Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H](C1C=CC=CC=1)[C@@H](N(C)[C:6](=[O:18])[C@H:7]([NH2:17])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.[OH2:26]>>[NH2:17][C@H:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([OH:18])=[O:26]
Reactant: O
Reactant: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)[C@H](N)CCCc1ccccc1
Product: N[C@H](CCCc1ccccc1)C(=O)O

Procedure:
A solution of the compound of Example 199, Step A (400 mg, 1.18 mmol) in water (10 mL) was heated to reflux for 20 h. The reaction was diluted with water (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were back extracted with water (2×20 mL) and the combined aqueous extracts were concentrated down to a white solid. The solid was triturated with EtOH to remove residual pseudoephedrine and deliver Example 199, Step B (135 mg, 60%): +APcI MS (M+1)+ 194.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([O:24]C)=[O:23])[S:21][C:11]1=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>CO.O>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([OH:24])=[O:23])[S:21][C:11]1=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1cc2c3ccccc3n(Cc3ccccc3)c2s1
Reaction time: 8 h

Procedure:
KOH (3 g) was dissolved in methanol-water (1/1) (50 ml). (5) (3 g) was added and the mixture refluxed until the compound was in solution and subsequently 1 h in addition. After cooling the mixture was acidified with acetic acid to pH=6, and the mixture was stirred overnight. The formed precipitate was filtered off, washed with water and dried in vacuo at 50° C. The crude product (3 g) was boiled in water once more, cooled, filtered and dried again giving analytically pure (8), m.p. 194-195° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:21]([N:28]1[CH:36]=[C:35]2[C:30]([CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:34]2)=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:32]3[CH:33]=[CH:34][C:35]4[C:30]([CH:31]=3)=[N:29][N:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:36]=4)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: COc1cc(-c2cc(Br)c3c(N)ncnn23)ccc1O
Product: COc1cc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)ccc1O
Yield: 9 %

Procedure:
Using a procedure similar to that of Example 4 with 4-(4-Amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-phenol and 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole as starting materials, 21.5 mg (9%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.80 (s, 3 H); ES-MS m/z 463.49 [M+H]+, HPLC RT (min) 2.99.
Reaction SMILES: C(O)(C)(C)C.C(NCC)C.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Br[CH2:22][C:23]([C:25]1[CH:26]=[N:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:24].OS(O)(=O)=O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][CH2:22][C:23]([C:25]2[CH:26]=[N:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:24])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: O=C(CBr)c1ccc(Cl)nc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCNCC
Solvent: c1ccccc1
Product: O=C(CCC(=O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
The zinc chloride (3.04 g, 22.82 mmol), tert-butyl alcohol (1.576 mL, 16.71 mmol) and diethylamine (1.731 mL, 16.71 mmol) were combined in benzene (12 mL). The resulting slurry was stirred at room temperature for 2 hours until all solid dissolved. To this slurry was added 1-(6-chloropyridin-3-yl)ethanone (2.60 g, 16.71 mmol; reference: Bioorganic & Medicinal Chemistry Letters, 1998, 8, 3087-3092), followed by 2-bromo-1-(6-chloropyridin-3-yl)ethanone (2.61 g, 11.14 mmol; reference: Bioorganic & Medicinal Chemistry Letters, 1998, 8, 3087-3092). The resulting clear yellow solution was stirred at room temperature for 88 hours. The thick reaction mixture was treated with 5% H2SO4 (10 mL), stirred for 30 minutes, filtered and dried to give the title compound (2.91 g, 85%) as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[OH:18].CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Cc1cc(CN2CCN(C)CC2)ccc1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCN(C)CC2)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.50 g, 11.