Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](O)=[O:14])[C:7]([CH3:16])=[CH:6]2)#[N:2].O[NH:22][C:23]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)=[NH:24]>>[F:32][C:31]([F:33])([F:34])[C:29]1[CH:30]=[C:25]([C:23]2[N:24]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:18])([F:20])[F:19])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH3:16])[O:14][N:22]=2)[CH:26]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:28]=1
Reactant: N=C(NO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)no1

Procedure:
Synthesized as described in Example 37 using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and N-hydroxy-3,5-bis(trifluoromethyl)benzenecarboximidamide: 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 2H), 8.02 (s, 1H), 7.61 (m, 2H), 6.71 (s, 1H), 5.62 (s, 2H), 2.65 (s, 3H); MS (ES) m/z 519 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[CH2:15](OCC)C.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:15][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([F:12])([F:13])[F:14])=[C:2]([NH2:1])[CH:3]=1
Reactant: CCOCC
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(C(F)(F)F)c(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g of 3-Amino-4-trifluoromethyl-benzoic acid were dissolved using 50 ml of diethyl ether and 25 ml of methanol. Then, 6.1 ml of a 2M solution of trimethylsilyldiazomethane in hexane were added at 10-20° C. The reaction mixture was stirred at room temperature for 1 h. Then, 6.1 ml of a 2M solution of trimethylsilyldiazomethane in hexane were added at 10-20° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then evaporated. Chromatography on silica gel using EA/HEP 1:2 yielded 2.3 g of the title compound, viscous oil.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][C:18]1[S:17][CH:16]=[C:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([C:2]([NH:37][CH2:36][CH2:35][N:32]3[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27][CH2:26][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:34][CH2:33]3)=[O:3])[C:5]=12
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: NCCN1CCC(CCCN2CCCCC2)CC1
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCN3CCCCC3)CC1)c1ccccc1NC2=O
Yield: 9 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[3-(piperidin-l-yl)propyl]-piperidin-l-yl]ethanamine in a yield of 9% of theory. Colourless crystals, m.p. 170°-171° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16]1[C:17]2[C:24]([CH3:25])=[C:23]([C:26]([NH2:28])=[O:27])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1.C(N(CC)C(C)C)(C)C.C(Cl)Cl.[C:41](Cl)(=[O:43])[CH3:42]>O>[C:41]([NH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16]1[C:17]2[C:24]([CH3:25])=[C:23]([C:26]([NH2:28])=[O:27])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1)(=[O:43])[CH3:42]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@@H]3N)c12
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(N)=O)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.15 g (1S,2S) 4-[2-(2-amino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl thieno[2,3-d]pyrimidine-6-carboxylic acid amide and 0.32 ml N,N-diisopropylethylamine were mixed with DCM. 0.027 g acetylchloride were added to the mixture and stirred for 1 hour at rt. Then the reaction mixture was diluted with water and filtrated. The solid was air-dried.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH3:17][O:16][CH2:15][CH2:14][O:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:18])=[O:2])=[CH:6][CH:7]=1
Reactant: COCCOCOc1ccc(CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOCOc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(2-Methoxy-ethoxymethoxy)-phenyl]-acetic acid methyl ester (192 mg, 0.76 mmol) in MeOH (3 ml) is added 2 M NaOH (3 ml). The reaction mixture is stirred for 16 hours at room temperature. The solvent is removed in vacuo and the residue dissolved in EtOAc and washed with sat. aq. NH4Cl solution, dried (MgSO4) and concentrated in vacuo to yield [4-(2-Methoxy-ethoxymethoxy)-phenyl]-acetic acid
Reaction SMILES: FC1C=CC([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=CC=1.CN1CCCNCC1>CS(C)=O>[O:16]=[C:10]1[NH:9][CH:8]=[CH:15][CH:14]=[C:11]1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Agent: CN1CCCNCC1
Solvent: CS(C)=O
Product: N#Cc1ccc[nH]c1=O

Procedure:
From 12.9 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 13.8 g. of N-methylhomopiperazine in 180 ml. of dimethyl sulfoxide, there is obtained 6-[p-hexahydro-4-methyl-1H-1,4-diazepin-1-yl)phenyl]-1,2-dihydro-2-oxonicotinonitrile.
