Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6]([OH:8])=[O:7].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6]([O:8][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7]
Reactant: CC(C)CCC(=O)C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)CCC(=O)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of 5-methyl-2-oxohexanoic acid (0.288 g.) in methylene chloride (1 ml.) was added during 15 minutes to a stirred solution of dicyclohexylcarbodiimide (0.412 g.) and benzyl alcohol (0.432 g.) in methylene chloride (10 ml.) which was cooled to -15° C., and the mixture was stirred at that temperature for 1 hour, then at laboratory temperature for 30 minutes, and was then evaporated to dryness. Water (1 ml.), diethyl ether (2 ml.) and acetic acid (0.01 ml.) were added and the mixture was kept at laboratory temperature for 12 hours and then evaporated to dryness. The residue was purified by chromatography on a silica gel column using toluene as eluant and there was thus obtained benzyl 5-methyl-2-oxohexanoate as an oil.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[CH2:1]([C:35]1[CH:36]=[C:31]([Cl:30])[CH:32]=[CH:33][C:34]=1[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: OCc1ccccc1
Agent: Oc1ccccc1Cc1ccccc1
Solvent: Oc1ccccc1
Product: Oc1ccc(Cl)cc1Cc1ccccc1
Temperature: 200 °C
Yield: 25.4 %

Procedure:
A German patent, Ger.Offen 2,547,0310 (1977), disclosed the preparation of o-benzyl-toluenes by the reaction of o-methylbenzyl halides with substituted benzenes in the presence of Al-silicate. The 2-CH3C6H4CH2Cl was stirred with toluene and Al-silicate (25% Al2O3) at 110° C. to give 81% 2-methylbenzyltoluene. According to a Japanese patent, Jpn. Kokai Tokkyo Koho JP 59,186,937 (1984), o-benzylphenol was prepared by the liquid phase reaction of benzyl alcohol with phenol in the presence of γ-Al2O3. For example 7.5 g γ-Al2O3 was added to a mixture of 32.5 g benzyl alcohol and 47 g phenol at 190° C. under stirring to give a product containing 49.9% o-benzylphenol. A German patent, Ger. Offen DE 3,700,917 (1988), disclosed the preparation of p-substituted o-benzylphenols by benzylation of p-substituted phenols with benzylalcohol in the presence of Na—Y type zeolite. A mixture of 0.5 mole 4-ClC6H4OH, 0.1 mole C6H5CH2OH and 0.6 g of Na—Y type zeolite was heated at 200° C. for 3 hrs to give 25.4% 2-benzyl-4-chlorophenol.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+:13].[F:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[F:14][C:15]1[CH:22]=[CH:21][C:18]([C:19](=[NH:13])[NH2:20])=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
4.12 mL (8.24 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 10 mL of toluene containing 441 mg (8.24 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 1 g (8.25 mmol) of 4-fluorobenzonitrile was added thereto and the resulting mixture was heated to 85° C. for 9 hours. After completion of a reaction, the reaction solution was cooled, then poured into 100 mL of chloroform containing 500 g of silica gel and filtered off. The residue was washed with 100 mL of methanol and distillation was conducted to give 821 mg (5.9 mmol) of the title compound in a yield of 71%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:20]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH3:20])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)C1CNCCN1Cc1ccccc1
Product: CCOC(=O)C1CN(C)CCN1Cc1ccccc1
Yield: 72.8 %

Procedure:
Ethyl 1-benzylpiperazine-2-carboxylate (3.03 g, 12.2 mmol) was reacted with iodomethane (1.73 g, 12.2 mmol) according to the procedure as described in Example 48, Step A to give the title compound as yellow oil (2.33 g, 73%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH-:30].[Na+]>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[OH:30])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2O)cn1)c1ccc(Cl)s1
Yield: 6.2 %

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared in Example 11 (80 mg, 0.19 mmol) and 5 N aq. NaOH (0.5 mL, 2.5 mmol) in DMSO (2 mL) in a sealed tube was heated at 130° C. overnight. The mixture was purified by HPLC to give the title compound (5 mg). MS 427.0 and 429.0 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:16][CH2:17][CH3:18])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[C:20]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:16][CH2:17][CH3:18])=[C:6]2[C:10]=1[N:9]([CH3:20])[CH:8]=[C:7]2[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: CCOc1c(F)cc(Cl)c2[nH]cc(CC(=O)OC)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOc1c(F)cc(Cl)c2c1c(CC(=O)OC)cn2C
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 30-10 (2 g, 7 mmol) in acetone (40 mL) was added K2CO3 (3 g, 21 mmol) and MeI (1.2 g, 8.4 mmol). The reaction mixture was refluxed overnight before it was cooled to room temperature. The solid was filtered off and the filtrate was evaporated to give the crude product, which was purified on silica gel column chromatography eluting with hexane/ethyl acetate (1:5) to afford 30-11 (1.4 g, 67%) as a yellow solid. LRMS: calc 299.1 and found: 300.1 [M+1].
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].Cl[C:24]([O:26][CH3:27])=[O:25]>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Reactant: COC(=O)Cl
Product: COC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCC(C)C

