Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8](=[O:10])[CH3:9])[N:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[N:6]([CH2:7][CH:8]([OH:10])[CH3:9])[N:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CC(=O)Cn1nc([N+](=O)[O-])cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])nn1CC(C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.9 %

Procedure:
A solution of 1-(5-methyl-3-nitro-pyrazol-1-yl)-propan-2-one (500 mg, 2.9 mmol) in ethanol (15 ml) was treated with sodium borohydride (111 mg, 0.29 mmol). The reaction was stirred at 25° C. for 2.5 h. At this time, the reaction was poured onto water and was extracted into ethyl acetate. The organics were concentrated in vacuo to afford 1-(5-methyl-3-nitro-pyrazol-1-yl)-propan-2-ol (440 mg, 88%) which was used without further purification; ES+-HRMS m/e calcd for C7H11N3O3 [M+H+] 186.0873, found 186.0873.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C@H:9]1[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[O:10]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:16][C:11]1([CH3:17])[O:10][C@@H:9]([CH2:8][CH2:7][OH:6])[C:13]([CH3:15])([CH3:14])[O:12]1
Reactant: CC1(C)O[C@@H](CCO[Si](C)(C)C(C)(C)C)C(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O[C@@H](CCO)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
Step F To the solution of tert-butyl-dimethyl-[2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethoxy]-silane (4.56 g, 15.8 mmol) in tetrahydrofuran (20 mL) at 0° C. was added a solution of tetrabutylammonium fluoride (1 M, 20 mL, 20 mmol). The reaction mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethanol as a yellow oil (2.7 g, 100%).
Reaction SMILES: [CH3:1]O.S(=O)(=O)(O)O.[Cl:8][C:9]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:10]=1[C:11]([NH:13][C@H:14]([C:23]([OH:25])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:12]>O>[CH3:1][O:24][C:23](=[O:25])[C@H:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([I:22])=[CH:20][CH:21]=1)[NH:13][C:11](=[O:12])[C:10]1[C:9]([Cl:8])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:30]
Reactant: CO
Reactant: O=C(N[C@@H](Cc1ccc(I)cc1)C(=O)O)c1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Methanol (40 mL) and 0.98 mL of concentrated sulfuric acid were added to 8.0 g of Nα-(2,6-dichlorobenzoyl)-4-iodo-L-phenylalanine and the reaction was carried out for 4 hours while heating the reaction system at 40° C. After confirming the completion of the reaction, the reaction system was cooled to 10° C. and 20 mL of water was dropwise added to separate out solid. The solid thus precipitated was isolated through filtration under reduced pressure, washed with 40 mL of water and then dried at 70° C. under reduced pressure to thus give 7.40 g of the desired product as a solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[NH2:12][C:13]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:14]=1[C:15]([NH:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16].O>O1CCOCC1>[CH2:19]([O:18][N:17]1[C:15](=[O:16])[C:14]2[C:13](=[CH:29][C:28]([F:30])=[C:27]([F:31])[CH:26]=2)[NH:12][C:1]1=[O:2])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)NOCc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1

