Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=[O:5]>CC(OC(C)=O)=O.OS(O)(=O)=O>[C:2]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:7](=[O:11])[CH3:8])[C:3]=1[C:4]([OH:6])=[O:5])(=[O:1])[CH3:3]
Reactant: O=C(O)c1c(O)cccc1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc(OC(C)=O)c1C(=O)O
Reaction time: 2 h
Yield: 162.3 %

Procedure:
A solution of 2,6-dihydroxybenzoic acid (4.72 g, 30 mmol) in Ac2O (16 g, 14.2 mL) containing 5 drops of conc. H2SO4 was heated with stirring at 80° for 2 hr until tlc analysis indicated the reaction was complete. The solution was poured onto ice/H2O and extracted 3× with EtOAc. The combined organic phases were washed 4× with H2O and once with brine prior to drying over Na2SO4. After removal of the volatiles using a rotary evaporator, 5.8 g of 2,6-diacetoxybenzoic acid was obtained as a white solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[N:9]=[CH:10][CH2:11][C:3]=12.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:12][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]=2[CH2:11][CH:10]=[N:9]1
Reactant: CN1N=CCc2c(Cl)ncnc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1N=CCc2c(-c3ccccc3)ncnc21
Temperature: 100 °C
Yield: 91.9 %

Procedure:
The 5-chloro-1-methyl-1,4-dihydropyridazino[3,4-d]pyrimidine (310 mg), phenyl boronic acid (208 mg) and potassium carbonate (235 mg) were dissolved in toluene (10 mL) and water (1.0 mL). The reaction mixture was degassed with nitrogen for 30 minutes and Pd(PPh3)4 (98 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes and then heated to 100° C. for 1 hour in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by column chromatography using MeOH/CHCl3 (1.0:9.0) as eluent to afford 1-methyl-5-phenyl-1,4-dihydropyrimido[4,5-c]pyridazine (350 mg) as off white solid. 1H NMR (DMSO-d6): δ 3.41 (s, 3H), 3.52-3.53 (d, 2H), 6.86 (t, 1H), 7.47-7.49 (m, 3H), 7.56-7.60 (m, 2H), 8.66 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([O-])([O-:11])=[O:10].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:8]
Reactant: Oc1ccccc1Br
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
2-Bromophenol (50.0 g, 0.29 mol) was added slowly to a cold (10° C.) solution of sodium nitrate (36.9 g, 0.43 mol) in conc. sulfuric acid (79 g) and water (100 mL) and the resulting mixture was allowed to stir at room temperature for 2 h. Water (400 mL) was added and the resulting mixture was extracted with diethyl ether and the extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 5% ethyl acetate/hexane). The partly purified product was triturated with hexane to afford the title compound (19.2 g, 30%) as a bright, yellow solid. 1H NMR (300 MHz, CDCl) δ 11.10 (S, 1h), 8.13 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 6.90 (t,J=7.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>O>[CH2:17]([N:14]1[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=2)[CH2:16][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C#CC=C2CCN(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound of Example 3 (0.22 g, 1.04 mmol), benzaldehyde (0.13 mL, 1.25 mmol), sodium triacetoxyborohydride (0.33 g, 1.56 mmol) and 15 mL of CH2Cl2 was stirred overnight at r.t. Afterwards, it was diluted with water, the organic layer was separated, washed with brine (2×15 mL), dried (Na2SO4) and evaporated to dryness in vacuo the give a crude, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with a gradient Petroleum Ether-EtOAc from 85:15 to 0:100 affording the title compound, which was further purified by preparative RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient (0.12 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc2[nH]ncc2c1
Product: O=C(c1ccccc1)n1ncc2ccccc21

