Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)#[N:2].[Li]CCCC.[O:21]1[CH:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22]1.O>C1COCC1>[OH:21][CH:23]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22][N:7]1[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: N#Cc1ccc2[nH]c3ccccc3c2c1
Reactant: c1ccc(OCC2CO2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2c(c1)c1ccccc1n2CC(O)COc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-9H-carbazole (0.4998 g, 2.6 mmol, 1 equiv) in THF (40 mL) was added nBuLi (1.6 M in hexane, 3.25 mL, 5.2 mmol, 2 equiv). The mixture was stirred at −78° C. for 2 hours. 1,2-epoxy-3-phenoxypropane (0.7809 g, 5.2 mmol, 2 equiv) was added and the mixture was stirred at 45° C. overnight. Water (50 mL) was added and the mixture was extracted by dichloromethane (3×30 mL). The combined dichloromethane layers were washed by brine (2×30 mL) and then dried over Na2SO4. The solvent was removed under reduced pressure, and the product was chromatographed on silica gel with dichloromethane to yield 0.7736 g white foamed solid (86%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCO[CH2:26][CH2:25]1.O.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(OCC)(=O)C>[CH:25]([C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[N:6][CH:7]=1)=[CH2:26]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)cnc21
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1cnc2c(c1)CCN2C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a mixture of 1100 mg of tert-butyl 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, 1062 mg of a 2,4,6-trivinylboroxine/pyridine complex, 1020 mg of potassium carbonate, 3 mL of 1,4-dioxane/water (4/1) was added 215 mg of tetrakis(triphenylphosphine)palladium. The reaction mixture was stirred at 80° C. overnight. To the reaction mixture were added water and ethyl acetate and the aqueous layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 783 mg of tert-butyl 5-vinyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[N:4][CH:3]=1.Cl.CCOC(C)=O.O>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)=[N:4][CH:3]=1
Reactant: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCC(O)(c2ncc(Br)s2)CC1
Yield: 81.9 %

Procedure:
The product of Step 1 (3.0 g, 9.4 mmol) was dissolved in 30 mL of 1:1 THF:HCl (3N) and heated at 50° C. for 8 hours and the solution neutralized with solid KHCO3 and then EtOAc (100 mL) and water (20 mL) were added. The aqueous layer was then extracted with EtOAc (50 mL) and the combined organic layers were washed with brine (50 mL), evaporated to a slurry which was treated with hexanes (20 mL). Filtration and drying afforded 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexanone as a white solid (2.1 g, 7.7 mmol).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH2:30][C:31]1[N:36]=[C:35](Cl)[CH:34]=[C:33]([CH3:38])[N:32]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(O)CO>[NH2:30][C:31]1[N:36]=[C:35]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:34]=[C:33]([CH3:38])[N:32]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)nc(N)n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 4.00 g (0.010 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 1.43 g (0.010 mol) of 2-amino-4-chloro-6-methylpyrimidine, 1.39 ml (0.01 mol) of triethylamine, and 125 ml of ethylene glycol is stirred at 100° C. for 5 hours. The reaction mixture is shaken with aqueous sodium carbonate and methylene chloride and the remaining solid is then collected by filtration. The product, 1-(2-amino-6-methyl-4-pyrimidinyl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (4.06 g, 80%), is crystallized twice from methanol/methylene chloride; it has a melting point of 283°-286° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[CH3:33]
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 33.6 %

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, Step 3) (2.11 g, 5.5 mmol) and ethyl bromoacetate (1.09 g, 6.5 mmol) were stirred vigorously in 15 mL dry DMF with finely powdered potassium carbonate (1.38 g, 10 mmol) under nitrogen at 25° C. for 3 hours. The mixture was diluted with ethyl acetate and filtered to remove solids. The organic filtrate was washed with two portions of water followed by brine, dried over MgSO4 and concentrated in vacuo. The desired isomer was isolated by chromatography on silica gel, using 10% ethyl acetate/90% heptane as the eluant, to give ethyl[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate as a white solid (0.87 g, 34%). Elemental analysis for C21H18N2F4SO4Calc'd: C, 53.62, H, 3.86, N, 5.96, S, 6.82. Found: C, 53.69, H, 3.97, N, 5.87, S, 7.05.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([NH2:10])=[CH:5][CH:4]=1
Reactant: CNc1ccc([N+](=O)[O-])c(C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(N)c(C)n1
Yield: 100.7 %

