Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:11][CH2:10][CH3:9]
Reactant: CCCCOCCCCCl
Reactant: O=C1CCNCC1
Product: CCCCOCCCCN1CCC(=O)CC1

Procedure:
1-(4-Butoxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-butoxybutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14]S(C(C)(C)C)=O)[CH:12]=[CH2:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl>CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH2:14])[CH:12]=[CH2:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C=CC(NS(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CO
Product: C=CC(N)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(1-(1,4-dioxaspiro[4.5]decan-8-yl)allyl)-2-methylpropane-2-sulfinamide (1.38 g, 4.58 mmol), prepared in the previous step, was dissolved in methanol (100 mL) and treated with HCl (15 mL. 18.7 mmol, 1.25 M in MeOH), stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, triturated with ether, decanting the supernatant several times and the residue dried under high vacuum afford the product as a white foam (HCl salt).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].CC(C)(CCC=C)C(OCC)=O>>[CH2:16]([C:2]1([CH2:3][O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:6])[CH2:20][CH2:1]1)[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: C=CCCC(C)(C)C(=O)OCC
Product: C=CCCC1(COC(=O)N[C@H](C(=O)O)C(C)(C)C)CC1

Procedure:
N-{[(1-But-3-en-1-ylcyclopropyl)methoxy]carbonyl}-3-methyl-L-valine was prepared according to the procedure for N-{[(2,2-dimethylhex-5-enyl)oxy]carbonyl}-3-methyl-L-valine (Steps 2 and 3) by using ethyl 1-but-3-en-1-ylcyclopropanecarboxylate_instead of ethyl 2,2-dimethylhex-5-enoate in Step 2. LRMS (ESI) m/z 284.3 [(M+H)+; calcd for C15H26NO4: 284.2].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[C:26]([O:29][C:30]1[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:32](Cl)=[O:33])(=[O:28])[CH3:27]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[O:29][C:26](=[O:28])[CH3:27])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3OC(C)=O)ccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-1-methyl-indole-2-carboxylic acid ethyl ester (12.86 g, 58.92 mM) and diisopropylethylamine (20.5 mL, 117.84 mM) in CH2Cl2 at 0° C. was added a solution of acetyl salicyloyl chloride in CH2Cl2 over 30 minutes. After the addition was complete the cooling bath was removed and the mixture was allowed to warm to room temperature and stirred at that temperature for 2 hours. The mixture was transferred to a separatory funnel and the solution was washed with 1N HCl (150 mL) and aqueous NaHCO3. The organic fraction was dried over MgSO4 and filtered. The solvent was removed under reduced pressure to provide the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[CH:10][CH:9]=1.S(=O)(=O)(O)[O-:18].[Na+]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]=[O:18])=[CH:10][CH:9]=1
Reactant: CC(O)c1ccc(OC2CCCCO2)cc1
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CCc1ccc(OC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 740 g. of Celite diatomaceous earth and 396 g. of chromium trioxide-dipyridine complex (Collins' reagent) in 4 l. of anhydrous methylene chloride, cooled to 0°C is added dropwise a solution of 58 g. of 4-(tetrahydropyran-2-yloxy)phenylethanol in 3 l. of anhydrous methylene chloride, maintaining the temperature of the reaction mixture at 0°-5°C. After completion of the addition, the reaction mixture is stirred for 30 minutes further at 0°C, 396 g. of sodium bisulfate are added and the mixture stirred for 15 additional minutes. It is then filtered through anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, to yield 4-(tetrahydropyran-2-yloxy)phenylacetaldehyde.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].Cl.[O:14]([NH2:16])[CH3:15]>>[CH3:15][O:14][N:16]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C=O
Reactant: CON
Agent: Cl
Product: CON=Cc1ccccc1OC(C)C

Procedure:
Reaction of 2-isopropoxybenzaldehyde (Hach, Collect. Czech. Commun., 23, 1958, 1902-1907) with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (96% yield). 1HNMR indicated a 95:5 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 1.33 (6H, d, J=6.1 Hz, CH3), 3.97 (3H, s, OCH3), 4.56 (1H, m, CH), 6.90 (2H, m, aromatics), 7.30 (1H, m, aromatic), 7.79 (1H, dd, J=2.0 Hz and J=7.6 Hz, aromatic), 8.47 (1H, s, CH).
Reaction SMILES: Br[CH:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([CH3:15])[C:12]([CH3:14])=[CH:13][C:6]=2[NH:5][C:4](=[O:16])[CH2:3]1>C(Cl)(Cl)Cl>[CH3:15][C:11]1[C:12]([CH3:14])=[CH:13][C:6]2[NH:5][C:4](=[O:16])[CH:3]=[CH:2][C:8](=[O:9])[C:7]=2[CH:10]=1
Reactant: Cc1cc2c(cc1C)C(=O)C(Br)CC(=O)N2
Solvent: ClC(Cl)Cl
Product: Cc1cc2[nH]c(=O)ccc(=O)c2cc1C

