Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2S[CH:15]=[CH:16][CH:17]=2)[N:3]=1.Cl.[C:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([CH3:21])=[CH2:20].C1CCN2C(=NCCC2)CC1.[OH2:41]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:41][CH:15]=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([NH:27][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:19]([CH3:21])=[CH2:20])=[CH:29][CH:28]=2)[N:7]=1
Reactant: C=C(C)c1ccc(CN)cc1
Reactant: O
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Reaction time: 16 h
Yield: 15 %

Procedure:
To a stirred suspension of 1.00 g (4.03 mmol) 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile in 30 ml DME were added 1.48 g (8.06 mmol) 4-isopropenyl-benzylamine hydrochloride and 1.50 ml (10.1 mmol) DBU and stirring continued for 16 hours at room temperature. 100 ml water was then added and the resulting crystals collected by filtration to afford 200 mg (15%) 2-amino-4-furan-2-yl-6-(4-isopropenyl-benzylamino)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 332 (M+H+, 100).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](=[S:11])=[O:10].[CH2:12]1CCN2C(=NCCC2)CC1>C1COCC1>[C:9](=[O:10])([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[S:11][CH3:12]
Reactant: O=C=S
Reactant: OCc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CSC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Carbonyl sulfide may provide an effective reagent for the carbonylation reaction. The carbonylation of benzyl alcohol with carbonyl sulfide may be done under an ambient pressure and at about 20° C. for about 1 hour in the presence of DBU in THF. The formed carbonothioate salt may be quenched by methyl iodide at about 0° C., and the resulting mixture may be stirred under an ambient pressure, at about 20° C. for an additional about 2 hours to provide S-methyl O-benzyl carbonothioate at a yield of about 87%. Next, the chlorination of S-methyl O-benzyl carbonothioate by sulfuryl chloride may be done by the slow addition of sulfuryl chloride to the S-methyl O-benzyl carbonothioate at about 0° C. with vigorous stirring at about 20° C. for about 1 hour to provide the benzyl chloroformate in a quantitative yield and in an almost pure form. Additional purification may be done by vacuum distillation.
Reaction SMILES: O[CH:2]([CH2:10][CH2:11][CH2:12][CH2:13]C)[CH2:3][CH2:4][CH2:5][C:6](=[O:9])C=C.CC1C(=[O:21])CCC1=O.C1(C)C(C)=CC=CC=1>C(O)(=O)C>[O:9]1[C:13]2[CH2:12][C:11](=[O:21])[CH:10]=[CH:2][C:3]=2[CH:4]=[CH:5][CH2:6]1
Reactant: CC1C(=O)CCC1=O
Reactant: C=CC(=O)CCCC(O)CCCCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: O=C1C=CC2=C(C1)OCC=C2

Procedure:
A mixture of the optically active 7-hydroxy-1-dodecen-3-one, obtained as described in Example 4, 2.25 grams of 2-methylcyclopentane-1,3-dione, 50 milliliters of xylene, and 25 milliliters of acetic acid was refluxed for 11/2 hours under a nitrogen atmosphere. After evaporation under vacuum, the residue was extracted with cold benzene leaving 400 milliliters of unreacted methylcyclopentanedione as an insoluble residue. The benzene solution was then evaporated to yield 5.56 grams of optically active 3-pentyl-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta]f][1]benzopyran-7(8H)-one. After chromatographing the crude product on alumina, followed by crystallization from methanol-water, the product melted at 60°-61°C., [α]D25 -166°.
Reaction SMILES: C([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)C1C=CC=CC=1.[CH3:21][CH2:22][OH:23]>[Pd]>[O:23]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:13]=1)[C:22]1[CH:10]=[CH:9][CH:8]=[CH:13][CH:21]=1
Reactant: CCO
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2)cc1
Agent: [Pd]
Product: CCOC(=O)CCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl (E)-3-(4-benzylphenyl)acrylate (S28, 500 mg, 1.97 mmol) in EtOH (20 mL) was treated with 10% Pd/C (45 mg) and purged with H2. The reaction mixture was stirred overnight at 25° C., filtered through Celite and concentrated to afford S29 (502 mg, 1.96 mmol, 99%) as a yellow oil: 1H NMR (CDCl3, 500 MHz) 7.34 (dd, 2H, J=8.4, 7.4 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.09 (dt, 1H, J=7.7, 1.1 Hz), 7.00 (dd, 2H, J=8.8, 1.1 Hz), 6.95 (d, 2H, J=8.8 Hz), 4.14 (q, 2H, J=7.0 Hz), 2.94 (t, 2H, J=7.7 Hz), 2.63 (t, 2H, J=7.7 Hz), 1.25 (t, 3H, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(Br)cc1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
A solution of N-(4-bromophenyl)methanesulfonamide (200 mg, 0.80 mmol), potassium carbonate (2 eq) and methyl iodide (2 eq) in DMF (2 mL) was heated at 60° C. for 18 h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give N-(4-bromophenyl)-N-methylmethanesulfonamide.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]1[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].Cl.[NH:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:10]1[CH2:11][CH2:12]1)[C:13]([N:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1)=[O:15])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
In a round-bottomed flask Boc-D-cyclopropylglycine (500 mg, 2.32 mmol) and azetidine-3-carbonitrile hydrochloride (441 mg, 3.72 mmol) were dissolved in DMF (10 ml). N,N-Diisopropylethylamine (1.2 ml, 6.87 mmol) was added followed by HATU (972 mg, 2.56 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether to afford 384 mg (59%) of [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](O)=[O:22])=[O:18])=[CH:11]2>>[CH2:24]([CH:20]([NH:19][C:17]([C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:7])=[CH:16][CH:15]=2)=[O:18])[C:21]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: C1COCCN1
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCOCC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 18 h