Procedure:
A suspension of 0.4 g (2.39 mmol) of 6-methylamino-2-methyl-3-nitropyridine (Prace Naukowe Akedimii Ekonomicznej imienia Oskara Langego we Wroclawiu (1988), 435, 119-28) and 0.1 g of 10% palladium-on-charcoal in 50 ml of methanol is stirred at 20° C. for 6 hours under 4 atmospheres of hydrogen. The reaction mixture is subsequently filtered through a celite plug and then concentrated under reduced pressure. 0.33 g of the expected product is thus isolated in the form of an oil which will be used as is in the continuation of the synthesis.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[C:13]([O:15]CC)=[O:14])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[C:13]([OH:15])=[O:14])[CH3:2]
Reactant: CCOC(=O)C1c2ccccc2C(=O)N1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN1C(=O)c2ccccc2C1C(=O)O
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 103.6 %

Procedure:
A solution of ethyl 2-ethyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylate (0.283 g, 1.2 mmol) in ethanol (6 ml) and water (6 ml) was treated with 2M aqueous sodium hydroxide solution (0.6 ml) and stirred at 20° C. for 1.5 hrs. Starting material was still evident at this stage so a further aliquot of 2M aqueous sodium hydroxide solution (0.8 ml) was added and stirring continued for a further 4 hrs. The mixture was evaporated to remove the ethanol and the aqueous residue was diluted with water (40 ml), washed with diethyl ether (25 ml), then acidified to pH2 using 2M aqueous hydrogen chloride, and extracted with dichloromethane (4×25 ml). The organic extracts were combined, filtered through a hydrophobic frit, and evaporated to give 2-ethyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic acid as a white solid (0.255 g) which was used without further purification.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]2[CH:24]=[CH:23][NH:22][C:21]=2[C:25]([O:27]CC)=O)[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[C:20]3[CH:24]=[CH:23][NH:22][C:21]=3[C:25](=[O:27])[NH:9][C:10]2=[S:11])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1[nH]ccc1Nc1cccc(Cl)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(-c2cccc(Cl)c2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
Benzoyl isothiocyanate (0.035 g, 0.22 mmol) in CH2Cl2 (0.5 mL) was added to ethyl 3-[(3-chlorophenyl)amino]-1H-pyrrole-2-carboxylate (0.052 g, 0.20 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred at r.t. overnight. Additional benzoyl isothiocyanate (0.035 g+0.035 g+0.035 g) were added over 6 h and the reaction was continued stirring at 50° C. for 3 days. The solvent was removed in vacuo and the residue was dissolved in ammonia (7N in methanol, 4 mL). The reaction was heated at 50° C. for 2 h. The crude product was purified by preparative chromatography, obtaining 0.009 g (15%) of the title compound as a solid.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]4[C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH2:16][C@@H:15]2[NH:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10].Cl>CO.O1CCCC1>[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]4[C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH2:16][C@@H:15]2[NH:34][CH:35]([CH2:36][CH3:37])[CH2:38][CH3:39])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](NC(CC)CC)C3)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(c3nc4cccc(C(=O)O)c4s3)C[C@@H]2NC(CC)CC)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A 2 N aqueous lithium hydroxide solution (439 μL, 0.877 mmol) was added to a mixed solution of ethyl 2-{(3S,4R)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-[(1-ethylpropyl)amino]piperidin-1-yl}-1,3-benzothiazole-7-carboxylate obtained in Example (202f) (48.0 mg, 0.088 mmol) in methanol (0.3 mL) and tetrahydrofuran (0.3 mL) at room temperature, and the mixture was stirred at 70° C. for two hours. The reaction solution was concentrated under reduced pressure and water was added. The aqueous layer was washed with diethyl ether. A 1 N aqueous hydrochloric acid solution (877 μL, 0.877 mmol) was added to the aqueous layer, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure to obtain 42 mg of the title compound (92%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][OH:13])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccccc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)Oc1ccccc1C=O
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred solution of 7 (3.8 g, 21 mmol) in 250 mL CH2Cl2, MnO2 (11 g, 126 mmol) was added. The reaction mixture was stirred overnight, filtered on Celite® and the solvent was distilled under reduced pressure. The crude product was purified by a silica gel column with 17% EtOAc/83% Hexane as eluents. The product was isolated as pale yellow oil (70% yield). 1H NMR (CDCl3) δ 7.286 (dd, 1H, Ar), 7.195 (ddd, 1H, Ar), 7.063 (d, 1H, Ar), 7.003 (ddd, 1H, Ar), 4.669 (s, 2H, —CH2—), 1.447 (s, 9H, —C(CH3)3). Mass Spec.=203.09 (M+H)++Na+.
Reaction SMILES: [F:1][C:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]([F:32])([F:31])[F:30])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3].[Li+].[OH-]>CCO.O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:2]([F:1])([F:4])[CH3:3])[CH2:10][CH2:9]3)[C:13]=2[C:29]([F:31])([F:32])[F:30])[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(R)-4-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (530 mg, 1.16 mmol) was dissolved in EtOH (5 mL). Then LiOH (835 mg, 34.8 mmol, 30.0 eq.) in 2 mL water was added to the mixture. The mixture was heated to 80° C. and stirred for 15 h. Solvent was removed. DCM was added and filtrated. The filtrate was concentrated and purified by silica gel chromatography using DCM/methanol (10/1) to give the title compound (200 mg, 40%) as a slight yellow solid. EDI-MS (M−NH2): 415.2. HPLC: 99.36%. 1H NMR (400 MHz, CD3OD) δ 8.13 (t, 1H), 8.02 (d, 1H), 7.86 (s, 1H), 7.58 (dd, 1H), 7.48 (d, 1H), 4.45-4.41 (m, 1H), 3.85-3.72 (m, 2H), 2.14-2012 (m, 2H), 1.89-1.86 (m, 2H), 1.74-1.68 (m, 4H), 1.51-1.32 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[CH2:22]([N:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH2:31][NH2:32])[CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:32][CH2:31][C@H:27]2[CH2:28][CH2:29][CH2:30][N:26]2[CH2:22][CH:23]([CH3:25])[CH3:24])[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: CC(C)CN1CCC[C@@H]1CN
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Product: Cc1c(Cl)nc(NC[C@H]2CCCN2CC(C)C)c(=O)n1CC(=O)OCc1ccccc1

