Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][N:4]2[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[N:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Mg]Br>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:3]2[N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1][N:2]=2)[OH:11])=[CH:22][CH:21]=1.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:3]1[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]2[CH2:1][N:2]=1)[OH:11]
Reactant: Cc1ccccc1[Mg]Br
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C(C1=NCC2CCCCN12)c1ccccc1
Product: COc1ccc(C(O)(C2=NCC3CCCCN23)c2ccccc2)cc1
Product: Cc1ccccc1C(O)(C1=NCC2CCCCN12)c1ccccc1

Procedure:
In an analogous manner, reaction of the ketone of Example 2 with m-chlorophenylmagnesium bromide and p-chlorophenylmagnesium bromide gives respectively α-(m-chlorophenyl)-α-phenyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridine-3-methanol and α-(p-chlorophenyl)-α-phenyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridine 3-methanol. Similarly, reaction of the ketone of Example 2 with p-methoxyphenylmagnesium bromide and o-methylphenylmagnesium bromide gives respectively α-(p-methoxyphenyl)-α-phenyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridine-3-methanol and α-(o-methylphenyl)-α-phenyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridine-3-methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](O)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.C1C=CC2N(O)N=[N:27]C=2C=1.N.O1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:27])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1
Reactant: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 96.8 %

Procedure:
A 20 mL microwave reaction vessel was charged with 5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxylic acid (0.50 g, 1.40 mmol) EDC (0.81 g, 4.22 mmol), HOBT (0.22 g, 1.40 mmol), and dissolved in DMF (4.65 mL). A 0.5 M solution of ammonia in 1,4 dioxane (5.6 mL, 2.81 mmol) was then added and the reaction was heated in a microwave for 20 minutes, at 100° C. The solution was then dissolved in ethyl acetate and washed with water (3×'s). The aqueous layers were backwashed with ethyl acetate. The organic layers were combined and washed with 6 M sodium hydroxide, brine, dried with magnesium sulfate, and concentrated to give 0.484 g (96%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:19]([C:22]1[O:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[O:23][CH:24]=[C:25]([C:27]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:28])[N:26]=1)(=[O:21])[CH3:20]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1nc(C(=O)O)co1
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)co1
Yield: 11.6 %

Procedure:
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (600 mg, 2.301 mmol) and 2-acetyloxazole-4-carboxylic acid (428 mg, 2.76 mmol). The product was purified by Flash-chromatography. Yield 11.6%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.68 (s, 3H), 4.26-4.33 (m, 1H), 4.40-4.47 (m, 1H), 4.55-4.68 (m, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.67 (d, 1H), 7.72 (d, 1H), 7.88 (dd, 1H), 7.93 (d, 1H), 8.31 (s, 1H).
Reaction SMILES: [N:1]1([CH2:7]C#N)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(OC)(OC)(=O)=O>C(OCC)(=O)C>[C:2](#[N:1])[CH3:3].[CH3:7][NH+:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: CC#N
Product: C[NH+]1CCOCC1
Temperature: 40 °C
Yield: 79 %

