Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][C@H:57]1[CH2:62][N:61]([CH2:63][CH2:64][C@@H:65]([NH:74][C:75]2[CH:80]=[CH:79][C:78]([S:81]([NH2:84])(=[O:83])=[O:82])=[CH:77][C:76]=2[S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH2:66][S:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:60][CH2:59][O:58]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:84][S:81]([C:78]3[CH:79]=[CH:80][C:75]([NH:74][C@H:65]([CH2:64][CH2:63][N:61]4[CH2:60][CH2:59][O:58][C@@H:57]([CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:62]4)[CH2:66][S:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:76]([S:85]([C:88]([F:89])([F:90])[F:91])(=[O:86])=[O:87])[CH:77]=3)(=[O:83])=[O:82])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)[Si](OC[C@H]1CN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CCO1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCO[C@@H](CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Yield: 63.8 %

Procedure:
The title product (77 mg, 66%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 33. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 51.7 mg, 0.10 mmol) and 4-((R)-4-((R)-2-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethyl sulfonyl)benzenesulfonamide (INTERMEDIATE 98, 72 mg, 0.09 mmol) were used as starting materials. The title product was used in the preparation of EXAMPLE 22 without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[C:26]([F:54])=[C:27]([C@@H:31]2[C@:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@H:34]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:33][C@H:32]2[C:51](O)=[O:52])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:13][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:51]([C@@H:32]2[C@@H:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=3[F:54])[C@@:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@@H:34]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:33]2)=[O:52])=[CH:7][CH:6]=1)([C:9](=[O:10])[NH:11][CH3:12])[CH3:14]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CNC(=O)C(C)(C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)C(C)(C)c1ccc(NC(=O)[C@H]2N[C@H](CC(C)(C)C)[C@@](C#N)(c3ccc(Cl)cc3F)[C@@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
Reagent 2-(4-amino-phenyl)-N-methyl-isobutyramide (130 mg, 0.676 mmol) was dissolved in dichloromethane (4 mL) then iPr2NEt (0.375 mL, 2.15 mmol) was added and stirred at 25° C. In three portions chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.214 mmol) and 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 106 mg, 0.278 mmol) was added in 30 min intervals. The reaction mixture was stirred at 25° C. for 5 hours, complete by LCMS. The mixture was then diluted with CH2Cl2 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (30-95% acetonitrile/water) to afford chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1-methyl-1-methylcarbamoyl-ethyl)-phenyl]-amide as an off-white solid (56 mg, 40.8%) HRMS (ES+) m/z Calcd for C34H36Cl2F2N4O2+H [(M+H)+]: 641.2256. found: 641.2256.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[Br:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O.C1C=CC=CC=1.C(O)CCC>[Br:7][CH2:8][C:9]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[O:5][CH:2]([CH2:3][OH:4])[CH2:1][O:6]1
Reactant: OCC(O)CO
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCO
Product: COc1ccc(C2(CBr)OCC(CO)O2)cc1

Procedure:
A mixture of 69 parts of 1,2,3-propanetriol, 142 parts of 2-bromo-1-(4-methoxyphenyl)-ethanone, 6.3 parts of 4-methylbenzenesulfonic acid, 80 parts of 1-butanol and 450 parts of benzene was stirred and refluxed for 20 hours with water separator. The reaction mixture was cooled and poured into a diluted sodium hydroxide solution. The layers were separated and the aqueous phase was extracted twice with methylbenzene. The combined organic phases were washed with water, dried, filtered and evaporated, yielding 186.5 parts of 2-(bromomethyl)-2-(4-methoxyphenyl)-1,3-dioxolane-4-methanol as a residue (interm. 1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][C:17](Br)=[CH:16][C:15]=1[CH2:23][CH3:24])([CH3:10])([CH3:9])[CH3:8].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O.CC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][C:17]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[CH:16][C:15]=1[CH2:23][CH3:24])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCc1cc(Br)cc(CC)c1NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CC(C)=O
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of cesium carbonate (89.12 g, 0.27 mol) in water (600 ml) is added to a degassed solution of (4-bromo-2,6-diethylphenyl)carbamic acid tert-butyl ester (30 g, 0.091 mol) and 4-chlorophenylboronic acid (21.54 g, 0.138 mol) in acetone (3 L), and the mixture is stirred at room temperature under an atmosphere of nitrogen. Palladium acetate (1.02 g, 0.004 mol) and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (4.33 g, 0.009 mol) are added and the reaction mixture is stirred at room temperature for 12 hours. The mixture is filtered through diatomaceous earth, and the filtrate is evaporated under reduced pressure to remove most of the acetone. The remaining solution is extracted with ethyl acetate (3×300 ml). The organic extracts are combined and concentrated under reduced pressure to give (4′-chloro-3,5-diethylbiphen-4-yl)carbamic acid tert-butyl ester (22 g).