Procedure:
To prepare 1-substituted 1H-indazoles of formula 1 wherein R1 is formyl, alkanoyl, cycloalkylalkanoyl ##STR43## R2'OCO or R5CO wherein R2', R5, X", p" and q' are as above, a 1-unsubstituted 1H-indazole 8 wherein R is as above, with the proviso that R is not hydrogen, and X, m, n and p are as before, is treated, respectively, with a formyl, alkanoyl or cycloalkylalkanoyl chloride, bromide or iodide, a compound of the formula ##STR44## R2'OCOHal or R5COHal wherein R2', R5, X", p" and q' are as above and Hal is iodo, bromo or chloro, or the corresponding acid anhydrides thereof, at an elevated temperature of about the reflux temperature of the reaction medium. For example, treatment of a 1H-indazole 8 wherein R is methyl with acetic anhydride at the reflux temperature of the reaction mixture affords a 1-acetyl-1H-indazole 14 wherein R2 is methyl, and treatment of a 1H-indazole 8 wherein R is methyl with benzoyl chloride at a reaction temperature of about 100° C. yields a 1-benzoyl-1H-indazole 14 wherein R2 is phenyl.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1Br
Temperature: 60 °C
Yield: 87.8 %

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1, Step 2, 7.0 g, 27.0 mmol) in EtOH (210 mL) was added a 5 N aqueous solution of NaOH (16 mL, 80.0 mmol). The resulting mixture was heated at 60° C. for 1 hour. The reaction mixture was cooled to RT and concentrated under vacuum. The residue was taken up with water and washed with EtOAc. The aqueous layer was then acidified with a 1N aqueous solution of HCl and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated under vacuum to give the title compound as a yellow solid (5.81 g, 87%). 1H NMR (DMSO-d6, 300 MHz) 13.19 (br s, 1H), 8.00 (m, 1H), 7.77 (m, 2H), 4.49 (s, 2H), 3.40 (s, 3H). LC/MS (Method B): 245.0 (M−H)−. HPLC (Method A) Rt 3.63 min (purity: 97.4%).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=O.N12CCN(CC1)CC2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:9][C:5]1[CH:6]=[C:7]2[CH:13]=[C:11]([C:10]([OH:15])=[O:14])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(F)cc1I
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(F)cnc2[nH]1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
0.5 g (2.10 mmol) of 2-amino-3-iodo-5-fluoropyridine obtained in Stage 5.1, 0.55 g (6.3 mmol) of pyruvic acid, 0.71 g (6.3 mmol) of 1,4-diazabicyclo[2.2.2]octane (DABCO) and 15 mL of anhydrous dimethylformamide are introduced into a 25-mL sealed tube, equipped with a magnetic stirrer and bubbled with argon. After some minutes, 0.05 g (0.22 mmol) of palladium acetate is added. The reaction mixture is stirred and bubbled with argon for 20 minutes, then it is quickly sealed and heated to 100° C. for 2.5 h. The cooled solution is concentrated at reduced pressure. The residue is then taken up in ethyl acetate (100 mL) and water (75 mL). The organic phase is washed with water then extracted with 2×50 mL of aqueous solution of 2N sodium hydroxide. The basic aqueous phases are combined, cooled to 0° C. then acidified by adding hydrochloric acid (pH 3). The mixture is extracted with ethyl acetate (4×50 mL), the combined organic phases are dried over sodium sulfate and then concentrated at reduced pressure. We obtain 0.158 g (0.88 mmol) of the expected product in the form of a yellow powder.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:41])[C:11]([OH:40])([CH2:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][NH:9][C:10](=[O:41])[C:11]([OH:40])([CH2:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)CC(O)(CS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)CC(O)(CS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-benzyloxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-phenylbenzenesulfonyl)-propionamide (0.152 g), 10% palladium on carbon, and 50 mL of absolute ethanol is placed under 20 psi of hydrogen, and agitated overnight at ambient temperature. The mixture is filtered through a Celite pad, rinsing with ethanol and with ethyl acetate. Concentration of the filtrate affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[N:23](C3CCCCO3)[N:22]=2)=[N:4][C:5]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([CH3:19])[CH:10]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:66][N:67]([CH3:71])[CH2:68][CH2:69][NH2:70].Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:4][C:5]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:12]([C:13]([NH:70][CH2:69][CH2:68][N:67]([CH3:71])[CH3:66])=[O:15])=[C:11]([CH3:19])[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c(C)cc1Nc1ncc(Cl)c(Nc2cc(C)n(C3CCCCO3)n2)n1
