Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:36])[C:22]([OH:35])([C:27]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=1)[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.Cl([O-])=[O:38].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:36])[C:22]([OH:35])([C:27]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=1)[C:23]([F:25])([F:26])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:38])=[O:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: CC(c1ccc(Oc2ccc(C=O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Na+]
Product: CC(c1ccc(Oc2ccc(C(=O)O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 214, step 2, 4-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-propyl]-phenoxy}-2-trifluoromethyl-benzaldehyde was oxidized with sodium chlorite to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=548.1 [M−H+].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:42])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][O:31][Si](C(C)C)(C(C)C)C(C)C)=[CH:26][CH:25]=3)[CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[OH:31][CH2:30][C:27]1[CH:26]=[CH:25][C:24]([CH:13]([C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[O:42])[CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:29][CH:28]=1
Reactant: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propyl(methyl)carbamate (E205) in THF under N2 at 0° C. was added TBAF, and the solution was stirred for 30 min at 0° C. The reaction was warmed to room temperature and stirred another 4.5 h. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-20% MeOH/CH2Cl2 gradient) gave pure tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropyl(methyl)carbamate (E205-1)
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][CH:39]([S:48][C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:40][C:41]1[O:42][CH2:43][C:44]([CH3:47])([CH3:46])[N:45]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.O>[OH:36][CH2:37][CH2:38][CH:39]([S:48][C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:40][C:41]1[O:42][CH2:43][C:44]([CH3:47])([CH3:46])[N:45]=1
Reactant: CC1(C)COC(CC(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Sc2cc3ccccc3[nH]2)=N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(CC(CCO)Sc2cc3ccccc3[nH]2)=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
1 ml of a 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran was added to a solution of 460 mg of 2-[4-tert-butyldiphenylsilyloxy-2-(indol-2-ylthio)butyl]-4,4-dimethyl-2-oxazoline [prepared as described in Example 78b)] in 20 ml of tetrahydrofuran, with stirring, at room temperature, and stirring was continued at this temperature for 30 minutes. After this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography, using a mixture of 60% v/v ethyl acetate in hexane as the eluent, to afford 165 mg of the title compound as an oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([F:21])[CH:20]=2)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]3)[CH2:6]1)=O.[NH3:24]>CO>[F:21][C:19]1[CH:20]=[C:11]([N:7]2[CH2:6][C@H:5]([C:3]([NH2:24])=[O:2])[O:9][C:8]2=[O:10])[CH:12]=[C:13]2[C:18]=1[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]2
Reactant: N
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)CCC(=O)N3C)C(=O)O1
Solvent: CO
Product: CN1C(=O)CCc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (Step 5, 0.300 g, 9.31 mmol) is dissolved in 2M ammonia in methanol solution (8 ml) and stirred overnight at room temperature. The resulting precipitate is filtered, washed with methanol, and dried under vacuum to give the title compound as a white solid (0.185 g, 65%), mp 260-2° C.; 1H NMR (300 MHz, CDCl3) δ 2.48-2.52 (m, 2H), 2.85-2.89 (m, 2H), 3.28 (d, 3H), 4.00 (dd, 1H), 4.24 (t, 1H), 5.03 (dd, 1H), 7.27 (s, 1H), 7.46 (dd, 1H), 7.62 (br s, 1H), 7.87 (br s, 1H); MS for C14H14FN3O4 m/z 308 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.IC[C:45]1[N:49](C)[C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:49]([CH3:45])[C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[N:47][N:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1c(CI)nnc1S(C)(=O)=O
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cn1c(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)nnc1S(C)(=O)=O

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole and isolated as white solid. MS (m/e): 456.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O>CS(C)=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1nc2cc(C)ccc2nc1Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc3ccc(C)cc3nc2OC)c(OC)c1
Temperature: 60 °C
Reaction time: 45 h
Yield: 90.4 %

Procedure:
To 2-chloro-3-methoxy-6-methylquinoxaline (3.05 g, 14.6 mmol) dissolved in dimethylsulfoxide (40 ml), 2,4-dimethoxybenzylamine (9.77 g, 58.4 mmol) was added at room temperature. The mixture was stirred at 60° C. for 45 hours and then water was added thereto. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (13:1) mixture and concentration gave 4.48 g of the titled compound (yield, 90%).
Reaction SMILES: [F-].[K+].[C:3]([O:7][C:8](=[O:26])[CH2:9][C@H:10]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:11](=[O:14])[CH2:12]Br)([CH3:6])([CH3:5])[CH3:4].[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([F:35])=[C:30]([F:36])[C:29]=1[OH:37]>CN(C=O)C>[C:3]([O:7][C:8](=[O:26])[CH2:9][C@H:10]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:11](=[O:14])[CH2:12][O:37][C:29]1[C:30]([F:36])=[C:31]([F:35])[CH:32]=[C:33]([F:34])[C:28]=1[F:27])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)CBr
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)COc1c(F)c(F)cc(F)c1F
Reaction time: 18 h
Yield: 93.5 %