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl)amide (precursor 5c) and methyl chloroformate, according to the general working procedure followed by extraction with EA and purification by flash chromatography 29 mg of 2′-(methoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained as a resin.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC.O>CN(C)C=O.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]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccccn3)cc12
Yield: 75.1 %

Procedure:
A solution of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), tri-n-butyl(2-pyridyl)tin (0.37 g, 1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in N,N-dimethylformamide (10 ml) was stirred at 100° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-pyridyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.36 g, 75.0%) as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].I[C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:15].CC#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:28]2[CH:27]=[C:13]([CH:12]=[CH:11][C:29]=2[CH3:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)=[O:15])=[CH:4][N:5]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1C#Cc1cnc(N)nc1
Temperature: 90 °C

Procedure:
To a sealable tube containing 5-ethynylpyrimidin-2-amine (172 mg, 1.44 mmol), PdCl2(PPh3)2 (25 mg, 0.036 mmol), 3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (292 mg, 0.72 mmol) was added MeCN (10 mL) and Et3N (3 mL) followed by CuI (6.8 mg, 0.036 mmol). The tube was sealed and heated at 90° C. for 1 h. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The resulting brown solid was reconstituted in MeOH:CH2Cl2 (1:1, 10 mL) and silica gel was added and reconcentrated. The silica-gel combined crude mixture was purified via automated flash chromatography (silica gel, 0 to 5% MeOH in CH2Cl2, gradient elution) to afford 3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide. MS m/z=397 [M+H]+. Calc'd for C21H15F3N4O: 396
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]1([N:13]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH:21]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:19][CH2:18]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.[H][H]>[Pd].C(O)(=O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:34]1([N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[CH2:21][CH2:22]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1cccc(OC2=CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(OC2CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Yield: 65.6 %

Procedure:
A mixture of 7.7 g. (0.014 moles) of 3,6-dihydro-N,N-diphenyl-4-[3-(trifluoromethyl)phenoxy]-1(2H)-pyridinepropanamine ethanedioate (1:1) (preparation described in Example 16), 90 ml. of methanol, 10 ml. of acetic acid and 0.5 g. of 20% Pd/c is shaken under 50 psi. of hydrogen at room temperature for about 4 hours. The reaction mixture is then filtered, and the solvent is evaporated. The residue is initially recrystallized from aqueous isopropanol, then recrystallized from aqueous isopropanol, and again recrystallized from aqueous ethanol to give 5.0 g of N,N-diphenyl-4-[3-(trifluoromethyl)phenoxy]-1-piperidinepropanamine ethanedioate (1:1), mp 189°-190.5° C.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]3)=[CH:18][NH:19]2)=[CH:15][CH:14]=1.CCN(CC)CC.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:37](=[O:39])[CH3:38])[CH2:25][CH2:24]3)=[CH:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a suspension of 1-[6-(benzothiazol-2-yloxy)-1H-indol-3-ylmethyl]-piperidin-4-ylamine 2HCl (200 mg, 0.44 mmol) in DCM (4 mL) was added Et3N (0.37 mL, 270 mg, 2.7 mmol) and acetic anhydride (0.067 mL, 68 mg, 0.66 mmol) and the resulting reaction mixture was stirred (rt, 24 h). The reaction mixture was partitioned with EtOAc (50 mL) and brine (50 mL) and the organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified silica gel flash column chromatography using MeOH (0.2 M NH3):DCM (0-15%) to provide the title compound as a white solid (111 mg, 60%). MS (ESI): mass calcd. for C23H24N4O2S, 420.5; m/z found, 421.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.00 (s, 1H), 7.73 (d, J=6.0, 1H), 7.71 (d, J=5.2, 1H), 7.63 (d, J=7.5, 1H), 7.39-7.36 (m, 1H), 7.31 (br s, 1H), 7.26-7.24 (m, 1H), 7.10 (br s, 1H), 7.07 (dd, J=8.6, 2.1, 1H), 5.55 (br d, 1H), 3.80-3.70 (m, 1H), 3.68 (s, 2H), 2.89 (d, J=11.7, 2H), 2.17-2.13 (m, 2H), 1.96 (s, 3H), 1.89 (d, J=11.0, 2H), 1.48-1.40 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.Cl>C(O)C>[NH2:9][C:4]1[N:3]=[C:2]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=2)[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(CO)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(Nc2ccc(CO)cc2)n1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A mixture of 4,6-dichloro-pyrimidin-2-yl-amine (6.6 g, 40 mmol), 4-aminobenzyl alcohol (8.0 g, 65 mmol) and N,N-diisopropylethylamine (15 ml) in ethanol (200 ml) was heated under reflux for 72 hours. Concentration under reduced pressure provided a solid which was stirred with 1.0 M hydrochloric acid (200 ml) for 1 hour, filtered, dried under reduced pressure, stirred with ethyl acetate (200 ml) for 2 hours, filtered, and dissolved in methanol (300 ml). Aqueous sodium carbonate solution (1.0 M, 50 ml) was added. After stirring for 2 hours, volatiles were evaporated under reduced pressure and water (200 ml) was added. Filtration and drying provided [4-(2-amino-6-chloro-pyrimidin-4-yl-amino)-phenyl]-methanol (6.3 g, 63% yield) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[OH:33][CH:34]([CH:45]([OH:56])[C:46]([O:48]N1C(=O)CCC1=O)=O)[C:35]([O:37]N1C(=O)CCC1=O)=O>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:35](=[O:37])[CH:34]([OH:33])[CH:45]([OH:56])[C:46]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[O:48])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Reactant: O=C(ON1C(=O)CCC1=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)C(O)C(O)C(=O)NCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
To a solution of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (intermediate 175.1) (110 mg, 0.22 mmol) in DMF (2.0 mL) was added bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (Intermediate 168.1) (34 mg, 0.10 mmol) and the reaction was stirred for 10 minutes. The solvent was removed under vacuum and the residue was purified by preparative HPLC to give the title compound (23 mg) as a TFA salt. 1H-NMR (400 mHz, CD3OD) δ 7.81 (m, 4H), 7.44 (s, 1H), 7.37 (m, 2H), 6.75 (s, 1H), 4.64 (m, 4H), 4.37 (m, 4H), 3.72 (m, 2H), 3.46 (m, 10H), 3.38 (m, 12H), 3.02 (m, 10H). MS (m/z): 1117.02 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[H-].[Na+].[CH:23]1(I)[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.CN(C=O)C>[CH:23]1([O:20][C:4]2[CH:5]=[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[B:15]([OH:16])[O:14][CH2:13][C:12]=4[CH:17]=3)[CH:18]=[CH:19][C:3]=2[C:1]#[N:2])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: IC1CCCC1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.3 %

