Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12]C(OCC2C=CC=CC=2)=O)[C:7]1=[O:23])[CH3:5]>[Pd].CO>[NH2:12][C:8]1[C:7](=[O:23])[N:6]([CH:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:24])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(C)n1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)n1cccc(N)c1=O
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A mixture of 2(S) methyl-2[3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl)propionate (49a) (2.75 g, 8.33 mmol), methanol (100 ml), and 10% palladium on carbon (300 mg) was stirred under an atmosphere of hydrogen for 30 min. The mixture was filtered and concentrated to afford 1.63 g (100%) of a colorless solid: 1H NMR (d6 -DMSO) δ 8.35 (1H, brs), 7.46 (1H, d), 7.22 (1H, d), 6.29 (1H, t), 5.22 (1H, q), 3.63 (3H, s), 1.55 (3H, d).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:8][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ncccc1Br
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccnc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
3-bromo-2-hydroxypyridine (1.74 g, 10 mmol) was added to a suspension of NaH (440 mg of 60% dispersion in mineral oil, 11 mmol) in DMF (10 mL), and the resultant mixture was stirred at rt for 30 min. Benzyl bromide (1.3 mL, 11 mmol) was then added, and the reaction was stirred at rt overnight. It was then quenched by the addition of water, and the product extracted with ethyl acetate (2×50 mL). The extracts were combined, washed with 1N HCl solution, then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography using hexanes to 100% ethyl acetate in hexanes as eluent to give the title compound as a colorless thick oil, (1.37 g, 52% yield). MS m/z 264, 266(MH+); 1H NMR (500 MHz, CDCl3) δ ppm 5.17 (s, 2 H) 6.05 (t, J=7.02 Hz, 1 H) 7.27-7.88 (m, 6 H) 7.70 (dd, J=7.17, 1.98 Hz, 1 H)
Reaction SMILES: FC1C=CC([C:8]2[C:17]3[C:12](=[CH:13][C:14](CN4CC(C(F)(F)F)NC[C@@H]4C)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:30]#[N:31])[CH:9]=2)=CC=1.Cl.C(=O)([O-])[O-:34].[K+].[K+]>>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[C:30]([NH2:31])=[O:34]
Reactant: C[C@H]1CNC(C(F)(F)F)CN1Cc1ccc2c(-c3ccc(F)cc3)cc(C#N)nc2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: NC(=O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(4-fluorophenyl)-7-(((2S)-2-methyl-5-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carbonitrile (275 mg, 0.642 mmol) was dissolved in conc HCl (2636 μl, 32.1 mmol) and then stirred at ambient temperature for 4 hours. The yellow solution was slowly poured into aq potassium carbonate (12.8 ml, 5M, 64 mmol) at 0° C. The resulting mixture was extracted with chloroform. The organic portion was dried over MgSO4 and concentrated. The residue was purified by preparative HPLC Chiralpak AD, 5 cm×500 cm, 50 ml/min eluting with 20% IPA/hexanes+0.1% Et□NH, to provide isomers A and B of 4-(4-fluorophenyl)-7-(((2S)-2-methyl-5(R or S)-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carboxamide as colorless foams. Isomer A, LRMS m/z (M+H)+ 447.3 found, 447.4 required 1H NMR (500 MHz, CDCl3): 8.22 (1H, s), 8.10 (2H, d, J=12.11 Hz), 7.91 (1H, d, J=8.69 Hz), 7.65 (1H, dd, J=8.72, 1.66 Hz), 7.52 (2H, dd, J=8.44, 5.36 Hz), 5.64 (1H, s), 3.89 (1H, d, J=13.93 Hz), 3.77 (1H, d, J=13.94 Hz), 3.39-3.34 (1H, m), 3.08-3.04 (1H, m), 2.94-2.87 (2H, m), 2.73 (1H, dd, J=11.54, 8.93 Hz), 2.60 (1H, dd, J=11.55, 3.62 Hz), 1.17 (3H, d, J=6.41 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:24][CH:23]([CH3:25])[CH2:22][CH:21]([CH3:26])[CH2:20]3)=[O:18])[CH:14]=[C:13]([CH2:27][S:28][CH3:29])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=O.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:34][NH2:35]>>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:34][NH:35][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:20][CH:21]([CH3:26])[CH2:22][CH:23]([CH3:25])[CH2:24]3)=[O:18])[CH:14]=[C:13]([CH2:27][S:28][CH3:29])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:2]
Reactant: COC(=O)c1nc2n(CC(=O)N3CC(C)CC(C)C3)cc(CSC)n2c(=O)c1O
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CSCc1cn(CC(=O)N2CC(C)CC(C)C2)c2nc(C(=O)NCc3ccc(Cl)c(Cl)c3)c(O)c(=O)n12
Yield: 76.4 %

