Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:24]=1[CH2:25]Br.C(Cl)Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH2:10][CH2:11][CH2:12][O:13][CH2:25][C:24]1[CH:27]=[C:28]([Br:31])[CH:29]=[CH:30][C:23]=1[F:22])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CCCO)NC(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)cc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CCCOCc1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A stirred solution of 4-(t-butoxycarbonylamino)-4,4-dimethylbutan-1-ol (1.11 g, 5.11 mmol) in tetrahydrofuran (49 ml) at −45° C. was treated with potassium t-butoxide (1 M in tetrahydrofuran, 5.62 ml, 5.62 mmol). The anion was stirred for 30 minutes at −45° C., then cooled to −78° C. and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow mixture was slowly warmed to 0° C. and stirred for about four hours. The reaction mixture was diluted wtih methylene chloride (100 ml) and washed with 1 M potassium carbonate (20 ml). The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.53 grams (74%) of the title intermediate as a colorless oil.
Reaction SMILES: ClC1C(C)=C(S(Cl)(=O)=O)C=CC=1.[Cl:13][C:14]1[C:15]([CH3:45])=[C:16]([S:20]([NH:23][C:24]2[CH:44]=[CH:43][C:27]3[N:28](S(C4C=CC=C(Cl)C=4C)(=O)=O)[C:29]([CH3:31])=[N:30][C:26]=3[CH:25]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.ClC1C(C)=C(S(NC2C=CC3N=C(C)N(S(C4C=CC=C(Cl)C=4C)(=O)=O)C=3C=2)(=O)=O)C=CC=1.ON1C2C=CC=CC=2N=N1>C1COCC1.O.CO.CO.C(Cl)Cl>[Cl:13][C:14]1[C:15]([CH3:45])=[C:16]([S:20]([NH:23][C:24]2[CH:44]=[CH:43][C:27]3[NH:28][C:29]([CH3:31])=[N:30][C:26]=3[CH:25]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2c(c1)nc(C)n2S(=O)(=O)c1cccc(Cl)c1C
Agent: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2nc(C)n(S(=O)(=O)c3cccc(Cl)c3C)c2c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The coupling reaction of 3-chloro-2-methylbenzenesulphonyl chloride (2 eq.) with 2-methylbenzimidazoel (1 eq.) under the condition described above yielded a mixture of 3-chloro-N-[1-(3-chloro-2-methylbenzenesulphonyl)-2-methyl-1H-benzoimidazol-5-yl]-2-methyl-benzenesulphonamide and 3-chloro-N-[1-(3-chloro-2-methylbenzenesulphonyl)-2-methyl-1H-benzoimidazol-6-yl]-2-methyl-benzenesulphonamide in 1:1 ratio as judged by HNMR. 1H NMR (270 MHz, DMSO): δ 10.7 (2H, s, 2×NH), 7.86-7.96 (3H, m, ArH), 7.65-7.78 (5H, m, ArH), 7.52-7.58 (5H, m, ArH), 7.25-7.40 (3H, m, ArH), 7.07 (2H, t, J=8.2 Hz, ArH), 2.61 (3H, s, CH3), 2.58 (3H, s, CH3), 2.54 (6H, s, 2×CH3), 2.39 (3H, s, CH3), 2.33 (3H, s, CH3). The mixture (200 mg) was dissolved in THF (15 mL), N-hydroxybenzotriazole (200 mg) was added. After stirred at rt for 48 h, the mixture was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulphate and concentrate in vacuo to give a yellow residue, which was purified with flash chromatography (methanol/DCM gradient elution). Off white amorphous powder was obtained. TLC single spot at Rf 0.38 (10% methanol/DCM); HPLC purity 99% (tR 2.0 min in 10% water-methanol); 1H NMR (270 MHz, DMSO): δ 12.1 (1H, s, NH), 10.3 (1H, s, NH), 7.78 (1H, d, J=7.9 Hz, ArH), 7.68 (1H, d, J=7.9 Hz, ArH), 7.29-7.35 (2H, m, ArH), 7.12 (1H, s, ArH), 6.83 (1H, dd, J=8.4, 1.8 Hz, ArH), 2.63 (3H, s, CH3), 2.41 (3H, s, CH3); APCI-MS 334 (M−H+); FAB-HRMS calcd for C15H15ClN3O2S (MH+) 336.0573, found 336.0583.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:14]([O:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OCC(O)COCc1ccccc1
Product: CCCCCCCCCCCC(=O)OCC(COCc1ccccc1)OC(=O)CCCCCCCCCCC
Yield: 76.2 %

