Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([N:12]3[CH2:17][CH2:16][N:15]4[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]4[CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NCc1nccnc1Cl)N1CCn2c(nnc2C(F)(F)F)C1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1nnc2n1CCN(c1ncc3c(Cl)nccn13)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a stirred solution of N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide (1.25 g, 3.46 mmol) in Acetonitrile (10 ml) was added pyridine (2.73 g, 34.6 mmol) and finally phosphoryl trichloride (2.65 g, 17.28 mmol). The resulting reaction mixture was then stirred at room temperature for 15 hours overnight. The reaction was quenched by slowly addition of NaHCO3 and extracted with ethyl acetate (3×). The organic layer was dried by MgSO4, filtered and concentrated. The residue was purified by MPLC (24 g silica gel, 20 to 60% ethyl acetate in hexaes, 18 CV) to afford white solid product 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (550 mg, 1.600 mmol, 46.3% yield). LC-MS: C12H9ClF3N7,343. found 344.11 [M+H]+, RT=1.22 min.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]2[C:19](=[O:50])[CH:20]([CH:23]([OH:49])[C:24]3[N:25]=[CH:26][N:27]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:28]=3[CH3:29])[CH2:21][CH2:22][C:11]=12)[CH3:9]>N1C=CC=CC=1>[C:1]([O:49][CH:23]([C:24]1[N:25]=[CH:26][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:28]=1[CH3:29])[CH:20]1[C:19](=[O:50])[N:12]2[C:13]3[C:18]([C:10]([CH2:8][CH3:9])=[C:11]2[CH2:22][CH2:21]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: c1ccncc1
Product: CCc1c2n(c3ccccc13)C(=O)C(C(OC(C)=O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Acetic anhydride (2.0 ml) was added to a solution of 10-ethyl-8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (2.15 g) in pyridine (10 ml). After being stirred at room temperature for 20 hours, the solution was evaporated in vacuo. The residue was dissolved in toluene (30 ml) and the solution was evaporated in vacuo to remove pyridine and acetic anhydride. This operation was repeated further three times to give 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-ethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one as an amorphous powder. This crude product was used in the next reaction without further purification.
Reaction SMILES: ClCCl.[OH-].[Na+].[NH2:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.S(O[CH2:27][CH2:28][CH2:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(C)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:31]1([CH:30]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:29][CH2:28][CH2:27][NH:6][C:7]2[C:8]3[C:13]([N:14]=[C:15]4[C:20]=2[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: CS(=O)(=O)OCCCC(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1CCCc2nc3ccccc3c(NCCCC(c3ccccc3)c3ccccc3)c21
Temperature: 3 °C
Reaction time: 72 h
Yield: 7.7 %

Procedure:
In a mixture consisting of 480 ml of dichloromethane and 320 ml of 50% NaOH were combined 8.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one, 68 g (6 eq) of 1-mesyloxy-4,4-diphenylbutane and 2.56 g (0.20 eq) of tetrabutylammonium hydrogensulfate used as a phase transfer catalyst. The biphasic mixture was jacket cooled to 3° C. and was then mechanically stirred for 3 days. As no further reaction occurred, the reaction mixture was diluted with water and the organic phase was separated. Analysis by thin layer chromatography indicated a 1:1 mixture of the end product and the starting material. The dichloromethane layer was evaporated to a gum. The gum was diluted with dichloromethane and mixed with 1:1 alumina/sand to immobilize it as a solid for Soxhlet extraction. The dichloromethane was evaporated and the solid was put into a Soxhlet extraction thimble and extracted with hexane for 4 hours. Since no further extraction occurred after 4 hours, the hexane solution was evaporated to an oil. The oil was chromatographed over silica gel (EtOAc) and the resultant solid rechromatographed through alumina (Et2O) to yield a solid. The solid was recrystallized from Et2O/hexanes to yield 1.22 g (8%) of product, melting point 86°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=O)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>C1COCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]([C:15]([O:17][CH3:18])=[O:16])([C:11]([O:13][CH3:14])=[O:12])[CH2:19][C:20]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(CC(=O)c1ccc(F)cc1)(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a vigorously stirred mixture of 50.4 g (771 mmol) of zinc dust in 640 mL of THF at -78° C. under an atmosphere of nitrogen was added dropwise 60.4 mL (551 mmol) of titanium(IV) chloride. The reaction was warmed to ambient temperature with a water bath and then stirred at reflux for 1 hour. To the resulting dark mixture under reflux was added a solution of 15 g (32.3 mmol) of dimethyl 2-[2-(4-fluorophenyl)-2-oxoethyl]-2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]propanedioate (prepared above) in 20 mL of THF. The resulting mixture was stirred at ambient temperature for 16 hours, filtered through a pad of Celite, rinsed with ethyl acetate, and concentrated in vacuo. The residue was partitioned between water and ethyl acetate; the organic phase was washed with brine, dried MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 6.26 g (44%) of 1-[2-(4-fluorophenyl)-4,4-dicarbomethoxycyclopenten-1-yl]-4-(methylsulfonyl)benzene which was identical to the material prepared in Step 8, Method A.
Reaction SMILES: Cl[C:2]1[CH:23]=[C:22]([F:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:5].[CH2:28](OB(C=C)OCCCC)[CH2:29]CC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:22]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[O:5])=[C:2]([CH:28]=[CH2:29])[CH:23]=1
Reactant: C=CB(OCCCC)OCCCC
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(F)cc2Cl)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(F)c([N+](=O)[O-])cc1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C

