Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:33]O>>[CH3:33][O:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(O)c1cccc(Nc2nccc(-c3ccnc(NCCCO)c3)n2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Nc2nccc(-c3ccnc(NCCCO)c3)n2)c1
Temperature: 25 °C

Procedure:
2.0 g (5.4 mmol) of N-[3-carboxy-phenyl]-4-(2-(3-hydroxy-propyl-amino)-4-pyridyl)-2-pyrimidineamine and 0.28 ml (5.4 mmol) of conc. sulfuric acid are boiled under RF in 150 ml of methanol for 24 h. After cooling to RT, the reaction mixture is concentrated to half the volume, diluted with 100 ml of ethyl acetate and extracted twice with 50 ml of buffer (pH 7) each time. The organic phase is dried (Na2SO4) and concentrated. Crystallisation (methylene chloride/methanol) gives N-[3-methoxycarbonylphenyl]-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine; m.p. 162°-163°, FAB-MS: 380 (M+ +H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]([C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[CH:10]=1)=[O:8])[C:3]([OH:5])=[O:4].O.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C@@H:2]([CH2:6][C:7]([C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[CH:10]=1)=[O:8])[C:3]([OH:5])=[O:4])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](CC(=O)c1ccc2oc3ccccc3c2c1)C(=O)O
Solvent: O
Product: CC(=O)N[C@@H](CC(=O)c1ccc2oc3ccccc3c2c1)C(=O)O

Procedure:
A suspension of (S)-2-amino-4-dibenzofuran-2-yl-4-oxo-butyric acid (0.025 g, 0.000082 mol) obtained above in Example 3 in acetic anhydride (2 mL) and water (4 mL) was sonicated (Cole Parmer 8850 Ultrasound Bath) for 15 minutes at room temperature. The resulting solution was then concentrated in vacuo, and the resulting residue was recrystallized from ethyl acetate/diethyl ether (50:50, v/v) to yield the title product as a white solid; mp 166-170° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].[C:17]1([O:23][C:24](Cl)=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:13][C:24](=[S:25])[O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(N)c1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NC(=S)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Triethylamine (0.87 g, 8.63 mmol) was added to a solution of 3-methoxyaniline (1 g, 8.63 mmol) dissolved in dichloromethane (20 ml), and thereto phenylchlorothioformate (1.49 g, 8.63 mmol) was added by dropping. The resulting solution was stirred for 2 hours at the room temperature, washed with distilled water, concentrated and purified by column chromatography to give the titled compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[C:14](OC)=[O:15])[CH3:9]>C1COCC1.CCOCC>[CH3:9][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([CH2:14][OH:15])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=1)[CH3:7]
Reactant: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)c(CN(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 45.8 %

Procedure:
A solution of lithium aluminium hydride in THF (1 M, 7 mL, 7 mmol) was added dropwise to a stirring solution of the ester compound of Example 151 (1.66 g, 4.7 mmol) in THF (25 mL) at room temperature under nitrogen. The mixture was stirred for 3 h before being diluted with ether (100 mL) and quenched by the cautious addition of sodium hydroxide (2 M) (approximately 1 mL). The mixture was stirred for 10 min before being dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography {SiO2; [(MeOH/ 880 NH3) 9:1] in DCM (2% →4%)] gave the desired alcohol compound (0.7 g, 48%); Example 90: δH(CDCI3, 400 MHz) 2.13 (6 H, s), 3.39 (2 H, s), 4.70 (2 H, s), 6.93-6.98 (3 H, m), 7.30 (1 H, d), 7.52-7.56 (3 H, m); MS m/z (TS+) 326 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24](Br)[N:25]=3)[NH:20][CH:19]=2)=[O:17])([CH3:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CCO.[Pd]>[CH2:1]([O:8][CH:9]1[CH2:10][CH2:11][C:12]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][N:25]=3)[NH:20][CH:19]=2)=[O:17])([CH3:15])[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCC(OCc2ccccc2)CC1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C(=O)c2c[nH]c3nccnc23)CCC(OCc2ccccc2)CC1
Yield: 85.9 %

Procedure:
A solution of (4-benzyloxy-1-methyl-cyclohexyl)-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone (13 mg, 0.03 mmol), KOH (1 mg, 0.02 mmol), and 10% Pd/C (10 mg), in EtOH (8 ml), was hydrogenated for 2 days under H2 atmosphere (1 atm). The reaction mixture was filtered through a plug of celite using THF and DCM. The filtrate was concentrated to a white solid, which was purified by silica gel chromatography using 0-70% Et2O in DCM as eluant providing 9 mg (82%) of (4-benzyloxy-1-methyl-cyclohexyl)-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone as a white solid. M+H=350.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:3]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:3]
Reactant: COC(=O)c1cc(CO)cc(CN(C)C)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C=O)cc(CN(C)C)c1
Temperature: 105 °C