Procedure:
Potassium fluoride (2.8 g) was added portionwise to a stirred solution of (S)-3-benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (18.6 g) and 2,3,5,6-tetrafluorophenol (9.3 g) in anhydrous DMF (250 mL) under nitrogen at room temperature. The mixture was then stirred for 18 hours before being quenched with ethyl acetate and water. The organic layer was removed and washed with sodium bicarbonate solution, dried (magnesium sulfate) and concentrated to give the sub-title product as an off-white solid (21.1 g, 96%). 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 2.76 (1H, dd), 3.06 (1H, dd), 4.67-4.71 (1H, m), 5.12 (1 h, d), 5.22 (1H, d), 5.86 (1H, d), 7.35-7.38 (5H, m) ppm; 19F NMR (376 MHz, CDCl3) (proton decoupled) δ −139.98, −140.00, −140.04, −140.06, −157.05, −157.07, −157.11, −157.13; MS ES (+) 486.23 (M+H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[C:15]([NH:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CS(C)=O>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[C:15]([NH:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:24]4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(C(F)(F)F)c4)n3n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(C(F)(F)F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of trans-N1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (130 mg, 0.35 mmol) and DIPEA (135.7 mg, 10.5 mmol) in DMSO (1.75 mL) was added dropwise MeSO2Cl (47.6 mg, 0.42 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed most of starting material was converted. The mixture was partitioned between brine (100 mL) and EtOAc (50 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-90 (30 mg, 18.9%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[F:42])[C:12]2[C:13]([C:30]([O:32]CC)=[O:31])=[N:14][N:15]([C:20]3[C:21]([O:28][CH3:29])=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[C:16]=2[CH:17]([CH3:19])[CH3:18])[CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[F:42])[C:12]2[C:13]([C:30]([OH:32])=[O:31])=[N:14][N:15]([C:20]3[C:21]([O:28][CH3:29])=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[C:16]=2[CH:17]([CH3:18])[CH3:19])[CH:3]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3F)c2C(C)C)c(OC)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A solution of 465 mg (0.743 mmol) ethyl 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chloro-2-fluorophenyl)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (product from step 184.2) in 7.42 ml THF/MeOH (1:1) under N2 atmosphere was cooled down to 0° C. After that 2.60 ml (5.20 mmol) of a 2M NaOH solution was added drop wise and the solution was stirred at 0° C. for 10 min and at RT for 1.5 hour. The solvent was evaporated, diluted in 50 ml CH2Cl2 and washed with 1M citric acid aqueous solution (30 ml). The water phase was extracted twice with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated to give 461 mg (0.741 mmol, 100% yield) of the title compound as a foam, which was used in the next step without purification. LCMS: (M+H)=591/593; tR=0.97 min (LC-MS 4). HPLC: tR=4.69 min (HPLC 7). TLC: R=0.14 (CH2Cl2/MeOH 20:1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25][Cl:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CO)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Yield: 89.9 %

Procedure:
To a solution of 4-butoxy-6-ethoxy-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (0.43 g, 1.2 mmol) in tetrahydrofuran (10 ml) and toluene (10 ml) was added thionyl chloride (0.18 ml, 2.4 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-butoxy-6-ethoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (0.41 g, 91.1%) as an oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.O>C1COCC1>[N:9]1[CH:8]=[C:7]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:23][CH2:13][CH2:14][O:15]3)[CH2:17][CH2:18]2)[CH:12]=[N:11][CH:10]=1
Reactant: Brc1cncnc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2cncnc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 12.1 %

Procedure:
A solution of n-butyllithium (4.32 mL of 1.6 M solution in hexane, 6.92 mmol) was added to 5-bromopyrimidine (1.0 g, 6.29 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (0.982 g, 6.29 mmol) in THF (10 mL) was added to the lithiated compound solution via syringe and stirred for 4 h at −78° C. Water (5 mL) was added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and chromatographed to yield 0.18 g of 8-pyrimidin-5-yl-1,4-dioxaspiro[4,5]decan-8-ol in 12% yield. MS (EI) calcd: (M+H)+=237.1. Found: 237.2.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][C@@H:62]([CH2:76][C:77]1[CH:82]=[C:81]([F:83])[CH:80]=[C:79]([F:84])[CH:78]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1>C(Cl)Cl>[F:83][C:81]1[CH:82]=[C:77]([CH:78]=[C:79]([F:84])[CH:80]=1)[CH2:76][C@H:62]([NH:61][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:25][CH2:26][CH3:27])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccn2COCC)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2nccn2COCC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 3-[(dipropylamino)carbonyl]-5-[1-(ethoxymethyl)-1H-imidazol-2-yl]benzoic acid (177 mg, 0.47 mmol), diisopropylethylamine (651 mg, 0.5 mmol), and HBTU (209 mg, 0.55 mmol) in methylene chloride (5 mL) is added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (196 mg, 0.48 mmol) and diisopropylethylamine (130 mg, 1.0 mmol) in methylene chloride (5 mL). The reaction mixture is stirred at room temperature for 15 h and concentrated under reduced pressure. The residue is diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 methanol/methylene chloride) provides the title compound. APCI MS m/z 690.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:29])([F:28])[F:1])[CH:4]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.[N:25]([CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29]([O:31][CH3:32])=[O:30])=[C:26]=[O:27]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:26]([NH:25][CH:28]([C:29]([O:31][CH3:32])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNCC(=O)O
Reactant: COC(=O)C(N=C=O)c1ccccc1
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)N(CCCNC(=O)OC(C)(C)C)CC(=O)O)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2.8 g (12 mmol) of (3-tert-butoxycarbonylaminopropyl)glycine and 1.4 g (12 mmol) of N-ethylmorpholine are dissolved in 300 ml of dimethylformamide. 2.3 g (12 mmol) of methyl α-isocyanatophenylacetate are added dropwise at 100° C. The mixture is stirred at 100° C. for 1 h, allowed to cool down to room temperature, concentrated and chromatographed on silica gel using ethyl acetate/methanol 8:2.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:17]1([C:23]2[S:27][C:26]([CH2:28][C:29]([OH:31])=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[N:12]1([C@@H:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:3]2[N:2]([CH3:1])[C:29](=[O:31])[CH2:28][C:26]2[S:27][C:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:24][CH:25]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)s1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN(C(=O)Cc1ccc(-c2ccccc2)s1)[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Yield: 68.6 %