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-water bath. A solution of 9A (2.0 g, 9.1 mmol) in DMF (15 mL) was added drop-wise over 15 minutes. The mixture was stirred for 15 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.0 g, 11.8 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water and some aqueous NaOH were added and the mixture was extracted three times with DCM. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 2.18 g (64%) of 9B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.22 (s, 3H), 2.28 (s, 3H), 2.30-2.63 (bm, 8H), 3.40 (s, 2H), 3.96-4.04 (m, 2H), 4.24-4.34 (m, 2H), 4.79-4.89 (m, 1H), 6.37 (d, 1H), 7.03 (d, 1H), 7.11 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:18].C(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: N
Reactant: O=C(O)c1ccc(I)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(I)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 2-fluoro-4-iodobenzoic acid (5.00 g, 18.0 mmol), oxalyl chloride (2.0 mL, 22.0 mmol), ammonia gas, DCM (100 mL) and THF (100 mL) to afford 2.00 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.40 (t, J=7.8 Hz, 1H), 7.63-7.76 (m, 1H); MS (m/z): 266.19 (M+H)+.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:52])[C:38]([C:40]2[CH:51]=[CH:50][C:43]3[N:44]([CH3:49])[C:45](=[O:48])[N:46]([CH3:47])[C:42]=3[CH:41]=2)=[O:39])=[C:33]([Cl:53])[CH:32]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O.CO>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:52])[C:38]([C:40]2[CH:51]=[CH:50][C:43]3[N:44]([CH3:49])[C:45](=[O:48])[N:46]([CH3:47])[C:42]=3[CH:41]=2)([OH:39])[C:23]([F:25])([F:24])[F:22])=[C:33]([Cl:53])[CH:32]=1
Reactant: CC(C(=O)c1ccc2c(c1)n(C)c(=O)n2C)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrabutylammonium fluoride trihydrate (31 mg) was added to a solution of (trifluoromethyl)trimethylsilane (1 ml of a 2M solution in THF) and 5-[2-(4-bromo-2-chloro-phenyl)-propionyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (410 mg) in THF (20 ml) at room temperature. The mixture was stirred for 30 min at room temperature. MeOH (1 ml) and 1M tetrabutylammonium fluoride in THF (1 ml) were added and the mixture was stirred 1 h at room temperature. Water (50 ml) was added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 100% EtOAc/heptane) to give the title compound (400 mg) as a colorless oil. MS (m/e)=479.0 [M+H+].
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:28]([OH:31])#[C:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl.O>[OH:31][CH2:28][C:29]#[C:30][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2cc3ccc(OS(=O)(=O)C(F)(F)F)cc3oc2=O)cc1
Reactant: CC#CO
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1ccc(-c2cc3ccc(C#CCO)cc3oc2=O)cc1

Procedure:
6.90 g (17.2 mmol) of 3-(4-methoxyphenyl)-2-oxo-2H-chromen-7-yl trifluoromethanesulfonate, 1.5 ml (25.4 mmol) of propyn-1-ol, 12.0 g (36.8 mmol) of caesium carbonate, 150 mg (0.578 mmol) of bis(acetonitrile)palladium(II)chloride and 800 mg (1.68 mmol) of 2-dicyclohexylphosphino-2′-4′-6′-triisopropylbiphenyl are stirred in 100 ml of dioxane at 60° C. for 3 h, added to 400 ml of water and acidified using 2 N hydrochloric acid. The aqueous phase is extracted three times with ethyl acetate, and the combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with toluene/ethyl acetate (4:1). Crystallisation of the crude product from toluene/ethyl acetate (10:1) gives 7-(3-hydroxyprop-1-ynyl)-3-(4-methoxyphenyl)chromen-2-one as yellow crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][S:10]([C:13]1[CH:31]=[CH:30][C:16]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:32][C:33]1([C:39](OC)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O)(=O)C.[BH4-].[Na+]>CCCCCC.CCCCCCC.C(C1C=CC=CC=1)C.O1CCCC1.O>[CH3:29][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH2:9][CH:39]([C:33]3([CH3:32])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[OH:40])(=[O:12])=[O:11])=[CH:31][CH:30]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: Cc1cc(COc2ccc(S(C)(=O)=O)cc2)c2ccccc2n1
Reactant: COC(=O)C1(C)CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COc2ccc(S(=O)(=O)CC(O)C3(C)CCOCC3)cc2)c2ccccc2n1
Reaction time: 0.83 h
Yield: 74.1 %

Procedure:
