Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:34])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=3)[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=2)[N:8]=1)(=O)[CH3:2].[CH3:35][O:36][NH3+:37].[Cl-]>N1C=CC=CC=1>[Cl:32][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH:29]([CH3:30])[CH3:31])[C:21]([NH:20][C@H:16]([CH2:17][CH2:18][OH:19])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([C:1](=[N:37][O:36][CH3:35])[CH3:2])[N:5]([CH3:34])[CH:6]=2)=[CH:10][CH:11]=1)=[O:33]
Reactant: CO[NH3+]
Reactant: CC(=O)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: [Cl-]
Solvent: c1ccncc1
Product: CON=C(C)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
80 mg (0.031 mmol) of (S)-N-(1-(4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide in 2 mL of pyridine was treated with 27.6 mg (0.033 mmol) of hydroxylamine methyl ether hydrochloride. The reaction was stirred overnight after which the solvents were evaporated and the residue purified via reverse phase HPLC (acetonitrile/water). 11.2 mg (70% yield) of 2 was obtained and characterized by LCMS and HNMR.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([O:31]C)=[O:30])[CH:23]=3)[NH:18]2)[CH:13]=[CH:14][C:15]=1[F:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=[O:30])[CH:23]=3)[NH:18]2)[CH:13]=[CH:14][C:15]=1[F:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)c2ccccc2)c1
Yield: 43.8 %

Procedure:
To a round bottom flask, a mixture of methyl 2-(3-benzamido-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (130 mg, 0.30 mmol) in methanol (3 mL) and water (0.6 mL) was treated with a solution of sodium hydroxide (204 mg, 5.1 mmol) in water (0.6 mL). The resultant mixture was heated for reflux for 1 h. The methanol was removed under vacuum. The residue was acidified with 1 M hydrochloric acid to pH=5. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=2:1, 5% methanol) to afford 55 mg (44%) of 2-(3-benzamido-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a colorless solid. MS (ESI+APCI) M+1=419.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[C:3]1=O.C1([SiH2]C2C=CC=CC=2)C=CC=CC=1>C1COCC1.[C-]#[O+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Rh]>[CH3:1][N:2]1[C@H:11]([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)C[C@@H](C)N(C)C2=O
Agent: [Rh]
Agent: [C-]#[O+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C[C@@H](C)N(C)C2
Reaction time: 2 h

Procedure:
60 mg (257 μmol) methyl (R)-2,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylate are dissolved in 2 ml THF under an argon atmosphere and at RT combined with 100 μl (542 μmol) diphenylsilane. Then 20 mg (21 μmol) carbonylhydridotris(triphenylphosphine)rhodium(I) are added and the mixture is stirred for two hours. A further 50 μl diphenylsilane and 10 mg carbonylhydridotris(triphenylphosphine)rhodium(I) are added and the mixture is stirred for a further 2.5 hours. Then the reaction mixture is evaporated down i. vac. and purified by flash chromatography on silica gel (eluant DCM/MeOH 95:5).
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N-]=[N+]=[N-].[Na+].Br[C:19]1[N:24]=[C:23]([C@:25]2([CH3:43])[CH2:30][C@@H:29]([C:31]([F:34])([F:33])[F:32])[O:28][C:27]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:26]2)[C:22]([F:44])=[CH:21][CH:20]=1.C[NH:46][C@@H]1CCCC[C@H]1NC>[Cu]I.O>[NH2:46][C:19]1[N:24]=[C:23]([C@:25]2([CH3:43])[CH2:30][C@@H:29]([C:31]([F:34])([F:33])[F:32])[O:28][C:27]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:26]2)[C:22]([F:44])=[CH:21][CH:20]=1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [N-]=[N+]=[N-]
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 70 °C
Yield: 230.8 %