Reaction SMILES: [F:1][C:2]([F:7])=[C:3]([F:6])[CH:4]=[CH2:5].[C:8](=[O:11])([O-])[O-].[K+].[K+].[Br:14]Br>CO>[Br:14][CH2:5]/[CH:4]=[C:3](\[F:6])/[C:2]([O:11][CH3:8])([F:7])[F:1]
Reactant: O=C([O-])[O-]
Reactant: C=CC(F)=C(F)F
Reactant: BrBr
Agent: [K+]
Solvent: CO
Product: COC(F)(F)/C(F)=C/CBr
Temperature: -70 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 5.30 g (49.1 mmol) 1,1,2-trifluoro-1,3-butadiene in methanol (70 mL) at 0° C. in a round-bottom 250 mL flask was added 12.50 g of potassium carbonate (anhydrous powder). The flask was equipped with a magnetic stirrer, and the stirred contents cooled to ca. -70° C. Bromine (2.50 mL, 48.4 mmol) was slowly added to the -70° C. reaction mixture over two hours, and the resulting mixture stirred for further two hours at -50° C. At this point the contents of the flask were poured into a large excess of ice-water, and the liquid extracted twice with diethyl ether. The ether layers were combined, washed once with brine, then dried over anhydrous magnesium sulfate. Evaporation of solvent gave 7.50 g (70.2%) of (Z)-4-bromo-1-methoxy-1,1,2-trifluoro-2-butene as a clear liquid which was distilled at 74° C. (40 mm Hg). H-NMR (300 MHz, CDCl ): δ 3.62(3H, s), 3.98(2H, d, J=9 Hz), 5.76(1H, dt, J=9, 31 Hz). Mass spectrum: m/e=218,220 (M+). 19F-NMR (CDCl3): φ79.2(d, J=14.2 Hz) 126.5(dtt, J=31.0, 14.0, 2.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[C:6]([OH:8])[CH:7]=1.[CH3:11][C:12]1[CH:17]=[CH:16]C(S([O-])(=O)=O)=[CH:14][CH:13]=1.CC(C(=O)C)C(=O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:17]([CH3:16])=[C:12]([CH3:11])[C:13]([CH3:14])=[N:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: NNc1ccc(Br)cc1O
Agent: CC(=O)C(C)C(C)=O
Product: Cc1nn(-c2ccc(Br)cc2O)c(C)c1C
Yield: 47.3 %

Procedure:
320 mg of the title compound was prepared in a manner similar to Example 54b) by using 5-bromo-2-hydrazinylphenol 4-methylbenzenesulfonate (0.9 g), which was prepared in a manner similar to Example 54a), and 3-methylpentane-2,4-dione (0.9 g).
Reaction SMILES: [C:1]([CH2:9][C:10](OCC)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:24][CH2:25][CH3:26])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:2]1([C:1]2[CH2:9][C:10](=[O:11])[C:19]3[C:17](=[C:16]([C:15]([O:24][CH2:25][CH3:26])=[O:23])[CH:22]=[CH:21][CH:20]=3)[N:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cccc2c1N=C(c1ccccc1)CC2=O
Yield: 39.4 %

Procedure:
A mixture of 7 grams of ethyl benzoylacetate, 6 grams of ethyl anthranilate and 0.5 gram of p-toluenesulfonic acid is dehydrated (by heating) in 300 ml of benzene for three days. Benzene is evaporated therefrom, and the resulting oil is heated at 250° to 280° C. for 0.5 hour in 20 ml of diphenyl ether. After cooling, 250 ml of n-hexane is added thereto, and crystals which separate out therefrom are collected by filtration and recrystallized from methanol to give 4.2 grams of ethyl 2-phenyl-4-quinolone-8-carboxylate, pale brown needles, melting point 218° to 219° C.