Procedure:
Morpholine (0.33 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.30 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 48 hour reaction time). The crude product was chromatographed on silica gel eluted with 1:1 ethyl acetate/hexanes, the desired fractions concentrated, the residue dissolved in chloroform and methanol and the resulting solution stirred 18 hours with approx. 128 mg dimethylaminopyridine-polystyrene resin (Fluka Chemical Co.). The solution was filtered, concentrated and the residue triturated with ether: Yield, 51%; HPLC (60/40) 5.92 min (98%);
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO.Cl.O1CCOCC1>[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Tert-butyl 4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (0.587 g, 1.04 mmol) was dissolved in 1:1 CH2Cl2/methanol and 4N HCl in dioxane was added and stirred at ambient temperature for 1 hour. The reaction was concentrated and dried in vacuum oven. The HCl salt was partitioned between 5% MeOH in CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give N-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (0.473 g, 98.0% yield).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)=[O:5].[CH2:12]([Mg]Br)[CH3:13]>C1COCC1>[O:8]1[CH2:9][CH2:10][CH:6]([C:4](=[O:5])[CH2:12][CH3:13])[CH2:7]1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)C1CCOC1
Solvent: C1CCOC1
Product: CCC(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (4.1 g) in THF (40 ml) was added ethylmagnesium bromide (3 M in ether, 13.0 ml) at 0° C. The reaction mixture was then slowly warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with saturated 1 M HCl (10 ml), and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The mixture was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (3.0 g) as a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([F:10])[CH:16]=2)=[C:4]([F:9])[CH:3]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Fc1cc(Br)ccc1I
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Fc1cc(-c2ccc(Br)cc2F)ccn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added 4-bromo-2-fluoro-1-iodobenzene 207-1 (600 mg, 2.0 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (282 mg, 2.0 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Na2CO3 (636 mg, 6.0 mmol), toluene (2 mL), H2O (2 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 120° C. overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give 4-(4-bromo-2-fluorophenyl)-2-fluoropyridine 207-3. MS m/z 270.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:19])[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[CH2:20]=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1.Cl>C(O)(C)C>[CH3:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:9]([C:7]([CH:4]1[CH2:5][CH2:6][N:1]([CH:30]([CH3:20])[C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[O:31])[CH2:2][CH2:3]1)=[O:8])=[CH:10][CH:11]=[CH:12]2
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Cc1cccc2cccc(C(=O)C3CCNCC3)c12
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Product: Cc1cccc2cccc(C(=O)C3CCN(C(C)C(=O)c4ccc(F)cc4)CC3)c12