Procedure:
3-O-Benzylglycerol (7 g) is reacted with 18.5 g of lauroyl chloride in the same manner as in Starting Material Synthesis 2. Recrystallization of the crude crystals from ethanol gives 16 g of white crystals. Melting point: 30°-31° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=[C:9]([C:21]#[N:22])[C:8]([CH2:23][CH3:24])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([OH:27])C.OO.[OH-].[Na+]>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:22][C:21](=[O:27])[C:9]3=[C:8]([CH2:23][CH3:24])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c(NC(=O)Cc2ccccc2)c1C#N
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-4-cyano-5-(phenylmethylcarbonylamino)-1H-pyrazole (2.4 g, 7.4 mmol), ethanol (100 ml), 30% H2O2 (4.5 ml, 40 mmol), NaOH (0.3 g, 7.5 mmol) and water (10 ml) was stirred at room temperature for 1 hour, then at reflux for 1 hour. Additional 30% H2O2 (2.5 ml) was added and the mixture was refluxed for another 1 hour. The solvent was concentrated in vacuo, the residue was treated with water (25 ml) and acetic acid (3 ml) and the yellow precipitate which formed was collected by filtration, washed with water and recrystallized from isopropanol to afford 0.79 g of 1-cyclopentyl-3-ethyl-6-(phenylmethyl)-pyrazolo[3,4-d]pyrimdin-4-one, as orange needles, m.p. 175-176° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]12[C:16]3[C:8](=[CH:9][C:10]([NH:17][C:18]4[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=4)=[CH:11][C:12]=3[CH2:13][CH2:14][CH2:15]1)[CH2:7][CH2:6][CH2:5]2.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.[Cl-].[NH4+]>CN(C)C=O>[CH:31]1([CH2:30][N:17]([C:10]2[CH:9]=[C:8]3[C:16]4[C:4]([CH3:3])([CH2:5][CH2:6][CH2:7]3)[CH2:15][CH2:14][CH2:13][C:12]=4[CH:11]=2)[C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=2)[CH2:33][CH2:32]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1ccc(Nc2cc3c4c(c2)CCCC4(C)CCC3)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(CC2CC2)c2cc3c4c(c2)CCCC4(C)CCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of sodium hydride (60%, 0.013 g) in N,N-dimethylformamide (2 ml) was added with ethyl 4-[(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.055 g) dissolved in N,N-dimethylformamide (2 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added with bromomethylcyclopropane (0.035 ml), the mixture was stirred overnight at room temperature, and then added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:50) to quantitatively obtain the title compound (0.063 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:31][CH:30]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccc(Cl)cc4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(4-chlorophenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 452 (M++1)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:28])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)=[CH:23][CH:22]=2)[O:17]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: ClCc1ccc2ccccc2n1
Product: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Yield: 90 %

Procedure:
Alkylation of 2-Chloromethyl-quinoline with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A for Example 3.32 to give 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-quinoline in 90% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.2 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 1 H) 7.6 (dd, J=11.4, 8.6 Hz, 3 H) 7.7 (m, 1 H) 7.8 (dd, J=8.1, 1.5 Hz, 1 H) 7.9 (d, J=8.6 Hz, 1 H) 8.3 (d, J=8.6 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)c(C=Cc2cccc(Cl)c2)c1
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccc(C(=O)O)c(CCc2cccc(Cl)c2)c1

Procedure:
For the synthesis of the title compound, 6.0 g of 2-[2-(3-chlorophenyl)-vinyl]-4-methoxybenzoic acid, 0.6 g of Pd/C (10%) and 41 of hydrogen are employed in method J (variant 2). The solvent mixture comprises 75 ml of acetonitrile, 75 ml of ethyl acetate and 20 ml of methanol. C16H15ClO3(Mr=290.75)
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:21])[N:8]([C:12]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[CH3:22][N:23]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:21])[N:8]([C:12]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])[CH:9]=[C:10]([C:25]3[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=3)[C:5]=2[NH:4][N:3]=1
Reactant: N#Cc1cccc(F)c1-n1cc(Br)c2[nH]nc(N)c2c1=O
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc(-c2cn(-c3c(F)cccc3C#N)c(=O)c3c(N)n[nH]c23)n1
Temperature: 130 °C
Yield: 27.4 %

