Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[C:22]([N:31]2[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]2)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:37][CH:34]2[CH2:33][CH2:32][N:31]([C:22]3[C:21]([Cl:20])=[CH:26][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:24][N:23]=3)[CH2:36][CH2:35]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 78.4 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (200 mg, 0.667 mmol) was dissolved in dry DMF (2 mL) under nitrogen atmosphere. 1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (188 mg, 0.674 mmol) was added followed by TEA (68 mg, 0.667 mmol) and the reaction mixture was heated in a microwave reactor at 120° C. for 20 mins. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (284 mg, 77.6%). 1H NMR (500 MHz, CDCl3): δ 1.46-1.54 (m, 2H), 1.73-1.79 (m, 1H), 2.51 (t, 2H), 3.12-3.19 (m, 1H), 3.79-3.82 (m, 2H), 5.28 (d, 1H), 7.44-7.46 (m, 3H), 7.53-7.55 (m, 2H), 7.72 (s, 1H), 8.33 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 27.82, 32.36, 47.43, 50.27, 61.80, 107.32, 120.35 (q, J=33.4 Hz), 121.28, 123.48 (q, J=271.3 Hz), 125.36, 128.94, 130.17, 131.85, 134.16, 136.15, 143.10, 159.87, 160.06; Mass Spectrum: M+H+ 543.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][C:4](=[O:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18].[N+:20]([O-])([OH:22])=[O:21]>C(OC(=O)C)(=O)C.C(O)(=O)C>[OH:1][C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:20]([O-:22])=[O:21])[CH:9]=2)[CH2:6][CH2:5][C:4](=[O:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)C1=C(O)C(c2ccc(C)cc2)CCC1=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)C1=C(O)C(c2ccc(C)c([N+](=O)[O-])c2)CCC1=O
Temperature: 5 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
3-hydroxy-2-propionyl-4-(4-methylphenyl)cyclohex-2-ene-1-one (1.2 g) in acetic anhydride (3 g) was cooled to 5° C. A solution of fuming nitric acid (0.42 g) in glacial acetic acid (0.3 g) and acetic anhydride (0.3 g) was added dropwise over a period of 5 minutes. After stirring for a further 1 hour at 5° C. and 2 hours at room temperature, the mixture was poured onto ice-water (100 ml). The aqueous solution was extracted with diethyl ether. The extracts were washed with aqueous sodium bicarbonate, dried over magnesium sulphate, filtered and the ether evaporated in vacouo. The residue was purified on a silica gel column using chloroform as eluant to give the title compound (0.5 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCCO1
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-chlorophenyl)piperazine (1.62 g, 8.2 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.06 g, 8.6 mmol). The mixture was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound L, 2.11 g (81%).
Reaction SMILES: [H-].[Na+].[C:3]12([OH:13])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Cl[CH2:15][C:16]([OH:18])=[O:17]>C1COCC1>[C:3]12([O:13][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH2:4]1)[CH2:12]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a stirred, ice-cooled suspension of sodium hydride (60% dispersion in mineral oil, 39.4 g, 985 mmol) in THF (250 mL) was added dropwise a solution of 1-adamantanol (50.0 g, 328 mmol) in THF (250 mL) over a period of 30 minutes. The resultant suspension was allowed to warm to ambient temperature and stirred at this temperature for 10 minutes. The suspension was re-cooled in ice/water and a solution of chloroacetic acid (46.5 g, 492 mmol) in THF (250 mL) was added slowly over 30 minutes (CARE VERY EXOTHERMIC). The coolant was removed and the suspension was stirred at ambient temperature for 30 minutes and then heated at reflux for 18 hours. The suspension was allowed to cool and carefully quenched with water (750 mL). The mixture was washed with diethyl ether (2×500 mL) and the combined organic phases were discarded. The pH of the aqueous phase was adjusted to 1 with concentrated HCl. The resultant suspension was filtered and the filter-cake washed with water (500 mL). The solid residue was dissolved in chloroform (750 mL) and then washed with saturated brine (750 mL). The organic phase was then dried over magnesium sulfate and the filtrate was evaporated at reduced pressure to give the title compound as a white solid (57.25 g, 83%). 1H NMR (CDCl3) 10.0-9.00 (1H, br s), 4.09 (2H, br s), 2.20 (3H, br s), 1.78-1.77 (6H, m), 1.70-1.58 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].Cl>O1CCCC1.O.C(OCC)(=O)C>[C:10]([C:3]1[CH:4]=[C:5]([Br:9])[C:6]([CH3:8])=[CH:7][C:2]=1[NH:1][C:20](=[O:22])[CH3:21])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(Br)c(C)cc1N