Procedure:
A mixture of 25.5 g (0.1 mole) of 8-methyl-1-naphthyl 4-piperidyl ketone, 9 g (0.3 mole) of paraformaldehyde and 13.8 g (0.1 mole) of 4'-fluoroacetophenone in 100 ml of isopropyl alcohol containing 2 drops of concentrated hydrochloric acid is refluxed for 24 hours. The mixture is filtered and the filtrate concentrated to about 100 ml and cooled. The resulting precipitate is recrystallized from ethanol to give 2-[4-(8-methyl-1-naphthoyl)piperidyl]-1-(4-fluorophenyl)-1-propanone.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH3:12][CH:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:14][CH2:15]Br>CO>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:15][CH2:14][CH:13]([CH3:12])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CC(C)=CCCC(C)CCBr
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Na]
Solvent: CO
Product: CC(C)=CCCC(C)CCSc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2 g. of sodium in 50 ml. of methanol at about 0° is added about 35 g. of p-nitrophenyl mercaptan. After about 0.5 hour, about 15 g. of 3,7-dimethyloct-6-enyl bromide is added and then the mixture refluxed for about 3 hours. Then the solvent is evaporated and the concentrate taken up in petroleum ether which is washed with water, dried over magnesium sulfate and evaporated to yield 3,7-dimethyloct-6-enyl p-nitrophenyl sulfide which is used as the starting material in the process of Example 2 to yield 7-ethoxy-3,7-dimethyloctyl p-nitrophenyl sulfide.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C=O)C>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2cccc3nccn23)cc1
Yield: 69.9 %

Procedure:
A solution of 5-chloroimidazo[1,2-a]pyridine (2.0 g), 4-aminothiophenol (2.46 g) and triethylamine (1.7 ml) in DMF (10 ml) was stirred for 5 days at 90° C. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 2:1→ethyl acetate), to give 5-(4-aminophenylthio) imidazo[1,2-a]pyridine (2.21 g) as pale yellow crystals.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]([CH3:33])[C:26]([O:28]C(C)(C)C)=[O:27])[CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:34])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[Cl:42]CCl>>[ClH:42].[CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]([CH3:33])[C:26]([OH:28])=[O:27])[CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:34])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCN(C(C)C(=O)OC(C)(C)C)CC1)c(=O)n2C(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(C(C)C(=O)O)CC1)c(=O)n2C(C)C
Product: Cl

Procedure:
A solution of tert-butyl 2-[4-({[(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-yl)carbonyl]amino}methyl)piperidin-1-yl]propanoate (299 mg, 0.64 mmol, step 1) in trifluoroacetic acid/dichloromethane (1:1, 20 mL) was stirred at room temperature for 16 h. Then, the solvent was removed in vacuo. To the residue was added 10% hydrogen chloride in methanol, and evaporated in vacuo. This was repeated three times to give 295 mg (quant.) of the title compound as a yellow amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:43][CH:44]1[C:49]2[CH:50]=[CH:51][S:52][C:48]=2[CH2:47][CH2:46][NH:45]1>C(#N)C.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:45]3[CH2:46][CH2:47][C:48]4[S:52][CH:51]=[CH:50][C:49]=4[CH:44]3[CH3:43])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2sccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC1c2ccsc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.7 g, 2.9 mmol, 1.0 equiv) and TBTU (1.0 g, 3.1 mmol, 1.1 equiv) in dry acetonitrile (20 mL), triethylamine (1 mL, 7.25 mmol, 2.5 equiv) and 4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (0.45 g, 2.9 mmol, 1 equiv) are added. The reaction mixture is stirred at 50° C. for 2 h and then at room temperature for 8 h. The reaction mixture is diluted with water (10 ml). The precipitate is filtered, washed sequentially with 50% aqueous ethanol, water, 5% aqueous ammonia, and diethyl ether, and then dried to provide 0.524 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Li]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([OH:15])[CH2:14][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: c1ccc(COCCCC[C@@H]2CO2)cc1
Product: CC[C@H](O)CCCCOCc1ccccc1