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C(=O)NCCN(C)C)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-chloro-4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylbenzoic acid (35.0 mg, 0.077 mmol) in DMF (0.5 mL) was added HATU (29.1 mg, 0.077 mmol), DIEA (26.7 μL, 0.153 mmol) and N1,N1-dimethylethane-1,2-diamine (25.2 μL, 0.230 mmol). The reaction mixture was stirred at room temperature overnight. 1N HCl aqueous solution (0.5 mL) was then added and the reaction mixture was heated at 100° C. for 1.5 hours to remove the tetrahydro-2H-pyran-2-yl protecting group. The mixture was purified by preparative RP-HPLC to provide 4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-N-(2-(dimethylamino)ethyl)-2,5-dimethylbenzamide; ESMS m/z 443.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[CH3:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][NH2:26])=[N:23][CH:24]=1>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(-n3ccc(O)cc3=O)nc2C)cn1
Yield: 14 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with (5-methylpyrazin-2-yl)methanamine, the title compound was obtained as a colorless solid in 14% yield: 1H NMR (300 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.80 (t, J=5.2 Hz, 1H), 8.59 (d, J=7.8 Hz 1H), 8.44 (s, 2H), 6.26 (d, J=7.8 Hz, 1H), 5.81 (s, 1H), 4.47 (d, J=5.2 Hz, 2H), 2.52 (s, 3H), 2.43 (s, 3H); MS (ES+) m/z 358.1 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:30]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:30][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]2[C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[CH:24][N:25]=[C:20]12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(C)(C)O)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL, 26.9 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(1-hydroxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (100 mg, 0.24 mmol) in dichloromethane (3 mL). After 1 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 322.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10][C:9]2[C:4](=[N:5][CH:6]=[C:7](/[CH:24]=[CH:25]/[C:26](=[O:39])[N:27]3[CH2:32][CH2:31][C:30]([CH2:33][C:34]4[S:35][CH:36]=[CH:37][N:38]=4)=[CH:29][CH2:28]3)[CH:8]=2)[NH:3]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[O:39]=[C:26]([N:27]1[CH2:32][CH2:31][C:30]([CH2:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[CH:29][CH2:28]1)/[CH:25]=[CH:24]/[C:7]1[CH:8]=[C:9]2[C:4](=[N:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:11]1([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2)N1CC=C(Cc2nccs2)CC1
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
To a stirred solution of (E)-tert-butyl 2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (Compound 1) (0.6 g, 1.52 mmol) in CH2Cl2 (15 mL) was added trifluoro acetic acid (0.58 mL, 7.61 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 4 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was triturated with diethyl ether to get the desired compound as a yellow solid (500 mg, 82%); 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.50-8.32 (m, 3H), 8.07 (s, 1H), 7.71 (d, J=3.4 Hz, 1H), 7.61 (d, J=3.4 Hz, 1H), 7.46 (d, J=15.7 Hz, 1H), 7.28-7.14 (m, 1H), 5.68-5.65 (m, 1H), 4.26-4.20 (m, 1H), 4.08-4.02 (m, 1H), 3.78-3.72 (m, 3H), 3.68-3.62 (m, 1H), 3.16-3.06 (m, 4H), 2.97 (s, 2H), 2.20-2.04 (m, 2H), 2.03-1.92 (m, 2H), 1.62-1.48 (m, 2H); ES-MS: 450.2 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[C:13]3[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[C:13]3[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OC)c(C)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)c2c(-c3ccc(O)cc3)sc3ccccc23)ccc1O
Temperature: 0 °C
Reaction time: 6 h
Yield: 104 %

