Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].O1CCCCC1[O:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:27][CH2:26][CH2:25][C:24]#[C:23][CH2:22][OH:21])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: ClCCCC#CCOC1CCCCO1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC#CCO)ccc(C(C)=O)c1O
Reaction time: 52 h
Yield: 81 %

Procedure:
A mixture of 9.77 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 10.90 g of 1-(tetrahydro-2-pyranoxy)-6-chloro-2-hexyne [R. B. Moffet, P. H. Seay and W. R. Reid, J. Med. Pharm. Chem., 14, 1075 (1971)]. 10.43 g of anhydrous potassium carbonate and 8.36 g of potassium iodide in 250 ml of anhydrous acetone was stirred at reflux for 18 hours. Anhydrous dimethyl formamide (100 ml) was added and reflux with stirring was continued for 52 hours. The solvent was removed in vacuo, the residue was stirred with hexane and filtered. The filtrate was concentrated in vacuo to an oil which was dissolved in 300 ml of methanol and 200 ml of 3 N hydrochloric acid and heated on the steam bath for 45 minutes. As the solvent was being removed in vacuo, crystallization occurred. Water was added and the solid was filtered to give 11.78 g, 88°-90°, (81% yield) of 1-[2-hydroxy-4-[(6-hydroxy-4-hexynyl)oxy]-3-propylphenyl]ethanone, the titled compound.
Reaction SMILES: C(O)=O.[CH:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C([Si]([O:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH:65]2[CH2:67][O:66]2)=[CH:59][CH:58]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([CH2:27][CH2:28][NH:29][CH2:67][C@H:65]([OH:66])[CH2:64][O:63][C:60]4[CH:61]=[CH:62][C:57]([OH:56])=[CH:58][CH:59]=4)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC2CCN(C(=O)NCCCC3CCCCC3)CC2)cc1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: O=C(NCCCC1CCCCC1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 36 %

Procedure:
tert-Butyl 4-[(1-{[(3-cyclohexylpropyl)amino]carbonyl}-4-piperidinyl)amino]phenethylcarbamate formate (0.35 g, 0.809 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.327 g, 0.809 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.23 g, 0.291 mmol).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[C:14]([CH:22]([CH3:26])[C:23](O)=[O:24])=[CH:13][C:12]2=[O:27])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[C:14]([CH:22]([CH3:26])[C:23]([Cl:3])=[O:24])=[CH:13][C:12]2=[O:27])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(Cn2c(=O)cc(C(C)C(=O)O)c3cc(C)ccc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cn2c(=O)cc(C(C)C(=O)Cl)c3cc(C)ccc32)cc1

Procedure:
Thionyl chloride (0.109 ml.) was added by syringe to a suspension of α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionic acid (0.335 g.) in toluene (3.5 ml.) (dried over sodium wire). The mixture was heated under reflux until evolution of gas ceased, and was then evaporated in vacuo. The residue was mixed with further dry toluene (5 ml.) and then evaporated in vacuo, and dried at ambient temperature under high vacuum, to give α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionyl chloride, which was dissolved without purification in dry toluene (2.5 ml.). The solution thus obtained was added by syringe to a solution of phenol (0.052 g.) in pyridine (0.044 ml.). The mixture was then stirred at ambient temperature for 45 minutes and then at 80° C. for 30 minutes. After being left at ambient temperature overnight, the reaction solution was mixed with ethyl acetate (20 ml.). The solution was then washed successively with 2 N-hydrochloric acid (20 ml.), water (20 ml.), 2 N-sodium hydroxide solution (2×20 l ml.), water (20 ml.) and then saturated sodium chloride solution (20 ml.). The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was recrystallised from cyclohexane to give phenyl α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionate, m.p. 111°-113° C., in 58% yield.
Reaction SMILES: C(O[C:4]1([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][S:6][S:5]1)C.[Cl:18]([OH:22])(=[O:21])(=[O:20])=[O:19].O>C(O)C>[Cl:18]([O-:22])(=[O:21])(=[O:20])=[O:19].[CH2:9]([C:8]1[CH:7]=[S+:6][S:5][C:4]=1[C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CCOC1(C(C)(C)C)SSC=C1CC(C)(C)C
Solvent: CCO
Solvent: O
Product: CC(C)(C)Cc1c[s+]sc1C(C)(C)C
Product: [O-][Cl+3]([O-])([O-])[O-]
Yield: 100.3 %

