Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C([O-])=O.[K+]>CC#N.[Ir].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:14]([OH:19])[C:15]([F:17])([F:18])[F:16])=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: O=C(c1ccc(Br)cc1-c1ccccc1)C(F)(F)F
Agent: [Ir]
Agent: O=C[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O[C@H](c1ccc(Br)cc1-c1ccccc1)C(F)(F)F
Temperature: 40 °C
Reaction time: 12 h

Procedure:
1-(5-Bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone (1.3 g, 3.9 mmol) in CH3CN (10 mL) was reduced to the chiral alcohol using the chiral iridium catalyst (METHOD A) at RT. The reaction mixture was then charged with potassium formate (725 mg, 8.6 mmol) and the mixture was stirred at 40° C. for 12 h. Then the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by normal phase silica gel column (EtOAc:PE=1:10) to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:27](S(C3C=CC=CC=3)(=O)=O)[C:13]3=[N:14][CH:15]=[CH:16][C:17](B4OC(C)(C)C(C)(C)O4)=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1.Br[C:39]1[C:40]([C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[N:41][N:42]([CH:44]([CH3:46])[CH3:45])[CH:43]=1>>[CH3:1][N:2]([CH3:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:27][C:13]3=[N:14][CH:15]=[CH:16][C:17]([C:39]4[C:40]([C:47]5[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=5)=[N:41][N:42]([CH:44]([CH3:46])[CH3:45])[CH:43]=4)=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CN(C)Cc1ccc(-c2cc3c(B4OC(C)(C)C(C)(C)O4)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)n1cc(Br)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CC(C)n1cc(-c2ccnc3[nH]c(-c4ccc(CN(C)C)cc4)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described in Intermediate 100 and Intermediate 21 using N,N-dimethyl-1-{4-[1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanamine and 4-bromo-1-(1-methylethyl)-3-(4-nitrophenyl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 481.4
Reaction SMILES: C(OC([NH:8][C@H:9]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][F:29])=[CH:22][N:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[F:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:30]([OH:32])=[O:31])[NH2:8])=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](C[C@H](Cc1ccc(CCCF)cn1)C(=O)O)C(=O)O
Reaction time: 24 h

Procedure:
Di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(3-fluoropropyl)pyridin-2-yl]methyl}-L-glutamate (68 mg, 0.13 mmol) was solved in 3 ml trifluoroacetic acid and stirred for 24 h. To the mixture was added toluene (10 ml) and the resulting solution was concentrated in vacuo. The crude product was purified by HPLC. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]([O:27][C:28]([NH:30][C@H:31]([C:39](O)=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:39](=[O:40])[C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added N-t-butyloxycarbonyl-L-phenylalanine (382 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (315 mg, 39%).
Reaction SMILES: [F:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:20].O1CCOCC1>O1CCOCC1>[ClH:20].[F:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(F)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g, 3.89 mmol) in 1,4-dioxane (10 mL) was added HCl-dioxane (4.0 M, 15 mL) solution and the mixture stirred at rt for 30 min. After completion of reaction (By TLC), solvent was evaporated to obtain brownish solid material (0.78 g) that was carried forward to the next step without purification. MS: 176.20 [M+H]+.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[C:19]([F:33])=[C:20]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>O1CCOCC1>[F:33][C:19]1[C:18]([N:17]=[C:1]=[S:2])=[C:31]([F:32])[CH:30]=[CH:29][C:20]=1[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(N)c1F
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(N=C=S)c1F

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (546 mg, 2.35 mmol) was added to a mixture of N-(3-amino-2,4-difluoro-benzyl)-2,2-dimethyl-propionamide (570 mg, 2.35 mmol) and dioxane (20 mL) and stirred at reflux overnight. The mixture was concentrated, diluted with DCM and filtered over silica gel. The filtrate was concentrated to give the sub-title compound.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(C(C)=O)cc1

Procedure:
The reaction between anisole and acetic anhydride was performed in substantially the same manner as in Example 49, except that each of the compounds as synthesized in Examples 42 and 43 was individually used as the Lewis acid catalyst. The yields of the reaction product (i.e., p-methoxyacetophenone) are shown in Table 2.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[N:22]=[C:23](Cl)[C:24]2[S:29][CH:28]=[CH:27][C:25]=2[N:26]=1.[Cl:31][C:32]1[S:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])(O)=O.[Na+]>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:20][C:21]1[N:22]=[C:23]([C:35]2[S:36][C:32]([Cl:31])=[CH:33][CH:34]=2)[C:24]2[S:29][CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(-c2ccc(Cl)s2)c2sccc2n1
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
A solution of Pd(OAc)2 (12 mg, 5 mol %) and PPh3 (52 mg, 20 mol %) in THF (2 mL) was stirred for 5 min, treated dropwise with a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in THF (1 mL), stirred for 5 min, treated with 5-chlorothiophene-2-boronic acid (244 mg, 1.5 mmol) then saturated aqueous NaHCO3 (1 mL) refluxed for 4 h, cooled, diluted with H2O and filtered to give the title compound (268 mg, 94%) as a grey solid; NMR δH (400 MHz, CDCl3) 7.10 (1H, d, J 4.0 Hz), 7.55 (1H, d, J 5.5 Hz), 7.85 (1H, d, J 4.5 Hz) and 8.08 (1H, d, J 5.5 Hz)
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])=[O:17].[F-].[Cs+].O1CCOCC1>[Pd].O>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1nc(Br)ns1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc(S(C)(=O)=O)cc2)ns1
Temperature: 80 °C