Procedure:
A 0° C. solution of 700 mg (1.80 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 3-methyl-4-methoxyphenyl ketone (Part B) in 25 mL of CH2Cl2 was treated with 7.2 mL of BBr3 (1.0 M in CH2Cl2). The reaction was stirred at 0° C. for 6 h, then cooled to −78° C., and was treated carefully with 50 mL of MeOH. The mixture was allowed to warm to room temperature over 1.5 h, and the volatiles were evaporated in vacuo. The dark red residue (monomethyl ether) was taken up in 75 mL dichloroethane and was treated with AlCl3 and ethanethiol according to the conditions of Example 1, Part D to afford 675 mg of an oil. Purification by radial chromatography (SiO2; gradient of 20-30% EtOAc in hexanes) afforded 410 mg (1.14 mmol; 63%) of the title compound as an orange solid.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]/[C:9]([OH:11])=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(OCC)(=O)C.C(OCC)C>[CH2:24]([NH:31][C:9](=[O:11])/[CH:8]=[C:7](\[CH3:12])/[CH2:6][CH2:5]/[CH:4]=[C:3](/[CH2:2][OH:1])\[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/C(=O)O)CO
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/C(=O)NCc1ccccc1)CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.0 g of (E,Z,E) and (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraenoic acid in 10 ml of ethyl acetate were added 0.41 ml of benzylamine, 0.84 ml of diphenylphosphoric acid azide and then 0.5 ml of triethylamine under ice-cooling and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was diluted with ethyl ether, washed successively with dilute hydrochloric acid, aqueous sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate. The solvent was distilled off to give an oily substance, which was then purified by a column chromatography using silica gel (25 g) to afford 960 mg of the end product.
Reaction SMILES: [OH:1][C:2]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)[CH3:3].Br[C:20]1[CH:21]=[C:22]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=2)[CH:23]=[C:24]([CH3:26])[CH:25]=1.CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[OH:1][C:2]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)([C:4]1[CH:5]=[N:6][N:7]([C:20]2[CH:21]=[C:22]([NH:27][C:28]3[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:23]=[C:24]([CH3:26])[CH:25]=2)[CH:8]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(O)c2cn[nH]c2)cc1
Reactant: Cc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(C)(O)c2cnn(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)c2)cc1
Temperature: 130 °C
Reaction time: 0.83 h

Procedure:
A mixture of methyl 4-[1-hydroxy-1-(1H-pyrazol-4-yl)ethyl]benzoate (17 mg, 0.053 mmol), N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (13 mg, 0.053 mmol), copper(I) iodide (1 mg, 0.005 mmol), N1,N2-dimethylethane-1,2-diamine (0.47 mg, 0.005 mmol), and cesium carbonate (52 mg, 0.16 mmol) in 1,4-dioxane (2 mL) was stirred at 130° C. for 50 minutes. After being cooled to room temperature, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was concentrated and the residue was purified by preparative thin layer chromatography to afford methyl 4-{1-hydroxy-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-4-yl]ethyl}benzoate. MS ESI calc'd. for C25H23F3N5O3 [M+H]+ 498. found 498. 1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 8.02-8.06 (m, 3H), 7.78 (s, 1H), 7.59-7.63 (m, 3H), 7.51 (s, 1H), 7.18 (s, 1H), 7.06 (s, 1H), 3.92 (s, 3H), 3.79 (s, 1H), 3.49 (s, 1H), 2.41 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:79])[C@H:40]([NH:48][C:49](=[O:78])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][C:49]([NH:48][C@@H:40]([C@H:39]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11]1)[OH:79])[C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[O:78]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NC(=O)CCCCCCCCCCNC(=O)OCC4c5ccccc5-c5ccccc54)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Solvent: C1CCNCC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NC(=O)CCCCCCCCCCN)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 64.6 %

Procedure:
By using an analogous procedure to that described for Reference Example 32, tert-butyl (2S,3R)-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-2-[(11-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}undecanoyl)amino]-3-hydroxypropanoate (73 mg, 0.065 mmol, obtained from Example 22) was stirred with piperidine (1.5 ml) for 1 hour under nitrogen at room temperature. The product was purified by chromatography (flash column, silica gel, 50-60% methanol in methylene chloride) to provide tert-butyl (2S,3R)-2-[(11-aminoundecanoyl)amino]-3-[(3R,4R,5R)-3,4-bis{[tert-butyl (dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (38 mg, 65%) as a white solid.