Procedure:
Following the same procedure for Example 49 but using 1-[2-(3,5-dimethyl-piperidin-1-yl)-2-oxo-ethyl]-6-hydroxy-3-methylsulfanylmethyl-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester from step 2 and 3,4-dichlorobenzylamine, the title product was obtained in 76.4% yield as a yellowish amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[O:14])[CH:3]=1.C(NC(C)C)(C)C.Br[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][CH2:32][C:33]([OH:35])=[O:34])=[CH:21][CH:22]=2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCc2ccc(N)cc2)cc(N)c1C#N
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCOc1nc(C(=O)NCc2ccc(NCC(=O)O)cc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 115 (63 mg, 0.2 mmol) and N,N-diisopropylamine (40 μL, 0.22 mmol) in 0.5 mL of anhydrous N,N-dimethylformamide, was added tert-butyl bromoacetate (40 μL, 0.3 mmol). The resulting mixture was stirred at room temperature overnight, after which water was added, and the precipitate filtered. The solid was dissolved in 1 mL of trifluoroacetic acid, then stirred at room temperature for an additional hour. The mixture was concentrated, and purified via reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give 35 mg (41%, 2 steps) of the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.1 Hz, 3H), 3.46 (s, 2H), 4.30 (d, J=6.1 Hz, 2H), 4.46 (q, J=7.3 Hz, 2H), 6.46 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.3 Hz, 2H), 7.07 (s, 1H), 7.28 (bs, 2H), 8.76 (t, J=6.2 Hz, 1H). MS (ESI+) m/e=370 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].C[CH2:37][N:38]([CH:42]([CH3:44])C)[CH:39]([CH3:41])C.[C:45]([O:63]N1C(=O)CCC1=O)(=O)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([O:54]N1C(=O)CCC1=O)=O>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH3:35])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:52](=[O:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:44]3[C:32]4[C:41](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=4)[CH2:39][N:38]([CH3:37])[CH2:42]3)[CH:18]=2)(=[O:16])=[O:15])=[O:63])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCCCCCC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)CCCCCCC(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 28.3 %

Procedure:
To a solution of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (compound 28) (54.5 mg, 0.1 mmol) in DMF (0.20 mL) was added DIEA (15.5 mg, 0.12 mmol) and bis(2,5-dioxopyrrolidin-1-yl) octanedioate (18.4 mg, 0.05 mmol). The reaction was stirred at room temperature for 3 hours at which point an additional 0.03 mmol of compound 28 was added. After a further hour the solvent was removed and the resulting residue dissolved in acetonitrile/water (1:1) and purified by preparative HPLC to give the title compound (17.4 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): 7.89 (d, 2H), 7.78 (s, 2H), 7.64 (t, 2H), 7.52 (m, 4H), 6.83 (s, 2H), 4.81 (m, 4H), 4.45 (d, 2H), 3.89 (dd, 2H), 3.61 (m, 18H), 3.55 (m, 10H), 3.47 (m, 5H), 3.33 (m, 5H), 3.14 (s, 7H), 3.04 (t, 4H), 2.16 (t, 4H), 1.55 (m, 4H), 1.29 (m, 4H). MS (m/z): 1231.87 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10]C(=O)C[C:7]2=[O:13].C([O:18]O)(C)(C)C.C[O-].[Na+].O>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([OH:13])=[O:18])[C:11]=1[NH2:10]
Reactant: O=C1CC(=O)c2cccc(F)c2N1
Reactant: CC(C)(C)OO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Nc1c(F)cccc1C(=O)O
Reaction time: 48 h
Yield: 376 %