Procedure:
The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preperation 170 and [(2R)-1-isobutylpyrrolidinyl]methanamine [see preparation 60]. The crude product was purified by column chromatography on silica gel using ethyl acetate as the eluant, to afford the product as a yellow oil, (94%).
Reaction SMILES: [S:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][NH:11][CH2:12][C:13]2[N:14]([CH2:18][C:19]([N:21]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[C:40]([O:44][C:45](=[O:78])[CH2:46][CH2:47][C:48]([NH:67][C:68](=[O:77])[CH2:69][N:70]1[CH:74]=[CH:73][N:72]=[C:71]1[CH:75]=O)([CH2:58][CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:43])([CH3:42])[CH3:41].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[C:26]([O:25][C:23](=[O:24])[CH2:22][N:21]([CH2:30][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:19](=[O:20])[CH2:18][N:14]1[CH:15]=[CH:16][N:17]=[C:13]1[CH2:12][N:11]([CH2:75][C:71]1[N:70]([CH2:69][C:68]([NH:67][C:48]([CH2:58][CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])([CH2:47][CH2:46][C:45]([O:44][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:78])[CH2:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:77])[CH:74]=[CH:73][N:72]=1)[CH2:10][CH2:9][C:8]1[CH:38]=[CH:39][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:6][CH:7]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)Cn1ccnc1C=O
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CNCCc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of di-tert-butyl 2,2′-((2-(2-(((4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (200 mg, 0.353 mmol), di-tert-butyl 4-(3-(tert-butoxy)-3-oxopropyl)-4-(2-(2-formyl-1H-imidazol-1-yl)acetamido)heptanedioate (195 mg, 0.353 mmol), AcOH (0.10 mL) in DCE (10 mL) at 0° C. was treated with NaBH(OAc)3 (148 mg, 0.70 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for overnight and decomposed with water. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by biotage over silica gel to afford di-tert-butyl 4-(2-(2-((((1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetamido)-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (237 mg, 61%). 1H NMR (400 MHz, DMSO-d6) 7.76 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.22 (s, 2H), 7.01 (d, J=1.2 Hz, 1H), 6.99 (d, J=1.6 Hz, 2H), 6.83 (d, J=0.8 Hz, 1H), 6.80 (d, J=0.8 Hz, 1H), 5.02 (s, 2H), 4.55 (s, 2H), 4.31 (s, 2H), 3.97 (s, 2H), 3.63 (s, 2H), 3.60 (s, 2H), 2.77-2.73 (m, 2H), 2.66-2.60 (m, 2H), 2.10 (t, J=8.2 Hz, 6H), 1.78 (t, J=8.2 Hz, 6H), 1.36 (s, 45H); MS (ESI), 551.4 (M/2+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.I[CH2:45][C:46]([NH2:48])=[O:47]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:45][C:46]([NH2:48])=[O:47])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: NC(=O)CI
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NCC(N)=O)CC1