Procedure:
Under nitrogen, the mixture of tert-butyl 4-(2-chloro-4-fluoro-5-nitrobenzamido)piperidine-1-carboxylate (Step 1, 1.52 g, 3.88 mmol), vinylboronic acid dibutyl ester (0.86 mL, 3.88 mmol), dichlorobis(triphenylphosphine)palladium (II) (136 mg, 0.2 mmol) and sodium carbonate (2.9 g, 27.2 mmol) in THF (40 mL) and water (10 mL) was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, partitioned between EtOAc and brine. The organic extracts were dried (Na2SO4), concentrated, and purified by silica gel chromatography (EtOAc/Hexanes:1/4) to afford tert-Butyl 4-(4-fluoro-5-nitro-2-vinylbenzamido)piperidine-1-carboxylate; ESMS m/z 394.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.Cl.[NH:24]1[CH2:29][CH2:28][C:27](=[C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:31]#[N:32])[CH2:26][CH2:25]1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:24]3[CH2:29][CH2:28][C:27](=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:31]#[N:32])[CH2:26][CH2:25]3)=[O:21])[C:4]=12
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: N#CC(=C1CCNCC1)c1ccccn1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(C#N)c4ccccn4)CC3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (1.5 g), 2-(piperidin-4-ylidene)-2-(pyridin-2-yl)acetonitrile hydrochloride (1.5 g), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (2.1 g) and Hunig's Base (2 ml) were combined in 20 ml of DMF. The mixture was stirred at room temperature for 16 hours. DMF was removed via evaporation at reduced pressure and the residue was partitioned with MeOH (80 ml). The precipitate was collected via filtration to provide 0.85 g of the product, 2-(1-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pynolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperidin-4-ylidene)-2-(pyridin-2-yl)acetonitrile (IVe). 1H NMR (500 MHz, DMSO-d6) δ12.42 (s, 1H), 9.23 (m, 1H), 8.69 (m, 1H), 8.27 (m, 1H), 7.89 (m, 2H), 7.58 (m, 1H), 7.52 (m, 1H), 3.98 (s, 3H), 3.99-2.70 (m, 8H), 2.60 (m, 3H). MS m/z: (M+H)+ calcd for C25H23N8O3 483.19, found 483.18.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([NH:9]C(=O)OC(C)(C)C)=[CH:3]1.[ClH:17]>O1CCOCC1>[ClH:17].[NH2:9][C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)ccc1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(N)ccc1=O
Temperature: 70 °C

Procedure:
To a stirred solution of tert-butyl 1-methyl-6-oxo-1,6-dihydropyridin-3-ylcarbamate (1.20 g, 5.35 mmol) in dioxane (15 mL) at RT was added HCl (4M in dioxane, 5.35 mL, 21.4 mmol). The reaction mixture was heated at 70° C. for 9 h, cooled to RT and filtered to give the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([CH:9]=O)=[CH:3][CH:2]=1.[CH3:11][C:12]([O:15][C:16](=[O:39])[C:17](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:18][CH3:19])([CH3:14])[CH3:13]>>[CH3:11][C:12]([O:15][C:16](=[O:39])/[C:17](/[CH2:18][CH3:19])=[CH:9]/[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]=[O:8])([CH3:14])[CH3:13]
Reactant: O=Cc1ccccc1C=O
Reactant: CCC(C(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC/C(=C\c1ccccc1C=O)C(=O)OC(C)(C)C

