Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:13][O:12][CH2:11]2)=[O:7])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>ClCCl>[CH:14]1([C:10]23[CH2:9][O:8][C:6]([C:5]4[CH:4]=[CH:3][C:2]([I:1])=[CH:19][CH:18]=4)([O:7][CH2:13]2)[O:12][CH2:11]3)[CH2:15][CH2:16][CH2:17]1
Reactant: O=C(OCC1(C2CCC2)COC1)c1ccc(I)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Ic1ccc(C23OCC(C4CCC4)(CO2)CO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a stirred solution of (3-cyclobutyloxetan-3-yl)methyl 4-iodobenzoate (7.42 g, 20 mmol) in dry dichloromethane (80 ml) at -70° C. under nitrogen atmosphere was added boron trifluoride etherate (2 ml). The solution was allowed to warm to room temperature, stirred overnight and then quenched with dry triethylamine (3 ml). The mixture was evaporated to dryness, partitioned between water and dichloromethane and the organic layer was separated, dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed on basic alumina. Elution with hexane: dichloromethane (9:1 v/v) gave 4-cyclobutyl-1-(4-iodophenyl)-2,6,7-trioxabicyclo[2.2.2]octane (2.8 g, 38%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)(=[O:29])=[O:28]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:29])=[O:28]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCCO
Yield: 95.8 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(3-hydroxypropyl)-6-chlorohexanesulfonamide (515.6 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuc, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(3-hydroxypropyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (976.6 mg) as a pale yellow oil (95.8%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O.ClCCl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:19][O:1][CH2:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5]
Reactant: Nc1ccc([N+](=O)[O-])cc1CO
Reactant: COS(=O)(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCc1cc([N+](=O)[O-])ccc1N
Yield: 42 %

Procedure:
2-Hydroxymethyl-4-nitroaniline (1.0 g, 5.75 mmol) is suspended in petroleum ether (10 mL). Sodium hydroxide solution (50%, 618 mg, 15.46 mmol) and benzyltriethylammonium chloride (20 mg) are added with stirring. Dimethyl sulfate (728 uL, 7.7 mmol) is added and the reaction mixture is stirred at room temperature for 16 h. Dichloromethane (50 mL) and water (25 mL) are added and the layers are separated. The organic layer is washed with saturated NaHCO3 and evaporated affording 440 mg of 2-methoxymethyl-4-nitroaniline (Ma) in 82% purity.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([O:28][C:29]([NH:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCC(O)C(N)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCC(O)C(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To a stirred mixture of Racemate-ethyl 3-amino-4-hydroxycyclohexanecarboxylate (4.7 g, 25 mmol) in 120 mL of dichloromethane was added triethylamine (3.03 g, 30 mmol), followed by the addition of N-(benzyloxycarbonyloxy)succinimide (6.55 g, 26.3 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and then diluted with 200 mL of dichloromethane. The solution was washed with 5% citric acid solution (2×150 mL), 5% potassium carbonate solution (2×150 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure. The resultant oily matter was purified by silica gel chromatography (ethyl acetate:petroleum ether=1:4˜2:5), to thereby give the title compound (7.0 g, 87%) as a yellow oil. MS (ES+) C17H23NO5 requires: 321, found: 322 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23](O)[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CS(C)=O>[N:29]([CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:24]([F:27])([F:26])[F:25])=[N+:30]=[N-:31]
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 110 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.44 mmol) in tetrahydrofuran (4.0 mL) were added thionyl chloride (0.065 mL, 0.891 mmol) and 1 drop of N,N-dimethylformamide at room temperature. After stirring at room temperature for 2 hr, aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated an vacuo to give 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.43 mmol, 93%) as pale yellow solid. A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (68.6 mg, 0.146 mmol) and sodium azide (19 mg, 0.292 mmol) in dimethylsulfoxide (5.0 mL) was stirred at 110° C. for 20 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (68.2 mg, 0.143 mmol, 98%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6]>[Pd].CO>[NH2:12][C:3]1[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(F)cc(F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1c(F)cc(F)cc1C(=O)O