Procedure:
Using the procedure of Step C of Example 1, 0.432 g of the product of Step B of Example 1, 0.567 g of 5-phenyl-2-thiophene-acetic acid and 0.422 g of carbonyldiimidazole were reacted to obtain 0.571 g of trans-(±)- N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-5-phenyl-2-thiophene-acetamide and then 0.457 g of its hydrochloride melting at ≃249° C.
Reaction SMILES: [N:1]([C:4]1[C:8]([CH3:9])=[CH:7][S:6][CH:5]=1)=[C:2]=[S:3].[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[NH2:20])[O:13][CH2:12][CH2:11]1>O1CCCC1>[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[NH:20][C:2]([NH:1][C:4]2[C:8]([CH3:9])=[CH:7][S:6][CH:5]=2)=[S:3])[O:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC12OCCO2
Reactant: Cc1cscc1N=C=S
Solvent: C1CCOC1
Product: Cc1cscc1NC(=S)NC1CCCCC12OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-isothiocyanato-4-methylthiophene (296.2 mg, see example 1a) in absolute tetrahydrofuran (10 ml) was added dropwise to a solution of 1,4-dioxaspiro[4.5]dec-6-ylamine (300 mg) in absolute tetrahydrofuran (10 ml), the mixture was stirred at room temperature for 2 hours and the solvent was then removed under reduced pressure. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. This gave 428 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+].Cl.[H][H]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][OH:6]
Reactant: [H][H]
Reactant: COc1cc(Cl)cc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Cl)cc(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To an ice-cold solution of 3-chloro-5-methoxybenzaldehyde (27 mmol, 4.60 g) in ethanol (90 ml) was added NaBH4 (30 mmol, 1.14 g) in one portion under stirring. After 0.5 h the mixture was allowed to reach room temperature and stirred for another 0.5 h. HCl (2 M, ˜25 ml)) was added slowly until no more hydrogen gas evolved, the resulting mixture was concentrated under reduced pressure and the residue separated between water and ether, the organic phase was washed with braine and dried (MgSO4). Filtration and evaporation of solvents afforded the title compound (4.53 g, 97%) as a white solid. The product was used without further purification in the next step. An analytically pure sample was obtained be means of flash chromatography (silica, hexane/ether grad.). 1H NMR (CDCl3, 500 MHz) δ 2.77 (br, 1H), 3.76 (s, 3H), 4.55 (s, 2H), 6.74 (s, 1H), 6.77 (s, 1H) and 6.88 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[C:23]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]([S:26]([NH:29][C:30]5[CH:31]=[C:32]([NH:36]C(=O)C)[CH:33]=[CH:34][CH:35]=5)(=[O:28])=[O:27])=[CH:20][C:21]=4[C:22]3=[O:25])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1>C1COCC1.CO.[OH-].[Na+]>[NH2:36][C:32]1[CH:31]=[C:30]([NH:29][S:26]([C:19]2[CH:18]=[CH:17][C:16]3[C:15]4[C:23](=[CH:24][C:12]([S:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=5)(=[O:10])=[O:11])=[CH:13][CH:14]=4)[C:22](=[O:25])[C:21]=3[CH:20]=2)(=[O:27])=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=O)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=O)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Reaction time: 24 h
Yield: 59.5 %

Procedure:
The product from Example 6A (289 mg, 0.554 mmol) in THF:MeOH (1:1, 20 mL) and 15% aq NaOH (10 mL) was heated at reflux. After 24 hours, the volatiles were evaporated at reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO3. The separated aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (80% ethyl acetate/hexanes) to provide the title compound as an orange solid (172 mg, 55% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.50 (1H), 7.97-8.1 (m, 4H), 7.92 (d, 2H), 7.00 (t, 1H), 6.83 (t, 1H), 6.58 (t, 1H), 6.53 (m, 1H), 6.42 (m, 1H), 6.35 (t, 1H), 6.22 (m, 2H), 5.14 (bs, 2H). MS (ESI) 520 (M−H)−.