Procedure:
To a chloroform solution of the 4-bromo-2,3,4,5-tetrahydro-7,8-dimethyl-2,5-dioxobenz(f)azepine was added hydrated sodium acetate. On shaking, filtration, and storage, yellow 2,5-dihydro-7,8-dimethylbenz(f)azepine-2,5-dione, mp 258° C. (from propanol) was deposited.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]2[C:9](=[O:14])[NH:10][S:11](=[O:13])(=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1N.N([O-])=O.[Na+].[I-:20].[K+]>O.C(O)(=O)C>[CH3:2][C:3]1[C:8]2[C:9](=[O:14])[NH:10][S:11](=[O:13])(=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[I:20]
Reactant: Cc1c(N)ccc2c1C(=O)NS2(=O)=O
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(I)ccc2c1C(=O)NS2(=O)=O
Temperature: 50 °C

Procedure:
A mixture of 205 ml of glacial acetic acid, 160 ml of water and 40 ml of conc. HCl is initially taken and 23.4 g (0.11 mol) of 4-methyl-5-amino-1,1,3-trioxo-2,3-dihydro-1λ6 benz[d]isothiazole are introduced with stirring at 15°-20° C. 7.9 g (0.115 mol) of sodium nitrite are added dropwise to the resulting suspension at 5°-10° C. and it is stirred at 5° C. for 30 min. The diazonium salt, which is present as a suspension, is then added dropwise in portions to a solution of 19.1 g (0.115 mol) of potassium iodide in 170 ml of water which is warmed to 50° C., nitrogen being formed. After cooling to room temperature, the deposited product is isolated by filtering off with suction, washed with water and dried under reduced pressure at 50° C. 32.5 g (0.1 mol=91% of theory) of a solid of m.p.: 257°-258° C. are obtained. A combustion analysis gave an iodine content of 38.5% (theory 39.3%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[O-]CC.[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl>C(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][S:5][CH2:4][CH2:3][NH2:2]
Reactant: COc1ccccc1CCl
Reactant: NCCS
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1CSCCN
Reaction time: 8 h
Yield: 36.7 %

Procedure:
Cysteamine hydrochloride (2.12 g) was added to a solution of sodium ethoxide (from 0.87 g sodium) in ethanol (50 ml) stirred under nitrogen in an ice-bath. 2-Methoxybenzyl chloride (2.93 g) was added dropwise and the mixture was stirred in an ice-bath for 0.5 hr. and allowed to stand at room temperature overnight. The mixture was evaporated to dryness. Water was added to the residue and the mixture was extracted at pH 3 with chloroform (discarded), adjusted to pH 13 and extracted a second time with chloroform. This second extract was purified by elution from silica gel with chloroform/methanolic ammonia (50:1) to give 2-(2-methoxybenzylthio)ethylamine (1.35 g) as an oil which was treated with hydrogen chloride in ethanol to give the hydrochloride m.p. 128°-30° (ethanol/ether).
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)[C:8]2[CH:12]=[C:11]([C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[S:10][C:9]=2[CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([N:34]([CH3:33])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:30])=[CH:31][CH:32]=2)[C:8]2[CH:12]=[C:11]([C:13]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:14])[S:10][C:9]=2[CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(C(=O)C2CCCCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1sc(C(=O)C2CCCCC2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a mixture of 4-({cyclohexyl[5-(cyclohexylcarbonyl)-2-ethylthiophen-3-yl]methyl}amino)benzoic acid (130 mg) synthesized in Example 291 (2), ethyl 3-(methylamino)propanoate (56.5 mg), 1-hydroxybenzotriazole monohydrate (66.0 mg) and triethylamine (60 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (82.6 mg), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (118 mg, 77%) as a pale-yellow solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[NH2:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: BrCc1ccccc1
Reactant: NC(=O)c1ccc(O)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCc2ccccc2)cc1N
Temperature: 15 °C
Reaction time: 20 h
Yield: 42.1 %

