Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)(C)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)Nc1ccc(CN)cc1
Yield: 35.8 %

Procedure:
Add a solution of 4-(tert-butoxycarbonylamino)-benzonitrile (1 g, 4.58 mmol) in THF/iso-propanol (1:1, 142 mL) to 10% Pd/C (Degussa type E101, 0.56 g, 0.26 mmol) via syringe under N2. Purge the reaction mixture with nitrogen and submit the mixture to hydrogenation at 50 psi overnight. Filter the catalyst through Celite® and wash thoroughly with iso-propanol (100 mL) and THF (100 mL). Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with DCM/2M ammonia in methanol (1:0 to 95:5 gradient over 30 min; 95:5 over 3 min; 95:5 to 9:1 gradient over 30 min and 9:1 over 30 min) to obtain the desired intermediate (0.364 g, 36%). MS (ES−) m/z: 220.1 (M−2H)−.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:10][C:11](=[CH2:14])[CH:12]=[O:13].Cl>C(OCC)C.BrCCCCCCC>[CH3:14][C:11]([CH:12]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH2:10]
Reactant: C=C(C)C=O
Reactant: CCCCCCCBr
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: C=C(C)C(O)CCCCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
Under an atmosphere of nitrogen the reaction flask is charged with 9.85 g magnesium and 100 ml diethyl ether. The Grignard reaction is started with 3.00 g bromo-heptane. Then a solution of 70.00 g bromo-heptane in 50 ml diethyl ether is added dropwise within 90 minutes, the reaction mixture is kept at mild reflux and subsequently cooled to 0° C. to add now within 30 minutes a solution of 28.70 g 2-methyl-2-propenal in 30 ml diethyl ether. After further stirring for 2 hours at room temperature the reaction mixture is again cooled to 0° C. and 50 ml of diluted hydrochloric acid (3.5%) are carefully added. The organic layer is washed with water, dried with sodium sulfate and subsequently concentrated to give 86.7 g crude material. Distillation over a 10 cm-column (Widmer type) gives 40.5 g 2-methyl-1-decen-3-ol having a boiling point of 75° C. at 0.12 bar.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15](=[O:17])[CH3:16].[N+:18]([O-])([OH:20])=[O:19]>O>[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([N+:18]([O-:20])=[O:19])=[CH:9][C:8]=1[C:15](=[O:17])[CH3:16]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(F)c(C(C)=O)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
Sulfuric acid (157 g, 85.2 ml, 1.6 mol) was cooled to −20° C. and 1-(2-fluoro-4-methoxyphenyl)ethanone (25 g, 149 mmol) was added portionwise in a manner that the temperature was kept below −15° C. Thereafter, a solution of sulfuric acid (64.4 g, 35 ml, 657 mmol) and fumic nitric acid (18.7 g, 12.4 ml, 297 mmol) was added dropwise within 20 minutes keeping the temperature below −15° C. After completion of the addition the viscous reaction mixture was stirred for additional 20 minutes at −15° C. For the workup, the reaction mixture was poured into a mixture of ice and water (400 ml) and stirring was continued for 10 minutes. The off-white suspension was filtrated and washed several times with water. The light yellow solid was dried at 45° C. before it was crystallized from a mixture of ethyl acetate and heptane (200 ml-600 ml, addition of charcoal). The 1-(2-fluoro-4-methoxy-5-nitro-phenyl)-ethanone (26.1 g, 82% yield) was obtained as pale yellow crystals. MS (ISP): m/z=214.2 [M+H]+. In addition, the regioisomer 1-(2-fluoro-4-methoxy-3-nitro-phenyl)-ethanone (0.6 g, 2% yield) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2].[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A flame-dried 200 mL round bottomed flask was charged with 3-(2-formyl-4-hydroxyphenyl)acrylic acid tert-butyl ester (10.0 g, 40.3 mmol), tert-butylchlorodiphenylsilane (12.6 mL, 48.3 mmol), and dry CH2Cl2 (150 mL). Triethylamine (11.2 mL, 80 mmol) and N,N-dimethylaminopyridine (1.0 g, 1.0 mmol) were added, and the mixture was stirred at ambient temperature under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with additional CH2Cl2, washed with brine (2×), dried (Na2SO4), and concentrated to an oil. The crude product was purified using the Biotage medium pressure chromatography system (EtOAc:hexanes 5:95) to give a pale yellow oil (18.3 g, 93%). 1H NMR (400 MHz, CDCl3) δ 1.12 (s, 9H), 1.51 (d, J=15.1 Hz, 9H), 6.15 (d, J=5.1 Hz, 1H), 6.87 (dd, J=8.6, 2.7 Hz, 1H), 7.34-7.47 (m, 7H), 7.68-7.73 (m, 5H), 8.28 (d, J=15.6 Hz, 1H), 10.1 (s, 1H). MS (ES) m/e 487 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:20]([NH2:21])=[C:19]([CH3:25])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OCC)(=O)C>C1COCC1>[Br:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:20]([NH:21][C:2]2[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=2)=[C:19]([CH3:25])[CH:18]=1
