Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[N:18]1[C:22]([NH:23][CH3:24])=[C:21]([S:25][C:26]([F:29])([F:28])[F:27])[C:20]([C:30]#[N:31])=[N:19]1.[H-].[Na+].CCCCCCC.C(OCC)(=O)C>O1CCCC1.O>[Cl:5][CH2:4][CH2:3][CH2:2][N:23]([C:22]1[N:18]([C:8]2[C:9]([Cl:17])=[CH:10][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:7]=2[Cl:6])[N:19]=[C:20]([C:30]#[N:31])[C:21]=1[S:25][C:26]([F:29])([F:28])[F:27])[CH3:24]
Reactant: CNc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(CCCCl)c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
1-Bromo-3-chloropropane (1.62 g, 1.6 mmol) was added to a mixture of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-methylamino-4-trifluoromethylthiopyrazole (3.0 g, 6.9 mmol) and sodium hydride (0.35 g, 8.9 mmol) in tetrahydrofuran (45 ml) under a nitrogen atmosphere, and the mixture heated under reflux for 6 hours. After extractive workup (heptane-ethyl acetate, water) and chromatography the title product was obtained as a solid (1.83 g); 1H-NMR: 1.81 (2H), 2.88 (3H), 3.21 (2H), 3.37 (2H), 7.80 (2H); 19F-NMR: −44.8; −64.2 ppm.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:17]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[N:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])(=O)C.[K+].[ClH:37]>CN(C=O)C.CCO.O.CCOC(C)=O.C(OCC)C.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>[ClH:37].[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:9]2[CH:10]=[C:11]3[C:17]([NH:18][C:19]([CH:21]4[CH2:22][CH2:23]4)=[O:20])=[N:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:27]=1
Reactant: CC1(C)OB(c2cnc3[nH]nc(NC(=O)C4CC4)c3c2)OC1(C)C
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(Nc1n[nH]c2ncc(-c3cccnc3)cc12)C1CC1

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) was added to a stirred and degassed solution of cyclopropanecarboxylic acid [5-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]amide (Description 7; 200 mg, 0.61 mmol), 3-bromopyridine (193 mg, 1.22 mmol) and potassium acetate (179 mg, 1.83 mmol) in DMF (2 mL), EtOH (1 mL) and H2O (1 mL) and the reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was dissolved in EtOAc (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic extracts were dried (magnesium sulfate) and concentrated. The crude residue was triturated with dichloromethane and a white solid was obtained. This solid was treated with hydrogen chloride (g) in diethyl ether to afford the corresponding salt as a powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=O)[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:39]1[C:43]2C=CC=C[C:42]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O1CCCC1.C(N)C>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH2:43]([NH:39][C:34](=[O:36])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:32][CH2:31]1)[CH3:42]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.7 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and 2M ethylamine tetrahydrofuran solution (0.29 mL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and crystallized from acetonitrile. The obtained crystals were recrystallized from ethyl acetate and diethyl ether to give the title compound (80 mg, yield 51%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][C:16]1([CH3:22])[CH2:20][CH2:19][CH2:18][C@H:17]1[NH2:21].C(C1C=NN2C=C(C(OCC)=O)C=C2C=1N[C@@H]1CCCC1(C)C)(=O)N.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:21][C@@H:17]3[CH2:18][CH2:19][CH2:20][C:16]3([CH3:22])[CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC1(C)CCC[C@H]1N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: CCOC(=O)c1cc2c(N[C@@H]3CCCC3(C)C)c(C(N)=O)cnn2c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 300 mg, 1.093 mmol) and (R)-2,2-dimethylcyclopentanamine (from Step 3 of Intermediate 5, 164 mg, 1.093 mmol) in DMF (4 mL) was added DIPEA (0.573 mL, 3.28 mmol). The mixture was heated at 120° C. for 60 min in a microwave reactor. Water (4 volumes) was added and the resulting suspension was stirred for 1 h. The solids were filtered, rinsed with water (2×), and then dried to afford the title compound (324 mg, 84% yield) as a pale yellow solid. HPLC (conditions 0): retention time=4.07 min; LCMS: 351.01 (M+), 353.00 (M+2); 1H NMR (methanol-d4, 400 MHz) δ 8.14 (s, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H), 4.15 (t, J=7.3 Hz, 1H), 2.32 (m, 1H), 1.61-1.86 (m, 5H), 1.13 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: Nc1ccc(I)cc1F
Reactant: Cn1nc(C(=O)O)c(Cl)cc1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 130.1 %