Procedure:
A solution of 0.1 g (0.6 mmol) of 8-fluoroquinolin-2,4-dione, 0.1 g (7.8 mmol) of 70 percent t-butyl hydroperoxide, 0.2 g of 25 percent sodium methoxide in methanol and an additional 2 mL of methanol was heated at 75° C. with stirring for 48 hr. An additional 0.2 g of t-butyl hydroperoxide and 0.5 mL of 25 percent sodium methoxide in methanol were added and heating was continued for 24 more hr. The reaction mixture was cooled, poured into water, and neutralized with acetic acid. The mixture was extracted with methylene chloride and the organic phase was collected. Evaporation of the solvent gave 0.35 g (40 percent yield) of 3-fluoroanthranilic acid, mp 172° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.[Br:13][CH3:14]>C(#N)C>[Br-:13].[CH3:14][N+:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:6]=[C:2]([NH2:1])[S:3][CH:4]=2)[CH:8]=1
Reactant: Nc1nc(-c2cccnc2)cs1
Reactant: CBr
Solvent: CC#N
Product: C[n+]1cccc(-c2csc(N)n2)c1
Product: [Br-]
Temperature: 90 °C
Reaction time: 20 h

Procedure:
A suspension of 3-(2-amino-thiazol-4-yl)pyridine (12.84 g) in acetonitrile (450 ml) containing bromomethane (6.84 g) was heated in stirring autoclave at 90° C. for 20 h.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#N)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[CH2:14]([Mg]Cl)[CH2:15][CH3:16].C1C[O:22]CC1>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:22])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2cc(C#N)ccc21
Reactant: C1CCOC1
Reactant: CCC[Mg]Cl
Product: CCCC(=O)c1ccc2c(c1)CCCN2C
Temperature: 50 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 1-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (4.53 g, 26.3 mmol) in THF (30 mL) was added n-PrMgCl (2.0M in ether, 26.3 mL, 52.6 mmol, 2.0 eq) at room temperature. Then the mixture was heated to 50° C. and stirred overnight. The reaction was quenched with ice cold 1N HCl and stirred overnight. The biphasic mixture was extracted by CH2Cl2 (3×40 mL). The combined organic layers were dried over Na2SO4 then concentrated to give a crude product which was purified by flash column chromatography (0-25% EtOAc in hexanes) to afford the title compound (2.94 g, 13.5 mmol, 51%).
Reaction SMILES: OCCCCCC[N:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[CH:9]1.[NH+]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(C[CH2:28][O:29][P:30](=[O:33])([O-:32])[O-:31])#N.[NH+]1C=CC=CC=1>>[CH3:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]2[N:10]=[C:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:28][O:29][P:30](=[O:31])([OH:33])[OH:32])[NH:8][C:12]=2[CH:13]=1
Reactant: c1cc[nH+]cc1
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: Cc1cc2ncn(CCCCCCO)c2cc1C
Product: Cc1cc2nc(CCCCCCOP(=O)(O)O)[nH]c2cc1C

Procedure:
Using 0.2 g of the crude 1-(6-hydroxyhexyl)-5,6-dimethylbenzimidazole and 2 ml of a 2-cyanoethylphosphoric acid pyridinium salt solution (1 mmol/ml), and subsequently following the same procedures as in Example 1, 0.35 g of crude 6-(5,6-dimethylbenzimidazolyl)hexylphosphoric acid was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1.[O:33]1[CH2:38][CH2:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH2:34]1>>[O:33]1[CH2:38][CH2:37][CH:36]=[C:35]([C:12]2[N:11]=[CH:10][C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:26]2[CH:27]=[N:28][CH:29]=[C:24]([F:23])[CH:25]=2)=[CH:7][CH:6]=4)[CH2:34]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: OB(O)c1cncc(F)c1
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cncc(F)c3)ccc1Oc1cnc(C3=CCCOC3)cc12

