Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[NH:16][CH:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[O:20])[CH2:11]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[N:16]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[O:20])[CH2:11]1
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a suspension of 60% sodium hydride (0.18 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindol-4-one (1.0 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added methanesulfonylchloride (0.53 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 9 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-chlorophenyl)-1-methanesulfonyl-3-methyl-4,5,6,7-tetrahydroindol-4-one (0.3 g).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:11]2[CH:23]=[CH:22][C:14]3[O:15][C:16]([CH3:21])([CH3:20])[O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:49]([C:56]1[CH:63]=[CH:62][C:59]([CH2:60][NH2:61])=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.Cl>C1COCC1>[CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:61][CH2:60][C:59]3[CH:62]=[CH:63][C:56]([O:49][C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[CH:57][CH:58]=3)=[O:30])=[CH:32][CH:33]=2)[C:11]2[CH:23]=[CH:22][C:14]3[O:15][C:16]([CH3:21])([CH3:20])[O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)O)cc3)C(=O)CCC3CCCC3)ccc2O1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)NCc4ccc(Oc5ccccc5)cc4)cc3)C(=O)CCC3CCCC3)ccc2O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of 4-{[(3-cyclopentylpropanoyl)(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)amino]methyl}benzoic acid (212 mg) in THF (2 mL) was added NMM (57 mg). The mixture was chilled at 0° C. and isobutyl chloroformate was added at once (86 mg). The mixture was stirred for 15 min. at 0° C. then 4-phenoxybenzylamine (103 mg) was added and the resulting reaction mixture was stirred 3 h at rt. An aqueous solution oh HCl (1N, 2 mL) was added and the resulting mixture was extracted with Et2O. The combined organic layers were washed with water, brine, dried over MgSO4 filtered and evaporated to give a light yellow oil. Purification by chromatography (SiO2) gave the title compound as a colorless oil (241 mg, 81%). 1H NMR (CDCl3) δ 7.56-7.42 (m, 3H), 7.21-7.00 (m, 6H), 6.95-6.67 (m, 7H), 6.21 (t, J=4.9 Hz, 1H), 4.69 (s, 2H), 4.42 (s, 1H), 4.40 (s, 1H), 1.87 (t, J=7.2 Hz, 2H), 1.54 (s, 6H), 1.48-1.14 (m, 9H), 0.85-0.64 (m, 2M). M+(ESI): 633.0; M−(ESI): 631.0. HPLC, Rt: 5.3 min (purity: 97.7%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:5]
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1c(C(=O)c2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2-Methyl-3-nitrobenzoyl chloride (9.98 grams; 0.05 mole) was dissolved in 35 mls. of dry benzene and the solution was added to a slurry of aluminum chloride (13.3 grams; 0.10 mole) in 40 mls. of dry benzene over a period of 10 minutes. The resulting reaction mixture was stirred at room temperature for 21/2 hours, then heated at reflux for 2 hours and cooled to room temperature. The cooled reaction mixture was poured into 200 mls. of dilute hydrochloric acid, stirred for about 15 minutes and allowed to settle. The organic phase was separated and the aqueous phase was back extracted with 200 mls. of benzene. The benzene layer was separated and combined with the organic phase and the combined solution was washed successively with water, a dilute aqueous solution of sodium carbonate, and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and distilled to obtain 2-methyl-3-nitrobenzophenone (11.45 grams; 95% yield; b.p. 183° C. at 2 mm; m.p. 42° C. after recrystallization from
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[N:22]1([CH2:31][C:32](O)=[O:33])[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24]>>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:33])[CH2:31][N:22]3[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]3=[O:24])[CH2:14][C:13]2=[O:18])(=[O:10])=[O:11])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)N2CCNCC2=O)c([N+](=O)[O-])c1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N2CCN(C(=O)Cn3cc(C)c(=O)[nH]c3=O)CC2=O)c([N+](=O)[O-])c1
Yield: 95.4 %

Procedure:
The title compound (888 mg, 95%) was synthesized by reaction of 1-(4-methyl-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (672 mg, 2.0 mmol) with (thymin-1-yl)-acetic acid (369 mg, 2.0 mmol) as per the procedure of example 64. 1H-NMR (500 MHz; DMSO-d6) δ 11.33 (s, 0.6H), 11.32(s, 0.4H), 8.22(m, 1H), 7.96(s, 1H), 7.78(m, 1H), 7.35(s, 0.6H), 7.28(s, 0.4H), 4.66(s, 1.2H), 4.58 (s, 0.8H), 4.39 (s, 0.8H), 4.24 (s, 1.2H), 4.01 (m, 1.2H), 3.93 (m, 1.2H), 3.88˜3.81 (m, 1.6H), 2.49 (s, 3H), 1.74 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Br)nccc2c1
Reaction time: 0.5 h

Procedure:
1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (see Example 70, step 3; 0.100 g, 0.150 mmol) was dissolved in DCM (1 mL). TFA (0.1 mL, 1.298 mmol) was added and the reaction was stirred for 30 minutes. The reaction was concentrated and the material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM) to afford 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.92 (br. s., 1H), 8.74 (d, J=5.8 Hz, 1H), 8.62 (d, J=1.4 Hz, 1H), 8.31-8.18 (m, 2H), 7.97 (d, J=7.9 Hz, 1H), 7.91 (dd, J=1.7, 8.9 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.29 (d, J=4.3 Hz, 1H), 6.88 (d, J=4.5 Hz, 1H). m/z (ESI) 514.0 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([Sn](C=C)(CCCC)CCCC)[CH2:27]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH:26]=[CH2:27])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1

Procedure:
The title compound was prepared from 44 mg of 2-[(S)-1-phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine, 87 μL tributylstannyl ethylene and 1.15 mg Pd(PPh3)4 using the procedure described in EXAMPLE 273 to give 8.5 mg of the title compound. RF: 0.45 (5% MeOH in CH2Cl2). 1H NMR (500 MHz, 1:1 CD3OD/CDCl3): δ 1.59 (d, J=6.8 Hz, 3H), 5.13 (m, 1H), 5.24 (d, J=11.2 Hz, 1H), 5.76 (d, J=17.4 Hz, 1H), 6.79 (dd, J=17.6, 11 Hz, 1H), 6.87 (d, J=5.7 Hz, 1H), 7.21 (br s, J=7.3 Hz, 1H), 7.27-7.34 (m, 3H), 7.41 (br s, J=7.3 Hz, 2H), 7.6-7.8 (m, 1H), 7.67 (br s, 1H), 8.31 (br s, J=5.7 Hz, 1H), 8.55-8.7 (m, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 342.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>ClCCl>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19])=[CH:3][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0° C. under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10° C. After the addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2×200 mL), saturated ammonium chloride solution (2×200 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford a white solid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g, 98%): mp 157-159° C. 1H NMR (CDCl3/300 MHz) 7.61 (ab, 4H, J=8.7, Δν=28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H+, Calc'd 246.1106). Anal. Calc'd for C12H14F3NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:16][CH2:17][CH2:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>>[NH2:19][CH2:18][CH2:17][CH2:16][N:15]([C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1ccccc1N(CCCN1C(=O)c2ccccc2C1=O)c1ncccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Product: NCCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
Alternately, the product of Example 10, 2-[3-[(2-benzoylphenyl)(3-nitro-2-pyridinyl)amino]propyl]-1H-isoindole-1,3-(2H)dione is reacted with alcoholic hydrazine hydrate and acid to give the title compound.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26].[Li+].CC([N-]C(C)C)C.C(Br)C=C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]([CH2:7][CH:5]=[CH2:6])[C:28]([O:30][CH3:31])=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC(C(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a solution of N,N-diisopropylamine (1.79 mL, 12.8 mmol) in tetrahydrofuran (10.0 mL, 123 mmol) was added 2.50 M of n-butyllithium in hexane (4.68 mL, 11.7 mmol) dropwise at 0° C. The solution was stirred under an atmosphere of Nitrogen for 10 min, and then cooled to −78° C. A solution of methyl 3,4-dichlorophenylacetate (2.27 g, 10.4 mmol) in tetrahydrofuran (10.0 mL) was added to the LDA solution dropwise via cannula. After 10 min of stirring, the reaction was warmed to 0° C. for 1 hr. The solution was cooled back to −78° C., and allyl bromide (2.24 mL, 25.9 mmol) was added in one portion. In 10 min, the reaction was warmed back to 0° C. After 1 hr of stirring, the reaction was quenched with NH4Cl sat soln and extracted with EtOAc (×3). The combined organic layer was dried and concentrated to provide an orange oil. Further purification on a silica gel column (gradient elution, 0-10% EtOAc/hexanes) provided methyl 2-(3,4-dichlorophenyl)pent-4-enoate as a colorless oil (2.47 g, 92.0% yield). 