Procedure:
(R)-6-Benzyloxyhex-1-ene oxide was prepared by copper catalyzed addition of 3-benzyloxypropyl-1-magnesium bromide to R-epichlorohydrin to form R-1-chloro-6-benzyloxyhexan-2-ol, which was then ring closed under basic conditions to (R)-6-benzyloxyhex-1-ene oxide. This epoxide was then treated with methyl lithium (1.5 M in diethyl ether) in the presence of dilithiotetrachlorocuprate (0.02 molar equivalents, 0.1 M in tetrahydrofuran) to yield (S)-1-benzyloxy-5-hydroxyheptane.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:2][CH2:3][C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1.C(N(CC)CC)C.Cl>ClCCl.CN(C)C=O>[CH:30]1([CH2:33][NH:34][C:4](=[O:5])[CH2:3][CH2:2][NH2:1])[CH2:32][CH2:31]1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCC1CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCCC(=O)NCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To solution of Fmoc-β-Ala-OH (1.0 g, 3.212 mmol) and oxalyl chloride (0.428 g, 0.29 mL, 3.373 mmol) in dichloromethane (20.0 mL) was added a few drops of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 1 hr followed by addition of cyclopropylmethylamine (0.229 g, 0.28 mL, 3.212 mmol) and triethylamine (0.65 g, 0.90 mL, 6.424 mmol). After 10 min, the mixture was treated with 1 M hydrochloride (10.0 mL) and the aqueous mixture was extracted with dichloromethane (3×30.0 mL). The organic solution was concentrated in vacuo to dryness. The residue was treated with a solution of 20% piperidine in N,N-dimethylforamide (20.0 mL) for 0.5 hr. After removal of the solvent in vacuo, the residue was treated with 1 M hydrochloride (20.0 mL) and ethyl acetate (20.0 mL). The mixture was separated and the aqueous layer was basified with solid sodium hydroxide to pH=8. The precipitate was removed by filtration and the aqueous solution was subjected to ion exchange column eluted with 20% pyridine to give 0.262 g (57%) of N-cyclopropylmethyl β-alanine amide. 1H NMR (200 MHz, CD3OD) δ—0.22 (m, 2H), 0.49 (m, 2H), 0.96 (m, 2H), 2.40 (t, 2H), 2.92 (t, 2H), 3.05 (d, 2H); MS (ES): 143.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][S:23][C:21]1[O:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH:14]=2)=[N:19][N:20]=1
Reactant: Fc1cccc(CBr)c1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(F)c5)o4)cc23)cc1
Yield: 85 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 85%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.O>CC(C1C=C(C(C)(C)C)C(=O)/C(=C/N[C@H]2[C@H](N/C=C3/C=C(C(C)(C)C)C=C(C(C)(C)C)C/3=O)CCCC2)/C=1)(C)C.[Co].C(O)(=O)C.O1CCCC1>[CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C@H:2]1[O:4][CH2:3]1
Reactant: CC(C)(C)OCC1CO1
Agent: [Co]
Agent: CC(C)(C)C1=C/C(=C/N[C@@H]2CCCC[C@H]2N/C=C2\C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)C(=O)C(C(C)(C)C)=C1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC[C@@H]1CO1
Temperature: 0 °C
Yield: 43.5 %

Procedure:
In a 500 ml round bottomed flask equipped with thermometer and a magnetic stirrer and an ice bath 6.04 g (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicylidene) cobalt (II) (10 mmol; Strem Chemicals) and 260.38 g rac tert-butyl glycidyl ether (2000 mmol) and 2.40 g acetic acid (40 mmol) and 20 ml THF (tetrahydrofurane) were cooled under stirring to 0° C. and 19.82 g deionized water (1100 mmol) were added all at once. The dark red reaction mixture was stirred under an air atmosphere for 0.5 h at 0° C. and for 23 h at RT. Vacuum distillation over a column filled with “Fenske” glass rings (20×2 cm column; “Fenske” glass rings Ø≅4 mm) afforded 113.2 g (43.5%) (S)-tert-butyl glycidyl ether (S)-1 as colorless liquid, b.p. 84-86° C./100 mbar.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([OH:13])=O.S(Cl)(Cl)=O.[NH3:18]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([NH2:18])=[O:13]
Reactant: N
Reactant: O=C(O)CC1Cc2ccccc2C1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: NC(=O)CC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
35.3 g (0.20 mol) of (indan-2-yl)acetic acid was dissolved in 350 ml methylene chloride, to which was added 26.5 g (0.22 mol) of thionyl chloride and stirred for 4 hours at room temperature, followed by refluxing for further 1.5 hours. After cooled and condensed under reduced pressure, the obtained oily residue was dissolved in 100 ml ethyl acetate and added dropwise to 200 ml conc. aqueous ammonia while stirred vigorously under ice-cooling. After stirring for 20 minutes, the precipitates were collected by filtration and recrystallized from a solvent mixture of ethyl acetate and ethanol. 32.1 g of colorless crystal was obtained. Yield: 95%