Under an atmosphere of argon, 1.7 mL (3.45 mmol) of 2 mol/L lithium diisopropylamide in hexane-heptane-ethylbenzene was dropped, at −78° C., into a solution of 1.03 g (3.14 mmol) of 4-(4-methanesulfonylphenoxymethyl)-2-methylquinoline (VI-1) in tetrahydrofuran (40 mL), and then stirred for 50 minutes. Into this solution, 3.1 mL (3.10 mmol) of 1 mol/L lithium(bistrimethylsilyl)amide in tetrahydrofuran was dropped at −78° C., and then 745 mg (4.71 mmol) of methyl 4-methyltetrahydropyran-4-carboxylate was dropped and stirred for 6 hours. To the reaction mixture, 471 mg (7.85 mmol) of acetic acid was added, and after stirring for 5 minutes, the reaction mixture was concentrated under a reduced pressure. After the residue was dissolved in ethanol (5 mL), 415 mg (11.0 mmol) of sodium borohydride was added thereto at 0° C. and stirred for 1 hour. Water (15 mL) was added to the reaction mixture, and after stirring for 5 minutes, the reaction mixture was concentrated under a reduced pressure. The residue was extracted by partition between ethyl acetate and water, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by medium pressure column chromatography (developing solvent; hexane-ethyl acetate) to give 1.06 g (yield 74.2%) of 2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]-1-(4-methyltetrahydropyran-4-yl)ethanol (VIII-60). Its physical properties are shown below.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][C@H:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[C:13](O)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][C@@H:46]([C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[NH:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN1CCOCC1>CCOCC.C1COCC1>[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][C@@H:46]([C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[N:45]1[C:13](=[O:14])[C@@H:12]([N:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(NCCc1ccccc1)[C@@H]1CCCN(C(=O)OCc2ccccc2)N1
Reactant: O=C(CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(CC[C@@H](C(=O)N1[C@H](C(=O)NCCc2ccccc2)CCCN1C(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
To a solution of (S)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanedioic acid 5-benzyl ester (580 mg, 1.59 mmol) in ether (25 mL) at 0° C., is added PCl5 (920 mg, 4.38 mmol) in one portion. After stirring at 25° C. for 40 minutes, ether is removed by evaporation, and the residue is dissolved in 20 mL of THF, and is added to a solution of (S)-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (580 mg) and N-methylmorpholine (0.74 mL, 6.77 mmol) in THF (10 mL) at 0° C. slowly. After stirring at room temperature for 2 hours, the reaction mixture is diluted with 100 mL of ether and washed with 2×20 mL of water. The combined organic layers is dried over Na2SO4 and concentrated, and purified by chromatography (CH2Cl2/MeOH:97/3) to give (S)-2-[(S)-4-benzyloxycarbonyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyryl]-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (1.13 g, 99.2%) as pale solid. (NMR and MS data confirmed, U-3133-62).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])/[C:5](=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]2)=[C:16]([O:26][CH3:27])[CH:15]=1)/[CH2:6][CH2:7][CH:8]1OCC[O:9]1)[CH3:2].C(O)(=O)C.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:28])/[C:5](=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]2)=[C:16]([O:26][CH3:27])[CH:15]=1)/[CH2:6][CH2:7][CH:8]=[O:9])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
To an aqueous solution of (243 mg) of (E)-4-[1,3]dioxolan-2-yl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid ethyl ester, acetic acid (2 mL) and trifluoroacetic acid (2.0 mL) were added one by one, and the reaction solution was agitated at room temperature for 4 hours. After confirming disappearance of the starting materials, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and 110 mg of the title compound was obtained by condensing under reduced pressure. The physical properties of the compound are as follows.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:48]([OH:50])=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:17](=[O:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:83][CH2:84][CH2:85][CH2:86][CH2:87][O:88][C:89]1[CH:98]=[CH:97][CH:96]=[C:95]([OH:99])[C:90]=1[C:91]([O:93][CH3:94])=[O:92].C(N(CC)CC)C>CN(C=O)C.O>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:48]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][O:88][C:89]1[CH:98]=[CH:97][CH:96]=[C:95]([OH:99])[C:90]=1[C:91]([O:93][CH3:94])=[O:92])=[O:50])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34][CH:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C:17](=[O:25])[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[CH:14][CH:15]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)O