Procedure:
3,5-Difluoro-2-nitro-benzoic acid (2.908 g, 0.01432 mol), 10% Palladium on Carbon (50% Wet) (0.61 g). and Methanol (15 mL) was shaken under an atmosphere of Hydrogen at 38 PSI overnight. The reaction mixture was filtered through celite and concentrated under reduced pressure and azeotroped with toluene to give 2-Amino-3,5-difluoro-benzoic acid as off white solids (2.44 g, 99%). 1H-NMR (CDCl3): 7.45 (d, 1H, J=9.3 Hz), 7.03 (m, 1H), 5.65 (br s, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[N:8]([CH3:23])[N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[CH:11]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:23][N:8]1[C:7]([CH2:6][CH2:5][CH2:4][OH:3])=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:14][CH:13]=2)=[N:9]1
Reactant: CCOC(=O)CCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCCO

Procedure:
In analogy to the procedure described for example 1 a], 3-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-propionic acid ethyl ester was reduced with lithium aluminium hydride in diethyl ether to give 3-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-propan-1-ol as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[N:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.N1CCCCC1.[BH4-].[Na+]>C(O)C.CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([NH:1][CH2:20][C:19]3[C:18]([Cl:17])=[N:25][CH:24]=[CH:23][CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1cccnc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1NCc1cccnc1Cl
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 2-chloronicotinaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product C28 was scraped and collected. (100 mg)
Reaction SMILES: [H-].[Na+].[Br-].[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1)([CH3:32])[CH3:31].Cl>CN(C)C=O.O>[CH:30]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:38][CH2:10][CH2:9][CH:5]2[O:4][CH2:8][CH2:7][O:6]2)=[CH:40][CH:41]=1)([CH3:32])[CH3:31]
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(CCCC2OCCO2)cc1
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
Sodium hydride (oily, 60%, 4.60 g) was added little by little to a solution of 2-(1,3-dioxolan-2-yl)ethyltriphenylphosphonium bromide (51.0 g) in N,N-dimethylformamide (200 ml) at 0° C. After stirring for 15 minutes, 4-isopropoxybenzaldehyde (18.0 g) was added, and the mixture was stirred at 80 to 85° C. for 5 hours. Water was added to the reaction mixture, acidified with 2N hydrochloric acid, and extracted with ether. The ether layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. An oil of the intermediate which was obtained from the fractions eluted with ethyl acetate-hexane (1:4, v/v) was dissolved in ethanol (250 ml), and 5% palladium-carbon (5.00 g) was added. The mixture was subjected to catalytic hydrogenation at 1 atm and room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:5, v/v) to give 2-[3-(4-isopropoxyphenyl)propyl]-1,3-dioxolane (6.70 g, 24%) as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)C>[N:16]1[CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1ccccn1
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2cnc3ccccn23)cc(O)c1O
Temperature: 25 °C

Procedure:
A mixture of 987.5 mg of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 1.01 g of 2-aminopyridine is melted at 110°. After 30 minutes the melt is treated with 15 ml of ethanol and heated to boiling under reflux for 3 hours. The reaction mixture is then cooled to room temperature and the crystals are removed by filtration under suction. There is obtained 5-(imidazo[1,2-a]pyridin-3-yl)-3-nitropyrocatechol of m.p. 250°-252° (from N,N-dimethylformamide/methanol).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][N:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C:3]=12.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][N:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C:3]=12
Reactant: CCOC(=O)c1cnc2c(c1O)CN(C(=O)OC)C2
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(c1Cl)CN(C(=O)OC)C2
Temperature: 25 °C

Procedure:
A mixture of 8.44 g of ethyl 4-hydroxy-5,7-dihydro-6-methoxycarbonylpyrrolo[3,4-b]pyridine-3-carboxylate and 50 ml of phosphorous oxychloride is refluxed for four hours, cooled to room temperature, and evaporated to dryness. The residue is taken up in methylene chloride, cooled by the addition of ice and basified with 10N sodium hydroxide. The layers are separated, and the aqueous phase is re-extracted with methylene chloride. The combined organic extract is dried, filtered, and evaporated to dryness to give ethyl 4-chloro-5,7-dihydro-6-methoxycarbonylpyrrolo[3,4-b]pyridine-3-carboxylate
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[I-].[Li+]>ClC1C=CC=CC=1>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: [I-]
Agent: [Li+]
Solvent: Clc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 115 °C
Yield: 94.09 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in chlorobenzene (70 mL) respectively, then heated to 115° C. and lithium iodide (0.23 g, 1.72 mmol) was added. The mixture was reacted for 4 h, white solid was obtained by filtration (6.85 g, yield: 94.09%).
Reaction SMILES: [CH3:1][N:2]([CH2:26][C:27]1[O:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]=1[CH3:32])[C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:24]=[N:23][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C:8]=2[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:10]1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:8]2[CH:7]=[C:6](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:26][C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]=3[CH3:32])=[O:25])[CH:24]=[N:23][C:9]1=2
Reactant: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C(=O)OC(C)(C)C)CCCN3)oc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCCCN3)oc2ccccc12
Reaction time: 1.5 h