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C@@:22]([OH:52])([CH2:46][N:47]1[CH:51]=[N:50][CH:49]=[N:48]1)[C@H:23]([S:25][C@@H:26]1[CH2:31][O:30][C@@H:29]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[C:37]([C:42](OC)=[O:43])[CH:36]=[CH:35]3)[O:28][CH2:27]1)[CH3:24].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([NH:5][C:42]([C:37]2[CH:36]=[CH:35][C:34]3[C:39](=[CH:40][CH:41]=[C:32]([C@H:29]4[O:28][CH2:27][C@H:26]([S:25][C@H:23]([CH3:24])[C@:22]([C:16]5[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=5[F:14])([OH:52])[CH2:46][N:47]5[CH:51]=[N:50][CH:49]=[N:48]5)[CH2:31][O:30]4)[CH:33]=3)[CH:38]=2)=[O:43])=[CH:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)c1ccc2cc([C@H]3OC[C@H](S[C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)CO3)ccc2c1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc3cc(C(=O)Nc4ccc(C#N)cc4)ccc3c2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Trimethylaluminium (0.67 ml, 1.07M n-hexane solution, 0.72 mmol) was added dropwise to a solution of commercially available 4-aminobenzonitrile (85 mg, 0.72 mmol) in anhydrous toluene (4 ml) at room temperature with stirring under a nitrogen atmosphere. After stirring the mixture at room temperature for 10 minutes, a solution of methyl 6-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthalenecarboxylate (100 mg, 0.18 mmol) in anhydrous toluene (3 ml) was added dropwise to the resulting mixture. This mixture was stirred at 80C for 2.5 hours. At the end of this time to the reaction mixture were added sequentially water and 0.5N aqueous potassium sodium (+)-tartrate solution at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel column using ethyl acetate-hexane (3:1) as the eluant to afford the title compound (99 mg, yield 85%) as a colorless oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20].O>O1CCCC1>[F:11][C:8]([F:9])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:19](=[O:20])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1C(F)(F)F)Oc1ccccc1
Reaction time: 4.5 h

Procedure:
2-Aminobenzotrifluoride (5 mL) and pyridine (6.44 mL) were dissolved in tetrahydrofuran (100 mL), and phenyl chloroformate (5.5 mL) was added dropwise under ice-cooling. After dropwise addition of the reagent, the mixture was brought back to room temperature and stirred for 4.5 hours. Water was added to the reaction solution and the mixture was concentrated under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was washed with 2 N hydrochloric acid and brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (12.1 g). The property values of the compound are as follows.