Procedure:
A mixture of 2-(3-amino-7-bromo-4-oxo-1,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-3-fluorobenzonitrile obtained in Step G (160 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (191 mg), tetrakis(triphenylphosphine)palladium(0) (53 mg), aqueous sodium carbonate solution (2 M, 0.460 mL) and N,N-dimethylformamide (10 mL) was heated with microwave irradiation at 130° C. for 90 min under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (basic silica gel, methanol/ethyl acetate) to give a crude product. The crude product was crystallized from ethyl acetate/diethyl ether to give the title compound (44 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[O:7][CH2:6][CH2:5][N:4]([CH2:8][C@H:9]2[CH2:14][N:13]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][N:10]2[C:23]2[CH:28]=[CH:27][C:26]([C@:29]([OH:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH2:3]1.CC1(C)OCCN(C[C@@H]2CN(S(C3SC=CC=3)(=O)=O)CCN2C2C=CC([C@@](O)(C)C(F)(F)F)=CC=2)C1.CC1(C)OCCN(C[C@H]2CN(S(C3SC=CC=3)(=O)=O)CCN2C2C=CC([C@@](O)(C)C(F)(F)F)=CC=2)C1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[CH3:1][C:2]1([CH3:36])[O:7][CH2:6][CH2:5][N:4]([CH2:8][C@@H:9]2[CH2:14][N:13]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][N:10]2[C:23]2[CH:28]=[CH:27][C:26]([C@:29]([OH:35])([CH3:34])[C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[CH2:3]1
Reactant: CC1(C)CN(C[C@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc([C@@](C)(O)C(F)(F)F)cc2)CCO1
Agent: CC1(C)CN(C[C@@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc([C@](C)(O)C(F)(F)F)cc2)CCO1
Agent: CC1(C)CN(C[C@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc([C@](C)(O)C(F)(F)F)cc2)CCO1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: CC1(C)CN(C[C@@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc([C@@](C)(O)C(F)(F)F)cc2)CCO1

Procedure:
(2R)-2-(4-((2S)-2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2R)-2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(4-((2S)-2-((2,2-dimethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.07-8.05 (m, 1H), 7.68-7.66 (m, 1H), 7.37-7.35 (m, 2H), 7.32-7.29 (m, 1H), 6.88-6.86 (m, 2H), 4.15-4.12 (m, 1H), 3.91-3.88 (m, 1H), 3.46-3.42 (m, 4H), 3.13-3.07 (m, 1H), 2.60-2.55 (m, 1H), 2.49-2.38 (m, 3H), 2.27-2.22 (m, 1H), 2.16-2.05 (m, 3H), 1.61 (s, 3H), 1.11 (s, 3H), 1.07 (s, 3H). m/z (ESI, +ve ion) 548.2 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.182 μM; GK-GKRP EC50 (LC MS/MS)=0.295 μM.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].C[C@H]1CC[C@H](NC([C@@H]2C[C@H]2COS(C)(=O)=O)=O)CC1.Cl.[F:41][C:42]([F:56])([F:55])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:45][CH:44]=1.Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:52]2[CH2:51][CH2:50][N:49]([C:46]3[CH:45]=[CH:44][C:43]([C:42]([F:55])([F:56])[F:41])=[CH:48][CH:47]=3)[CH2:54][CH2:53]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: CS(=O)(=O)OC[C@@H]1C[C@H]1C(=O)N[C@H]1CC[C@H](C)CC1
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for methane sulfonic acid 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(4-trifluoromethyl-phenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound MS m/z=438 (M+H)+, 78.5% pure by HPLC assay.
Reaction SMILES: [CH:1]([C:4]([CH2:7][OH:8])([F:6])[F:5])([F:3])[F:2].N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl.N1C=CC=CC=1>>[CH:1]([C:4]([CH2:7][O:8][S:16]([CH3:15])(=[O:18])=[O:17])([F:6])[F:5])([F:3])[F:2]
Reactant: OCC(F)(F)C(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(F)(F)C(F)F