1H NMR (400 MHz, CDCl3) δ 7.43-7.37 (m, 2H), 7.18-7.12 (dd, J=8.3, 2.1 Hz, 1H), 5.73-5.60 (ddt, J=17.1, 10.2, 6.8 Hz, 1H), 5.12-4.98 (m, 2H), 3.70-3.64 (s, 3H), 3.63-3.55 (t, J=7.8 Hz, 1H), 2.85-2.71 (m, 1H), 2.55-2.43 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH2:23](Br)[C:24]#[CH:25].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH2:25][C:24]#[CH:23])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 1-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and propargyl bromide with sodium hydride in dimethylformamide there is obtained 1-[4-bromo-2-fluoro-5-(2-propynyloxy)-phenyl]-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 136°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[O:4][CH:5]([CH3:9])[C:6]([NH2:8])=O.F[B-](F)(F)F.C[O+](C)C.C(Cl)Cl.[CH2:27](N)[CH2:28][NH2:29]>C(O)C>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[O:4][CH:5]([C:6]1[NH:29][CH2:28][CH2:27][N:8]=1)[CH3:9]
Reactant: NCCN
Reactant: CC(Oc1c(Cl)cccc1Cl)C(N)=O
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC(Oc1c(Cl)cccc1Cl)C1=NCCN1
Temperature: 0 °C

Procedure:
A mixture of 25 (25 g, 106.8 mmol), trimethyloxonium tetrafluoroborate (16.6 g, 110 mmol) and CH2Cl2 (600 mL) was stirred for 36 hours, during which the coarse suspension changed to a clear, colorless solution. Cooling of this solution of 0° C. was followed by a dropwise addition of ethylene diamine (7.00 g, 1.1 equiv) over 10 minutes. The resulting solution was warmed to room temperature, diluted with absolute ethanol (200 mL) and then evaporated to dryness. The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. Recrystallization of the residue from boiling hexanes (500 mL) afforded pure 3 as white needles that were removed by filtration and dried in air (23.52 g, 85%). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.46-7.44 (m, 2H, Ar), 7.14 (t, J=7.8 Hz, 1H, Ar), 6.45 (s, 1H, NH), 4.79 (q, J=6.6 Hz, 1H), 3.43-3.37 (s, br, 4H), 1.47 (d, J=6.6 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ ppm 166.3, 150.0, 130.0, 129.6, 129.5, 129.2, 126.6, 77.3, 50.4 (very broad), 19.2; mp=129-130° C. (hexanes); [α]23D=−80.2° (c 1.0, EtOH) (lit.4 [α]20D=−76.4° (c 1.0, EtOH).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20](OC2C=CC([N+]([O-])=O)=CC=2)=[O:21])[C:3]1=[O:32].[CH2:33]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1)[CH3:34].C(N(CC)CC)C>CN(C=O)C>[CH2:33]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:20]([NH:19][C@@H:4]2[N:5]=[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:32])=[O:21])[CH:38]=1)[CH3:34]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CN1C(=O)[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
(R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (150 mg, 0.35 mmol), 3-aminobenzoic acid ethyl ester (61 mg, 0.37 mmol), and triethylamine (52.5 mg, 0.52 mmol) were combined in DMF (2 ml) and heated at 45° overnight. The DMF was removed in vacuo and the residue crystallized from ethyl acetate to provide the title compound: (mp 140°-142° C.).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:17][CH2:18][NH2:19])[CH3:3].C(N(CC)CC)C.[C:28]([C:30]1[CH:31]=[CH:32][C:33]([O:40][CH3:41])=[C:34]([S:36](Cl)(=[O:38])=[O:37])[CH:35]=1)#[N:29]>O1CCCC1.O>[CH2:2]([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:17][CH2:18][NH:19][S:36]([C:34]1[CH:35]=[C:30]([C:28]#[N:29])[CH:31]=[CH:32][C:33]=1[O:40][CH3:41])(=[O:38])=[O:37])[CH3:3]
Reactant: COc1ccc(C#N)cc1S(=O)(=O)Cl
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.5 %

Procedure:
To a stirred solution of 326 mg of ethyl[2-(2-aminoethyl)-5-isopropylphenoxy]acetate hydrochloride and 0.452 mL of triethylamine in a mixture of 10 mL of tetrahydrofuran and 5 mL of water was added 238 mg of 5-cyano-2-methoxybenzenesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added 30 mL of water, and the mixture was extracted with 120 mL of ethyl acetate. The organic layer was washed with 100 mL of water, and 100 mL of brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 343 mg of ethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[NH2:13]Cl>CN(C=O)C>[NH2:13][N:4]1[CH:5]=[CH:6][C:2]([Cl:1])=[C:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: NCl