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C)c(Br)cc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a solution of 6.95 g of 1-(2-amino-5-bromo-4-methylphenyl)ethanone and 8.5 mL of triethylamine in 104 mL of tetrahydrofuran was slowly added 3.25 mL of acetyl chloride. After stirring at room temperature for 2 hours, the reaction mixture was poured into a mixture of water/ethyl acetate, followed by stirring for 30 minutes and adjusting to pH 3 with 6 M hydrochloric acid, and the aqueous layer was separated. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 6.33 g of N-(2-acetyl-4-bromo-5-methylphenyl)acetamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[CH:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)[CH2:7][C:8]([O:10]C)=[O:9])=[N:2]1.[Li+].[OH-]>C1COCC1.CO>[O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[CH:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)[CH2:7][C:8]([OH:10])=[O:9])=[N:2]1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1)c1ccon1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc([C@H](CC(=O)O)c2ccon2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 62.9 (64 mg, 0.13 mmol) in 3:1 THF/MeOH (2.8 mL) was added 1N LiOH (0.7 mL). The mixture was stirred for 1 hour at room temperature, quenched with 1N HCl (0.8 mL), and extracted with EtOAc. The combined organics were washed with water and brine, dried (Na2SO4), and concentrated to afford 62 (45 mg, 70%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.65 (d, 2H), 7.60 (d, 2H), 7.20 (d, 2H), 7.15 (s, 1H), 6.95 (d, 2H), 6.07 (d, 1H), 5.10 (s, 2H), 4.55 (t, 1H) 3.35 (dd, 1H), 2.98 (dd, 1H), 2.28 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].C(N(CC)CC)C.[C:22]12([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=3[O:41][CH3:42])[C:35](Cl)=[O:36])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.O>C1COCC1>[C:22]12([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=3[O:41][CH3:42])[C:35]([O:14][C:12]3[CH:11]=[CH:10][C:3]([C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[C:2]([F:1])[CH:13]=3)=[O:36])[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]3)[CH2:31]1)[CH2:29]2
Reactant: C=CCOC(=O)c1ccc(O)cc1F
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1ccc(OC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
To a mixture of 1.96 g (10 mmoles) of allyl 2-fluoro-4-hydroxybenzoate, 1.53 ml (11 mmoles) of triethylamine and 25 ml of THF, there is slowly added a solution of 3 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride in 50 ml of THF. The reaction medium is stirred at ambient temperature for 12 hours and then poured into water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column, eluted by a 50:50 mixture of dichloromethane and hexane. After evaporation of the solvents, 3.63 g (78% yield) of the expected ester having a melting point of 102°-104° C. are obtained.
Reaction SMILES: [N-:1]=[C:2]=[S:3].[C:4]([O:8][CH2:9][CH3:10])(=[O:7])[NH:5][NH2:6]>>[C:4]([NH:5][NH:6][C:2]([NH2:1])=[S:3])([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)NN
Reactant: [N-]=C=S
Product: CCOC(=O)NNC(N)=S

Procedure:
For the synthesis of compounds of formula (I) wherein E=--S--, Reaction Schemes 13 and 14 may be utilized. In Reaction Scheme 13, the isothiocyanate 22 is reacted with ethyl carbazate (8) to give the 1-(carbethoxy)thiosemicarbazide 48. By standard conditions, 48 is S-alkylated to yield 49, which can be cyclized to the triazolinone 50 by heating, optionally in the presence of base or acid [F. Kurzer and D. R. Hanks, Chem. Ind. (London), 1143 (1966)]. Finally, alkylation of the triazolinone as in Reaction Scheme 1 provides the fully substituted product 51. ##STR58##
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[Br:17]Br>O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:17])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncccc1N
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1nc(Br)ccc1N
Temperature: 0 °C
Yield: 50 %

Procedure:
20 g of methyl 3-aminopyridine-2-carboxylate are suspended in 120 ml of water in a flask. After addition of 100 ml of sulfuric acid (2 mol/l), the mixture is cooled to 0° C., 6.73 ml of bromine are added dropwise, and the mixture is stirred at 25° C. until the acid has reacted completely (HPLC check, about 24 hours). A precipitate precipitates out of the reaction solution. This is filtered off, dissolved in EA, washed with sodium thiosulfate solution, the organic phase is dried and purified by means of column chromatography (gradient heptane: EA 5-100% in 30 min.), giving 15 g of methyl 3-amino-6-bromo-pyridine-2-carboxylate as red-brown solid (yield 50%, content 98%); MS-FAB (M+H+)=232.9; Rf (polar method): 1.518 min.