Procedure:
To a solution of 95% NaH (1.82 g, 72.30 mmol) in DMF (100 mL) at 10° C. was added 2-amino-4-hydroxybenzamide (10.0 g, 66.72 mmol) in portions, maintaining the internal temperature at ca. 15° C. The cooling bath was removed, and the solution was allowed to warm to 40° C. over 25 min. The mixture was cooled to 10° C. and a solution of benzyl bromide (7.8 mL, 66.72 mmol) in DMF (20 mL) was added dropwise, and the mixture was allowed to warm to rt. After stirring for 20 h at rt, the mixture was cooled in an ice bath and quenched by addition of aq ammonium chloride. The solution was concentrated and diluted with water. The precipitate was collected by filtration, and the filtrate was extracted with EtOAc. The precipitate from above and the ethyl acetate extracts were combined and chromatographed on silica gel eluting with 20-80% EtOAc/DCM to afford 2-amino-4-(benzyloxy)benzamide as a solid (6.8 g, 43%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.04 (s, 2H) 6.14 (dd, J=8.76, 2.54 Hz, 1H) 6.27 (d, J=2.64 Hz, 1H) 6.71 (bs, 2H) 7.26-7.58 (m, 6H). LC-MS (ESI) m/z 243 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:25][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 87.9 %

Procedure:
By conducting a procedure similar to that in Synthesis Example 3 except using 2.0 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone, 15 ml of N,N-dimethylformamide, 1.3 g of anhydrous sodium carbonate and 1.6 g of 4-tert.-butylbenzyl chloride, there were obtained white needle-like crystals having the following physical properties (yield: 87.9%):
Reaction SMILES: CO[C:3](=O)[CH2:4][CH2:5][CH:6]([NH:13][C:14]([O:16]CC1C=CC=CC=1)=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCO.[Pd]>[C:7]1([CH:6]2[NH:13][C:14](=[O:16])[CH2:3][CH2:4][CH2:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CCC(NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCC(c2ccccc2)N1
Temperature: 65 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
4-Benzyloxycarbonylamino-4-phenyl-butyric acid methyl ester was dissolved in EtOH (30 mL), and 10% palladium on activated carbon (1.1 g) was added. The mixture was stirred under hydrogen atmosphere at 45 psi (3.1 bar) for 22 hours at room temperature and 4 hours at 65° C. The mixture was filtered and the filtrated was concentrated under reduced pressure. The residue was recrystallized from a mixture of methanol, diethyl ether and hexanes to give 1.85 g (81%) of 6-phenyl-piperidin-2-one as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]([NH2:17])=O)=[N:6]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]#[N:17])=[N:6]1
Reactant: NC(=O)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1nc(-c2nccs2)n(Cc2ccccc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxamide (Intermediate-4, 0.86 mmol) in pyridine (3.0 mL) at 0° C. was treated with trifluoroacetic anhydride (2 equiv) dropwise over the course of 5 min. The reaction was then warmed to ambient temperature and stirred for 2 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with CH2Cl2. The organic phases were dried over MgSO4, filtered and conc. The crude product was purified using SiO2 chromatography and an appropriate solvent gradient (EtOAc/hexanes) to give 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carbonitrile as white solid (88% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5])(=[O:15])[CH3:14]
Reactant: Cc1c(Br)ccc(O)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)c(C)c1C(=O)O
Reaction time: 16 h