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)ccn1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a stirred solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (1.00 g, 6.30 mmol) in DMF (15 mL) was added NaH (0.45 g, 18.80 mmol, 99%, dry) and the contents were stirred for 1 h at ambient temperature. NH2Cl (42.0 mL, 0.327 g, 6.30 mmol) was added at −10° C. to the reaction mixture and the contents were stirred for another 30 min at −10° C. The solvents were removed under reduced pressure and the residue was extracted with MTBE. The MTBE layer was passed through anhydrous Na2SO4 and concentrated under reduced pressure to give a brown solid. The crude residue was purified by CombiFlash (REDISEP®, silica gel, 40 g, 20% EtOAc/hexanes) to give a methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (0.750 g, 69.0%) as a yellow solid. LCMS Condition B-23: retention time 0.68 min, [M+1]=175.1. 1H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 6.11 (d, J=2.8 Hz, 1H), 6.28 (s, 2H), 7.06 (d, J=2.8 Hz, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[S:27]([CH3:30])(=[O:29])=[O:28])[CH:12]=[CH:11][C:10]=1[N:31]1[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[S:27]([CH3:30])(=[O:28])=[O:29])[CH:12]=[CH:11][C:10]=1[N:31]1[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]1
Reactant: CS(=O)(=O)N1Cc2ccccc2C[C@H]1/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)N1Cc2ccccc2C[C@H]1CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-{2-benzyloxy-4-[(E)-2-((S)-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-vinyl]-phenyl}-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.090 g, 0.16 mmol) in EtOH (4 mL) is added a slurry of 10% Pd/C (0.1 g) in EtOH (6 mL). The reaction vessel is flushed twice with H2 and stirred at RT for 18 h under balloon pressure of H2. The mixture is filtered and purified by reverse phase chromatography using a gradient of 15 to 40% EtOH/water to afford the title compound as a white solid: LC retention time=1.0 min (Method A); (M+NH4)+=465.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@H:12]([O:14]S(C)(=O)=O)[CH2:11][CH2:10][N:9]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:3]=1.[C:26]([O-])(=[O:28])[CH3:27].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:26]([O:14][C@@H:12]1[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13]1)(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C[C@H]1c1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(F)cc2)C1
Yield: 55.6 %

Procedure:
A solution of (±)-(2S,4R)-tert-butyl 2-(4-fluorophenyl)-4-(methylsulfonyloxy)piperidine-1-carboxylate (0.30 g, 0.80 mmol) and sodium acetate (0.33 g, 4.0 mmol) in dimethylsulfoxide (15 mL) was heated to 90° C. for 2.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate (40 mL), and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes 1:10) to give (±)-(2R,4R)-tert-butyl 4-acetoxy-2-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 49% yield). 1H NMR (400 MHz, d6-DMSO): 7.24 (m, 4H), 5.14 (br s, 1H), 4.63 (m, 1H), 4.00 (br d, 1H), 2.72 (m, 1H), 2.56 (br d, 1H), 1.88 (s, 3H), 1.84 (br d 1H), 1.78 (m, 1H), 1.44 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: Cl.O.[Br:3][C:4]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:5]=1[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(CC)CC>CO.[Fe]>[Br:3][C:4]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:5]=1[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCN(CCCCCC)c1ccc(N)cc1Br
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
A mixture of concentrated hydrochloric acid (4.0 mL), water (100 mL) and iron powder (13.44 g, 241 mmol) was stirred at 65° C. for 15 min. The aqueous layer of the mixture was poured out, and a solution of 2-bromo-N,N-dihexyl-4-nitroaniline (9.28 g, 24.1 mmol) in MeOH (150 mL) was added to the above processed iron powder. The mixture was acidified to pH 3 with hydrochloric acid and stirred at 65° C. for 30 min. The mixture was then cooled to rt, adjusted to pH 10 with Et3N and filtered and the filtrate was concentrated. The residue was dissolved in 150 mL of DCM and the solution was washed with water (100 mL×3) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=20:1) to give the title compound as colorless oil (4.40 g, 51%).