Reactant: CCC(COC)n1cc(Cl)nc(Cl)c1=O
Reactant: Cc1cc(Br)cc(C)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(COC)n1cc(Cl)nc(Nc2c(C)cc(Br)cc2C)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
To (+/-)-3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone (300 mg) and 4-bromo-2,6-dimethylaniline (238 mg) in THF (anhydrous, 9.4 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1.0 M/THF, 2.6 mL). The mixture was stirred at 0° C. for 10 minutes. Ethyl acetate (100 mL) was added and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4 and concentrated and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent. The product was then crystallized from ethyl acetate/hexane to afford the title compound (419 mg). Elemental analysis calcd. for C17H21N3O2BrCl: C, 49.23; H, 5.10; N, 10.13. Found: C, 49.33; H, 5.05; N, 10.09.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[C:10]([O:14][C:15]([C@:17]12[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:21]1[CH2:20][O:19][C:18]2=[O:29])=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl>ClCCl>[C:10]([O:14][C:15]([C@:17]1([C:18](=[O:29])[N:3]([O:4][CH3:5])[CH3:2])[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:21]1[CH2:20][OH:19])=[O:16])([CH3:12])([CH3:11])[CH3:13]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)[C@@]12C(=O)OC[C@@H]1[C@@H]2c1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)[C@]1(C(=O)OC(C)(C)C)[C@H](CO)[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
In a 100 mL round-bottomed flask, a solution of N,O-dimethyl hydroxylamine HCl was suspended in 20 mL of dichloromethane. After cooling to 0° C., trimethyl aluminum (2 M in toluene. 3.83 mL, 7.66 mmol) was added dropwise and the mixture was stirred at 0° C. for 45 min. A solution of the previously described (1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid tert-butyl ester (0.3 g, 1 mmol) in 10 mL of dichloromethane was added dropwise to the cooled stirring solution. After stirring at 0° C. for 5 min, the reaction mixture was warmed to room temperature and stirred for 3 hours. After the reaction was completed, the reaction mixture was again cooled in an ice bath and acidified with 10 mL of 1N HCl, extracted with dichloromethane (×3), dried over MgSO4 and concentrated to afford 0.32 g (86%) of the desired product as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:18])=[CH:8][C:9](=[O:17])[N:10]2[CH2:13][CH2:14][CH:15]=O)=[CH:5][CH:4]=1.[NH2:19][C@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:18])=[CH:8][C:9](=[O:17])[N:10]2[CH2:13][CH2:14][CH2:15][NH:19][C@H:20]2[CH2:24][N:23]([C:25]3[CH:26]=[CH:27][C:28]4[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=4[N:34]=3)[C:22](=[O:36])[CH2:21]2)=[CH:5][CH:4]=1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2c(C)cc(=O)n(CCC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1ccc2c(C)cc(=O)n(CCCN[C@@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
To a solution of 3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propanal (150 mg, 1.13 mmol) in N,N-dimethylformamide (5 ml) was added 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (synthesized using [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21 and 22; 303 mg, 1.22 mmol) and the mixture was stirred at room temperature for 1 hour. After cooling the reaction solution on ice, sodium triacetoxyborohydride (388 mg, 1.83 mmol) was added thereto and the mixture was stirred at room temperature for 2 hours. A sodium hydrogen carbonate aqueous solution was added, the reaction solution was extracted with ethyl acetate and the extract was washed with water and saturated sodium chloride solution. The obtained organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) so as to yield 15 mg (3%) of the title compound.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)/[C:6](=[O:8])[N:7]=1.Cl.[O:28]1CCCC1>>[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2/[CH:9]=[C:5]2/[C:6](=[O:8])[NH:7][C:3](=[O:28])[S:4]/2)[CH:22]=[CH:21][CH:20]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccccc2Nc2cccc(C(F)(F)F)c2)S1
Reactant: C1CCOC1
Agent: Cl
