Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>[Ni].CO>[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:19]=[CH:20][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A suspension of 4-(4-nitro-phenoxy)-2-trifluoromethyl-pyridine (1.16 g, 4.08 mmol) and Raney Nickel (0.4 9, in EtOH) in MeOH (70 mL) is stirred at rt and under a hydrogen atmosphere for 7 h. Additional Raney Nickel (tip of spatula) is then added and the reaction mixture is stirred for 17 h. The mixture is filtered through a pad of celite and the filter cake is washed with copious amount of MeOH. After removal of the solvents in vacuo, the residue is purified by silica gel (50 g) column chromatography (CH2Cl2/Et2O, 95/5) to afford the title compound as a white solid: ES-MS: 255.0 [M+H]+; single peak at tR=5.97 min (System 2); Rf=0.40 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: O(C1C=CC(C2C3C(=NC=NC=3N)NN=2)=CC=1)C1C=CC=CC=1.[H-].[Na+].BrC1C=CC([N+]([O-])=O)=NC=1.[N+:36]([C:39]1[N:44]=[CH:43][C:42]([N:45]2[C:49]3=[N:50][CH:51]=[N:52][C:53]([NH2:54])=[C:48]3[C:47]([C:55]3[CH:60]=[CH:59][C:58]([O:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[CH:57][CH:56]=3)=[N:46]2)=[CH:41][CH:40]=1)([O-])=O.[H][H]>CN1CCCC1=O.C(O)C.[Pd].CN(C)C=O>[NH2:36][C:39]1[N:44]=[CH:43][C:42]([N:45]2[C:49]3=[N:50][CH:51]=[N:52][C:53]([NH2:54])=[C:48]3[C:47]([C:55]3[CH:56]=[CH:57][C:58]([O:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[CH:59][CH:60]=3)=[N:46]2)=[CH:41][CH:40]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Agent: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Nc1ccc(-n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00079 mol) in N-methylpyrrolidinone (10 mL) was reacted with 60% sodium hydride in oil (0.032 g, 0.00079 mol). After gas evolution ceased, the mixture was stirred at ambient temperature for 30 minutes, and 5-bromo-2-nitropyridine (0.161 g, 0.00079 mol) was added and heated at 40° C. for 18 hours. Additional 60% sodium hydride in oil (0.032 g, 0.00079 mol) was added and the mixture was stirred an additional 2 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (15 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organics were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica using heptane/ethyl acetate (1:2) as an eluent to give two products. The less polar compound, 1-(6-nitro-3-pyridyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, was suspended in absolute ethanol (10 mL) and N,N-dimethylformamide (5 mL) and 10% palladium on carbon (0.007 g) was added. The mixture was stirred under a balloon atmosphere of hydrogen for 18 hours. The mixture was filtered through pad of Celite® 521, washing with absolute ethanol. The solvent was removed in vacuo to give 1-(6-amino-3-pyridyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.007 g, 0.00002 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.53 (d, 1H) 8.31 (s, 1H), 7.97 (dd, 1H), 7.73 (d, 2H), 7.44 (t, 2H), 7.12-23 (m, 5H), 6.60 (d, 1H), 6.20 (s, 2H); RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-85% acetonitrile—0.1M ammonium acetate over 20 min, 1 mL/min) Rt 15.38 min.; MS: MH+ 396.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:13])[CH2:11][CH3:12].[CH2:14](Br)[CH2:15][C:16]([CH3:18])=[CH2:17]>[OH-].[K+]>[OH:1][C:2]1[C:7]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[C:6]([OH:8])[C:5]([CH2:7][CH:2]=[C:3]([CH3:10])[CH3:4])=[C:4]([OH:9])[C:3]=1[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: C=C(C)CCBr
Reactant: CCC(=O)c1c(O)cc(O)cc1O
Agent: [K+]
Agent: [OH-]
Product: CCC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