Procedure:
A sealable vial was charged with (+)-sodium L-ascorbate (0.026 g, 0.13 mmol, Aldrich), sodium azide (0.102 g, 1.56 mmol, Aldrich), copper(I) iodide (0.026 g, 0.13 mmol, Acros), and tert-butyl ((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7i, 0.238 g, 0.52 mmol). The sealed vial was evacuated and backfilled with Nitrogen. EtOH (2.5 mL) was added followed by water (1 mL) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.021 mL, 0.130 mmol, Aldrich). The reaction mixture was heated to 70° C. for 3 hs. The cooled reaction mixture was partitioned between NH4Cl/NH4OH (9:1) (10 mL) and EtOAc (10 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography (gradient 10-50% EtOAc in hexanes) to afford the title compound as a white solid (0.119 g, 0.3 mmol, 58% yield). MS m/z=393.2 [M+H]+. Calculated for C16H20F4N4O3: 392.3
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:17]([O:24][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(CSc2nsc(Cl)n2)cc1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2nsc(OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
Into 2 ml of N,N-dimethylformamide were dissolved 200 mg of 5-chloro-3-(4-methoxybenzyl)thio-1,2,4-thiadiazole and 87 mg of benzyl alcohol, 35 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 165 mg of 5-benzyloxy-3-(4-methoxybenzyl)thio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (33)).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][C:8]#[CH:9])[C:3]1=[O:18].I[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:21]=1.N(CC)CC>C1COCC1.[Cu](I)I>[CH3:1][N:2]1[CH2:6][CH2:5][C@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])([CH2:7][C:8]#[C:9][C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:21]=2)[C:3]1=[O:18]
Reactant: C#CC[C@@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
Copper iodide (22.64 mg, 0.1200 mmol), followed by PdCl2(Ph3P)2 (41.73 mg, 0.060 mmol) was added portionwise to a solution of tert-butyl N-[(3R)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 10) (300 mg, 1.19 mmol), 2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 12) (584.44 mg, 1.61 mmol) and Et2NH (0.62 mL, 5.95 mmol) in THF (10 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. The solvent was evaporated and the residue was purified by Biotage SP4, using a 25 g SNAP cartridge, eluting with 0 to 100% EtOAc/i-hexane affording tert-butyl N-[(3R)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (D13) (482 mg, 0.987 mmol, 83.0% yield) as a pale yellow foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([O:16][CH:17]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=3[Cl:27])[CH3:18])[C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Cl[CH2:29][P:30](=[O:33])([CH3:32])[CH3:31]>>[CH3:29][P:30]([CH2:32][N:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([O:16][CH:17]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=3[Cl:27])[CH3:18])[C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:7][CH:8]=1)[CH2:29][P:30]([CH3:32])([CH3:31])=[O:33])([CH3:31])=[O:33]
Reactant: CC(Oc1cc(-c2ccc(CN)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CP(C)(=O)CCl
Product: CC(Oc1cc(-c2ccc(CN(CP(C)(C)=O)CP(C)(C)=O)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
the title compound (di-alkylation product) was prepared from 5-[4-(aminomethyl)phenyl]-3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridin-2-amine and chloromethyl-dimethyl-phosphine oxide following the same procedure as Example 2. ESMS: m/z 584 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]([OH:25])[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])[CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]([O:25][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(C(O)CC2CCCN2C)c1
Reactant: CCCCCC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OC(CC1CCCN1C)c1cccc(OC)c1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A solution of 0.7 g of hexanoyl chloride in 10 ml of methylene chloride is added drop by drop to a mixture of 1.17 g of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol and 0.5 g of triethyl amine in 20 ml methylene chloride. The mixture is stirred for 2 hours and subsequently treated with water. The organic phase is separated, dried over sodium sulphate and concentrated. There are obtained 1.5 g of the title compound as tough, light oil.
Reaction SMILES: [CH2:1]([C:3]([CH2:11][OH:12])([CH2:9][OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])O.C(N)(N)=O.[OH-].[K+]>>[OH:10][CH2:9][C:3]1([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:1][O:12][CH2:11]1
Reactant: CCCCCC(CO)(CO)CO
Agent: NC(N)=O
Agent: [K+]
Agent: [OH-]
Product: CCCCCC1(CO)COC1
Temperature: 215 °C
Yield: 24.4 %

Procedure:
84.5 mmoles of trimethylolhexane and 70.9 mmoles of carbamide were together with 1.2 mole % of potassium hydroxide (based on total amount of reactants and catalysts) charged in a reaction vessel. The synthesis was performed in accordance with Example 1. The temperature uring the pyrolysis gradually raised to 215° C. 20.6 mmoles of 3-hydroxymethyl-3-pentyloxetane (trimethylolhexane oxetane) was yielded from the distillate and characterised by NMR. The remainder contained the spiro-orthocarbonate (3% on the carbamide) yielded as by-product.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][OH:9])[CH2:6][OH:7].[F:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[F:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[F:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:25]=[CH:24][C:21]([C@H:22]3[O:9][CH2:8][C@H:5]([CH2:4][CH2:3][CH2:2][F:1])[CH2:6][O:7]3)=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=Cc1ccc(-c2ccc(F)c(F)c2)cc1
Reactant: OCC(CO)CCCF
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FCCC[C@H]1CO[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)OC1