Product: O=C1NC(=O)/C(=C/c2ccccc2Nc2cccc(C(F)(F)F)c2)S1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a room temperature solution of (Z)-2-methylthio-5-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylene]-4(5 H)-thiazolone (507 mg, 1.28 mmols) in 14 mL of tetrahydrofuran is added 14 mL of 10% aqueous hydrochloric acid. The mixture is heated at reflux for 30 minutes, then allowed to cool to room temperature. The mixture is partitioned between water and ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate followed by brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 390 mg (83%) of (Z)-5-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylene]-2,4-thiazolidinedione. An analytical sample is obtained by recrystallization from ethyl acetate and hexane; mp 213°-214° C. dec.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([C:17]2[N:18]=[CH:19][N:20]([CH3:22])[CH:21]=2)[C:10]1=[O:23].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:55][C:56]1[CH:61]=[C:60]([Cl:62])[CH:59]=[CH:58][C:57]=1[CH2:63][NH2:64]>ClCCl>[Cl:55][C:56]1[CH:61]=[C:60]([Cl:62])[CH:59]=[CH:58][C:57]=1[CH2:63][NH:64][C:14]([CH:13]1[CH2:12][N:11]([C:17]2[N:18]=[CH:19][N:20]([CH3:22])[CH:21]=2)[C:10](=[O:23])[N:9]1[CH3:8])=[O:16]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CN1C(=O)N(c2cn(C)cn2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2cn(C)cn2)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A solution of 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylic acid trifluoroacetate salt (0.105 g, 0.47 mmol) (prepared as described in step (ii) of Example 57) and N-ethyl morpholine (0.361 ml, 2.82 mmol) in dichloromethane (5 ml) was treated with 1-hydroxybenzotriazole hydrate (0.086 g, 0.564 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.090 g, 0.470 mmol) and stirred at room temperature for 10 minutes. 1-(2,4-Dichlorophenyl)methanamine (0.063 ml, 0.470 mmol) was added and the reaction mixture was stirred over the weekend. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine and separated using a hydrophobic frit. The filtrate was concentrated under vacuum and purified by mass-directed automated HPLC to give N-[(2,4-dichlorophenyl)methyl]-3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxamide (26 mg, 13.75% yield). LC/MS [M+H]+=382, retention time=1.83 minutes.
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.N#N.CN(C)CCN(C)C.[CH:42]([Li])([CH2:44]C)[CH3:43].C(Br)C=C>CCOCC.O>[CH2:44]([CH:21]1[N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:31])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1)[CH:42]=[CH2:43]
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3)cc1
Reactant: [Li]C(C)CC
Agent: CN(C)CCN(C)C
Agent: N#N
Solvent: CCOCC
Solvent: O
Solvent: C=CCBr
Product: C=CCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 16 h

Procedure:
Tert-butyl 2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 1) (500 mg, 1.203 mmol) in Et2O (10 ml) degassed with N2 was treated with 1,2-di(dimethylamino) ethane (0.400 ml, 2.65 mmol). The mixture was cooled to −70° C. and treated with sec-butyllithium (1.4M in cyclohexane, 0.945 ml, 1.324 mmol) dropwise, maintaining the temperature at −70° C. After stirring at −70° C. for 2 hours allyl bromide (0.115 ml, 1.324 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 16 hours. The resulting mixture was added dropwise to water (100 ml) and extracted with DCM (×3). The combined organic extracts were concentrated under reduced pressure and purification of the crude product by chromatography on silica eluting with 0-10% EtOAc in iso-hexane afforded the titled compound as a cream coloured solid;
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:25][O:26][NH2:27].C(N(CC)CC)C>CO>[CH3:25][O:26]/[N:27]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: CON
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 30 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a solution of 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (6.3 mg, 0.021 mmol) in methanol (3 mL) was added O-methylhydroxylamine hydrochloride (16.7 mg, 0.20 mmol), followed by addition of triethyl amine to adjust the pH to 5-6. The reaction mixture was stirred at 30° C. for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The resulting solution was washed with NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 5.3 mg (69%) of the title compound. 1H-NMR (400 MHz, CD3Cl) δ ppm 9.67 (s, 1H), 8.94 (m, 1H), 8.16 (t, 2H), 7.93 (d, 1H), 7.86 (dd, 1H), 7.53 (dd, 1H), 6.11 (s, 2H), 4.14 (s, 3H), 2.38 (s, 3H). LCMS (method A): [MH]+=334, tR=5.02 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[O:14])[C:9]=2[CH3:26])=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:37][C@H:38]1[C@H:42]([CH3:43])OS(=O)(=O)[O:39]1.Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C@H:42]([CH3:43])[C@@H:38]([OH:39])[CH3:37])[CH:11]=[C:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=3)=[O:14])[C:9]=2[CH3:26])=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:3]=1
Reactant: C[C@@H]1OS(=O)(=O)O[C@H]1C