Procedure:
The titled compound was synthesized by steps analogous to those described in method A1 above, but using intermediate 18B, 5-fluoropyridin-3-ylboronic acid and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH3:2].[Li+].[CH3:14]C([N-]C(C)C)C.CN(P(N(C)C)(N(C)C)=O)C.CI.Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH3:14])[CH3:2]
Reactant: CCOC(=O)CC1CCOCC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)C1CCOCC1
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of (Tetrahydro-pyran-4-yl)-acetic acid ethyl ester (2.0 g, 11.6 mmol) in 50 mL of THF at −78° C. LDA (1.0 M, 17.4 mL, 34.8 mmol) is added dropwise. The solution is stirred for 0.5 h and treated with HMPA (3.2 mL, 9.3 mmol) and MeI (4.94 g, 34.8 mmol). The reaction mixture is stirred at the same temperature for 0.5 h and for 1.5 h at 0° C., acidified with aqueous 1 N aqueous HCl solution, and extracted twice with ether (2×40 mL). The organic phase is washed with saturated aqueous NaCl solution, dried (MgSO4), and concentrated in vacuo to give 1.8 g of 2-(Tetrahydro-pyran-4-yl)-propionic acid ethyl ester which is hydrolyzed without further purification. A solution of the crude ester (500 mg, 2.68 mmol) and 5 N aqueous NaOH solution (2.68 mL, 13.4 mmol) in dioxane-water (4 mL/2 mL) is heated at 60° C. for 2 h. The solution is cooled to room temperature, acidified with 1 N aqueous HCl solution, and extracted with ether. The ether layer is washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated in vacuo to give 400 mg of the title compound. MS: 159 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 2 min then 100% CH3CN+0.1% TFA for 1 min, flow 0.5 ml/min): 1.27 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51](O)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)([O-:41])=[O:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:51]2[CH:50]=[CH:49][C:48]([C:45]3[CH:46]=[CH:47][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=3)=[CH:53][CH:52]=2)[N:15]=1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)cs1
Yield: 74.1 %

Procedure:
To a solution of 2-{[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (2.7 g) synthesized in Example 4 in tetrahydrofuran (15 ml) were added triphenylphosphine (2.5 g) and 4-(4-nitrophenyl)phenol (12.1 g), and the mixture was stirred under ice-cooling for 5 min. To the solution was added diisopropyl azodicarboxylate (40% toluene solution, 4.7 ml), and the mixture was stirred at room temperature overnight. To the solution were further added triphenylphosphine (1.2 g) and diisopropyl azodicarboxylate (40% toluene solution, 2.4 ml), and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was concentrated, extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (3.3 g) as a pale-brown solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH2:16][CH3:17])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(C(C)C)C(C)C)C.[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:39][CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=3[NH:35][C:34]2=[O:44])[CH2:29][CH2:28]1.C1C[O:48][CH2:47]C1>>[CH2:16]([C:10]1[CH:9]=[C:8]([CH2:7][C@@H:2]([NH:1][C:47]([N:27]2[CH2:28][CH2:29][CH:30]([N:33]3[CH2:39][CH2:38][C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[NH:35][C:34]3=[O:44])[CH2:31][CH2:32]2)=[O:48])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:15])[CH3:17]
Reactant: C1CCOC1
Reactant: CCc1ccc(C[C@@H](N)C(=O)OC)cc1CC
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OC)cc1CC