Procedure:
(E)-tert-butyl 8-(3-(methyl((3-methylbenzofuran-2-yl)methyl)amino)-3-oxoprop-1-enyl)-1,2,3,4-tetrahydropyrido[2,3-b][1,5]diazocine-5(6H)-carboxylate (49 mg, 0.1 mmol) was dissolved in 5 mL of DCM followed by the addition of trifluoroacetic acid (5 mL). The solution was stirred for 1.5 h, then concentrated in vacuo, and subjected to prep HPLC purification to obtain the product as a white solid. Yield 25 mg (64%); 1H NMR (400 MHz, CDCl3) δ 10.1 (bs, 1H), 8.01 (m, 2H), 7.50-7.22 (m, 6H), 6.86 (d, J=16.0 Hz, 1H), 4.79 (s, 2H), 4.66 (s, 2H), 3.88 (s, 2H), 3.25 (s, 2H), 3.10 (s, 3H), 2.29 (bs, 5H); ESI MS m/z 391 [C23H26N4O2+H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1I.[C:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)#[N:11].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[C:15]1[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Clc1nccc(I)c1Br
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccnc(Cl)c2Br)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.7 %

Procedure:
A suspension of impure 3-bromo-2-chloro-4-iodopyridine (2.23 g), 4-cyanophenylboronic acid (1.62 g, 11.0 mmol), 2 M aqueous Na2CO3 solution (6 mL, 12 mmol), and toluene (40 mL) was purged with argon, then (Ph3P)4Pd (1.1 g, 0.95 mmol) was added in one portion. The resulting yellow mixture was vigorously stirred under argon at 100° C. for 4 h. Analysis by HPLC/MS indicated the reaction was not complete, and additional 4-cyanophenylboronic acid (0.82 g, 5.57 mmol), 2 M aqueous Na2CO3 solution (3.5 mL) and (Ph3P)4Pd (850 mg) were added. The reaction mixture was stirred at 100° C. for 12 h more. Additional (Ph3P)4Pd (1.0 g) was added, and the reaction mixture was stirred for another 20 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (40 mL×3). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (80 g) eluted with a gradient of EtOAc (0-60%) in hexanes to obtain 590 mg (29%) of the title compound as an off-white solid. HPLC/MS: retention time=3.11 min, [M+H]+=292.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][C@@H:6]1[O:10][CH2:9][C@@H:8]([S:11]C(=O)C)[CH2:7]1)=[O:3].C[O-].CO.Cl.C(O)(C)C>O1CCCC1>[C:2]([O:4][CH2:5][C@H:6]1[CH2:7][C@H:8]([SH:11])[CH2:9][O:10]1)(=[O:3])[NH2:1]
Reactant: CC(=O)S[C@@H]1CO[C@@H](COC(N)=O)C1
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NC(=O)OC[C@H]1C[C@H](S)CO1

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.109 g of product from Example 7, 120 microliter of 25% methoxide/methyl alcohol, 1.75 ml of tetrahydrofuran, 280 microliter of 1.86N hydrochloric acid/isopropyl alcohol to give the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:10][CH2:9][CH:8]2[CH:6]1[CH2:7]2)=[O:4].[Na]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]2[CH:8]([CH2:9][N:10]=1)[CH2:7]2)=[O:4]
Reactant: COC(=O)C1NCC2CC21
Agent: [Na]
Solvent: CO
Product: COC(=O)C1=NCC2CC12
Yield: 70 %