Procedure:
A 10-L four-neck flask was equipped with a refluxing pipe and a dropping funnel to serve as a reactor. To the flask were added HCF2CF2CH2OH (445.35 g; 3.37 mol) and pyridine (306.31 g; 3.88 mol) in an ice bath, and the mixture was stirred. Using the dropping funnel, methanesulfonyl chloride (364.15 g; 3.20 mol) was dropped, with care for heat generation. The reaction solution changed its color gradually to milky white as pyridine hydrochloride was produced. After the end of the reaction, the reaction solution was washed with a 1 N HCl aqueous solution. The washed solution was separated to collect an organic layer.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:19][N:20]([CH3:28])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][CH:26]=1
Reactant: CN(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to the example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-dimethylamino-pyridin-3-yl)-amide was prepared from 2-phenyl-trifluoromethyl-oxazole-4-carboxylic acid and N2,N2-dimethyl-pyridine-2,5-diamine. LCMS calcd for C18H15F3N4O2 (m/e) 376.34 obsd 377.12 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([S:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3N)[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.O1CCOCC1.Cl.N(OCCC(C)C)=O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([S:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=3)[NH:13][C:14]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(C(F)(F)F)cc3N)[nH]c2-c2ccc(OC)cc2)cc1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(-c2nc(Sc3ccc(C(F)(F)F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
2.61 g of 4,5-bis(4-methoxyphenyl)-2-(2-amino-4-trifluoromethylphenylthio)imidazole hydrochloride is suspended in a mixture of 70 ml of absolute ethanol, 30 ml of absolute dioxane, and 365 mg of hydrochloric acid and combined at 0° with 0.586 g of isoamyl nitrite. The mixture is agitated for 30 minutes, then heated for 2 hours to boiling, and the solution evaporated to dryness under vacuum. The residue is distributed between ethyl acetate and sodium bicarbonate solution. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ether/methylene chloride, thus obtaining 2.01 g of 4,5-bis(4-methoxyphenyl)-2-(4-trifluoromethylphenylthio)imidazole, mp 184°-186°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O-:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH+](CC)CC)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:52]([CH3:54])[CH3:53]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]=1[C:35]([O:37][CH:52]([CH3:54])[CH3:53])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Br
Reactant: COc1ccc(-n2c(C(=O)[O-])c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(C(=O)OC(C)C)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
To a stirred suspension of triethylammonium 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (7) [prepared as example B-step (iv) using ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (6) as starting material] (360 mg, 0.60 mmol) and Cs2CO3 (429 mg, 1.32 mmol) in DMF (3 mL) was added 2-bromopropane (197 μL, 2.10 mmol) and the reaction stirred at 40° C. for 2 h then partitioned between EtOAc (50 mL) and water (20 mL). The organic was separated and washed with water (2×50 mL), brine (2×50 mL), dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil. The residue was purified by silica gel chromatography (40 g, 20-60% EtOAc in isohexane) to afford isopropyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (8) (108 mg, 33%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ: 7.51-7.43 (m, 2H), 7.43-7.28 (m, 8H), 7.19-7.05 (m, 2 H), 6.96-6.84 (m, 2H), 5.13 (s, 2H), 4.96 (s, 2H), 4.85 (sept., J=6.2 Hz, 1H), 3.78 (s, 3H), 2.72 (s, 3H), 2.71 (s, 3H), 1.10 (d, J=6.2 Hz, 6H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1.[CH3:43][C:44]1([CH3:56])[N:49]([O:50])[C:48]([CH3:52])([CH3:51])[CH2:47][CH:46](N=C=S)[CH2:45]1.O.O=C[C@@H]([C@@H]([C@@H](CO)O)O)O>CN(C=O)C>[CH3:51][C:48]1([CH3:52])[N:49]([O:50])[C:44]([CH3:56])([CH3:43])[CH2:45][CH2:46][CH2:47]1.[CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:15][CH:16]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1
Reactant: CC1(C)CC(N=C=S)CC(C)(C)N1[O]
Agent: NCCNC(=O)Cc1cccc(NC(=O)Cc2ccc(Nc3ncnc4c3ncn4[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Agent: O=C[C@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCCC(C)(C)N1[O]

Procedure:
ADAC, 2 (11.8 mg, 20 umol), was suspended in 0.5 ml DMF and treated with 4-isothiocyanato-TEMPO (2,2,6,6,-tetramethyl-1-piperidinyloxy, free radical (7 mg, Aldrich). After 1 hour 1.5 ml water was added to the solution, and the precipitate was collected, washed with a minimum of MeOH and ether, and recrystallized from DMF/ether/petroleum ether, to give a product which was homogeneous by thin layer chromatography and gave proton NMR and ESR spectra consistent with the structure. Yield 8.3 mg (51%). Cf-MS peak at 758 (m+1-MeO) and 626 (m+1 -ribose). IR shows a peak at 1580 cm-1, characteristic of a thiourea carbonyl stretch.