Procedure:
Phosgene, 12.5% solution in toluene, (16 mL, 20 mmol) was added to a solution of 2-amino-N-benzyloxy-4,5-difluoro-benzamide (Example A, 5.54 g, 19.9 mmol) in 160 mL of dioxane. The solution was heated at reflux for 5 hours and then poured into 450 mL of water. The aqueous solution was extracted with ethyl acetate; the combined organic extracts were washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 5.73 g of the title compound as a solid, mp>250° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2[C:14](=O)[CH2:15][O:16][C@H:10]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OP([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(OCC)=O)C.[H-].[Na+]>C1COCC1>[Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2/[C:14](=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])/[CH2:15][O:16][C@H:10]12)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=O)CO[C@@H]21
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 20 mL sample vial was charged (3R,3aS,6aS)-3-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (400 mg, 1.548 mmol), ethyl 2-(diethoxyphosphoryl)acetate (521 mg, 2.322 mmol) and THF (5 ml). The vial was flushed with nitrogen and cooled in an ice bath. To the mixture was then added slowly 60% sodium hydride (93 mg, 2.3 mmol) and the resulting reaction mixture was stirred at room temperature for 6 h. The reaction was partitioned between water (10 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The resulting residue was then purified by MPLC (40 g silica gel, 0 to 20% ethyl acetate in hexanes) to afford the desired product as a mixture of E/Z isomers. LC-MS: calculated for C16H28O5Si, [M+H]+Calc: 328.17. Found: 329.2, Rt=2.24 and 2.31 min (E and Z mix, 4 min run).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19]C[C@H](C=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)#[N:7].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH:3]([C@H:2]1[CH2:1][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=2)[CH2:15][CH2:16]1)=[CH2:4]
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2.51 g of methyltriphenylphosphonium bromide in 80 ml of absolute tetrahydrofuran was placed at -20° C. while gassing with argon in a sulphonation flask provided with a dropping funnel and thermometer and treated with 7.6 ml of an about 0.8M solution of butyl lithium in hexane. After stirring at -20° C. for 30 minutes, a solution of 1.0 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 10 ml of absolute tetrahydrofuran was added dropwise at -20° C. within 5 minutes to the yellow mixture, whereby the yellow colour disappeared. The mixture was now stirred at -20° C. for a further 30 minutes and then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 897 mg (91%) of p-(trans-4-vinylcyclohexyl)benzonitrile as colourless crystals; purity 99.4%. By additional crystallization from 22 ml of methanol there was obtained p-(trans-4-vinylcyclohexyl)benzonitrile in a purity of 99.95%; m.p. (C-I) 56.4° C., cl.p. 28.5° C.
Reaction SMILES: [CH:1]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])OC)([CH3:3])[CH3:2].[ClH:13]>>[CH:1]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])[Cl:13])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: CO[Si](C(C)C)(C(C)C)C(C)C
Product: CC(C)[Si](Cl)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 10 h
Yield: 98.5 %

Procedure:
A 500 ml-capacity, four-necked flask fitted with a stirrer, a thermometer and a Dimroth was charged with 37.7 g (0.2 moles) of triisopropylmethoxysilane. To the flask was then added 150 g of 35% hydrochloric acid, and the resulting mixture was stirred at 20° C. for 10 hours to effect the reaction. The resulting reaction solution was separated into the aqueous layer and the organic layer. The organic layer was distilled to afford 38 g of triisopropylchlorosilane as a fraction boiling at 78° C.-80° C./10 mm Hg (yield; 99%).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[C:18]([CH:26]=O)=[CH:17]1)[CH3:15].CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[C:18]([CH2:26][NH:6][CH3:5])=[CH:17]1)[CH3:15]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: CCn1cc(C=O)c2cc(F)ccc21
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CCn1cc(CNC)c2cc(F)ccc21
Yield: 50 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 1-ethyl-5-fluoro-1H-indole-3-carboxaldehyde (0.2 g,1.9 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.1 g, 50%) was prepared as a viscous oil: MS (ES) m/e 207 (M+H)+.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].C([O-])CCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Zr+4:31]>C(O)(C)C>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zr+4:31].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zr+4:31].[Zr+4:31]
Reactant: O=P(O)(O)O
Agent: [Zr+4]
Agent: CCCC[O-]
Solvent: CC(C)O
Product: O=P([O-])([O-])[O-]
Reaction time: 1.5 h

Procedure:
A solution consisting of 100 ml isopropanol and 13.0 ml orthophosphoric acid (commercially available concentrated reagent) was added to a second solution consisting of 300 ml isopropanol and 57.6 g zirconium tetrabutoxide butanolate. The product gel was filtered, dried, and screened to various sized fractions. The dried zirconium phosphate gel was activated by calcining at 300° C. in air for 90 minutes. Subsequent to being calcined the zirconium phosphate gel was flushed with nitrogen.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1.[C:24]1(C)[C:25](C)=[CH:26]C=[CH:28][CH:29]=1>O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([C:20]3[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=3)[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1.[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1
Reactant: Cc1ccccc1C
Agent: Cc1cc(C)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Solvent: O
Product: Cc1cc(-c2ccccc2)nc2c1c(C#N)cn2-c1ccc(C(C)C)cc1Br