Procedure:
Manganese(IV) oxide (0.72 g, 8.3 mmol) was added to methyl 3-[(dimethylamino)methyl]-5-(hydroxymethyl)benzoate (0.37 g, 1.6 mmol, from Step A) in Toluene (15 mL). The mixture was heated to 105° C. for 2 hours, then was cooled to room temperature and filtered. Solvent was removed from the filtrate in vacuo to afford the product as a colorless oil. Yield: 0.30 g (82%); LC-MS: 222.1 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 10.07 (s, 1H), 8.43 (dd, 1H), 8.25 (dd, 1H), 8.05 (dd, 1H), 3.96 (s, 3H), 3.54 (s, 2H), 2.26 (s, 6H).
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[N:26]1([C:30]([C:32]2[CH:37]=[CH:36][C:35](F)=[C:34]([F:39])[CH:33]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1.[CH3:40][O:41][C:42]([C:44]1[CH:54]=[C:53]([OH:55])[C:47]2[CH2:48][C:49]([CH3:52])([CH3:51])[O:50][C:46]=2[CH:45]=1)=[O:43]>>[CH3:40][O:41][C:42]([C:44]1[CH:54]=[C:53]([O:55][C:35]2[CH:36]=[CH:37][C:32]([C:30]([N:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])=[CH:33][C:34]=2[F:39])[C:47]2[CH2:48][C:49]([CH3:52])([CH3:51])[O:50][C:46]=2[CH:45]=1)=[O:43]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2F)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from azetidin-1-yl-(3,4-difluoro-phenyl)-methanone (32a) (90 mg, 0.46 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (117 mg, 0.53 mmol) to give a pale yellow oil (106 mg, 59% yield). 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J=10.86, 2.02 Hz, 1 H) 7.38-7.42 (m, 1 H) 7.21 (d, J=1.01 Hz, 1 H) 7.09 (d, J=1.01 Hz, 1 H) 6.99 (t, J=8.21 Hz, 1 H) 4.30-4.40 (m, 2 H) 4.20-4.29 (m, 2 H) 3.86 (s, 3 H) 2.97 (s, 2 H) 2.33-2.43 (m, 2 H) 1.50 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]([OH:19])=O.C(N(CC)CC)C.C(C(Cl)=O)C.[F:32][C:33]1[CH:52]=[CH:51][C:36]([CH:37]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1>ClCCl.C(OCC)(=O)C.CCCCCC.O>[F:32][C:33]1[CH:52]=[CH:51][C:36]([CH:37]([N:45]2[CH2:46][CH2:47][N:48]([C:17](=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][C:4]3[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=3[O:2][CH3:1])[CH2:49][CH2:50]2)[C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(C=CC=CC(=O)O)c(OC)c1OC
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CCC(=O)Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C=CC=CC(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Temperature: 0 °C
Yield: 72.5 %

Procedure:
7.30 g (27.6 mmol) of 5-(2,3,4-trimethoxyphenyl)-2,4-pentadienoic acid was dissolved in 300 ml of dry dichloromethane and 3.85 ml (27.6 mmol) of triethylamine was added thereto in the atmosphere of argon, and the mixture was stirred at 0° C. To the resulting mixture was added 2.64 ml (27.6 mmol) of ethylcarbonyl chloride followed by stirring for 1 hour and adding 9.59 g (33 mmol) of 4,4'-difluorobenzhydrylpiperazine in 50 ml of dry dichloromethane. Temperature of the mixture was raised to room temperature followed by stirring for additional 16 hours. After addition of water, the mixture was extracted with dichloromethane. The organic layer was washed successively with aqueous 1N-hydrochloric acid solution, a saturated aqueous sodium chloride solution, a saturated aqueous hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. There was obtained a residue, which was subjected to column chromatography on silica gel to give 10.6 g (20 mmol) of 1-(4,4'-difluorobenzhydryl)-4-(5-(2,3,4-trimethoxyphenyl)-2,4-pentadienoyl)piperazine from eluates of ethyl acetate-hexane (1:1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].CO.[OH-].[Na+]>C1COCC1.[OH-].[Na+]>[NH2:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[S:6][C:7]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: COC(=O)c1cc(-c2ccc(S(N)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2)cc1
Temperature: 45 °C
Yield: 98.8 %