Reaction SMILES: C1(=O)NC(=[O:6])C2=CC=CC=C12.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[S:21][CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH2:30]>>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[S:21]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH2:30])=[O:6]
Reactant: Nc1ccc(F)cc1CSc1nc2ccccc2[nH]1
Reactant: O=C1NC(=O)c2ccccc21
Product: Nc1ccc(F)cc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
A solution of 9.0 g (58 mMol) of 3-fluoro-6-nitrotoluene in 200 ml of ethyl acetate was hydrogenated at room temperature with 60 psi of hydrogen gas using 0.9 g of 5% palladium on charcoal as catalyst. The solution was filtered and concentrated to give 6.7 g of 4-fluoro-2-methylaniline as an oil. A mixture of 1.33 g of the oil and 1.57 of phthalic anhydride was heated at 160° C. for 30 minutes and cooled. The resultant solid was washed with methanol and air dried to give 1.96 of the phthalimide derivative of 4-fluoro-2-methylaniline, m.p. 189.5-190.5° C. [Anal. Calc'd. for C15H10NFO2 : C,70.58; H, 3.95; N, 5.49; S, 7.44. Found: C, 70.68; H,3.95; N, 5.42; F, 7.39.] Bromination of the methyl group was effected by heating at reflux under an incandescent light source a mixture of 567 mg (2.22 mMol) of the phthalimide derivative, 435 mg of N-bromosuccinimide, and 59 mg of benzoyl peroxide in 25 ml of carbon tetrachloride. After one hour the mixture was cooled to room temperature, filtered, and concentrated in vacuo to give 720 mg of the crude bromomethyl phthalimide derivative. Using the general method of Example 1 with 284 mg of this bromomethyl phthalimide derivative instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol produced the phthalimide derivative of 2-[(1H-benzimidazol-2-yl)thiomethyl]-4-fluorobenzenamine. The residue from the dichloromethane extraction (as in Example 1) was washed with diethyl ether and purified by column chromatography, giving 190 mg of the phthalimide derivative as a white solid. Using the method of Example 3 with 104 mg (0.248 mmol) of this phthalimide derivative of 2-[(1H-benzimidazol-2-yl)thiomethyl]-4-fluorobenzenamine instead of the title product of Example 2 produced the corresponding sulfoxide. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo to give 119 mg of the sulfoxide as an oil. The sulfoxide was stirred in a solution of 0.14 ml of hydrazine hydrate in 5 ml of ethanol for two hours to remove the phthalimide group. The mixture was concentrated in vacuo to a solid, which was washed sequentially with 3% aqueous ammonium hydroxide and water, and air-dried to give 50 mg of the title compound: m.p. 184-185° C. Anal. Calc'd. for C14H12N3F0S: C, 58.12; H, 4.18; N, 14.52; F, 6.57. Found: C, 58.11; H, 4.21; N, 14.54; F, 6.34.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH:22][C:39](=[O:40])[CH2:38][NH:37][C:35]([O:34][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:36])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NNC(=O)CNC(=O)OCc1ccccc1)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A solution of 2.15 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide and 1.86 g of N-(benzyloxycarbonyl)-glycine in 8 ml of dimethylformamide was cooled to 0° C. and treated with 2.0 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred overnight at room temperature, diluted with diethyl ether and washed sequentially with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate, water, and saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulphate and evaporated to give 2.96 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-2′-[N-(benzyloxycarbonyl)-glycinyl]-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:19][C:20]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[C:37]([F:40])([F:39])[F:38])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>>[NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([NH:10][C@@:11]1([C:16](=[O:18])[NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[C:37]([F:38])([F:39])[F:40])=[CH:27][C:20]=2[F:19])[CH2:15][CH2:14][O:13][CH2:12]1)=[O:9]
Reactant: COc1ccc(Nc2ccc(CN)c(F)c2)c(C(F)(F)F)c1
Reactant: Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Product: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cncc(N)c4)CCOC3)c(F)c2)c(C(F)(F)F)c1
Yield: 27 %

Procedure:
Analogously to Example 1e), (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (0.55 mmol) was reacted with 2-fluoro-4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzylamine (0.55 mMol, from 1b). The product was obtained in a yield of 27% of theory.
Reaction SMILES: C([Li])CCC.N1CCOCC1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1.C([Li])(CC)C.[CH3:24][C:25](=[O:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl>CCCCCC.O1CCCC1.C1CCCCC1>[OH:35][C:25]([C:16]1[O:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=1)([CH3:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCC(C)=O
Reactant: O=Cc1ccoc1
Agent: Cl