Procedure:
To a mixture of tert-butyl 3-bromo-1,2,4-thiadiazol-5-ylcarbamate (1.90 g, 6.78 mmol), 4-(methylsulfonyl)phenylboronic acid (2.07 g, 10.3 mmol), cesium fluoride (2.09 g, 13.8 mmol), and the palladium catalyst (0.271 g, 0.383 mmol) was added dioxane (20 mL) and water (2 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 min and the reaction mixture was heated to 80° C. for 3 h. The reaction mixture was diluted with EtOAc, and the organic phase was washed with saturated NH4Cl (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 10% to 50% EtOAc in hexanes) gave tert-butyl 3-(4-(methylsulfonyl)phenyl)-1,2,4-thiadiazol-5-ylcarbamate.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2CN(C)[CH2:10][N:9](C)[C:8]2=[N:15][N+:16]([O-:18])=[O:17])[CH2:2]1.Cl>C(O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([NH:9][CH3:10])=[N:15][N+:16]([O-:18])=[O:17])[CH2:2]1
Reactant: CN1CN(C)C(=N[N+](=O)[O-])N(CC2CCOC2)C1
Agent: Cl
Solvent: CCO
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Temperature: 40 °C
Yield: 72.7 %

Procedure:
A mixture comprising 0.7 g of 1-{(tetrahydro-3-furanyl)methyl}-2-(nitroimino)-3,5-dimethylhexahydro-1,3,5-triazine, 5 ml of 1N hydrochloric acid and 5 ml of ethanol was stirred at 40° C. for an hour. The reaction fluid was concentrated under a reduced pressure and purified by column chromatography to obtain 0.4 g of 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[C:29]([Br:31])[CH:30]=1)[C:18](OCC1C=CC=CC=1)=[O:19].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:18][OH:19])[CH:28]=[C:29]([Br:31])[CH:30]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Reaction time: 4 h

Procedure:
To a solution of benzyl 3-((8-(1,3-dioxolan-2-yl)octyl)oxy)-5-bromobenzoate in tetrahydrofuran (30 mL) at −78° C., was added a solution of lithium aluminium hydride in THF (2.0 M, 3.3 mL, 6.60 mmol). The reaction mixture was stirred for 4 hours, then quenched with water (0.25 mL), 2 M sodium hydroxide (0.25 mL) and water (0.75 mL). The coolant was removed and ethyl acetate and magnesium sulphate was added, and the mixture stirred at room temperature for 20 minutes. The suspension was filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-17% ethyl acetate in iso-hexane to afford the title compound as a 10:7 ratio of product to starting material (1.69 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]([CH3:13])[CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16](=O)[CH2:17][C:18](OCC)=[O:19]>>[O:19]=[C:18]1[NH:1][C:2]2=[N:11][C:10]3[N:9]([CH3:12])[CH2:8][CH2:7][CH:6]([CH3:13])[C:5]=3[CH:4]=[C:3]2[C:16]([C:15]([F:25])([F:24])[F:14])=[CH:17]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC1CCN(C)c2nc(N)ccc21
Product: CC1CCN(C)c2nc3[nH]c(=O)cc(C(F)(F)F)c3cc21

Procedure:
This is a representative procedure for making azaquinolones. 7-Amino-1,4-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine (0.9 g.) and 1.0 g. of ethyl trifluoroacetoacetate were heated at 145°-165° for 18 hours. The cooled, semisolid mass was slurried with 5 ml. of ether, filtered and washed with more ether, 1.3 g., m.p. 225°-230°, wet 200°. Other data are found in the table. 1H nmr (deuteriochloroform, 100 MHz): δ1.30 (d,3H, CH3CH, J=7 Hz), 1.74 (m, 1H, H7a or H7b), 1.89 (m, H, H7a or H7b), 2.92 (m, 1H, H6), 3.20 (s, 3H, NCH3), 3.49 (t, 2H, H8, H8, J=6 Hz), 6.62 (s, 1H, H3), 7.46 (q, 1H, H5, JH5 --CF3 =~1.5 Hz), 9.40 (broad s, 1H,NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=1.[OH-].[Na+].O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(OCC)(=O)C.CO.C(OCC)(=O)C.ClCCl>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:47][CH2:48][CH2:49][O:50][C:51]4[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=4)[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCCOc4ccc(F)cc4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Temperature: 35 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine (0.48 g, 0.78 mmol), 1-chloro-3-(4-fluorophenoxy)propane (0.15 g, 0.78 mmol), triethylbenzyl ammonium chloride (0.01 g), sodium hydroxide (2.0 g), water (2 mL), and dichloromethane (4 mL). Heat to about 35° C. After 18 hours, add ethyl acetate (100 mL) and separate the layers. Extract the organic layer with aqueous saturated sodium bicarbonate and brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3/1 ethyl acetate/methanol to give the title compound. Rf=0.20 (silica gel, 3/1 ethyl acetate/methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:34])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:35]([C:38]1[CH:39]=[CH:40][C:41](Br)=[N:42][CH:43]=1)(=[O:37])[CH3:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:34])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][N:31]([C:41]4[CH:40]=[CH:39][C:38]([C:35](=[O:37])[CH3:36])=[CH:43][N:42]=4)[CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)=O)cn3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
After removal of the Boc-protecting group under acidic conditions, in analogy to the procedure described for the synthesis of {(3R,4S)-4-(4-Chloro-phenyl)-1-[1-(5-cyano-pyrimidin-2-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester (example 7, g) the title compound was prepared from [(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and 5-acetyl-2-bromopyridine as off-white foam. MS m/e: 627.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5].Br[CH2:13][CH2:14][O:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[C:9]([O:10][CH2:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5]
Reactant: COCCBr
Reactant: N#Cc1c(I)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc(I)c(C#N)c1F
Temperature: 25 °C