Procedure:
To a solution of 4-(4-(aminosulfonyl)phenyl)-5-(4-fluoro-phenyl)thiophene-2-carboxylic acid methyl ester (Example 1, Step 5) (0.210 g) in THF (2.0 mL) were added MeOH (1.0 mL), NaOH 1N (1.0 mL) and a few drops of NaOH 10N. The resulting mixture was heated at 45° C. for 2 h and the reaction was then partitioned between EtOAc and HCl (3N) to provide the title product as a white solid (0.200 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2C=CC(Br)=CC=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Br:29][C:30]1C=CC2N=C(C3CCCN3)N[C:34]=2[CH:43]=1>>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]2[CH:21]=[C:30]([Br:29])[CH:43]=[CH:34][C:19]=2[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: Brc1ccc2nc(C3CCCN3)[nH]c2c1
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1)C(C)C

Procedure:
Prepared by the same method as (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester but using 6-bromo-2-pyrrolidin-2-yl-1H-benzoimidazole as the substrate. 193 mg crude solid were used for the next step.
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)[Cl:2].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.[K].C(Cl)Cl.O>CN(C=O)C>[C:6]1(=[O:16])[N:10]([CH2:4][C@H:3]([OH:5])[CH2:1][Cl:2])[C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC[C@@H]1CO1
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CCl
Reaction time: 4.5 h

Procedure:
(S)-epichlorohydrin (III, 98.9% enantiomerically pure, 99.3 chemical % purity, 4.9605 g, 53.61 mmol) is added to a slurry of potassium phthalimide (VI, 5.031 g, 27.161 mmol, 0.507 eq) and phthalimide (VI, 11.836 g, 80.45 mmol, 1.5006 eq) in DMF (32 ml) and the mixture stirred at 50° for 4.5 hrs. The mixture is added to methylene chloride (50 ml) and water (50 ml) added. The solids are removed by filtration with reduced pressure and washed with methylene chloride (20 ml). The phases are separated in the filtrate and the aqueous washed with methylene chloride (50 ml). The combined organics were washed with water (50 ml) and the aqueous backextraceted with methylene chloride (50 ml) after adding water (25 ml). The combined organics are dried over sodium sulfate and saturated with hydrogen chloride gas at 6°. Water (100 ml) is added and the phases separated. The aqueous phase is washed with methylene chloride (2×50 ml) and the combined organic phases are dried over sodium sulfate. The organic phase is concentrated under reduced pressure and toluene added (77 ml). The mixture is concentrated under reduced pressure to 31 g net weight and toluene (50 ml) and heptane (75 ml) added. The solids are filtered off and washed with toluene/heptane (1/1, 20 ml). The filtrate is concentrated under reduced pressure to 17 g net weight, heptane (100 ml) added and the mixture concentrated under reduced pressure to 15 g net weight. Heptane (100 ml) and methylene chloride (100 ml) is added and the mixture concentrated under reduced pressure to 130 g net weight. The solids are filtered off and washed with heptane/methylene chloride (2/1, 3×15 ml). The filtrate is concentrated under reduced pressure to 11 g net weight and toluene (90 ml) then heptane (400 ml) added. The resultant slurry is then cooled to −20° and the product collected by filtration with reduced pressure, washed with heptane and dried to give a crude solid. Flash chromatography of the crude solid (silica gel; eluting with a gradient of 15-45% ethyl acetate/cyclohexane) gives the title compound as an analytical sample, NMR 3.11, 3.62, 3.68, 3.87, 3.95, 4.14-4.20, 7.70-7.76 and 7.82-7.88δ; CMR 41.61, 47.27, 69.68, 123.53, 131.83, 134.26 and 168.65δ; MS (CI, NH3), M/Z (relative intensity) 259 (1.4), 257 (17), 242 (0.11), 240 (0.31), 221 (100); [α]25D=−33(C=0.712, CHCl3). NMR of the mosher ester derivative showed the product to have an enantiomeric purity of 96.2% upon comparison to the NMR of the mosher ester of the racemate.
Reaction SMILES: [Na].Cl[C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:15][CH3:16])[CH:4]=1.Cl.[CH3:18][OH:19]>>[CH3:16][O:15][C:5]1[CH:4]=[C:3]([O:19][CH3:18])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COc1cc(OC)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C

Procedure:
In a stream of argon, 0.30 g of metallic sodium was added to 5 ml of methanol under ice-cooling, the mixture was stirred at room temperature for a while and then 1.00 g of 4-chloro-2-methoxy-5-nitrobenzoic acid was added to the resulting solution in small portions, followed by stirring at 80° C. for 8 hours. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 0.80 g of 2,4-dimethoxy-5-nitrobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]([O:34]CC)=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)COCCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCOCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To a solution of ethyl ({3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propyl}oxy)acetate (D105) (80 mg) in THF (10 mL) was added NaOH (2 M, 2 mL). The reaction was stirred at 20° C. for 3 h. The mixture was acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford ({3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propyl}oxy)acetic acid (E80) (50 mg). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.89 (2H, m), 2.49 (2H, t), 3.52 (2H, t), 3.63 (3H, s), 4.01 (2H, s), 4.87 (1H, m), 7.17 (2H, m), 7.42 (2H, m), 7.77 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d), 12.56 (1H, br s). MS (ES): C25H26ClN3O5 requires 483; found 484.2 (M+H+).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)C(C)(C)C)cs2)ccc1-n1cnc(C)c1
Yield: 98.8 %