Procedure:
From o-phthalaldehyde and 2-(triphenylphosphoranylidene)-butanoic acid 1,1-dimethylethyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12]C)[CH:6]=2.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[C:3]([CH3:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2
Reactant: COc1ccc2cc(F)c(C)nc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2cc(O)ccc2cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Fluoro-7-methoxy-2-methylquinoline (0.16 g, 0.85 mmol) was taken up in dichloromethane (4 ml) under nitrogen and treated with boron tribromide solution (4 ml of a 11.0M solution in dichloromethane, 4.0 mmol). The reaction was stirred for 24 hours at ambient temperature followed by the slow addition of excess methanol. The solution was stirred for a further 2 hours and then evaporated to dryness to give 3-fluoro-7-hydroxy-2-methylquinoline which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([C:19]([O:21]C)=[O:20])[CH:16]=1)[CH2:11]2.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([C:19]([OH:21])=[O:20])[CH:16]=1)[CH2:11]2
Reactant: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 23 °C

Procedure:
A mixture of methyl (2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate (81.0 g, 276 mmol) and aqueous sodium hydroxide solution (5.52 N, 250 mL, 1.38 mol) in MeOH (2.5 L) was heated at reflux for 4 h. The mixture was allowed to cool to 23° C. before it was acidified to pH 2 with aqueous 1 N hydrochloric acid solution. The precipitate was filtered, washed with water, and dried under nitrogen atmosphere to give the title compound. MS: m/z=281.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:8]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1nc(-c2sccc2Cl)cs1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2sccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (9.4 mg) with purity >90%: MS (pos) m/z 439.1, 441.1; HRS m/z 437.8875 (calc. of monoisotopic mass for C14H9Cl3N2O2S3 gives 437.8892).
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH2:27])[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=1.C(O[K])(C)(C)C>CS(C)=O>[O:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:27][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(-c2nc3cccc(N)c3nc2-c2ccc(OC)cc2)cc1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: COc1ccc(-c2nc3cccc(Nc4ccc(N)cc4)c3nc2-c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
While agitating 5.0 g (14.0 mmol) of 2,3-di(4-methoxylphenyl)-5-aminoquinoxaline, 2.4 g (17.0 mmol) of 4-fluoronitrobenzene and 120 ml of dimethylsulfoxide, 5.7 g (50.8 mmol) of t-butoxy potassium was gently added. After completion of the addition, the reaction container was purged with nitrogen, followed by agitation at room temperature for 8 hours. After completion of the reaction, 100 ml of water was added while cooling, and an organic phase was extracted by use of a chloroform solvent, followed by concentration to obtain the intended product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCC#Cc1ccc(C#N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(C#N)cc1
Yield: 87.3 %

Procedure:
A suspension of [4-(4-cyanophenyl)but-3-ynyl]carbamic acid tert-butyl ester 56 (5.2 g, 19.2 mmol) and 10% palladium on carbon (2.5 g, wet) in ethanol/THF (30 mL, 1:1) was stirred overnight under 1 atmosphere of hydrogen. After purging with nitrogen, the reaction mixture was suction filtered through a pad of Celite. The solvent was removed from the filtrate by evaporation. The residue was chromatographed on silica gel, eluting with methylene chloride/ethyl acetate (30:1), to afford the pure product 57 (4.6 g, 87%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.51 (m, 2H), 1.65 (m, 2H), 2.69 (t, 2H), 3.14 (m, 2H), 4.52 (br s, 1H), 7.27 (d, 2H), 7.56 (d, 2H).
Reaction SMILES: [O:1]=[C:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=2)[CH:6]=[N:5]1>CO>[OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[CH:11]=2)[CH:6]=[N:5]1
Reactant: CC(=O)Cn1ncc2ccc(OC(=O)C(C)(C)C)cc21
Solvent: CO
Product: CC(O)Cn1ncc2ccc(OC(=O)C(C)(C)C)cc21
Yield: 79.4 %