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][CH:4](Cl)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:13])([Cl:14])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6]
Reactant: CCCCOC(=O)C(Cl)CC(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOC(=O)C=CC(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 76 %

Procedure:
6 g of butyl 4,4,4,2-tetrachloro-butanoate (22.4 mmoles) in 20 ml of anhydrous toluene are charged under inert gas into a 250 ml flask and 5 ml of 1,8-diazabicyclo[5.4.0]undecan-7-ene (DBU) are added with exothermy. The mixture is brought to 60° C. for 3 hours. Upon GC control, it is observed that the reaction is complete; the mixture is cooled, water is added, the mixture is extracted with ethyl ether and anhydrified on Na2SO4. The residue obtained after evaporation of the solvent and purification by silica gel chromatography (eluant: hexane/ethyl acetate=9/1) weighs 4 g (76% yield).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:25](O)(=[O:27])[CH3:26]>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[C:25](=[O:27])[CH3:26])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: CC(=O)O
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: CC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was coupled with acetic acid in analogy to experiment A1 to give (2S,4R)-1-acetyl-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 496.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH2:11]Br)[C:4]=1[CH2:13]Br.[SH:15][CH2:16][C:17]([O:19][CH2:20]C)=[O:18].C[O-].[Na+].CC[O-].[Na+]>C(Cl)Cl.CO>[C:17]([CH:16]1[CH2:13][C:4]2[C:5](=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:11][S:15]1)([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)CS
Reactant: COc1ccc(OC)c(CBr)c1CBr
Agent: CC[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1Cc2c(OC)ccc(OC)c2CS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
1,4-dimethoxy-2,3-dibromomethylbenzene (10.0 g, 30.88 mmol) was dissolved in CH2Cl2 and MeOH (750 ml, 6:4) followed by addition of ethyl 2-mercaptoacetate (4.02 ml, 37.06 mmol) with stirring under argon. The mixture was then cooled to 0° C. followed by dropwise addition of sodium methoxide (4.37M, 8.5 ml, 37.06 mmol) over a period of 2 h using an automatic syringe pump. After 5 minutes the solvent was evaporated and the crude was redissolved in THF (400 ml) and cooled to 0° C. again. NaOEt (2.10 g, 30.88 mmol) was then added. The ice bath was removed and the reaction was stirred for 2 more hours. The reaction mixture was then quenched with NH4Cl (sat.) and extracted with ether. The organic phases were combined, dried over MgSO4, filtered and concentrated. The crude residue was then treated with NaOME in MeOH and THF at 0° C. for 2 hours. The reaction mixture was extracted with ether (100 ml×2). The combined organic phases were washed with H2O, dried over MgSO4, filtered and concentrated to a residue that was purified by flash chromatography to give title compound in 45% yield. 1H NMR (300 MHz, CDCl3, ppm) d:2.97 (dd, 1H, J=16.51, 8.79 Hz, HCHaCHC=O), 3.36 (dd, 1H, J=16.7, 5.1 Hz, HCHeCHC=O), 3.73 (m, 2H, HCHa,e--O), 3.75 (s, 3H, OCH3), 3.78 (s, 6H, 2×OCH3), 3.85 (m, 1H, HC--S), 6.69 (m, 2H, ArH).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[N:18]=[C:17]([C:19](=O)[CH3:20])[C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:20][C:19]([C:17]1[C:16]([C:22]([F:23])([F:25])[F:24])=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[N:18]=1)=[N:1]2
Reactant: Nc1nccc(Cl)c1C=O
Reactant: COc1ccc(C(F)(F)F)c(C(C)=O)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)c(-c2ccc3c(Cl)ccnc3n2)n1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (156 mg, 1.0 mmol) and 1-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)-ethanone (219 mg, 1.0 mmol) in anhydrous THF (5 mL) and cool to −40° C. under a N2 atmosphere. Add in portions t-BuOK (168 mg, 1.5 mmol) to the reaction mixture and stir the mixture at −10° C. for 2 hours. Concentrate the reaction mixture by rotary evaporation, collect the solid by filtration and air-dry to afford the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10]([Br:39])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[CH:16]2[OH:38])=[CH:13][CH:14]=1)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=3)([C:20]([F:22])([F:23])[F:21])[CH:16]2[OH:38])=[N:11][C:10]=1[Br:39]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)nc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)nc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A