Procedure:
A mixture of 737 mg (2.00 mmole) of the product from Example 64 (Part B), 324 mg (2.00 mmole) of benzolyacetone and 25 mL of xylene was heated in a flask equipped with a water separator for 2 hours. The solvent was removed by evaporation, and the residue chromatographed on silica gel, eluting in step gradients with 0, 5, 10, and 15% ethyl acetate in hexane. Both 1-(2-bromo-4-isopropylphenyl)-3-cyano-4-methyl-6-phenyl-7-azaindole and 1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-methyl-7-azaindole were obtained. The Rf values were respectively 0.38 and 0.28 (silica gel with 80:20 hexane-ethyl acetate). The assignment of the structures was based on the nmr data of the de-cyanylated compounds in Example 67.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH2:10][C:9]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:8][CH2:7][C:5]=2[N:6]=1.C([O-])(=O)C.[Na+]>CO.[C].[Pd]>[CH2:13]1[CH2:12][O:11][C:9]2([CH2:8][CH2:7][C:5]3[N:6]=[CH:2][S:3][C:4]=3[CH2:10]2)[O:14]1
Reactant: Clc1nc2c(s1)CC1(CC2)OCCO1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc2c(s1)CC1(CC2)OCCO1
Reaction time: 17 h

Procedure:
In a 100-mL egg-plant type flask, 2-chloro-6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[d]thiazole (860 mg) was charged and was dissolved in methanol (10 mL). To the resulting solution were added 10% palladium-carbon (100 mg) and sodium acetate (305 mg), followed by stirring under a hydrogen gas stream of 4.5 atmospheric pressure. After 17 hours, palladium was filtered off and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel column (silica gel: 50 g, ethyl acetate:hexane=1:1), whereby the title compound (720 mg) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](N)[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3].S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.[O-]S([O-])(=O)=O.[Cu+2].C(O)C>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: CS(=O)(=O)n1ccc2ccc(N)cc21
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)n1ccc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-methansulfonyl-6-amino indole (2.10 g, 10.0 mmol), prepared as described in Forbes, et al., J. Med. Chem. (1996) 39:4968, was suspended in 40 ml of water, then cooled in an ice bath. Concentrated sulfuric acid (3 ml) was added slowly dropwise. The mixture was warmed to room temperature for 5 min then cooled back down to 0° C. A solution of NaNO2 (Mallinckrodt, 0.76 g, 11.0 mmol) in 10 ml of water was added slowly and the resultant foam was treated with 10 ml of ethanol. The mixture was added in portions to a boiling solution of CuSO4 (J. T. Baker, 16.0 g, 0.1 mol) in 75 ml of water. After 15 min, the mixture was cooled. The brown solid which had formed was broken up with a glass stirring rod. NaHCO3 was added to neutralize the reaction and the product was extracted with ethyl acetate (2×100 ml). The extracts were dried (anhydrous MgSO4) and concentrated to give 1-methansulfonyl-1H-indol-6-ol (1.62 g), a brown oil which was used with out purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[CH:11][N:12](C)C)[C:7](=O)[C:6]=2[CH:16]=1.O.[NH2:18]N.C(O)(=O)C>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3[CH:11]=[N:12][NH:18][C:7]=3[C:6]=2[CH:16]=1
Reactant: NN
Reactant: CN(C)C=C1COc2ccc(Cl)cc2C1=O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)-c1[nH]ncc1CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 6-chloro-3,4-dihydro-3-dimethylaminomethylene-4-oxo-2H-1-benzopyran (1.188 g), hydrazine hydrate (0.325 g), and acetic acid (0 39 g) in a mixture of chloroform (10 ml) and methanol (20 ml) was stirred overnight at room temperature and then evaporated in vacuo. The residual solid was washed with water, dried, and recrystallized form ethyl acetate to give 8-chloro-1,4-dihydro-[1]-benzopyrano[4,3-c]pyrazole (0.95 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1[OH:28]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C:19]2([NH2:18])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH:20]2[OH:28])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1c2ccccc2CC1O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)c2ccccc2CC1O