Procedure:
To a solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile (D10) (200 mg, 0.75 mmol) in THF (50 mL) and DMF (20 mL) was added NaH (47 mg, 95%, 1.87 mmol) portion-wise. The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of cyclopentyl iodide (0.26 mL, 2.25 mmol). The reaction was stirred at room temperature for 24 hours. After the reaction, all volatile components were evaporated under vacuum. The residue was purified using silica gel column chromatography, eluting with 25% EtOAc/hexane, afforded 36 mg of the title compound in 12.6% yield. 1H NMR 400 MHz (DMSO-d6) δ: 9.23 (s, 1H), 7.78 (d, J=7.8 Hz, 1H) 7.69 (d, J=8.6 Hz, 1H), 7.17 (s, 1H), 7.10 (dd, J=2.0, 8.2 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.56 (dd, J=1.9, 8.6 Hz, 1H), 4.96 (s, 2H), 4.95 (t, J=5.8 Hz, 1H), 1.95-1.55 (m, 8H); MS (ES) m/z: 336 (M+H)+; HPLC purity: 99.15% (220 nm), 99.62% (MaxPlot).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCc1nccn1-c1ccc(C)cc1[N+](=O)[O-]
Reaction time: 6 h
Yield: 92.9 %

Procedure:
1-Fluoro-4-methyl-2-nitrobenzene 239 mg, ethyl 3-(1H-imidazol-2-yl)propanoate 252 mg, potassium carbonate 415 mg and N,N-dimethylacetamide 10 mL were stirred at 100° C. for 11.5 hours, and then at 130° C., for 6 hours. The reaction liquid was diluted with diethyl ether, washed with water and saturated brine by the order stated, and dried over magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was subjected to silica gel chromatography (ethyl acetate) to provide 422 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][C@@H:48]([CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:47][C@@H:48]([CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (4.13 g, 13.18 mmole) and hydroxybenzotriazole (2.23 g, 16.48 mmoles) were dissolved in 70 mL THF and then dicyclohexyl-carbodiimide(2.71 g, 13.18 mmoles) was added in one portion to the stirred solution under nitrogen atmosphere. This mixture was stirred for 4 h at room temperature and then filtered to remove dicyclohexylurea precipitate. The product of Example 69B (5.1 g, 11.99 mmoles) was dissolved in 100 mL THF under nitrogen atmosphere. To this stirred solution was added the filtrate of HOBT-active ester and the resulting solution was stirred at room temperature for 4 h, and the solvent removed via rotary evaporation. The residue was dissolved in 150 mL ethyl acetate and washed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueous KHSO4 and the solvent was removed by rotary evaporation to afford a residue. The residue was dissolved in 175 mL 1N HCL, and the solution filtered to remove the small quantity of dicyclohexylurea. The filtrate solution was added to 175 mL ethyl acetate and the two phase mixture rapidly mixed. The pH of this rapidly stirred mixture was adjusted to pH=7 by dropwise addition of cold 3N NaOH. The organic layer was isolated, washed with 100 mL brine, dried over Na2SO4, filtered, and the solvent was removed to afford 8.6 g of a colorless foam. This material was crystallized from 42 mL EtOAc and 21 mL hexane to give 7.85 g of the desired product as a white solid. mp=122-123 °C. CIMS m/z 721 (M+H) +.