Reaction SMILES: C1([OH:7])C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[OH-].[Na+].ClC1C=CC=C(C(OO)=O)C=1>CN(C)C=O.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][C:18]([OH:7])=[CH:19][C:14]=1[CH3:13]
Reactant: COc1ccccc1C
Reactant: Oc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(O)cc1C
Reaction time: 2 h
Yield: 1 %

Procedure:
The synthesis for the phenol was a two step synthesis via the Vilsmer-Haack condensation to obtain the aldehyde and then by the Baeyer-Villiger oxidation to give the phenol. Phosphorus oxychloride (5.1 mL, 0.057 mol) was added the dropwise to a solution of 2-methylanisole (5.33 mL, 0.043 mol) in dimethylformamide (6 g) under nitrogen. After addition, the mixture was heated and refluxed for 4 h, cooled then added to 100 mL of water. An excess of 10% NaOH was added and the solution was extracted with 4×100 mL of ether. The ether layers were washed with water and then brine solution, dried over magnesium sulfate and evaporated under reduced pressure. The dark oil that remained (5.0 g, 77%) was purified by column chromatography (silica gel: 90% hexane, 10% ethyl acetate). The remaining oil (1.78 g, 28%) was dissolved in dichloromethane (100 mL) and then 3.03 g, (0.018 mol) 3-chloroperbenzoic acid was added. The mixture was refluxed under nitrogen for ˜5 h, cooled, and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The dark oil that remained was dissolved in 7 mL of methanol and 5.5 mL of 10% aqueous potassium hydroxide solution was added. The solution was stirred under nitrogen for ˜2 h, water was added, and the solution was extracted with ether. The ether layers were combined and washed with saturated sodium bicarbonate solution and then with water. The ether was dried over magnesium sulfate and evaporated under reduced pressure. The oil that remained (1.21 g, 74%) was recrystallized twice with hexane to give long white needles (0.34 g, <1%). The purity was assessed by NMR and GC-MS.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][NH2:33])[CH3:29]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([NH:33][CH2:32][CH2:31][N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[O:18])(=[O:7])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOC)CN1C(=O)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=361.2.
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:10]2[S:26][C:27]([C:29]([O:31]C)=[O:30])=[CH:28][C:9]1=2)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.CO>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[NH:8][C:9]3[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[S:26][C:10]=3[C:11]=2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3CCCCC3)c2s1
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A solution (0.5 M) of methyl 4-(tert-butoxycarbonyl)-5-(4-chlorophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DCM/TFA (1:1) was stirred at RT for 1 h. Evaporation of the solvent gave a solid that was dissolved in MeOH. The resulting solution (0.1N) was treated with aqueous NaOH (1 N solution, 12 eq.). The mixture was heated to reflux for 3 h then concentrated and acidified to pH 1 with aqueous HCl (1 N), the aqueous solution was diluted with MeCN and purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 5 micron, 19×150 mm; flow: 15 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 60% A isocratic for 2 min then linear to 0% A in 10 min) to afford the title compound (53%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]2[CH:20]=C[N+](C)=C2)=[O:15])[C@H:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1.NC1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([NH:16][CH:20]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:31][CH2:30]2)=[O:15])[C@H:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1
Reactant: C[n+]1ccn(C(=O)N2CC(c3cc(F)ccc3F)=C[C@H]2c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)N2CC(c3cc(F)ccc3F)=C[C@H]2c2ccccc2)CC1
Reaction time: 6 h

Procedure:
Crude 18-2 (115 mg, 0.24 mmol) was suspended in anhydrous CH2CL2 (3 mL) and treated successively with 4-amino-1-tert-butyloxycarbonyl-piperidine (235 mg, 1.17 mmol) and Et3N (0.1 mL, 0.7 mmol). The suspension was stirred for 6 hours and complete dissolution was observed. Upon completion, the reaction was diluted further with CH2Cl2 (20 mL) and washed with 1N HCl to remove all unbound amine and Et3N. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to yield crude 18-3 as a yellow oil: LRMS m/z (N C(CH3)3+H) 427.9 found, 428.1 required.
Reaction SMILES: FC1C=CC(CN)=CC=1.[NH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 57 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 3-(aminomethyl)pyridine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 57% yield: mp 153-154° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56-8.40 (m, 3H), 7.66 (d, J=7.8 Hz, 1H), 7.35-7.19 (m, 6H), 4.46-4.35 (m, 4H), 3.96 (t, J=7.5 Hz, 2H), 3.41 (t, J=7.5 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.3, 157.8, 155.5, 151.7, 149.3, 148.4, 136.7, 135.6, 135.5, 129.1, 128.2, 127.9, 123.9, 117.9, 47.3, 42.9, 42.4, 40.8, 14.5; MS (ES+) m/z 408.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[N+:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1)(=[O:31])=[O:32]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