Procedure:
A sample of 11.4 grams of 3ethoxy-3-t-butyl-4-neopentyl 1,2 dithiole dissolved in 15 grams of ethanol was treated with 14 grams of 70% perchloric acid. To the mixture was added 100 grams of water and the precipitate which formed was filtered off. There was isolated 13.7 grams (100% of theory) of 4-neopentyl-3-tertiarybutyl 1,2 dithiolium perchlorate.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]([CH2:33][O:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClCCl.N1C=CC=CC=1>[C:1]([O:10][CH:11]([CH2:33][O:34][C:35]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
Benzoyl chloride (30 mmol) is added dropwise at 0° C. to a solution of 10 (27.3 mmol) in 80 ml of dichloromethane/pyridine (1:1). Slow warming to room temperature is allowed to take place, and stirring is continued for another 4 hours at room temperature. The mixture is then concentrated, added twice with 50 ml of toluene and concentrated. The residue is added with 100 ml of H2O and extracted three times with 100 ml of dichloromethane. The combined organic phases are washed with 50 ml of cold 5% HCl and 50 ml of saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by silica gel chromatography using heptane/ethyl acetate (3:1). Yield: 87% of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.COC(OC)[N:15]([CH3:17])C.O.[NH2:21]N>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:10])=[N:21][NH:15][CH:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Cc1ccc(Br)cc1
Solvent: O
Product: Cc1n[nH]cc1-c1ccc(Br)cc1
Temperature: 90 °C

Procedure:
To 4-bromophenylacetone (5.0 g, 23.5 mmol, 1.0 equiv) (Acros Organics 34216) was added N,N-dimethylformamide dimethyl acetal (11.3 ml, 84.6 mmol, 3.6 equiv) and the mixture was heated to 90° C. for 6 hours. The solvents were removed and the resulting gum was dissolved in ethanol (235 ml) with additional heating. Hydrazine hydrate (1.37 ml, 28.2 mmol, 1.2 equiv) was added and the mixture was heated to reflux for 15 hours. The solvents were removed under reduced pressure and the solid was triturated with dichloromethane to afford the title compound, 2.24 g (40%); LCMS (PS-A) Rt 2.87 min [M+H]+ 238. Further material could be isolated from the mother liquor.
Reaction SMILES: FC1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.C[O:23][C:24]([C:26]1[C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[O:42][CH3:43])=[CH:28][CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)=[O:25]>>[Cl:41][C:37]1[C:36]([O:42][CH3:43])=[C:35]([C:27]2[C:26]([C:24]([OH:25])=[O:23])=[CH:31][C:30]([N+:32]([O-:34])=[O:33])=[CH:29][CH:28]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccc(Cl)c1OC
Agent: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1c(Cl)cccc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 95.5 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl(3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate) (230mg) to afford 0.21 g (99%) of 3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.76 (d, J=2.5, 1H), 8.50 (dd, J=8.4, 2.5, 1H), 7.74 (d, J=8.5, 1H), 7.51 (dd, J=7.9, 1.8, 1H), 7.31 (dd, J=7.4, 1.8, 1H), 7.24 (t, J=7.9), 3.47 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19].CCCCCC>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][N:8]([CH:18]([CH3:20])[CH3:19])[C:9]=2[CH:10]=1
Reactant: CC(C)Br
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