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)NCCCCOc1cccc(O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirring mixture of N-[(allyloxy)carbonyl]-4-{{2-[(benzhydryloxy)carbonyl]phenyl}[tert-butoxy(oxo)acetyl]amino}-L-phenylalanine (100 mg, 0.147 mmol), TBTU (67 mg, 0.206 mmol), and HOBT (3 mg, 0.02 mmol) in DMF (2 mL) was added methyl 2-(4-aminobutoxy)-6-hydroxybenzoate, followed by addition of triethylamine (75 μL, 0.53 mmol). The resulting mixture was then stirred at ambient temperature for 2 hours, diluted with the addition of water. The crude product was extracted with ethyl acetate (2×10 mL). The combined organic layer were washed with aqueous NaHCO3 (2×25 mL) and brine (2×25 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified on an AllTech sep-pak to provide the titled compound (89 mg, 68%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([NH:26][CH3:27])=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:21]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([N:26]([CH3:27])[C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:21]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(OC)cc1-c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (126 μL, 0.69 mmol, CAS RN 1271-19-8) was added to a solution of 6-methoxy-N-methyl-4-o-tolylpyridin-3-amine (105 mg, 0.46 mmol) and DIPEA (240 μL, 1.38 mmol) in CH2Cl2 and stirred for 2 h. The reaction mixture was then loaded directly onto a silica gel column Elution with 20% EtOAc in n-hexane gave the title product as a colorless foam (161 mg, 76%). MS (ESI): m/z=469.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:32]1[CH:43]=[CH:42][C:35]([C:36]([N:38]2[CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:34][C:33]=1[C:44]([F:47])([F:46])[F:45].[H-].[Na+].[Cl-].[NH4+]>CS(C)=O>[N:38]1([C:36]([C:35]2[CH:42]=[CH:43][C:32]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[C:33]([C:44]([F:45])([F:46])[F:47])[CH:34]=2)=[O:37])[CH2:41][CH2:40][CH2:39]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: O=C(c1ccc(F)c(C(F)(F)F)c1)N1CCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2C(F)(F)F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (119 mg, 0.276 mmol) synthesized in Example (38d) and 1-[4-fluoro-3-(trifluoromethyl)benzoyl]azetidine (145 mg, 0.587 mmol) synthesized in Example (54a) were dissolved in dimethyl sulfoxide (8.0 mL), and sodium hydride (60%, 39 mg, 0.97 mmol) was added, followed by stirring at 100° C. for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=45%-60%) to afford the desired compound (105 mg, yield 68%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:8]=2[N:9]=[C:10](SC)[N:11]=1>C(OCC)(=O)C.CO.C(Cl)Cl.[Ni]>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Agent: [Ni]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1cccc(C(F)(F)F)c1
Yield: 82.6 %

Procedure:
A solution of 173 mg (0.394 mmol) of [[2-(methylthio)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 5 mL of ethyl acetate and 1 mL of methanol was heated to reflux and treated with 1.05 g of Raney Ni in portions over 3 hours. The reaction was diluted with 2 mL of methylene chloride and the solids were removed by filtration through a filter aid. The reaction mixture was dried with sodium sulfate and concentrated to provide 128 mg (83%) of [[6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (500 MHz, CDCl3) δ1.29 (t, J=7.4 Hz, 3H), 2.63 (q, J=7.4 Hz, 2H), 3.80 (s, 3H), 5.10 (s, 2H), 5.51 (s, 2H), 6.43 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.38 (m, 1H), 7.44 (s, 1H), 7.51 (d, J=7.7 Hz, 1H), 8.38 (s, 1H)