 1H), 5.81 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3](=[O:4])[CH2:2][NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=2)=[O:37])[CH2:16]1)=[O:27])[CH3:24]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCN(CC)C(=O)C1CCCN(C(=O)CN(C(=O)CN)c2ccccc2)C1
Product: CCN(CC)C(=O)C1CCCN(C(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)C1
Yield: 37.7 %

Procedure:
Following a procedure analogous to that described in Example 106, but using 1.8 g of (RS)-2-amino-N-[2-(3-(N,N-diethylcarbamoyl)piperidino)-2-oxoethyl]-N-phenylacetamide and 0.64 g of 3-methylphenyl isocyanate as the starting material, 0.92 g of (RS)-N-[2-(3-(N,N-diethylcarbamoyl)piperidino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenyl acetamide melting at 156° C is obtained after recrystallization from an ethyl acetate/diisopropyl ether mixture (50/50 by volume).
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:9]=[C:8]([C:10]2[S:14][C:13]([NH:15][C:16]([N:18]3[CH:22]=[CH:21]N=C3)=[O:17])=[N:12][C:11]=2[CH3:23])[CH:7]=[C:6]([CH3:24])[N:5]=1)=[O:3].[CH2:25]([N:27]1[CH:31]=[C:30](CCN)[N:29]=[CH:28]1)[CH3:26]>>[CH2:25]([N:27]1[CH:31]=[C:30]([CH2:21][CH2:22][NH:18][C:16]([NH:15][C:13]2[S:14][C:10]([C:8]3[CH:7]=[C:6]([CH3:24])[N:5]=[C:4]([S:2]([CH3:1])=[O:3])[N:9]=3)=[C:11]([CH3:23])[N:12]=2)=[O:17])[N:29]=[CH:28]1)[CH3:26]
Reactant: Cc1cc(-c2sc(NC(=O)n3ccnc3)nc2C)nc(S(C)=O)n1
Reactant: CCn1cnc(CCN)c1
Product: CCn1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)c1

Procedure:
This compound is prepared from imidazole-1-carboxylic acid [5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-amide (imidazole-urea intermediate BD) and 2-(1-ethyl-1H-imidazol-4-yl)-ethylamine (thiourea intermediate CC1) using general procedure A.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1.Br[CH2:22][C:23]([NH2:25])=[O:24].O>CN(C)C=O>[CH:3]1([N:6]([CH2:22][C:23]([NH2:25])=[O:24])[S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1
Reactant: O=S(=O)(Cc1cccc(C(F)(F)F)c1)NC1CC1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CN(C1CC1)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.26 Gram of sodium hydride is added portionwise to a solution containing 2.77 g of N-cyclopropyl-3-trifluoromethylbenzylsulfonamide in 50 ml of dimethylformamide over an ice bath. The mixture is stirred 15 minutes at 0° C. and then 0.0105 moles of bromoacetamide is added dropwise with cooling. The mixture is stirred overnight at room temperature. Water is then added. This will result in the formation of a precipitate and oil. Water is continued to be added until no further precipitate or oil is formed. The mixture is cooled over an ice bath and then filtered. The filter cake is dissolved in hot cyclohexane and then recrystallized affording the title compound.
Reaction SMILES: [NH2:1][NH2:2].Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15])=O>C(O)C>[OH:15][C:14]1[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=2)=[N:2][N:1]=1
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)c1ccccn1
Agent: Cl
Solvent: CCO
Product: Oc1nnc(-c2ccccn2)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 3M-solution of hydrazine (20 ml, 60 mmol) in ethanol is added to the solution of crude 2-(2-pyridylcarbonyl)benzoic acid hydrochloride(4.54 g, 20 mmol), and the mixture is stirred at room temperature for 5 hours. Precipitation yields 1-hydroxy-4-(2-pyridyl)phthalazine.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1.[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[ClH:39].[OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc([N+](=O)[O-])ccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3cc([N+](=O)[O-])ccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(6-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 0.038 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(6-nitro-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.014 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:18]=[C:19]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:31])([F:32])[F:15])[CH:18]=4)=[CH:24][C:25](=[O:26])[NH:14][C:5]=23)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2c(C)n[nH]c2N)cc1
Reactant: CCOC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(C)nn3c(-c4cccc(C(F)(F)F)c4)cc(=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
3-Methyl-4-(4-methylphenyl)-1H-pyrazol-5-a mine (300 mg) and ethyl 3-(3-(trifluoromethyl)phenyl)-3-oxopropanoate (500 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 405 mg of the target compound.
Reaction SMILES: [CH2:1]([C:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl-:33].[Ca+2].[Cl-].Cl>C(Cl)Cl>[CH2:1]([C:11]([Cl:33])([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCC(O)(CCCCCCCCCC)CCCCCCCCCC
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCCCCCCCCC(Cl)(CCCCCCCCCC)CCCCCCCCCC
Yield: 90 %

Procedure:
One mole of tri-n-decylcarbinol was added to a mixture of 0.2 liters of methylene chloride and 0.32 moles calcium chloride. Approximately 1.5 moles of HCl gas was slowly bubbled through the solution. The product mixture is then washed with 1 liter of a 10% sodium carbonate solution. The organic layer is dried with magnesium sulfate and the methylene chloride evaporated off to give a 90% yield of tri-n-decylmethylchloride.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[ClH:39]>CO.ClCCl>[ClH:39].[ClH:39].[OH:38][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccccc3)CC2)cc1