To a cooled (0° C.) solution of methyl 6-bromo-1H-indole-4-carboxylate (1.0 g, 3.94 mmol) solid in N,N-dimethylformamide (25 mL) was added sodium hydride (0.173 g, 4.33 mmol). The reaction was stirred for 15 min, at which time 2-bromopropane (0.554 mL, 5.90 mmol) was added. The reaction was then allowed to warm to RT and was maintained overnight. LCMS showed about 25% starting material remaining. The reaction was heated at 45° C. for 4 h, but no further conversion was noted. The reaction vessel was put back into an ice bath and stirred for 15 min. Then excess NaH (60%) was added, stirred for 10 min, and then 2-bromopropane (excess) was added. The ice bath was removed and the reaction stirred for 1 h. Approximately half of the reaction volume was removed in vacuo and poured into saturated NH4Cl (200 mL). This was extracted with ether (2×) and the combined organics were washed with brine, dried (MgSO4), and concentrated. Purification by column chromatography (80 g Isco silica column; Gradient B: 5-25%, A: hexane, B: ethyl acetate) gave methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (0.53 g, 1.718 mmol, 43.7% yield).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[C:8]([OH:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:14])[CH:4]=1)[NH2:2].C(O[CH:18]=[CH:19][C:20](=O)[C:21]([F:24])([F:23])[F:22])C.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[CH3:14][C:5]1[CH:4]=[C:3]([N:1]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[N:2]2)[C:12]2[C:7](=[C:8]([OH:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: Cc1cc(NN)c2cccc(O)c2n1
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-n2nccc2C(F)(F)F)c2cccc(O)c2n1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of 4-hydrazino-2-methyl-quinolin-8-ol (21 mg, 0.11 mmol) and 4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (16 μL, 0.11 mmol) in ethanol (0.5 mL) was heated to 75° C. for 30 min. The solvent was than removed in vacuo and the residue was redissolved in acetic acid (0.5 mL). After the addition of concentrated H2SO4 (20 μL) and stirring for 1 h at 100° C., the reaction mixture was cooled to room temperature and a mixture of Na2CO3 (0.40 mg, 3.8 mmol) in water (1 mL) was added. The reaction mixture was then concentrated in vacuo and the residue was partitioned between DCM (10 mL) and water (5 mL). The pH of the aqueous layer was adjusted to 10 by the addition of saturated aqueous NH3 solution and the aqueous layer was extracted with DCM (1×320 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS (m/z): 294.2 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][CH:11]=2)[N:3]=1.N1C=CC=CC=1C1C=CC(CO)=CC=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:3]=2)=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCc2ccc(-c3ccccn3)cc2)n1
Agent: O=C([O-])[O-]
Agent: OCc1ccc(-c2ccccn2)cc1
Agent: [K+]
Product: c1ccc(-c2ccc(COc3cncc(N4CCNCC4)n3)cc2)nc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[{4-(2-pyridinyl)benzyl}oxy]pyrazine (2.73 g, 9.16 mmol; obtained according to the procedure of example 50, step 1, starting from 4-(2-pyridinyl)benzyl alcohol*), piperazine (2.41 g, 27.9 mmol) and K2CO3 (1.33 g, 9.62 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 2.06 g (65%) which was obtained as a beige colored oil that solidified when refrigerated. Purity 100% (HPLC). MS m/z 347 (M)+. HRMS m/z calcd for C20H21N5O (M)+ 347.1746, found 347.1749.
Reaction SMILES: [C:1]1(/[C:7](=[N:14]/[OH:15])/[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[C:1]1(/[C:7](=[N:14]/[O:15][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])/[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCOC(=O)CCCCBr
Reactant: O/N=C(\Cn1ccnc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCO/N=C(\Cn1ccnc1)c1ccccc1
Reaction time: 6 h
Yield: 53.6 %