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(Cl)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn([C@H](C)[C@H](C)O)c1-c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a solution of 5-[4-chloro-2-(trifluoromethyl)phenyl]-4-methyl-N-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxamide (21 g, 47 mmol) in anhydrous DMA (234 ml) was added sodium tert-butoxide (10 g, 0.11 mol) and stirred at room temperature for 30 min under N2. (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (11 g, 70 mmol) in anhydrous DMA (50 ml) was added to the solution and stirred at 70° C. for 2.0 h. The reaction mixture was cooled to 0° C. and added 2N HCl (100 ml) and concentrated on a rotary evaporator. To this residue was added anhydrous THF (120 ml) and 5N HCl (120 ml) and stirred at 60° C. for 90 min. The mixture was diluted with ethyl acetate and washed with water, satd NaHCO3 and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (1:1 to 1:9 hexane:ethyl acetate) to give an atropisomeric mixture of the title compound (10.9 g, 44%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>O.CN(C=O)C>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)[C:11]2=[O:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(Cn2c(=O)n(Cc3ccc([N+](=O)[O-])cc3)c3ccccc32)cc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of compound N (1.12 g, 4.0 mmol) in abs. DMF (30 mL) there were added 4-nitrobenzyl bromide (864 mg, 4.0 mmol), potassium carbonate (1.14 g, 8.30 mmol), and a catalytic amount of potassium iodide under a blanket of argon. The reaction mixture was heated to 75° C. over a period of 4 h. Following cooling, the reaction mixture was poured into a mixture of ice (300 g) and 2N hydrochloric acid solution in H2O (200 mL), and the reaction mixture was stirred for 1 hour. The resulting solid matter was separated through a frit and dried in vacuo over calcium chloride. The desired product 1-(4-tert-butylbenzyl)-3-(4-nitrobenzyl)-1,3-dihydrobenzimidazol-2-one (P) was obtained in an adequately pure form for synthetic purposes in a yield of 1.48 g (89% of theory).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([Si:15]([CH3:21])([CH3:20])[O:16][CH2:17][CH2:18][OH:19])([CH3:14])[CH3:13].Cl>ClCCl.C(N(CC)CC)C.N1C=CC=CC=1>[CH3:14][C:12]([Si:15]([CH3:21])([CH3:20])[O:16][CH2:17][CH:18]=[O:19])([CH3:11])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCC=O
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
Under nitrogen and with stirring, 4.71 ml of oxalyl chloride were dissolved in 120 ml of dichloromethane and the solution was cooled to -70° C. Over 12 minutes while maintaining the temperature at -65° C., a solution of 8 ml of dimethylsulfoxide and 26 ml of dichloromethane was introduced. Then, after 10 minutes of contact at this temperature, a solution of 8.81 g of the product of Step A, 50 ml of dichloromethane and 8.86 ml of pyridine was added over 12 minutes at -65° C. After 15 minutes of contact at this temperature, 35 ml of triethylamine were added over 8 minutes at -65° C. At +13° C., the pH was adjusted to 4 by adding N hydrochloric acid. After decanting, re-extracting with 50 ml of dichloromethane, drying the organic phase and distilling under reduced pressure, the crude product obtained was chromatographed over silica and eluted with dichloromethane to obtain 7.95 g of 2-[(1,1-dimethylethyl)dimethylsilyloxy]-acetaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][NH2:12])[CH:6]=[CH:7][CH:8]=1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][NH:12][C:14](=[O:15])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cccc(SCCN)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(SCCNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 20 (1.0 g) in EtOAc (50 mL) cooled to ˜0° C. was added benzyl chloroformate (1.1 eq.) and triethylamine (1.2 eq.). The reaction mixture was stirred for 4 hours at r.t. and washed with 1N HCl, and sat. NaHCO3 (2×10 mL). The solvents were removed by evaporation under reduced pressure to give crude title product. Purification by chromatography gave 21 as white solid. Yield: 1.61 g.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][C:21]([O:23]C)=[O:22])[N:19]=2)=[CH:11][CH:10]=1>O.O1CCCC1>[Cl:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][C:21]([OH:23])=[O:22])[N:19]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)Cc1coc(-c2ccc(OCCCCl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1coc(-c2ccc(OCCCCl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of lithium hydroxide hydrate (0.76 g, 18.11 mmol, 2 eq) in water (10 ml) is added to a solution of methyl {2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}acetate ax62 (2.8 g, 9.06 mmol, 1 eq) in tetrahydrofuran (100 ml). The mixture is stirred at room temperature for 1 h. The mixture is then poured into water and extracted with diethyl ether (2×75 ml). The aqueous layer is acidified with 6 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated under vacuum to give 2.1 g of {2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}acetic acid ax63 as a brown solid.