Procedure:
A mixture of 1B (6.93 g, 30 mmol), acetic anhydride (3.5 ml, 36 mmol) and pyridine (15 ml) is heated under reflux with stirring for 16 hours. The reaction mixture is diluted with water and ethyl acetate. The organic phase is acidified with dilute hydrochloric acid and washed with water twice. The organic phase is concentrated in vacuo and the residue is purified by flash chromatography (dichloromethane:methanol, 9:1 v/v) yielding the pure product as a yellow oil, 7.4 g, (90.3%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23]C[CH2:21]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1.[N:26]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[C:27]=[O:28]>CN(C=O)C.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:18]([N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:21]3)[C:27]([NH:26][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: O=C=NC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To an ice cold suspension of NaH (6 mg, 160 umol) in DMF (2.5 ml) under an argon atmosphere was added a solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (50 mg, 153 umol; example 11.1) in DMF (1 ml) within 10 min. The suspension was stirred for 1 h at 0° C. A solution of isocyanato-cyclopentane (34 mg, 306 umol; [4747-71-1]) in DMF (0.5 ml) was added within 5 min. The reaction mixture was stirred for 1 h at ambient temperature, poured onto ice water/1 N aqueous HCl solution/brine 1/1/1 and extracted two times with iPrOAc. The combined extracts were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (20 mg, 47 umol; 21%) as yellow foam. MS: m/e=423.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][CH2:9][C:10]2[N:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH:7]=1.[N:20]([O-])=O.[Na+]>CC(O)=O.Cl.O.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[N:20][N:8]([CH2:9][C:10]3[N:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[C:6]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccc(Cl)nn1
Reactant: O=N[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(Cn2nnc3ccc(Br)cc32)nn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of compound 10E (1.40 g, 4.08 mmol) in HOAc/HCl (50/5 mL) was added iron power (2.2 g, 40 mmol). The reaction mixture was stirred at 50° C. for 30 minutes, then cooled to room temperature and filtered. A solution of NaNO2 (0.35 g, 5 mmol) in water (2 mL) was then added drop wise into above acid solution at 0° C. The reaction solution was stirred for one hour and concentrated to dryness under reduced pressure. The resulting residue was sonicated in ethyl acetate/NaHCO3 solution and the precipitate was filtered off and rinsed thoroughly with ethyl acetate. The organic solution was separated and dried with MgSO4, filtered and concentrated to give 1.2 g of desired product (10F). ESI-MS:m/z 323.9 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:32](O)=[O:33])[CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[SH:47][CH2:48][CH2:49][C:50]([NH:52][C:53]([CH3:58])([CH3:57])[C:54]([OH:56])=[O:55])=[O:51].C(N1CCOCC1)C>CN(C)C=O>[CH:1]1([C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:32]([S:47][CH2:48][CH2:49][C:50]([NH:52][C:53]([CH3:58])([CH3:57])[C:54]([OH:56])=[O:55])=[O:51])=[O:33])[CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(NC(=O)CCS)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)C1CCCC1)C(=O)N[C@@H](Cc1cccs1)C(=O)O
Agent: CCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)C1CCCC1)C(=O)N[C@@H](Cc1cccs1)C(=O)SCCC(=O)NC(C)(C)C(=O)O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 10 mmoles of Nα -cyclopentanecarbonyl-Nε -tert-butyloxycarbonyl-L-lysyl-β-2-thienyl-alanine in redistilled dimethylformamide (DMF) is cooled in an ice-dry ice-acetone bath at -20° C. To this solution is added a cold solution of 10 mmoles of 1,1'-carbonyldiimidazole in DMF. The solution is stirred at -10° C. for two hours and then mixed with a cold solution of 10 mmoles of 2-[(3-mercaptopropanoyl)amino]-2-methylpropanoic acid (from Example 46) in DMF which is neutralized with N-ethyl morpholine. The reaction mixture is stirred at -10° C. for an additional hour and then slowly warmed to room temperature. The solvent is removed under reduced pressure at 40° C. and ethyl acetate is added to the residue. The mixture is cooled in an ice water bath and washed with 1N citric acid and then three times with saturated NaCl solution. The solvent is removed with a rotary evaporator after drying over anhydrous MgSO4. The product is purified by LH-20 column chromatography using a 1.2 cm by 95 cm column and eluted with THF:isopropanol, 3:7 (parts by volume). The peak fractions are pooled and the solvent is removed under reduced pressure yielding the named product.
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]3[NH:32][C:31](=[O:33])[C@H:30]([CH2:34][C:35]([O:37][CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[CH2:29]3)=[CH:22][CH:21]=2)=[N:18][CH:19]=1)=[NH:13])=O)C1C=CC=CC=1.[ClH:46]>[Pd].CN(C)C=O>[ClH:46].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C@H:28]3[NH:32][C:31](=[O:33])[C@H:30]([CH2:34][C:35]([O:37][CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:43])([CH3:42])[CH3:44])=[O:36])[CH2:29]3)=[CH:24][CH:25]=2)=[N:18][CH:19]=1)(=[NH:11])[NH2:13]
Reactant: CC(C)(C)C(=O)OCOC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C(=N)NC(=O)OCc4ccccc4)cn3)cc2)NC1=O
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C(=N)N)cn3)cc2)NC1=O

Procedure:
Prepared from (3S,5S)-5-[[4-(5-benzyloxycarbonylamidino-2-pyridyl)phenyl]oxymethyl]-3-[(pivaloyloxymethyloxycarbonyl)-methyl]-2-pyrrolidinone by hydrogenation with palladium on charcoal in dimethylformamide in the presence of hydrochloric acid.
Reaction SMILES: [Cl:1][GeH:2]([Cl:4])[Cl:3].[C:5]([O:15][CH3:16])(=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][Ge:2]([Cl:4])([Cl:3])[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][C:5]([O:15][CH3:16])=[O:14]
Reactant: Cl[GeH](Cl)Cl
Reactant: COC(=O)C=Cc1ccccc1
Product: COC(=O)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of 36.0 g (0.2 mol) of trichlorogermane and 32.4 g (0.2 mol) of methyl cinnamate was stirred for 2 hours and then distilled in vacuum to obtain 56.2 g of a fraction, b.p. 148°. Yield 82.2%.