Procedure:
To a solution of 30 g of morpholine acetonitrile in 75 ml of ethyl acetate was added 22.5 ml of dimethyl sulfate, corresponding to approximately equivalent molar amounts of the two reagents. The resulting solution was mechanically stirred in an oil bath maintained at 40° C. After 10 minutes of stirring, a semi-solid precipitate having a brownish coloration formed and settled on the bottom of the flask. HPLC (high pressure liquid chromatography) analysis showed at least 4 undesirable side products, which were removed. The remaining solution was again heated to 40° C. and reacted for an additional 16 hours. After this time, the resulting white paste was filtered and washed with ethyl acetate. MMA was isolated after drying this filtrate as a free flowing off-white solid in 79% yield, having a melting point of 99-101° C. The purity of the MMA was determined by HPLC to be greater than 95%.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:40])=[C:26]([CH:39]=1)[C:27]([NH:29][C:30]1[N:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1)=[O:28]>ClCCl.O>[CH:1]1[N:5]2[C:6]3[C:11]([N:12]([C:36]([C:33]4[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[C:26]5[CH:39]=[C:22]([F:21])[CH:23]=[CH:24][C:25]=5[CH3:40])=[N:35][CH:34]=4)=[O:37])[CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: c1ccc2c(c1)NCc1cccn1-2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a chilled (0° C.) solution of 0.341 g of 4,5-dihydropyrrolo[1,2-a]quinoxaline and 1.11 ml of triethylamine in 5 ml of dichloromethane is added 1.17 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. The mixture is stirred under argon at room temperature for 16 hours. The mixture is diluted with 50 ml of dichloromethane and 20 ml of water and the organic layer is separated. The organic layer is washed with 20 ml each of 1M NaHCO3 and brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the residue purified on silica gel prep-plates with ethyl acetate-hexane (1:1) as solvent to give a solid. The solid is crystallized from ethyl acetate to give 0.38 g of crystals, m.p. 190°-196° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[O:17]OC1C=C(C=CC=1)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N+:13]([O-:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)cn1
Reactant: O=C(O)c1cccc(OOCl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-benzyloxy-2-methyl pyridine described in Preparation Example 182 (5.99 g, 30.1 mmol) in methylene chloride (100 mL) was added 3-chloroperoxylbenzoic acid (8.79 g, 33.1 mmol, 65%) at 0° C., and the solution was stirred at room temperature for 2 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was partitioned with methylene chloride. This organic layer was separated, washed with an aqueous solution of saturated sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, and 5-benzyloxy-2-methyl-pyridine-1-oxide (7.71 g) was obtained as a crude product of a white solid. Next, acetic anhydride (77 mL) was added to 5-benzyloxy-2-methyl-pyridin-1-oxide (7.71 g), and the solution was stirred for 80 minutes at 120° C. This reaction mixture was cooled to room temperature, then, the solvent was evaporated in vacuo. Ethanol (50 mL) and an aqueous solution of 5N sodium hydroxide (7 mL) were added to the resulting residue, and the solution was stirred at room temperature for 50 minutes. The solvent was evaporated in vacuo, this residue was partitioned in brine and ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (heptane/ethyl acetate=1/1), and the title compound (4.17 g, 54%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2O.P(Br)(Br)[Br:15].O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:15][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: BrP(Br)Br
Reactant: COc1ccc2nccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nccc(Br)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
6-(Methyloxy)-1,5-naphthyridin-4-ol (21.5 g) (for a synthesis see WO2007016610 Preparation 2 (a)) was stirred in DMF (150 ml) at 0° C. under N2, and phosphorous tribromide (13.5 ml) was added slowly. The mixture was allowed to warm to room temperature and stirred for 90 minutes. H2O (375 ml) was added and the pH was adjusted to pH 7 by addition of solid Na2CO3. The solid was isolated by filtration with suction, dried on the sinter with suction for 2 h then dried under vacuum at 45° C. to give the desired compound (26.0 g, 90%). 1H-NMR (δ, ppm, DMSO-d6): 8.59 (d, 1H), 8.30 (d, 1H), 8.08 (d, 1H), 7.33 (d, 1H), 4.06 (s, 3H).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[H][H]>C(OCC)(=O)C.[Pd]>[S:1]1[C:5]([C@H:6]([OH:25])[CH2:7][CH2:8][C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCC[C@H]1C(=O)C[C@@H](O)[C@@H]1CC[C@@H](O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,3R)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoic acid (Example 7, 1 molar equivalent) is dissolved in ethyl acetate (0.05 M) under a nitrogen atmosphere. 10% Pd/C (10 mol %) is added and hydrogen gas is introduced. After stirring for several hours at room temperature the reaction mixture is filtered over Celite. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes (+0.4% acetic acid) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[CH3:21][C:22]1[N:30]2[C:25]([C:26]([CH3:31])=[CH:27][CH:28]=[CH:29]2)=[C:24]([CH2:32][N+](C)(C)C)[CH:23]=1.[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:32][C:24]2[CH:23]=[C:22]([CH3:21])[N:30]3[C:25]=2[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccn2c(C)cc(C[N+](C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cccc(C)c23)c2ccccc21
Yield: 26 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added (3,8-Dimethyl-indolizin-1-ylmethyl)-trimethyl-ammonium; iodide, CAS: (3,8-Dimethyl-indolizin-1-ylmethyl)-trimethyl-ammonium; iodide (93.4 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(3,8-Dimethyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (20 mg, 26%) as a colorless foam.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.C=O.[CH:28]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([NH:20][CH3:28])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(N2CCC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: O=C[O-]
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CNC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C)C1
Temperature: 0 °C
Yield: 25.3 %