Procedure:
A solution of the product of Step B (0.91 g, 3.6 mmol) in methanol (10 ml) was treated by the procedure described for Example 1, Step C to give an oil (0.79 g, 86%) that was used in the next reaction with further purification: 1H NMR δ (CDCl3) 7.99 (s, 1H), 7.98 (s, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.01 and 6.96 (dd, J=2.0 and 8.6 Hz, 1H,), 4.14–3.89 (m, 3H), 1.56 (s, 3H) 1.32 (s, 9H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23].[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([S:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:23])[N:2]([NH:1][C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[N:11]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1)#[N:22]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: N#Cc1ccc(S(=O)(=O)c2nn(N)c(=O)c3ccccc23)cc1
Product: N#Cc1ccc(S(=O)(=O)c2nn(NC(=O)Cc3ccc(F)cc3)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 224A and 2-(4-fluorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.86-11.86 (m, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.31-8.47 (m, 1H), 8.14-8.20 (m, 4H), 8.09-8.16 (m, 1H), 7.99-8.07 (m, 1H), 7.28-7.34 (m, 2H), 7.14-7.20 (m, 2H), 3.66 (s, 2H); MS (ESI−) M/Z 461 (M−H)−.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH:12]=[CH:13][C:14]=1[CH2:15]O.C([N:38](CC)CC)C.N>C1COCC1>[CH2:15]1[C:14]2[C:9](=[CH:10][C:11]([NH:17][C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:38]1
Reactant: O=C(Nc1ccc(CO)c(CCO)c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (0.085 mL) was added to a 0° C. solution of 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl]-amide (214 mg, 0.51 mmol) and triethylamine (0.18 mL) in THF (8.5 mL). TLC showed complete reaction after 30 min. The contents were cooled to -78° C., excess ammonia was added, and the contents were stirred for 18 hrs at 25° C. The solvents were removed under vacuum, methylene chloride (10 mL) and aqueous 1N HCl were added and the contents were stirred for 1 hr. The phases were separated and the aqueous phase was rendered alkaline with aqueous sodium hydroxide to a pH of 12. The organic phase was extracted with methylene chloride (4×10 mL), the solvent removed under vacuum to give a white solid (108 mg) which was chromatographed on silica eluting with 5% methanol/methylene chloride with 0.5% ammonium hydroxide. The product was obtained as a white solid (40 mg, 20%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][O:19][C:20]4[CH:24]=[CH:23][O:22][N:21]=4)[O:15][C:14]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3]1.C(N(CC)CC)C>CS(C)=O.O>[O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][O:19][C:20]4[CH:24]=[CH:23][O:22][N:21]=4)[O:15][C:14]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3]1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CC[C@@H](O)C2)c(F)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
3-(4-((3R)-3-Hydroxy-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one (700 mg, 1.9 mmol) was dissolved in DMSO(5 ml) under nitrogen and triethylamine (2.03 g, 20 mmol) added. A solution of sulfur trioxide pyridine complex (0.95 g, 6 mmol) in DMSO(5 ml) was added dropwise over 20 minutes. After stirring 1 hour at ambient temperature, the mixture was diluted with water (100 ml) and extracted into EtOAc (150 ml). The organics were washed with water (2×50 ml), brine (50 ml) and dried (magnesium sulfate). After evaporation, the residue was purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 3% MeOH in dichloromethane. Relevant fractions were combined and evaporated, and the residue crystallised from ethanol (35 ml) to give product (176 mg). MS (ESP): 362 (MH+) for C17H16FN3O5.
Reaction SMILES: C([O:9][CH:10]([C:35]([NH:37][C@@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:39])=[O:36])[C@@H:11]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(=O)C1C=CC=CC=1.[OH-].[Li+]>O1CCOCC1.O.C(OCC)(=O)C>[CH2:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:10]([OH:9])[C:35](=[O:36])[NH:37][C@@H:38]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH3:39])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](NC(=O)C(OC(=O)c1ccccc1)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexyl benzoate (28.0 g, 45.0 mmol) was dissolved in dioxane (200 mL), and a solution of lithium hydroxide (2.47 g, 174 mmol) in water (100 mL) was added. The resulting mixture was stirred for 24 h at room temperature. It was then diluted with ethyl acetate (500 mL), and washed with 1N hydrochloric acid (300 mL). The aqueous layer was back-extracted with two 100 mL portions of ethyl acetate. The extracts were then combined with the original ethyl acetate layer, washed with three 200 mL aliqouts of saturated aqueous sodium bicarbonate, followed by saturated aqueous sodium chloride (100 mL), and dried over magnesium sulfate. Volatiles were then removed under vacuum to afford tert-butyl (1S)-5-{[(benzyloxy)carbonyl]amino}-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as a waxy light yellow solid (25.61 g, quantitative crude yield). 1H NMR (300 MHz, DMSO-d6) δ 7.98-7.88 (m, 1H); 7.68-7.63 (m) and 7.49-7.42 (m) total 1H, 7.35-7.10 (m, 10H); 6.31 (d, J=9 Hz) and 6.02 (d, J=9 Hz) total 1H, 5.62-5.53 (br s) and 5.53-5.42 (br s) total 1H, 4.94 (s, 2H), 4.91-4.83 (m, 1H); 3.87 (br s) and 3.79 (br s) total 1H, 3.72-3.58 (m, 1H); 2.99-2.76 (m, 2H); 1.47-1.10 (m, 18H). ES-LCMS m/z 514 (M+H).