1-(2,4,6-trihydroxyphenyl)propan-1-one (2.0 g, 11.0 mmol) was dissolved in a 5% potassium hydroxide aqueous solution (20 mL). After the mixture was cooled below 0° C., isopentenyl bromide (3.3 g, 22 mmol) was slowly added dropwise within 30 min. The reaction mixture was stirred at room temperature for 2 hours, then poured into an ice water and acidified to pH 2. The reaction mixture was extracted with ethyl acetate. The extract was collected and dried over anhydrous sodium sulfate. After removal of solvent, The residue was purified by silica gel column chromatography (dichloromethane as eluent) to give the desired compound (0.63 g, yield 18%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([O:21][CH3:22])[CH:15]=1.ClC1C(Cl)=CN=C(OC)C=1[Li].[CH3:34][O:35][C:36]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[C:40]([CH3:48])[C:37]=1[CH:38]=[O:39]>O1CCCC1.O>[CH3:34][O:35][C:36]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[C:40]([CH3:48])[C:37]=1[CH:38]([C:15]1[C:16]([O:21][CH3:22])=[N:17][CH:18]=[C:19]([Cl:20])[C:14]=1[Cl:13])[OH:39]
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Reactant: COc1cc(Cl)c(Cl)cn1
Agent: [Li]CCCC
Agent: [Li]c1c(OC)ncc(Cl)c1Cl
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(C)c(C(O)c2c(OC)ncc(Cl)c2Cl)c(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
15.1 ml of n-butyllithium (1.57 mol/l hexane solution) was dropwise added at −20° C. to a solution having 2.40 g (23.7 mmol) of diisopropylamine dissolved in 30 ml of tetrahydrofuran, followed by stirring for 1 hour. The solution was cooled to −78° C., and a solution having 4.22 g (23.6 mmol) of 4,5-dichloro-2-methoxypyridine obtained in Step (e) dissolved in 20 ml of tetrahydrofuran was added, followed by stirring for 2 hours to prepare 4,5-dichloro-2-methoxy-3-pyridyllithium. Then, to this solution, a solution having 5.00 g (23.8 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 20 ml of tetrahydrofuran was added, followed by stirring for 30 minutes. 50 ml of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography to obtain 4.66 g (yield: 51%) of (2,3,4-trimethoxy-6-methylphenyl)(4,5-dichloro-2-methoxy-3-pyridyl)methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH3:19][C:20]([CH3:23])([O-:22])[CH3:21].[K+]>C1COCC1.O>[Cl:8][C:6]1[CH:7]=[C:2]([O:22][C:20]([CH3:23])([CH3:21])[CH3:19])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: CC(C)(C)[O-]
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (2 g) in THF (20 mL) was added potassium tert-butoxide (0.8 g) and the reaction mixture was stirred at ambient temperature for 20 h. Further potassium tert-butoxide (0.8 g) was added and the reaction mixture was stirred at ambient temperature for 4 h. The mixture was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed with H2O and dried (MgSO4), filtered and evaporated. The resulting oil was purified by column chromatography on silica gel using MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.68 g
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[N:6]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:51]=[C:49]1[C:48]2[C:47](=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:46](=[O:56])[N:50]1[CH2:2][CH2:3][CH2:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[N:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(-c2cc(CCCO)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(CCCN3C(=O)c4ccccc4C3=O)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reaction time: 8 h
Yield: 392.1 %

Procedure:
To a solution of alcohol 18c (0.1 g, 0.27 mmol), PPh3 (0.11 g, 0.40 mmol), and phthalimide (60 mg, 0.40 mmol) in 5 mL of THF was added dropwise DIAD (54 mg, 0.27 mmol) at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated, and the resulting solid was recrystallized from methanol to afford 0.53 g (87%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.84-7.76 (m, 1H), 7.70-7.65 (m, 1H), 7.34 (d, J=8.76 Hz, 1H), 7.11 (d, J=7.89 Hz, 1H), 7.00 (d, J=8.15 Hz, 1H), 6.33 (s, 1H), 4.96 (s, 1H), 3.85 (t, J=6.96, 6.96 Hz, 1H), 2.80 (t, J=7.47, 7.47 Hz, 1H), 2.35 (s, 1H), 2.24-2.13 (m, 1H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[CH:7][C:8]([C:11]#[N:12])=[CH:9]2)=[CH:4][C:3]=1[CH3:13].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[C:19]([O:18][C:16](=[O:17])[CH2:15][C:2]1[N:10]2[C:5]([CH:6]=[CH:7][C:8]([C:11]#[N:12])=[CH:9]2)=[CH:4][C:3]=1[CH3:13])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc2ccc(C#N)cn2c1Br
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Product: Cc1cc2ccc(C#N)cn2c1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
Under an atmosphere of argon, 3-bromo-2-methyl-indolizine-6-carbonitrile (500 mg, 2.12 mmol), Pd2(dba)3 (19.5 mg, 21.2 μmol, 0.01 equiv), 1,2,3,4,5-pentaphenyl-1-(di-tert-butylphosphino)ferrocene (15.1 mg, 21.2 μmol, 0.01 equiv) and the isolated, recrystallized Reformatsky reagent prepared from tert-butyl bromoacetate (609 mg, 2.33 mmol, 1.1 equiv) are placed in a 50-ml round bottom flask. After three careful degassing cycles, anhydrous THF (8 ml) is added, and the reaction mixture is stirred at room temperature. After 1 hour at room temperature, TLC analysis indicated incomplete conversion. Consequently, additional portions of the palladium salt, the phosphino ligand and the Reformatsky reagent are added (same quantities as above). After 1 additional hour, reagents are added again, to achieve complete conversion after a total reaction time of 4 hours at room temperature. The reaction mixture is diluted with water, and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (hexane/EtOAc 6:1) affords the title compound (390 mg, 68%). 1H NMR (400 MHz, CDCl3): δ=8.22 (t, J=1.2 Hz, 1H), 7.36 (d, J=9.2 Hz, 1H), 7.21 (s, 1H), 6.67 (dd, J=9.3/1.5 Hz, 1H). 3.61 (s, 2H), 2.31 (s, 3H), 1.44 (s, 9H). MS (ES+): 271 (M+H)+.
Reaction SMILES: [C:1]1([OH:15])[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH:6]([CH:7]=[CH:8]3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:4]1([OH:14])[C:5]2[CH:6]3[CH2:13][CH2:12][CH2:11][CH:9]([CH2:8][CH2:7]3)[C:10]=2[C:1]([OH:15])=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: Oc1ccc(O)c2c1C1C=CC2CCC1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(O)c2c1C1CCCC2CC1
Reaction time: 5 h

Procedure:
To a solution of the hydroquinone prepared in Step 1 in 100 mL ethanol was added Pd/C (250 mg) charged with hydrogen. The reaction was stirred under hydrogen for 5 h and the solid was removed through filtration. The solvent was removed and the residue was chromatographed to afford 5,6,7,8-tetrahydro-5,8-propano-naphthalene-1,4-diol as a light brown solid (3.9 g). 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.51 (s, 2 H), 3.33 (bs, 2 H), 1.96-1.89 (m, 2 H), 1.70-1.57 9 (m, 6 H), 1.18 (m, 2 H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+]([O-])=O)[C:4]=1[C:5]#[N:6].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+]>O1CCOCC1.O>[CH2:18]([O:25][C:7]1[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]#[N:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(C(F)(F)F)cc([N+](=O)[O-])c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 200 mg (0.813 mmol) 2-methoxy-6-nitro-4-trifluoromethyl-benzonitrile in 2 ml dioxane under argon at 0° C., was added 425.3 ul (4.065 mmol) benzyl alcohol, followed by a dropwise addition of a solution of 82.2 mg (1.260 mmol) potassium hydroxide in 600 ul water. The mixture was stirred at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was poured into ice water. The resulting suspension was filtered and dried in vacuo to provide 196 mg (y: 78.5%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([OH:35])=O)[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]([F:48])([F:47])[C:39]([O:42][S:43](=[O:46])(=[O:45])[NH2:44])([CH3:41])[CH3:40]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([NH:44][S:43]([O:42][C:39]([CH3:41])([CH3:40])[C:38]([F:37])([F:48])[F:47])(=[O:45])=[O:46])=[O:35])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(OS(N)(=O)=O)C(F)(F)F