Procedure:
A mixture of Example 68A (104 mg, 0.39 mmol), 1-bromo-2-methoxyethane (0.088 mL) and K2CO3 (163 mg) in acetone (3 mL) was heated to 60° C. for 18 hours, cooled to room temperature, and partitioned between diethyl ether and water. The extract was dried (MgSO4), filtered, and concentrated to provide 122 mg of the desired product. MS (ESI(+)) m/e 334 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:69]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:69])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(Cl)cc2)cc1)NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-chlorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (35.4 mg, 0.067 mmol)) in DMF (3 ml) was added N-methylmorpholine (35 μl, 0.23 mmol). TBTU (29.3 mg, 0.091 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-cyclohexyl-D-alanine (18.4 mg, 0.081 mmol) was added and the mixture was stirred at ambient temperature for 60 hours. The formation of the ketone of the title compound was confirmed. M/z: 736.67 (M+1) and 734.71 (M−1). Without further purification, methanol (2 ml) and sodium borohydride (28.0 mg, 0.740 mmol) was added and the mixture was stirred for 20 minutes. Ammonium acetate (38.4 mg) was added and the solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45 MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was passed through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained 1H-NMR (400 MHz, DMSO-d6): 0.70-1.68 (m, 13H), 2.78-2.88 (m, 2H), 3.75 (d, 2H), 4.13-4.21 (m, 1H), 4.23-4.28 (m, 1H), 4.49 (s, 2H), 4.56-4.64 (m, 1H), 5.02 (d, 0.5H), 5.04 (d, 0.5H), 5.56 (b, 1H), 6.70-6.79 (m, 2H), 6.82 (s, 1H), 6.96 (d, 2H), 7.18 (d, 2H), 7.30-7.37 (m, 4H), 8.04 (b, 1H), 8.20 (t, 1H). M/z: 736.69 (M−1).
Reaction SMILES: N[C:2]1C(C)=CC(C#N)=C[C:3]=1CC.Cl[C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:29])[C:23]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:17]([NH:19][OH:20])=[NH:18]>>[CH2:2]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:29])[C:23]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:17]([NH:19][OH:20])=[NH:18])[CH3:3]
Reactant: CCc1cc(C#N)cc(C)c1N
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1NS(C)(=O)=O
Product: CCc1cc(C(=N)NO)cc(C)c1NS(C)(=O)=O

Procedure:
The title compound is then prepared from the above 4-amino-3-ethyl-5-methyl-benzonitrile in analogy to 3-chloro-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine; LC-MS**: tR=0.26 min, [M+1]+=272.32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1.[I:19]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([I:19])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Agent: O=S(=O)(O)O
Product: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 1.0 gram (0.0036 mole—1.0 equiv.) of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole in 10 mL of concentrated sulfuric acid (% wt/vol. triazole to solvent—10%) was added in small portions 0.972 gram (0.0043 mole—1.2 equiv.) of N-iodosuccinimide. Upon completion of the addition the reaction mixture was stirred at ambient temperature and in absence of light for 30 minutes. After this time thin layer chromatographic (TLC) analysis of the reaction mixture indicated that the reaction was almost complete. The reaction mixture was then quenched with 50 mL of water, and the resulting mixture was extracted with two 25 mL portions of ethyl acetate. The extracts were combined and washed with one 15 mL portion of an aqueous 10% sodium bisulfite solution followed by one 15 mL portion of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.2 grams of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (83.2% yield). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+]([O-])=O)[CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:15]1([S:21][C:4]2[CH:3]=[C:2]([S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Sc2ccccc2)cc1Sc1ccccc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 9.2 %

Procedure:
A mixture of methyl 4-chloro-2-nitrobenzoate (25 g), thiophenol (20.4 g) and potassium carbonate (17.6 g) in N,N-dimethylformamide was stirred at 120° C. for five hours. Water was added and the mixture extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate, filtered and evaporated. The product was recrystallised from cyclohexane to give 3.0 g of methyl 2,4-bis(phenylsulphenyl)benzoate as a beige solid, m.p. 123.9° C.