Procedure:
By a method analogous to that of Example 1, this compound was prepared from 2-methoxycarbonyl-3-azabicyclo(3.1.0)hexane. Sodium dissolved in methanol instead of ethanol was used as dehydrohalogenating agent. The desired compound was obtained as a straw-colored liquid in 70% yield. Its identity was confirmed by elemental analysis, and by NMR and IR analyses.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:33]([NH:41]C(OC(C)(C)C)=O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:13][C:14]([NH:16][C@@H:17]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[C:18]([NH:20][C@@H:21]([CH:26]([CH3:28])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[O:19])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[NH2:41][C@@H:33]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:13][C:14]([NH:16][C@@H:17]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[C:18]([NH:20][C@@H:21]([CH:26]([CH3:28])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[O:19])=[O:15]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](NC(=O)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](NC(=O)OCc1ccccc1)[C@@H](N)Cc1ccccc1)C(=O)N[C@H](C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
Methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-benzyloxycarbonylamino-4-tertbutoxycarbonylamino-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutanoate (2.76 g; 4.04 mmol) were dissolved in 10 ml of HCl solution in dioxane (4 M) in a flask, and the mixture was stirred at RT for 5 h. Excess HCl was removed using the house vacuum, the solvent was removed in vacuo, and the residue was lyophilised overnight, giving 2.4 g of methyl (S)-2-[(2S,3S)-2-((3S,4S)-4-amino-3-benzyloxycarbonylamino-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate as a white solid. (Yield 92.2%, content 94%). MS-FAB (M+H+)=569.3 Rf (polar method): 1.67 min.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](OCC)=[O:9].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([NH:1][NH2:2])=[O:9]
Reactant: NN
Reactant: CCOC(=O)C(C#N)(CCCCl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(CCCCl)(C(=O)NN)c1ccccc1

Procedure:
Hydrazine (1.2 g) was added to a solution of ethyl 5-chloro-2-cyano-2-phenylpentanoate (CAS No. 52370-87-3, 1 g) in ethanol (5 mL), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was filtered through a silica gel, and the filtrate was concentrated under reduced pressure to obtain a crude product of 5-chloro-2-cyano-2-phenylpentanoic acid hydrazide.
Reaction SMILES: S(O[C@@H:6]1[CH2:10][C@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:8][C@@H:7]1[N:20]1[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]1=[O:22])(C)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Li+].CO>>[N:29]([C@H:6]1[CH2:10][C@H:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[O:8][C@@H:7]1[N:20]1[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]1=[O:22])=[N+:30]=[N-:31]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](OS(C)(=O)=O)[C@@H](n2cc(F)c(N)nc2=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@H](N=[N+]=[N-])[C@@H](n2cc(F)c(N)nc2=O)O1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
To a solution of 20 (442 mg, 1.01 mmol) in anhydrous dilmethylformamide (12 mL) was added lithium azide moistened with 10% methanol (265 mg, 4.87 mmol). The reaction mixture was stirred at 100° C. during 2.5 h, and then cooled to room temperature, poured onto ice/water (200 mL) and extracted with chloroform (3×100 mL). Combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution (2×100 mL), with water (5×100 mL) and then dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: methanol (4%) in chloroform] to give pure 21 (291 mg, 75% yield) as a white solid: mnp 147-148° C.; UV (ethanol): λmax 242 nm (ε7700), 283 nm (ε7400), λmin 226 nm (ε6600), 264 nm (ε5800); 1H NMR (DMSO-d6): δ8.05 (d, 1H, H-6, J6-F5=7.0 Hz), 7.9-7.4 (br d, 2H, NH2), 5.7 (br s, 1H, H-1′), 4.37 (d, 1H, H-2′, J2′-3′=5.5 Hz), 4.3 (m, 1H, H-4′), 4. (m, 1H, H-5′), 3.7 (m, 1H,H-5″), 2.0 (m, 1H, H-3′), 1.8 (m, 1H, H-3″), 0.88 (s, 9H, (CH3)3C—Si), 0.05 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 769 (2M+H)+, 385 (M+H)+, 130 (BH2)+; FAB<0 m/z 1151 (3M−H)−, 767 (2M−H)−, 383 (M−H)−, 128 (B)−; [α]D20=+25 (c, 0.95 DMSO).