Procedure:
To 1-cyclopropyl-7-(3-amino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.38 g) are added formic acid (3 ml), 37% formalin (3 ml) and sodium formate (0.4 g), and the mixture is refluxed for 5 hours. After cooling, the reaction mixture is poured into ice water and adjusted to below pH 8 with aqueous sodium hydrogen carbonate, and the mixture is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is recrystallized from ethanol-diethyl ether to give 1-cyclopropyl-7-(3-methylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 g), as white powder, m.p. 185.5°-187.5° C. (decomp.)
Reaction SMILES: C1([O:4][S:5](=[O:8])(=[O:7])[NH2:6])CC1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12]>>[F:9][C:10]([F:14])([F:13])[CH2:11][NH:6][S:5](=[O:8])(=[O:7])[O-:4].[F:9][C:10]([F:14])([F:13])[CH2:11][O:12][S:5](=[O:7])(=[O:4])[NH2:6]
Reactant: OCC(F)(F)F
Reactant: NS(=O)(=O)OC1CC1
Product: NS(=O)(=O)OCC(F)(F)F
Product: O=S(=O)([O-])NCC(F)(F)F

Procedure:
2,2,2-Trifluoroethylsulfamate was synthesized according to the method presented in the synthesis of sulfamic acid cyclopropyl ester in Example 1 with the exception of utilizing 2,2,2-trifluoroethylalcohol to obtain sulfamic acid 2,2,2-trifluoro-ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[CH:4][C:3]=1[CH3:14].[I:15]Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([I:15])=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[CH:4][C:3]=1[CH3:14]
Reactant: ClI
Reactant: Cc1cn(-c2ccc(N)c(C)c2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(C)c(N)c(I)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
A mixture of 2-amino-5-(4-methylimidazol-1-yl)toluene (100 mg), iodomono-chloride (104 mg) and acetic acid (1.3 ml) was stirred at room temperature for 2 hours. Solvent was removed under reduced pressure to give a residue. The residue was made to pH 10 with saturated sodium bicarbonate solution, extracted with chloroform. The extract was dried with MgSO4, filtered and removed solvent to give 68 mg (41%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([O:22][CH2:23][CH3:24])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])=[C:4]([F:25])[CH:3]=1.[OH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[OH:26])=[CH:3][C:4]=2[F:25])[O:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)#[N:21]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Br)cc1F
Reactant: OB(O)c1ccccc1O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2O)cc1F