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-amino-2-indanol, the title compound was prepared.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[NH:20][C:21]([C:28](O)=[O:29])=[C:22]2[C:27]=1[CH2:26][CH2:25][CH2:24][CH2:23]2>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:21]3[NH:20][N:19]=[C:27]4[C:22]=3[CH2:23][CH2:24][CH2:25][CH2:26]4)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1[nH]nc2c1CCCC2
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1[nH]nc2c1CCCC2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid (166 mg, 0.997 mmol). The product was triturated with ethanol. Yield 111 mg (35%). 1H-NMR (400 MHz; d6-DMSO): δ 1.09 (d, 3H), 1.58-1.72 (m, 4H), 2.54-2.61 (m, 4H), 4.24-4.46 (m, 3H), 6.94 (d, 1H), 7.82 (d, 1H), 7.99 (s, 2H), 8.05-8.08 (m, 2H), 12.68 (s, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:30][CH2:29]1.[C:43]([O:47][C:48]([N:50]([CH:63]([CH3:65])[CH3:64])[CH2:51][C@H:52]([C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=1)[C:53](O)=[O:54])=[O:49])([CH3:46])([CH3:45])[CH3:44].CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(=O)OCC>[Cl:62][C:59]1[CH:60]=[CH:61][C:56]([C@H:52]([C:53]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[CH2:29][CH2:30][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:54])[CH2:51][N:50]([CH:63]([CH3:64])[CH3:65])[C:48](=[O:49])[O:47][C:43]([CH3:45])([CH3:44])[CH3:46])=[CH:57][CH:58]=1
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
HBTU (0.469 g, 1.24 mmol) was added to a solution of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.360 g, 1.24 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.423 g, 1.24 mmol), and DIEA (0.646 ml, 3.71 mmol) in DCM (8 mL). The reaction mixture was stirred at room temperature for 2 hours, after which 2M Na2CO3 was added. The reaction mixture was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on a Biotage 40S (ca. 175 mL 4:1 DCM:EA flushed to elute DIEA, then gradient to 1:4 DCM:EA) to give tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.679 g, 101% yield) as a pale yellow syrup. LC/MS (APCI+) m/z 542.1 [M+H]+
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH:19]1([CH2:22][CH:23]=[O:24])[CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH2:22][CH:23]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[OH:24])[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: O=CCC1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC2CC2)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a −40° C. solution of methyl 4-iodobenzoate (0.39 g, 1.5 mmol) in tetrahydrofuran (7.5 mL) was added isopropylmagnesium chloride lithium chloride (1.5 mL, 1.3 M in THF, 1.95 mmol) dropwise. After stirring for 30 minutes at −40° C., 2-cyclopropylacetaldehyde (190 mg, 2.26 mmol) was added dropwise. The resulting mixture was then stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The layers were separated and the aqueous was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/−)-methyl 4-(2-cyclopropyl-1-hydroxyethyl)benzoate (150 mg, 45%). 1H NMR (400 MHz, CDCl3, δ): 7.89 (d, 2H), 7.32 (d, 2H), 4.75-4.72 (m, 1H), 3.79 (s, 3H), 1.60-1.51 (m, 2H), 0.60-0.51 (m, 1H), 0.49-0.25 (m, 2H), 0.07-−0.12 (m, 2H).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=O)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:44][C@H:45]([C:53]([OH:55])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([NH:44][C@H:45]([C:53]([OH:55])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:28])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 86.9 %

Procedure:
Starting from N-(3-hexadecanoyloxyoctadecanoyl)-β-alanine (1.52 g) prepared by the method of Example 31 and L-phenylalanine (1.65 g), N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-phenylalanine (1.64 g) was obtained as crystals according to a similar manner to that of Example 29.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=O.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][F:20])=[CH:11][CH:10]=1>C(O)(=O)C>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][F:20])[C:2]2[CH2:4][O:5][C:6](=[O:7])[CH:1]=2)=[CH:11][CH:10]=1
Reactant: FCCCNCc1ccc(Cl)nc1
Reactant: O=C1COC(=O)C1
Solvent: CC(=O)O
Product: O=C1C=C(N(CCCF)Cc2ccc(Cl)nc2)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.6 %

Procedure:
0.52 g (5.18 mmol) of tetronic acid is initially charged in 1.13 ml of acetic acid, and 1.00 g (4.93 mmol) of N-[(6-chloropyridin-3-yl)methyl]-3-fluoropropane-1-amine (III-2) is added slowly at room temperature. The entire reaction mixture is then stirred at room temperature for approximately a further 18 hours. The reaction mixture is concentrated under reduced pressure, the residue is then taken up in dichloromethane and the mixture is washed with water. After phase separation, the aqueous phase is extracted twice with dichloromethane. The combined organic phases are then made alkaline (pH>9) with 1 N sodium hydroxide solution and the phases are separated. The aqueous phase is extracted twice with dichloromethane, and, after phase separation, the combined organic phases are dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (9:1) gives 191 mg (14% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](3-fluoro-n-propyl)amino]furan-2(5H)-one.