Procedure:
The free base was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 28) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1. The free base was dissolved in methanol/dichloromethane and treated with hydrogen chloride gas. After concentrated the solvents the product was obtained as a yellowish solid; mp>160° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.60-1.90 (m, 2 H), 2.05-2.25 (m, 2 H), 2.80-3.30 (m, 7 H), 3.60-4.40 (m, 11H), 6.90-7.10(m, 3 H), 7.14(d, J=8.7 Hz, 2 H), 7.51 (d, J=8.7 Hz, 2 H), 7.57 (s, 1 H), 8.92(brs, 1 H), 9.36(brs, 1 H); MS (ES) m/z: 262.1 ((M+2H)2+, 100%); 523.1(MH+, 30%); HRMS Calcd. for C28H35N4O3S (MH+): 523.2379. Found: 523.2394.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:16]=[C:15]([C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:26]([OH:28])=[O:27])=O)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[CH:16]=[C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:26]([OH:28])=[O:27])=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)c2cc(C(=O)c3ccc(C)cc3)c(C(=O)O)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(Cc2cc(Cc3ccc(C)cc3)c(C(=O)O)cc2C(=O)O)cc1

Procedure:
A mixture of 21.1 grams of 4,6-bis(4-methylbenzoyl)isophthalic acid, 350 mL of acetic acid, and 2.10 grams of 5% palladium on carbon (as a catalyst) was heated to 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The resulting mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 4,6-bis(4-methylbenzyl)isophthalic acid.
Reaction SMILES: C([CH:5]1[C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][N:6]1[C:12]([O-])=O)(C)(C)C.CCOCC.[N+:20]([C:23]1[CH:30]=[CH:29][C:26](CBr)=[CH:25][CH:24]=1)([O-:22])=[O:21]>Cl>[CH3:11][O:10][CH:9]1[CH2:8][CH2:7][N:6]([CH2:12][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[CH2:5]1
Reactant: CO[C@@H]1CCN(C(=O)[O-])C1C(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Solvent: CCOCC
Product: COC1CCN(Cc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
An amount of 1.8 g (9.02 mmol) of tert-butyl-(3R)-3-methoxypyrrolidin-1-yl carboxylate is stirred in concentrated hydrogen chloride (10 mL) for two hours. Anhydrous ether (100 mL) is added and stirred for additional 30 minutes. The ether is decanted and this is repeated three times. The mixture is neutralized with excess triethylamine and after evaporating to dryness, the mixture is re-dissolved in methylene chloride (100 mL) and 1.5 g (6.94 mmol) of 4-nitrobenzylbromide is added and refluxed for two hours. After cooling, the mixture is washed three times with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to give 1.1 g (67% yield) of the nitro intermediates as a yellow oil.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[F:15][C:16]1[C:23]([F:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+].O>CO>[F:15][C:16]1[C:23]([F:24])=[C:22]([C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:17]=1[C:18]1[O:19][CH:2]=[N:1][C:3]=1[CH3:4]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1 0.0 g, 47.8 mmol), 2,3-difluoro-4-(trifluoromethyl)benzaldehyde (9.68 g, 46.1 mmol), and K2CO3 (13.1 g, 95.0 mmol) in MeOH (240 mL) was heated to reflux. After 2 hr, the reaction mixture was cooled to ambient temperature, water (700 mL) was added, and the product was extracted with EtOAc (700 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to an orange oil. The crude product was purified by chromatography on silica gel in five batches (Analogix® SF40-240G column, 100% CH2Cl2, 65 mL/min) to afford 7.22 g (60%) of the title compound as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.78-7.69 (m, 1H), 7.68-7.59 (m, 1H), 2.30 (d, J=2.5, 3H). MS (DCI+) m/z 264 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12](Cl)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[OH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.Cl>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([O:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc(O)n[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(Cl)c2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
Potassium carbonate (3.52 g, 25.5 mmol) and 2,4-dichloronitrobenzene (9.79 g, 51.0 mmol) were added to a solution of 3-hydroxy-5-methylpyrazole (5.00 g, 51.0 mmol) in DMF (130 ml) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (200 ml) and extracted with ethyl acetate (100 ml×3). An organic layer was washed with water (100 ml×3), dried over anhydrous magnesium sulfate and filtered to remove magnesium sulfate, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of 3-(3-chloro-4-nitrophenyloxy)-5-methylpyrazole (6.33 g, yield: 48.9%) [mp: 91-93° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.30 (s, 3H), 5.74 (d, J=0.6 Hz, 1H), 7.10 (dd, J=2.8 and 9.1 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 10.73 (br d, J=8.8 Hz, 1H)] and a yellow solid of 3-(5-chloro-2-nitrophenyloxy)-5-methylpyrazole (2.31 g, yield: 17.9%) [mp: 87-90° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.27 (s, 3H), 5.73 (d, J=0.6 Hz, 1H), 7.17 (dd, J=2.2 and 8.8 Hz, 1H), 7.26 (d, J=2.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 10.77 (br s, 1H)].