To a solution of (R)-6-amino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (0.200 g, 0.709 mmol) and 3-nitro-benzenesulfonyl chloride (0.157 g, 0.709 mmol) in 10 mL of dichloromethane, was added triethylamine (0.5 mL, 3.544 mmol). After stirring at room temperature under N2 for 16 h, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 20-50% ethyl acetate/hexanes to give the title compound as light yellow semi-solid (0.128 g, 39% yield). LC-MS: tR=9.5 min; m/z 468 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[C:6](=[S:18])[NH:5][C:4](=[O:19])[CH:3]=1.[N:20]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:20][C:3]1[C:4](=[O:19])[NH:5][C:6](=[S:18])[N:7]([CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=S)n1Cc1nc2ccccc2[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(N)n(Cc2nc3ccccc3[nH]2)c(=S)[nH]c1=O
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a suspension of 6-amino-1-(1H-benzimidazol-2-ylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.28 g, 1.0 mmol, obtained from Example 8(b)) in acetic acid (3 mL) was added, dropwise, a solution of sodium nitrite (0.080 g, 1.1 mmol) in H2O (0.5 mL). The reaction mixture was then stirred for an additional 40 minutes before sodium dithionite (0.36 g, 2.08 g) was added. The resulting mixture was stirred 15 minutes and then evaporated in vacuo. Water (50 mL) was added and the formed solid was collected by filtration, washed with water and dried which gave the title compound (0.19 g, 63%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].N1C=CC=CC=1>C(Cl)Cl>[Cl:7][CH:5]([O:4][C:2]([N:18]1[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]1)=[O:3])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood, 1.46 g, 1.1 mL, 10.2 mmol) was reacted with 1-Boc-piperazine (Alfa Aesar, 1.5756 g, 8.37 mmol) and pyridine (870 mg, 0.89 mL, 11.0 mmol) in methylene chloride (10 mL) from −78° C. for 1 h and then at room temperature overnight to give piperazine-1,4-dicarboxylic acid tert-butyl ester 1-chloro-ethyl ester. A portion of piperazine-1,4-dicarboxylic acid tert-butyl ester 1-chloro-ethyl ester (682 mg, 1.67 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (201.4 mg, 0.327 mmol) in the presence of cesium carbonate (743.4 mg, 2.28 mmol) in dimethylformamide (7 mL) overnight to give 1-tert-butyl 4-(1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl)piperazine-1,4-dicarboxylate as an off-white lyophilized solid (259.9 mg, 91% yield). MS (ES+) m/z calcd. for C34H36Cl2F2N4O4: [(M+H)+]: 872, found: 872
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])[CH2:55][CH2:54]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[N:53]2[CH2:58][CH2:57][CH:56]([NH:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[CH3:66])[CH2:55][CH2:54]2)=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NC1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Reaction time: 16 h
Yield: 24.6 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.1 g, 0.00038 mole) in DMF (1 mL) was added DIPEA (0.245 g, 0.0019 mole), HOBt (0.056 g, 0.00042 mole) and EDCI.HCl (0.145 g, 0.00076 mole). After 2 minutes piperidin-4-yl-o-tolyl-amine dihydrochloride (0.106 g, 0.00042 mole) was added and the resulting mixture was stirred for 16 hours. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel (60-120 mesh) (1% methanol in chloroform) afforded 0.04 g (25%) of N-biphenyl-4-yl-3-oxo-3-(4-o-tolylamino-piperidin-1-yl)-propionamide. LC-MS purity: 428.23 (M+1)+, 93.11%, 1H NMR (DMSO-d6): δ 7.7 (m, 6H), 7.5 (t, 2H), 7.3 (t, 1H), 7.2 (q, 2H), 6.65 (q, 2H), 4.5 (d, 1H), 4.0 (d, 1H), 3.6 (m, 1H), 3.5 (s, 2H), 3.3 (s, 1H), 3.0 (t, 1H), 2.2 (m, 3H), 2.1 (s, 2H), 1.5 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][O:38][C:39](=[O:41])[CH3:40].O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:36][CH2:37][O:38][C:39](=[O:41])[CH3:40])=[CH:26][CH:27]=1
Reactant: CC(=O)OCCBr
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Yield: 22 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol (38 mg, 0.093 mmol) in acetonitrile (0.9 mL) was added potassium carbonate (40 mg, 0.28 mmol) followed by the addition of acetic acid 2-bromo-ethyl ester (0.012 mL, 0.112 mmol) and the resulting mixture was heated to 50 degrees Celsius for 72 hours. The reaction showed some product formation but the majority of starting material remained. An additional 2 equivalents of acetic acid 2-bromo-ethyl ester was added and the mixture was heated at 50 degrees Celsius for an additional 24 hours. Water (20 mL) and ethyl acetate were added, the two phases separated and the aqueous phase was extracted 3 times with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (4 g silica gel column) and eluting with a gradient of 0 to 30% methanol in dichloromethane. 10 mg (22% yield) of a ˜2:1 mixture of the desired product contaminated with some unidentified compound was obtained. LCMS 539 M+HCOO−, negative mode).