Procedure:
To a solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (350 mg, 1.855 mmol) and 2-fluoro-4-iodoaniline (1.06 g, 4.453 mmol) in tetrahydrofuran (13.3 mL) was sparged with nitrogen for 5 minutes followed by the slow addition of lithium bis(trimethylsilyl)amide, 1.0 M in THF (7.4 mL). The reaction mixture stirred for an additional 4 hours at room temperature. The mixture was quenched with 1 N HCl and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N aqueous HCl. The aqueous layer was extracted (3×) with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (939 mg, 100% yield). 1H NMR (CDCl3): 7.27 (dd, 1H), 7.21 (d, 1H), 6.54 (t, 1H), 4.84 (broad s, 2H), 2.09 (s, 1H), 1.26 (t, 3H); MS (EI) for C12H9N3O3FI: 389 (MH+).
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].[H-].[Na+].I[CH2:41][CH3:42]>O1CCCC1>[C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([N:30]([CH2:41][CH3:42])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)piperidin-3-ylcarbamate (130 mg, 0.25 mmol) in tetrahydrofuran (2 mL) was added sodium hydride as a 60% dispersion in mineral oil (20 mg, 0.5 mmol) followed by iodoethane (0.06 mL, 0.75 mmol) and reaction mixture was stirred overnight at ambient temperature. The reaction was quenched with water (30 μL), diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-60% ethyl acetate in heptane) to afford the title compound as a colorless oil, which was used in the next step without any further purification (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.O=[C:23]([CH2:27][CH:28]=[CH2:29])[C:24]([OH:26])=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([C:24]([OH:26])=[O:25])[CH2:27][CH:28]=[CH2:29])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: C=CCC(=O)C(=O)O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Product: C=CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O

Procedure:
In the manner given in Example 9, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with 2-oxo-4-pentenoic acid at room temperature to give 7-chloro-2-[(1-carboxy-3-butenylidene)-hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.C([O-])(=O)C.[Na+].[Br:22]Br>C(O)(=O)C.O>[ClH:1].[Br:22][C:10]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N2CCNCC2)ccc1Br
Reaction time: 1 h

Procedure:
To a solution of 2.33 g (8.8 mmol) of 1-(3-Methoxyphenyl)piperazine dihydrochloride and 756 mg (9.7 mmol) sodium acetate in 70 mL of acetic acid and 15 mL of water at 0° C. was added 1.55 g (9.7 mmol) bromine. After 1 hour, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was acidified with 2M HCl in ether. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.36 (d, 1H), 6.73 (s, 1H), 6.50 (d, 1H), 3.75 (s, 3H), 3.32 (m, 8H) ppm.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[N:7]=[C:6]([CH2:17][CH3:18])[C:5]=1[C:19]#[N:20])[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl>[CH2:21]([N:3]([CH2:1][CH3:2])[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:7]=[C:6]([CH2:17][CH3:18])[C:5]=1[C:19]#[N:20])[CH3:22]
Reactant: CCc1nn(-c2ccc(OC)cc2)c(N(CC)CC)c1C#N
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCc1nn(-c2ccc(O)cc2)c(N(CC)CC)c1C#N
Yield: 97.4 %

Procedure:
The 5-(diethylamino)-3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (39 mg, 0.13 mmol) from above was dissolved in CH2Cl2 (5 mL) and BBr3 (1 M solution in DCM, 1 mL, 1.0 mmol) was added and stirred over night. CH2Cl2 and water were added and the phases were separated, the aqueous phase was again extracted with EtOAc/CH2Cl2 (1:1). The solution was dried using a phase separator and concentrated under reduced pressure. Purification using preparative IIPLC gave 5-(diethylamino)-3-ethyl-1-(4-hydroxyphenyl)-1H-pyrazole-4-carbonitrile (36 mg, 97%).
Reaction SMILES: [Br-:1].[CH3:2][C:3]1[N:4]=[C:5]([N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH2+:11][N:10]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:6][C:7]=1[CH3:8].N=NC=NN>C(=O)=O>[CH3:2][C:3]1[N:4]=[C:5]([N+:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[S:6][C:7]=1[CH3:8].[Br-:1]
Reactant: Cc1nc(N2N=C(c3ccccc3)[NH2+]N2c2ccccc2)sc1C
Agent: N=NC=NN
Agent: O=C=O
Agent: [Br-]
Product: Cc1nc(-[n+]2nc(-c3ccccc3)nn2-c2ccccc2)sc1C

Procedure:
Proliferation of splenocytes was measured using the MTT assay (Hansen et al., 1989), which measures the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide to formazan crystals. In this assay, the yellow MTT solution will be converted to a purple formazan product by the mitochondrial dehydrogenase of the viable cells. One-hundred microliters of splenocytes (1×107 cells/mL) were seeded in triplicates in flat-bottomed 96-well plates and cultured in the presence or absence of 1 μg/mL Con A or LPS or 10 μg/mL TT. After 72 hours at 37° C. in 5% CO2, the cells were incubated with 5 mg/mL MTT reagent for four-hours. The formazan precipitates were then dissolved by addition of 0.1 mL of HCl in isopropanol and mixed thoroughly by repeated pipetting. Cell proliferation was quantified using an ELISA reader at 570 nm.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:6][CH2:5]1.Cl[CH2:23][O:24][CH3:25].O>CN(C)C=O>[CH3:23][O:24][CH2:25][N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:6][CH2:5][C:4]1=[O:3]
Reactant: COCCl
Reactant: O=C1CCN(c2ccccc2F)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN1C(=O)CCN(c2ccccc2F)c2ccccc21
Reaction time: 1 h
Yield: 237.5 %