Reactant: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)O
Product: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC(C)(C)C(F)(F)F

Procedure:
2-[2-Ethyl-1-(2,2,2-trifluoro-1,1-dimethyl-ethoxysulfonylaminocarbonyl)-cyclopropylcarbamoyl]-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared according to the method presented in Example 27. Treatment of 2-(1-carboxy-2-ethyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.01 mmol) occurred under the same conditions, adjusted for scale with the exception of utilizing sulfamic acid 2,2,2-trifluoro-1,1-dimethyl-ethyl ester to afford acylsulfamate (450 mg, 65%): LCMS found 688.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:22])=[N:11][N:12]2[C:16](C(O)=O)=[C:15]([S:20][CH3:21])[S:14][C:13]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[Br:25]Br>C(=O)([O-])[O-].[Ag+2].C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([CH3:22])=[N:11][N:12]2[C:16]([Br:25])=[C:15]([S:20][CH3:21])[S:14][C:13]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc2c(NC(=O)OC(C)(C)C)c(C)nn2c1C(=O)O
Reactant: BrBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CSc1sc2c(NC(=O)OC(C)(C)C)c(C)nn2c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.2 %

Procedure:
To an aqueous solution (10 mL) of 7-[(tert-butoxycarbonyl)amino]-6-methyl-2-(methylthio)pyrazolo[5,1-b][1,3]thiazole-3-carboxylic acid (180 mg, 0.53 mmol), were added potassium hydroxide (34.7 mg, 0.53 mmol) and silver carbonate (93.6 mg, 0.55 mmol), and the mixture was stirred at room temperature for 1.5 hours. The solid was filtered, washed with water, and then dried. To a mixture of the obtained solid and carbon tetrachloride (3.6 mL) was added bromine (29.6 μL, 0.58 mmol), and the mixture was stirred at 75° C. for five hours. To the reaction mixture was added chloroform, and the insoluble matters were filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (n-heptane/ethyl acetate: 33% then 66%) to obtain 94.0 mg (0.25 mmol) of the title compound.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([C:26]([F:29])([F:28])[F:27])=[CH:19][C:18]=2[C:30]2[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])=[O:37])=[N:34][CH:35]=2)[CH:12]=[CH:11][C:10]=1[C:46]1[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][C:47]=1[CH3:56].Cl>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([C:26]([F:28])([F:29])[F:27])=[CH:19][C:18]=2[C:30]2[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[N:34][CH:35]=2)[CH:12]=[CH:11][C:10]=1[C:46]1[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:53])[F:54])=[CH:48][C:47]=1[CH3:56]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3C)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1-c1ccc(NCc2c(-c3ccc(C(=O)NCCC(=O)O)nc3)cc(C(F)(F)F)cc2C(C)C)cc1Cl
Temperature: 25 °C

Procedure:
A 3M aqueous NaOH solution (0.04 mL, 0.11 mmol) was added to a THF (2.0 mL) and MeOH (1.0 mL) solution of ethyl 3-(5-(2-(((2-chloro-2′-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)methyl)-3-isopropyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (13 mg, 0.02 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([O:14]CC)=[O:13])[O:4][N:3]=1.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([OH:14])=[O:13])[O:4][N:3]=1
Reactant: CCOC(=O)c1onc(C)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)noc1C(=O)O
Reaction time: 16 h

Procedure:
65 g of diethyl 3-methylisoxazole-4,5-dicarboxylate, dissolved in 100 ml of ethanol, are added dropwise to 18.9 g of potassium hydroxide in 100 ml of water at room temperature. After 16 hours, the mixture is poured onto 300 ml of water and extracted with ether, and the aqueous phase ia acidified with concentrated hydrochloric acid. Extracting with dichloromethane and evaporating down give 3-methyl-4-ethoxycarbonylisoxazole-5-carboxylic acid as colorless crystals of melting point 54°-58° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([OH:10])=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][C:5]=1[OH:19])(=[O:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[OH:19][C:5]1[CH:6]=[C:7]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:8]=[C:9]([OH:10])[C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)c1c(O)cc(OS(=O)(=O)C(F)(F)F)cc1O
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A solution of trifluoromethanesulfonic acid 4-acetyl-3,5-dihydroxy-phenyl ester (1.0 g, 3.33 mmol), morpholine (0.35 mL, 3.99 mmol), tris-(dibenzylideneacetone) dipalladium(0) (153 mg, 0.167 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (198 mg, 0.666 mmol), and K3PO4 (1.41 mg, 6.66 mmol) in THF (2 mL) was heated to 85° C. in a sealed tube for 2 h. The reaction mixture was allowed to cool to room temperature, and filtered through a ¾″ silica gel (60 Å) plug. The plug was washed with EtOAc (75 mL) and the filtrate concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 40% EtOAc/hexanes to yield 475 mg (60%) of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone. Rf=0.16 (50% EtOAc/hexanes).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:26][C:24]([F:25])([F:27])[C:21]1[CH:20]=[CH:19][C:18]([C:8]2[CH:9]=[CH:10][C:11]([CH:13]=[O:14])=[N:12][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure L, ethyl 5-(4-trifluoromethylphenyl)-6-phenylpyridine-2-carboxylate (Compound 25, 74 mg, 0.20 mmol) and DIBAL-H (0.3 ml, 0.30 mmol, 1.0 M in hexane) in CH2Cl2 (3 ml) were reacted to produce the title compound after purification by column chromatography (silica gel, 15% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>CCOC(C)=O.CN(C=O)C>[CH3:14][C:2]([CH3:1])([CH3:15])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C=Cc1ccc(C(=O)O)cc1
Reactant: COc1cccc(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(NC(=O)c2ccc(/C=C/C(C)(C)C)cc2)c1
Reaction time: 1 h

Procedure:
To a cooled (0° C.) and well stirred suspension of 4-(3,3-dimethyl-but-1-enyl)-benzoic acid (1.5 g, 7.34 mMol) in a mixture of EtOAc and DMF (1:1, 25 mL) is added oxalyl chloride (0.364 g, 4.04 mMol) slowly drop-wise and the mixture is agitated for one hour. m-Anisidine (1.36 g, 11.01 mMol) is then added in EtOAc (5 mL) and the mixture is stirred for 6.0 hours before being quenched with saturated potassium carbonate solution. The precipitate is filtered, washed with water and vacuum dried to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1
Reactant: [Br-]
Reactant: CCCc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCCc1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
2-propylphenol (3.0 g, 0.022 mol) was dissolved in CHCl3 (100 mL) and magnetically stirred at room temperature. To this solution was added a solution of Tetrabutyl ammonium tribromide (10.68 g, 0.022 mol) in CHCl3 (100 mL). The resulting yellow solution was allowed to stir at room temperature for 1 hour. The reaction was quenched with a 5% solution of sodium thiosulfate (200 mL). The biphasic mixture was stirred for 15 min. The organics were separated and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL) and brine (1×100 mL). The organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 3% EtOAc in Hexanes. The result was a yellow oil (4.54 g).