Procedure:
In a manner similar to the method described in example 160, (4-Amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with iodoacetamide (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2926.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[C:20]=[CH:21][CH3:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@H:3]1[C:23]([O:25]C(C)(C)C)=[O:24].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][C:2]1([CH3:1])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]=[C:20]=[CH:21][CH3:22])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[C@H:3]1[C:23]([OH:25])=[O:24]
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a solution of the product from Example 27 (200 mg, 0.44 mmol) in methylene chloride (4 mL) was added trifluoroacetic acid (1 mL) and the resulting mixture was stirred for 2 h at room temperature. The solvents were removed in vacuo and the residue was purified by silica gel column chromatagraphy to obtain the product (120 mg, 69%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15].Cl[C:17]1[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26].O>O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][C:17]1[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Potassium t-butoxide (0.30 g, 2.67 mmol) was suspended in anhydrous tetrahydrofuran (25 mL), 2,4-dichlorophenol (0.40 g, 2.43 mmol) was added and the resulting mixture was stirred at ambient temperature under nitrogen for 30 minutes. After this time, 1-(5-chloro-4-nitro-2-thienyl)ethanone (0.5 g, 2.43 mmol) was added, the resulting mixture was stirred at ambient temperature for 45 minutes, then it was poured into water (100 mL) and stirred at ambient temperature overnight. The resulting solid was collected by filtration, washed with water (2×10 mL) and dried in air. The crude product was dissolved in acetonitrile (7 mL), the resulting solution was evaporated to near dryness and the residue was triturated with diethyl ether (2 mL). The resulting solid was collected by filtration and dried in vacuo at 40° C. overnight to afford the title product as a solid (0.45 g, 55% yield). 1H NMR (300 MHz, d6-acetone) δ: 8.15 (1H, s), 7.68 (1H, d), 7.51 (2H, m), 2.45 (3H, s).
Reaction SMILES: [CH2:1]([NH-])C.Cl.C(N)C.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[N:40]=[CH:39][CH:38]=[CH:37][C:19]=3[C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:36])([C:32](=[O:35])[NH:33][CH3:34])[CH3:31])=[CH:26][CH:25]=3)=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1>>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[N:40]=[CH:39][CH:38]=[CH:37][C:19]=3[C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:32](=[O:35])[NH:33][CH2:34][CH3:1])([CH3:36])[CH3:31])=[CH:26][CH:25]=3)=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CC[NH-]
Reactant: CNC(=O)C(C)(C)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Agent: CCN
Agent: Cl
Product: CCNC(=O)C(C)(C)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1

Procedure:
The remaining portion of the tetrahydrofuran solution from Example 5a (10 mL) was converted to the ethyl amide with ethylamine hydrochloride using the same procedure.