mixture of t-butyl[(6-{3-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl}-2-bromopyridin-3-yl)methyl]carbamate (0.63 g), ethyl acetate (20 ml) and conc. hydrochloric acid (2 ml) was stirred at 60° C. for 1 hour. After cooling, the mixture was neutralized with sodium carbonate, extracted with ethyl acetate and dried. The solvent was distilled off to obtain 1-[5-(aminomethyl)-6-bromopyridin-2-yl]-3-[3,5-bis-(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-2-ol (0.43 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:34])([F:35])([F:36])[F:37])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc(O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
300 mg (1.04 mmol) of the compound of Example 6A, 301 mg (1.14 mmol) of the compound of Example 24A and 473 mg (1.24 mmol) of HATU were initially charged in 3.6 ml of DMF, 0.36 ml (2.07 mmol) of N,N-diisopropylethylamine was added and the mixture was stirred at RT for two days. The reaction was then directly separated into its components by preparative HPLC (Method 18). This gave 180 mg (31% of theory) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]1[N:15]=[C:14]([CH2:16][OH:17])[CH:13]=[CH:12][CH:11]=1)[CH3:8].CCN(CC)CC.O>C(Cl)Cl.CS(C)=O>[CH2:7]([O:9][C:10]1[N:15]=[C:14]([CH:16]=[O:17])[CH:13]=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCOc1cccc(CO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cccc(C=O)n1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
DMSO (0.50 mL, 6.4 mmol) in CH2Cl2 (10 mL) was added dropwise to a solution of oxalyl chloride (2M in CH2Cl2, 3.1 mL, 6.1 mmol) in CH2Cl2 (20 mL) at −60° C. The resulting mixture was stirred at −60° C. for 10 minutes. (6-Ethoxy-pyridin-2-yl)-methanol (0.85 g, 5.6 mmol) in CH2Cl2 (5 mL) and DMSO (4 mL) was added dropwise. The mixture was stirred at −60° C. for 3 h, and was then allowed to warm to −20° C. and Et3N (6 mL) was added. The resulting solution was stirred at ambient temperature for 40 minutes. Water was added and the mixture was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), and concentrated. Diethyl ether was added to the residue and insoluble material was removed by filtration. The filtrate was concentrated to yield the title compound (0.60 g) in 70% yield as a solid. This crude product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@@H:37]([C:42]([OH:44])=[O:43])[CH2:38][CH2:39][CH2:40][NH2:41])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@@H:37]([C:42]([OH:44])=[O:43])[CH2:38][CH2:39][CH2:40][NH2:41])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: NCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Yield: 85.7 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-ornithine (0.021 g, 0.032 mmole) was dissolved in methanol (1.5 mL). NaBH4 (0.0032 g, 0.085 mmole) was added and after about 15 min the reaction was complete according to LC-MS. A few drops of acetic acid was added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 37% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.018 g (85%) of the desired product was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32](S(C)(=O)=O)=[N:31][C:30]=2[CH:38]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[F:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([CH:16]5[CH2:20][CH2:19][CH2:18][CH:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[N:31][C:30]=2[CH:38]=1
Reactant: CS(=O)(=O)c1nc2cc(F)ccc2o1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(Cl)Cl
Product: O=C(O)C1CCCC1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4o3)cc2)cc1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate (100 mg, 0.31 mmol) in dichloroethane (3 mL), 5-fluoro-2-(methylsulfonyl)-1,3-benzoxazole (80 mg, 0.37 mmol) was added and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.93 mL, 0.93 mmol) was added and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.31 mL, 0.31 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2-({4′-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as a white solid (43.7 mg, 31.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2H), 7.90-7.80 (m, 6H), 7.50 (m, 1H), 7.30 (m, 1H), 6.95 (m, 1H), 4.05 (m, 1H), 3.20 (m, 1H), 2.20 (m, 1H), 1.95 (m, 1H), 1.80-1.60 (m, 4H); LC-MS ret. time 3.66 min (method 2), m/z 445.1 (MH+).