Procedure:
A mixture of 0.1 m of 2-(3-fluoropropyl)-1,3-propanediol, 0.1 m of p-(3,4-difluorophenyl)benzaldehyde (prepared by cross-coupling as described above), 1 g of p-toluenesulfonic acid and 200 ml of toluene is boiled for 1 hour on a water separator. Extractive work-up and purification by crystallization and chromatography give trans-2-(3,4-difluorobiphenyl-4'-yl)-5-(3-fluoropropyl)-1,3-dioxane.
Reaction SMILES: C(CC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[C:14]3[CH:31]=[CH:30][N:29](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=3)[N:18]=2)[CH2:8][CH2:7]1)=O)#N.[OH-].[K+]>O1CCOCC1.CO>[NH:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[C:14]3[CH:31]=[CH:30][NH:29][C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=3)[N:18]=2)[CH2:10][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCN(C(=O)CC#N)CC4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1ccc(Nc2nc(NC3CCNCC3)c3cc[nH]c3n2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of 4-(4-(1-(2-cyanoacetyl)piperidin-4-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (45 mg, 0.078 mmol) in dioxane (2 mL) and MeOH (1 mL), aq. 1N KOH (1.0 mL, 1.0 mmol) was added. The mixture was stirred at 70° C. for 4 h. It was concentrated in vacuo. The residue was acidified with HOAc (1 mL) before being purified by HPLC to give 4-(4-(piperidin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (20 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7](=[O:9])[CH3:8].[BrH:10].BrBr.C(OCC)C>C(O)(=O)C>[BrH:10].[Br:10][CH2:8][C:7]([C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:9]
Reactant: CC(=O)c1scnc1C
Agent: Br
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ncsc1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
220 mg (1.56 mmol) of 1-(4-methylthiazol-5-yl)ethanone are dissolved in 10 mL of glacial acetic acid. 769 μl (4.67 mmol) of hydrobromic acid and 88 μl (1.71 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(4-methylthiazol-5-yl)ethanone hydrobromide is filtered off, washed with ethyl ether and dried. The 350 mg of product obtained have the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[N:25]=[CH:24][C:23]4[C:18](=[C:19]([F:30])[CH:20]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:31])[C:11]=2[CH2:32][OH:33])[CH:3]=1.[F:34][C@H:35]1[CH2:37][C@H:36]1[C:38](O)=[O:39].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>[C:26]([C:21]1[CH:22]=[C:23]2[C:18](=[C:19]([F:30])[CH:20]=1)[C:17](=[O:31])[N:16]([C:12]1[C:11]([CH2:32][OH:33])=[C:10]([C:4]3[CH:3]=[C:2]([NH:1][C:38]([C@@H:36]4[CH2:37][C@@H:35]4[F:34])=[O:39])[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=3)[CH:15]=[CH:14][N:13]=1)[N:25]=[CH:24]2)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(N)c1=O
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: CN(C)C=O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(NC(=O)[C@@H]2C[C@@H]2F)c1=O
Yield: 73 %

Procedure:
A solution of 123d, (1S,2S)-2-fluorocyclopropanecarboxylic acid (15 mg, 0.14 mmol, 1.3 equiv), HATU (65 mg, 0.17 mmol, 1.5 equiv) and N,N-diisopropylethylamine (60 uL, 0.33 mmol, 3.0 equiv) in DMF (1.0 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm) to give 43 mg (73%) of 123 as an off white solid. LC-MS m/z: 536.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.80-7.72 (m, 2H), 7.49 (d, J=5.0 Hz, 1H), 5.03-4.73 (m, 1H), 4.89 (t, J=5.2 Hz, 1H), 4.43-4.36 (m, 2H), 3.60 (s, 3H), 2.50-2.41 (m, 1H), 1.68-1.52 (m, 1H), 1.39 (s, 9H), 1.20-1.08 (m, 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH3:14])[NH:12][C:11](=[O:15])[C:10]1([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH3:14])[N:12]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=2)[C:11](=[O:15])[C:10]1([CH3:16])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Reactant: C[C@@H]1NC(=O)C(C)(C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using (4S,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethylpyrrolidin-2-one (161.8 mg), 4-iodo-2-(trifluoromethyl)benzonitrile (205 mg), cesium carbonate (307 mg), tris(dibenzylideneacetone)dipalladium(0) (30 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 232.2 mg, yield: 87%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1)=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.8 %