Procedure:
To a stirred mixture of 5 g (0.025 moles) of (Z)-1-phenyl-2-(imidazol-1-yl)ethanone oxime and 20 ml of dimethylformamide, 0.9 g (0.03 moles) of sodium hydride dispersion 80% are added portionwise at room temperature. Upon completion, stirring is continued till hydrogen evolution stops. Then 4.74 ml (0.03 moles) of ethyl 5-bromopentanoate are added dropwise at room temperature and stirring is continued for 6 hours. The reaction mixture is evaporated under vacuum, diluted with water and extracted with chloroform. The organic phase dried over CaCl2 is evaporated to dryness. The residue is purified by column chromatography over silica gel (eluant: chloroform/methanol=97/3). The pure fractions are collected and evaporated, yielding 4.41 g (53%) of ethyl (Z)-5-[1-phenyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].[H-].[Na+].O>O1CCCC1.CN(C)C=O>[O:18]=[C:16]1[CH:17]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1]1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(-c2ccccc2)c2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of o-amino benzophenone (10 g) and acetic acid anhydride (10 ml) in tetrahydrofuran (150 ml) was refluxed for 8 hours. The mixture was thereafter evaporated and the residue was partitioned between sat NaHC03, (20ml) and diethylether (l5Oml). The organic phase was dried and evaporated to give an yellow oil which was redissolved in dimethyl formamide (150ml). To this solution was added NaH (5g) and the mixture was stirred at ll0° C. for 11/2 hour, whereafter it was cooled to room temperature, and poured into water (300ml). This treatment afforded a precipitate of the title compound as pale crystals, which were collected by filtration. The crystals were washed with water and dried. M.p.244°-247° C..
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][OH:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:13]=[O:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1[N+](=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A solution of (3,4-dinitro-phenyl)-methanol (95.3 g, 481 mmol) in methylene chloride (500 mL) was added all at once to a suspension of pyridinium chlorochromate (156 g, 722 mmol) in methylene chloride (900 mL). The mixture was stirred at room temperature for 1.5 h and then ether (1500 mL) was added. The supernatant was decanted from the resulting black gum, and the insoluble residue was washed thoroughly with methylene chloride (3×250 mL). The combined organic solution were filtered through a pad of florisil to afford a light bright yellow clear solution. Solvents were removed in vacuo and the residue was purified by silica gel chromatography using methylene chloride as eluent to afford the title compound as a yellow solid (71%). 1H-NMR (CDCl3, 300 MHz) δ 8.45 (d, J=1.5 Hz, 1H), 8.28 (dd, J=8.1, 1.5 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H). 13C NMR (CD3OD, 125 MHz) δ 187.7, 139.2, 134.2, 126.2, 125.7.
Reaction SMILES: C(=O)(OC)O[CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:15][CH2:16][CH:17]1[CH2:19][CH2:18]1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[CH:17]1([CH2:16][NH:15][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]=[CH2:3])[CH2:19][CH2:18]1
Reactant: COC(=O)OC/C=C/c1ccccc1
Reactant: NCC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CCO
Product: C=CC(NCC1CC1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of (E)-cinnamyl methyl carbonate (0.73 g) in EtOH (8 mL) at RT under N2 was added (aminomethyl)cyclopropane (1 mL), triphenyl phosphite (0.096 g) and [Ir(COD)Cl]2 (0.051 g). The reaction mixture was stirred at 85° C. overnight, then cooled to RT. MP-TsOH resin (1.3 mmol/g, 9 g) and EtOH (30 mL) were added to the reaction and the resulting mixture stirred for 2 hr. The resin was filtered from the reaction mixture and thoroughly washed with EtOH. The isolated resin was then washed separately with ammonia (7 N in MeOH) and the filtrate was concentrated to an oil. The crude material was purified via column chromatography (10% then 15% EtOAc/hexanes) to give the desired product (0.13 g, 18%). 1H NMR (300 MHz, CDCl3) δ 0.045-0.092 (m, 2H), 0.42-0.49 (m, 2H), 0.92-1.02 (m, 1H), 2.33 (dd, 1H), 2.47 (dd, 1H), 4.21 (d, 1H), 5.08 (d, 1H), 5.19 (d, 1H), 5.88-5.99 (m, 1H), 7.23(m, 5H). MS APCI, m/z=188 (M+1). LC/MS 1.25 min., Method A.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[C:15]([CH3:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)[N:6]=[N:5][N:4]=1.S(Cl)([Cl:23])=O.O>ClCCl.CN(C)C=O>[Cl:23][CH2:2][C:3]1[N:7]([C:8]2[C:15]([CH3:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C#N)c(C(F)(F)F)cc1-n1nnnc1CO
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(C(F)(F)F)cc1-n1nnnc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-5-methyl-2-(trifluoromethyl)benzonitrile (Intermediate 63, 147 mg, 0.519 mmol) in dichloromethane (3 mL) and N,N-Dimethylformamide (0.5 mL), cooled in an ice bath under argon, was added dropwise thionyl chloride (0.040 mL, 0.545 mmol). The reaction was stirred at 25° C. for two hours. To the reaction was added water (20 mL) and DCM (50 mL) and the reaction partitioned through a hydrophobic frit. The organic layer was evaporated to dryness under vacuum to afford 133 mg of the title compound as a colourless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]2)=[O:43])=[CH:36][CH:35]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14].FC(F)(F)C(O)=O.C(OCC)C>ClCCl>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]2)=[O:43])=[CH:38][CH:39]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14]
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
Step 2 The intermediate 59 (22.0 mg) was treated with trifluoroacetic acid (327 mg, 2.87 mmol) in anhydrous dichloromethane (0.12 ml). The reaction mixture was stirred at room temperature for 15 minutes, until disappearance of the starting material (HPLC-MS analysis). After that, the reaction mixture was treated with diethyl ether (20 ml) and the residue thus obtained was rinsed with diethyl ether (2×10 ml): the product N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N5-carbamoyl-N-(4-{[(piperazin-1-ylcarbonyl)oxy]methyl}phenyl)-L-ornithinamide 60 (white wax, 20.0 mg) was thus isolated and used without further purification in the next step. MS (ESI): 685 [M+H]+. Retention time=2.97 min (method 1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[CH3:17][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Yield: 93.6 %

Procedure:
Amine preparation: To a solution of 1-BOC-3-piperidine carboxylic acid (3.0 g) in DMF (25 mL) was added potassium carbonate (3.62 g) followed by iodomethane (4.07 mL). After 2.5 h the reaction was diluted with water and extracted into diethyl ether. The organic layer was washed with brine, separated and dried (MgSO4). The solvent was evaporated to give piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.98 g).