Procedure:
The mixture of 41.7 g (0.153 mol) methyl (R)-2-amino-3-(3,4-diethyl-phenyl)-propionate, 800 mL THF and 28 mL (0.161 mol) ethyldiisopropylamine was combined with 25.4 g (0.157 mol) CDT and then 38.0 g (0.155 mol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one while cooling with an ice bath and refluxed for 3 h with stirring. The reaction mixture was then extracted with 300 mL 10% citric acid solution, three times with 100 mL aliquots of water and 200 mL saturated NaCl solution, dried and evaporated down under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[C:15]1([C:21]2[O:25][CH:24]=[N:23][C:22]=2[C:26](O)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:26]([C:22]2[N:23]=[CH:24][O:25][C:21]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:27])[CH:9]=[N:8]1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Product: CC(F)(F)CCCCn1cc(NC(=O)c2ncoc2-c2ccccc2)cn1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[C:6]([C:8]([CH3:14])([CH3:13])[C:9](OC)=[O:10])#[N:7]>C1COCC1>[CH3:13][C:8]([CH3:14])([C:9](=[O:10])[CH2:2][C:1]#[N:3])[C:6]#[N:7]
Reactant: COC(=O)C(C)(C)C#N
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)C(=O)CC#N
Yield: 62.5 %

Procedure:
A solution of anhydrous acetonitrile (2.3 g, 56 mmol) in THF (100 mL) was added dropwise at 80° C. to a mixture of NaH (60%, 2.8 g, 70 mmol) and methyl 2-cyano-2-methylpropanoate (6 g, 47 mmol) in THF (100 mL). The resultant reaction mixture was heated at reflux for 8 hours. The solvent was removed in vacuo and the residue was diluted with EtOAc and washed with 10% HCl, water and brine. The organics were dried (MgSO4) and concentrated in vacuo to obtain crude 2,2-dimethyl-3-oxopentanedinitrile (4 g), which was used for the next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1([Cl:18])[C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26].O>CCOCC>[Cl:1][C:2]1([Cl:18])[C@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:25](=[O:27])[CH3:26])=[CH:15][CH:16]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccc([C@H]2[C@@H](c3ccccc3)C2(Cl)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Oc1ccc([C@H]2[C@@H](c3ccccc3)C2(Cl)Cl)cc1
Yield: 31.1 %

Procedure:
A 10 mL solution of 1,1-dichloro-cis-2-(p-hydroxyphenyl)-3-phenylcyclopropane (Compound 9) (0.009 mol) and pyridine (0.79 g, 0.01 mol) in Et2O was heated under nitrogen to a gentle reflux, while acetyl chloride (0.78 g, 0.01 mol) was added dropwise slowly via a cannula. A white precipitate was noted immediately, and the mixture was refluxed for 1 h. The reaction flask was cooled while 5 mL of water was added dropwise. Et2O was used to extract the aqueous layer, and the combined Et2O layers were washed with 5% H2SO4, followed b a saturated NaHCO3 solution. Drying with anhydrous Na2SO4, and evaporation of ether gave a dark-yellow oil, which was chromatographed on a silica gel column and eluted with (3:1) CH2Cl2 /petroleum ether to provide a light-yellow oil (0.9 g, 31%). 1H NMR (CDCl3) δ 2.28 (s, 3H, OCOCH3), 3.30 (s, 2H, ArCH), 7.04 (s, 5H, ArH), 7.28 (m, 4H, ArH).
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:36])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=3[S:20](=[O:34])(=[O:33])[N:19]=2)[C:8]1=[O:35].[OH-].[Na+:40]>O>[CH3:1][C:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:36])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O-:17])=[C:9]([C:18]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=3[S:20](=[O:34])(=[O:33])[N:19]=2)[C:8]1=[O:35].[Na+:40]
Reactant: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A suspension of the product of Example 37C (0.302 g) in water (10 mL) was treated with 0.997N sodium hydroxide solution (0.545 mL, 0.540 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.308 g, 98%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.58 m, 1 H) 0.73 m, 9 H) 0.95 m, 5 H) 1.38 m, 3 H) 1.71 m, 1 H) 2.13 m, 1 H) 2.94 m, 3 H) 7.32 m, 3 H) 7.46 m, 3 H) 8.04 m, 1 H) 9.88 m, 1 H) 15.46 m, 1 H). MS (ESI−) m/z 558 (M−H)−.