Procedure:
In 20 ml of pyridine was dissolved 2.19 g of N-t-butoxycarbonyl-L-alanine and the solution was added with 1 g of 2-amino-5-bromopyridine, 2.77 g of 1-(3-dimethyl(aminopropyl)-3-ethylcarbodimide hydrochloride and 1.41 g of 4-dimethylaminopyridine individually and stirred at room temperature for 15 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo to give 0.713 g of 2-(N-t-butoxycarbonyl-L-alanylamino)-5-bromopyridine. This compound was dissolved, along with 0.714 g of (S)-[N-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, in 20 ml of dimethylformamide. Reaction was conducted at 100° C. for 4 hours in the presence of 0.6 ml of triethyl amine with the catalytic aid of 0.36 g of dichlorobistriphenylphosphine palladium (II) with stirring after their addition at room temperature. Water was then added to the reaction mixture, followed by the extraction with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered and concentrated in vacuo. Recrystallization of the concentrate gave 0.27 g of (S)-[N-3-(4-(2-(N-t-buxotycarbonyl-L-alanylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl)methyl acetamide. This compound was reacted with 0.15 ml of trimethylsilyl iodide in chloroform at room temperature for 30 min under a nitrogen atmosphere. Following the addition of chloroform, the organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo. The concentrate was subjected to column chromatography to produce the title compound. 50 mg.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]1[O:16][C:15](=[O:17])[NH:14][C@@H:13]1[CH3:18].[F:19][C:20]1[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][C:23](B(O)O)=[C:22]([O:32][CH3:33])[CH:21]=1>>[F:19][C:20]1[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[C@H:12]2[O:16][C:15](=[O:17])[NH:14][C@@H:13]2[CH3:18])=[C:22]([O:32][CH3:33])[CH:21]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)ccc1I
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N[C@@H]1C

Procedure:
Following the procedure described in EXAMPLE 81, 240 mg of (4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]4-methyl-1,3-oxazolidin-2-one and 171 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78) gave the title compound. Mass spectrum (ESI) 412.3 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.79, 7.77 (s, 1H), 7.64, 7.62 (dd, J˜2.5 Hz, 8 Hz, 1H), 7.32, 7.31 (d, J˜8 Hz, 1H), 7.00, 6.95 (d, J=8.5 Hz, 1H), 6.70, 6.67 (d, J=12 Hz, 1H), 6.47, 6.43 (s, 1H), 5.08, 5.04 (d, J=5 Hz, 0.1H), 3.68-3.80 (m, 3.5H), 3.53 (m, 0.5H), 3.21 (m, 1H), 1.19-1.30 (m, 6H), 0.95, 0.77 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:11]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:12](=O)[O:13]C)=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[H][H].C(=O)([O-])[O-].[Na+].[Na+]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Pt]=O.O>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:11]1[C:4]2[N:5]=[C:6]([CH3:10])[CH:7]=[C:8]([CH3:9])[C:3]=2[CH2:1][NH:2][C:12]1=[O:13]
Reactant: [H][H]
Reactant: COC(=O)N(CCN(C)C)c1nc(C)cc(C)c1C#N
Agent: O=[Pt]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cc(C)c2c(n1)N(CCN(C)C)C(=O)NC2
Yield: 95 %

Procedure:
A solution of methyl N-(3-cyano-4,6-dimethyl-2-pyridyl)-N-(2-dimethylaminoethyl)carbamate (14.8 g, 53 mmol) in glacial acetic (200 ml) containing platinum oxide catalyst (1.1 g) is hydrogenated in a Parr apparatus until two equivalents of hydrogen are taken up (20 hours). The catalyst is removed by filtration and the solvent evaporated to give a residue which is dissolved in water, made basic with sodium carbonate, and the crude product extracted into methylene chloride. This dried solution is evaporated to give a crude product (12.5 g) which is crystallized from cyclohexane to yield 7.2 g of pure title C product; m.p.: 139°-141° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:26])[C@H:6]([CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([OH:18])=[O:17])[NH:7]C(OC(C)(C)C)=O)[CH:2]=[CH2:3]>FC(F)(F)C(O)=O>[CH2:1]([O:4][C:5](=[O:26])[C@H:6]([CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([OH:18])=[O:17])[NH2:7])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(Cc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)[C@@H](N)C(Cc1ccccc1)C(=O)O

Procedure:
N-t-Butyloxycarbonyl β-benzyl-L-aspartic acid allyl ester (3-1) (2.95 g; 8.11 mmol) was stirred in trifluoracetic acid (30 ml) at room temperature for 45 min. The solvent was removed in vacuo and the residue evaporated from ether (30 ml×2). The resultant yellow oil was dissolved in DCM (40 ml), washed with saturated sodium bicarbonate solution (30 ml), brine (30 ml×2) and dried (sodium sulphate). Filtration and evaporation of the solvent gave the product as a yellow oil which was used without further purification.