Procedure:
96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 25 mg (0.2 mmol) pivaloylchloride were suspended in methylene chloride (2 ml) and 101 mg (1 mmol) triethyl amine was added at room temperature. The reaction was stirred over night, diluted with methylene chloride, washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure to yield 90 mg (99%) N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-2,2-dimethyl-propionamide as a light yellow solid. MS ISP (m/e): 456.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.37 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.55 (d, 1H), 7.22 (d, 1H), 7.05-6.99 (m, 2H), 6.44 (s, 1H), 4.95 (m, 1H), 3.82 (s, 3H), 2.14 (s, 3H), 1.73 (m, 2H), 1.65 (m, 1H), 1.14 (s, 9H), 0.91 (d, 3H), 0.87 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([OH:22])=O)=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)C(C)C)(C)C.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:28])([F:29])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([NH:40][CH2:41][C:42](=[O:43])[NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:22])=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Reactant: NCC(=O)NCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2)NCC(F)(F)F
Yield: 84.8 %

Procedure:
Stir a mixture of 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid (1.0 g, 2.14 mmol), N,N-diisopropylethylamine (827 mg, 6.41 mmol), 2-amino-N-(2,2,2-trifluoroethyl) acetamide hydrochloride (658 mg, 2.56 mmol) and HATU (1.2 g, 3.2 mmol) in CH2Cl2 (10 mL) at room temperature for 2 hours. The reaction mixture is diluted with CH2Cl2 (50 mL) and is washed with water (10 mL×3) and brine. Then the organic layer is dried over anhydrous Na2SO4 and is concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide as a white solid (1.1 g, 84.6%). MS (m/z): 606.0 (M+1).
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]1([CH3:25])[O:24][C:11]2=[C:12]3[C:17](=[C:18]([CH3:20])[CH:19]=[C:10]2[CH2:9]1)[NH:16][C:15](=[O:21])[C:14]([CH2:22][CH3:23])=[CH:13]3.[N-:26]=[N+:27]=[N-:28].[Na+]>C(Cl)(Cl)Cl.CCCCCC>[N:26]([CH2:7][C:8]1([CH3:25])[O:24][C:11]2=[C:12]3[C:17](=[C:18]([CH3:20])[CH:19]=[C:10]2[CH2:9]1)[NH:16][C:15](=[O:21])[C:14]([CH2:22][CH3:23])=[CH:13]3)=[N+:27]=[N-:28]
Reactant: CCc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CBr)O3
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CN=[N+]=[N-])O3
Yield: 90.5 %

Procedure:
Dimethylformamide (21 ml) was added to a mixture of 2-bromomethyl-8-ethyl-2,5-dimethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (920 mg, 2.74 mmol) and sodium azide (1.30 g, 19.9 mmol). The procedure of Example 278 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane) to obtain 740 mg of the title compound as colorless needles (80.9%).
Reaction SMILES: [H-].[Li+].[CH3:3]OS(OC)(=O)=O.[C:10]([O:18][C:19]1[C:20]([C:40]([O:42][CH3:43])=[O:41])=[N:21][C:22]([C:26]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])([CH3:28])[CH3:27])=[N:23][C:24]=1[OH:25])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1>[C:10]([O:18][C:19]1[C:24](=[O:25])[N:23]([CH3:3])[C:22]([C:26]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])([CH3:27])[CH3:28])=[N:21][C:20]=1[C:40]([O:42][CH3:43])=[O:41])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1nc(C(C)(C)NC(=O)OCc2ccccc2)nc(O)c1OC(=O)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COC(=O)c1nc(C(C)(C)NC(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 38 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of LiH (1.1 eq) in dioxane, methyl 5-(benzoyloxy)-2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-6-hydroxypyrimidine-4-carboxylate was added and the mixture was stirred at 38° C. for 45 min. After cooling down to room temperature, dimethylsulfate (1.3 eq) was added and reaction mixture was heated at 60° C. for 2 h. Mixture was then cooled to room temperature, dioxane evaporated and residue was purified by flash chromatography, eluting with 65/55 v/v petroleum ether/ethyl acetate. Collection and evaporation of appropriate fractions afforded the title product.