Procedure:
Under argon atmosphere, 60% sodium hydride (0.38 g) was suspended in N,N-dimethylformamide (5 ml), a solution of 2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.89 g) in N,N-dimethylformamide (15 ml) was added dropwise over 15 minutes under ice-cooling, the mixture was stirred for one hour at same temperature. Chloromethylmethyl ether (0.89 g) was added thereto, the resultant mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, extracted with chloroform, the organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 5.26 g of the titled compound as colorless amorphous (Yield: 98.4%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][NH:13][C:14]([C@H:16]1[CH2:21][N:20]([C:22]([NH:24]C(C)(C)C)=[O:23])[CH2:19][CH2:18][N:17]1[S:29]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](=[O:46])[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)(=[O:31])=[O:30])=[O:15])(C)(C)C>>[OH:12][NH:13][C:14]([C@H:16]1[CH2:21][N:20]([C:22]([NH2:24])=[O:23])[CH2:19][CH2:18][N:17]1[S:29]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](=[O:46])[C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[CH2:34][CH2:33]1)(=[O:30])=[O:31])=[O:15]
Reactant: CC(C)(C)NC(=O)N1CCN(S(=O)(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)[C@@H](C(=O)NOC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1CCN(S(=O)(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)[C@@H](C(=O)NO)C1
Reaction time: 36 h
Yield: 55 %

Procedure:
Trifluoroacetic acid (15 ml) was added to N-tert-butoxy-4-tert-butylaminocarbonyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (0.45 g, 0.92 mmol) [prepared as described in Step 2 above] and the reaction was stirred for 36 h. The reaction was concentrated in vacuo, and the residue was chromatographed (SiO2, PTLC, 10% methanol/methylene chloride) to give N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-aminocarbonylpiperazine-2-(R)-carboxamide (55%) as a pale pink solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC.Cl>CCCCCC.O1CCCC1>[CH3:15][O:14][CH2:13][O:12][C:3]1[CH:4]=[C:5]([O:8][CH2:9][O:10][CH3:11])[CH:6]=[CH:7][C:2]=1[B:16]([OH:21])[OH:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOc1ccc(Br)c(OCOC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(B(O)O)c(OCOC)c1
Temperature: -78 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
To a solution of 1-bromo-2,4-bismethoxymethoxybenzene in hexane (250 ml) and tetrahydrofuran (110 ml) was added triisopropyl borate (45 g, 238 mmol), and the mixture was cooled to −78° C. A solution (151 ml, 238 mmol) of 1.58M n-butyllithium in hexane was added dropwise and the mixture was stirred for 5 hr. 1N Hydrochloric acid (240 ml) was added under ice-cooling, and the mixture was stirred for 15 min. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 2,4-bismethoxymethoxyphenylboronic acid (13.6 g, yield 35%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[C:33]([Cl:38])[CH:34]=5)[CH:29]=4)(=[O:27])=[O:26])[CH2:21][CH2:20]3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:41]I.[Cl-].[NH4+]>CN(C)C=O.O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:41])[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[C:33]([Cl:38])[CH:34]=5)[CH:29]=4)(=[O:26])=[O:27])[CH2:21][CH2:20]3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc2c1CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.17 h

Procedure:
To a solution of 5-(t-butoxycarbonyl)-2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (33.0 mg) in N,N-dimethylformamide (15 ml), sodium hydride (60% in oil, 3.5 mg) was added at 0° C. After stirring for 10 minutes, methyl iodide (4.5 μl) was added and the resulting mixture was stirred at 0° C. for 1 hour. To the reaction mixture, a saturated aqueous solution (10 ml) of ammonium chloride, methylene chloride (20 ml) and water (30 ml) were added to separate the organic layer. The resulting water layer was extracted with methylene chloride (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography on a silica gel (methylene chloride:acetone=9:1), whereby the title compound (32.3 mg) was obtained as a colorless, transparent viscous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:18])[C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:18])=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CN(c1ccc(C(=O)O)cc1)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 4-((3-fluorophenyl)(methyl)amino)benzoic acid (0.100 g, 0.407 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.094 g; 0.407 mmol), HATU (0.170 g; 0.448 mmol) and N,N-diisopropylethylamine (0.176 mL; 1.02 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 20% ethyl acetate in dichloromethane) to yield 0.048 g (28%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH3:6].[CH3:16]I.Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([C:7]1[N:8]([CH3:16])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCc1cc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 105.3 %

Procedure:
Sodium hydride (60% oil disperson; 1.52 g, 38.0 mmol) was added under nitrogen in portions over 5 minutes to a solution of 2-butyl-1H-indole (5.00 g, 28.9 mmol) in 150 mL of anhydrous DMF at room temperature. After the addition the reaction was stirred at room temperature for 1.25 h. Methyl iodide (3.60 mL, 57.8 mmol) was then added and the reaction stirred at room temperature for 3.5 h. 1 N HCl was added to the reaction until the evolution of gas ceased. The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole (5.70 g, 100%) as a yellow oil, MS m/z: 188 [M+H]+.