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)(O)c1cc(C=O)co1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (a 2.5M solution in hexane; 4.37 ml, 10.9 mmol) was added to a solution of morpholine (0.91 ml, 10.4 mmol) in tetrahydrofuran (40 ml) at -78° under argon. After 20 min., 3-furaldehyde (0.9 ml, 10.4 mmol) was added. After another 20 min., sec-butyl lithium (a 1.3M solution in cyclohexane; 8.4 ml, 10.9 mmol) was added dropwise and stirring continued at -78° for 7 hours before 2-undecanone (2.36 ml, 11.4 mmol) was added. Stirring was continued overnight (17 hours) while the cooling bath was allowed to attain room temperature. The solution was poured into ice cold 10% (v/v) hydrochloric acid (30 ml) and after stirring at 0° for 10 min., the layers were separated. The aqueous phase was extracted with diethyl ether. All the organic phases were combined, dried (magnesium sulfate) and evaporated down to give an oil, which was purified by flash chromatography on silica. Fractions with Rf of about 0.07 on evaporation gave the title compound as a yellow oil.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:13]C1(C)C)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH2:11][C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@@H:14]([OH:13])[CH:20]=[C:21]([CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CCOC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(=C[C@H](O)[C@@H](N)CC(C)C)CCOC1CCCCO1
Yield: 105.5 %

Procedure:
110 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoate was dissolved in 1.0 ml of ethanol, and hydrogenated by using 12 mg of 10% palladium carbon as catalyst at room temperature under atmospheric pressure. The catalyst was filtered off, and the solvent was distilled off under reduced pressure to obtain 77 mg of ethyl (4S,5S)-5-amino-4-hydroxy-2-[2-(2-tetrahydropyranyloxy)ethyl]-7-methyl-2-octenoate as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14]Br.[SH:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][S:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCBr
Reactant: O=C(O)Cc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1oc(-c2ccccc2)nc1CCSc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(5-methyl-2-phenyloxazol-4-yl)ethylbromide (136 mg) and 3-mercaptophenylacetic acid.methyl ester (78 mg) were dissolved in acetonitrile (5 ml) and thereto was added potassium carbonate and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and the mixture was extracted with ether. The extract was washed with an aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (chloroform:ethyl acetate=200:1→50:1) to give the compound of the present invention (92 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[CH:7]1([C:10]2[CH:11]=[C:12]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=3)[CH:13]=[CH:14][C:15]=2[N:16]2[C:25]3[C:20](=[CH:21][C:22]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:30])[CH2:9][CH2:8]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[CH:7]1([C:10]2[CH:11]=[C:12]([C:31]3[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=3)[CH:13]=[CH:14][C:15]=2[N:16]2[C:25]3[C:20](=[CH:21][C:22]([S:26]([NH:1][C:2]4[CH:6]=[CH:5][O:4][N:3]=4)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:30])[CH2:9][CH2:8]1
Reactant: O=c1ccc2cc(S(=O)(=O)Cl)ccc2n1-c1ccc(-c2cc(F)cc(F)c2)cc1C1CC1
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1ccc(-c2cc(F)cc(F)c2)cc1C1CC1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 3-aminoisoxazole (0.070 ml, 0.954 mmol) and 1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (0.150 g, 0.318 mmol) in 3 mL THF was cooled to 0° C. and was treated with LiHMDS 1N in THF (0.636 ml, 0.636 mmol). The cooling bath was removed and the reaction mixture was allowed to stir for one hour. TFA (0.122 ml, 1.589 mmol) was then added, and the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.06, 0.115 mmol, 36.3% yield). m/z (ESI) 520.1 (M+H)+. The atropisomers were separated using supercritical fluid chromatography (SFC). The column used was Chiralpak OJ-H. The mobile phase was run under isocratic conditions; CO2 with 25% Methanol to afford product as an off-white solid. First atropisomer (peak 1): (M)-1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.015 g, 0.029 mmol, 9.08% yield). NMR (ACETONITRILE-d3) □: 8.22 (d, J=2.1 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.80 (dd, J=8.9, 2.1 Hz, 1H), 7.65 (dd, J=8.2, 2.2 Hz, 1H), 7.35-7.42 (m, 3H), 7.30 (d, J=8.2 Hz, 1H), 6.95-7.04 (m, 1H), 6.76 (d, J=9.6 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 6.30 (d, J=1.8 Hz, 1H), 1.42-1.53 (m, 1H), 0.69-0.88 (m, 2H), 0.51-0.65 (m, 2H). m/z (ESI) 472.0 (M+H)+. Second atropisomer (peak 2): (P)-1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.016 g, 0.031 mmol, 9.69% yield). NMR (ACETONITRILE-d3) □: 8.22 (d, J=2.1 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.80 (dd, J=8.9, 2.1 Hz, 1H), 7.65 (dd, J=8.2, 2.2 Hz, 1H), 7.35-7.42 (m, 3H), 7.30 (d, J=8.2 Hz, 1H), 6.95-7.04 (m, 1H), 6.76 (d, J=9.6 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 6.30 (d, J=1.8 Hz, 1H), 1.42-1.53 (m, 1H), 0.69-0.88 (m, 2H), 0.51-0.65 (m, 2H). m/z (ESI) 520.2 (M+H)+.