Procedure:
In analogy to example 247.1, (RS)-2-(4-bromo-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide (example 248.1) was reacted with 2-hydroxyphenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-2′-hydroxy-biphenyl-4-yl)-2-ethoxy-acetamide. Off-white solid. MS 423.0 ([M+H]+)
Reaction SMILES: [NH2:1][C:2](N)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].[Br:28][CH2:29][C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>O>[Br:28][CH2:29][C:30]([NH:1][CH:2]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:12])([CH3:13])[S:11][C@H:7]12)=[O:4])=[O:31]
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)(N)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(O)CBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CBr)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred slurry of 4.27 g. (10 mmole) of 6-(2-amino-2amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml. of water, at 0° C., is added 1.39 g. (10 mmole) of bromoacetic acid in 6 ml. of water. The pH is adjusted to 6.0, and then 1.9 g. (10 mmole) of 1-ethyl-3-(dimethylaminopropyl)carbodimide hydrochloride in 9 ml. of water is added. The mixture is stirred for 3 hours at pH 6. At this point, the pH is raised to 7.0, and the reaction mixture is washed with ethyl acetate. The pH is then lowered to 2.0, and the product is extracted into ethyl acetate. The dried extracts are concentrated to dryness in vacuo to give 2.0 g. (40% yield) of the title compound, m.p. 128°-135° C. IR (KBr disc): 1800 cm-1 (β-lactam) and 1653 cm-1 (amide I). NMR (in DMSO-d6 /D2O): 7.43 ppm (s,5H), 5.73 ppm (s,1H), 5.63 ppm (m,2H), 5.23 ppm (s,1H), 4.02 ppm (s,2H), 160 ppm (s,3H), 1.00 ppm (s,3H).
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5]1.OC(C(F)(F)F)=O.[NH2:20][C@@H:21]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[C:22]([N:24]([CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)[CH3:25])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:36]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=[CH:34][C:33]([CH2:32][C@H:21]([NH:20][C:9]([C:4]2([CH2:3][C:2]([Cl:1])=[CH2:12])[CH2:5][CH2:6][CH2:7][CH2:8]2)=[O:11])[C:22]([N:24]([CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])=[O:23])=[CH:38][CH:37]=1
Reactant: CN(Cc1ccco1)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: C=C(Cl)CC1(C(=O)O)CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C(Cl)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)N(C)Cc2ccco2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 1-(2-chloroallyl)cyclopentanecarboxylic acid (80 mg, 0.42 mmol) in CH2Cl2 (3 mL) and DMF (3 mL) with (S)-2-amino-3-(biphenyl-4-yl)-N-(furan-2-ylmethyl)-N-methylpropanamide TFA salt (199 mg, 0.59 mmol) was added TEA (0.41 mL, 2.97 mmol) and HATU (161 mg, 0.42 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was quenched with aq. NaHCO3 and extracted with EtOAc. The organic layer was washed with water (seven times), brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography using 10% EtOAc/heptane to 100% EtOAc/heptane to give (S)—N-(3-(biphenyl-4-yl)-1-((furan-2-ylmethyl)(methyl)amino)-1-oxopropan-2-yl)-1-(2-chloroallyl)cyclopentanecarboxamide (151 mg). HPLC retention time=1.89 minutes (condition B); MS (m+1)=505.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.61-1.80 (m, 12H), 1.96-2.19 (m, 4H), 2.54-2.83 (m, 6H), 2.74 (s, 3H, major rotamer), 2.95 (s, 3H, minor rotamer), 2.01-3.13 (m, 2H), 4.23 (d, J=16.7 Hz, 1H, minor rotamer), 4.28 (d, J=15.2 Hz, 1H, major rotamer), 4.44 (d, J=16.7 Hz, 1H, minor rotamer), 4.77 (d, J=15.2 Hz, 1H, major rotamer), 5.06 (s, 1H, minor rotamer), 5.12 (d, J=1.3 Hz, 1H, major rotamer), 5.15 (d, J=1.3 Hz, 1H, minor rotamer), 5.19 (d, J=1.3 Hz, 1H, major rotamer), 5.17-5.28 (m, 1H, major rotamer), 5.39 (q, J=7.2 Hz, 1H, minor rotamer), 6.17 (d, J=2.8 Hz, 1H, minor rotamer), 6.24 (d, J=3.3 Hz, 1H, major rotamer), 6.30 (dd, J=3.3, 1.8 Hz, 1H, minor rotamer), 6.37 (dd, J=3.2, 1.9 Hz, 1H, major rotamer), 6.57 (d, J=8.1 Hz, 1H, minor rotamer), 6.68 (d, J=7.8 Hz, 1H, major rotamer), 7.21-7.65 (m, 18H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CCN(C(C)C)C(C)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([NH:3][CH:23]1[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]1)[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 111.1 %

Procedure:
Ethylamine (10 mL, 1 M in THF, 10 mmol) and DIEA (2.3 mL, 13.4 mmol) were dissolved in 100 mL of 1,2-dichloroethane under nitrogen. A solution of 1-tert-butoxycarbonyl-4-piperidone (1.3 g, 6.7 mmol) in 100 mL of 1,2-dichloroethane was added, followed by sodium triacetoxyborohydride (4.2 g, 20 mmol). The mixture was stirred at rt under nitrogen for 14 h, then diluted with CH2Cl2. The solution was washed twice with each of 1 N NaOH and brine, dried over Na2So4 and concentrated to afford 1.7 g (97%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Temperature: 25 °C
Yield: 45 %

Procedure:
2-Bromo-4-fluoronitrobenzene (949 mg, 4.31 mmol) was added in two portions to neat N-methypiperazine (8 mL) at 0° C. and allowed to warm to room temperature. The reaction was heated to 60° C. for 1 h, and then it was diluted with 50 mL of EtOAc and poured into H2O (50 mL). The layers were separated and the organic layer was washed with satd aq NaHCO3, dried (Na2SO4), and concentrated in vacuo to afford 580 mg (45%) of the title compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd. for C11H14BrN3O2, 300.0 (M+H). found 300.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:18]1([CH2:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:24]([NH:25][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
Combined 6-chloronicotinoyl chloride (1.76 g, 10.00 mmol) and DCM (20 mL) and cooled in an ice-bath then triethylamine (2.09 mL, 15.0 mmol) and phenylmethanamine (1.072 g, 10.00 mmol) were added. The reaction was then stirred at room temperature for 3 hours before being diluted in DCM (30 ml), washed with 1N aqueous HCl (50 ml), saturated aqueous sodium bicarbonate (50 ml), brine (50 ml), dried over Na2SO4, and concentrated to give the title compound (2.19 g, 89%) as a light beige solid which was used without further purification. MS m/z [M+H]+ 247.1.