Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[C:13]=2[F:22])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH3:4].C(O)(=[O:25])C.OO.S([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:25])=[C:14]([F:21])[C:13]=2[F:22])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCOC1CC=C(c2ccc(B(O)O)c(F)c2F)CC1
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCOC1CC=C(c2ccc(O)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (25) (8.5 g) and acetic acid (50 ml) were put in a reaction vessel under a nitrogen atmosphere, hydrogen peroxide (31% aqueous solution; 4.9 ml) was added dropwise thereto in the temperature range of 25° C. to 30° C., and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was poured into a vessel containing an aqueous solution of sodium hydrogensulfite (100 ml) and ethyl acetate (200 ml), and mixed. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water and brine, and then dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure, giving 2.8 g of 4-(4-butoxycyclohexenyl)-2,3-difluorophenol (26). The yield based on the compound (25) was 49.1%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:20]([Cl:26])(=O)[CH2:21][C:22]([Cl:24])=O.O=P(Cl)(Cl)Cl>C(#N)C>[Cl:24][C:22]1[CH:21]=[C:20]([Cl:26])[N:16]2[N:15]=[C:14]([S:11]([NH:10][C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[Cl:1])(=[O:13])=[O:12])[N:18]=[C:17]2[N:19]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2nc3nc(Cl)cc(Cl)n3n2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred solution of 6.44 g (0.02 moles) of N-(3-(((2,6-dichloro-3-methylphenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine in 100 mL of dry acetonitrile was added 2.82 g (0.02 moles) of freshly distilled malonyl chloride. The mixture was stirred at room temperature overnight after which time some starting material remained. Additional malonyl chloride (0.56 g) was added and stirring was continued for 4 hrs. The reaction mixture was concentrated to dryness and the residue was slurried with POCl3 (122 g; 0.8 moles) and heated at 90° C. for 9 hrs. The reaction mixture was cooled and concentrated under reduced pressure and the residue was poured into ice-water. The resulting precipitate was filtered and dried to give 8.35 g of product having a purity of 75 percent (73 percent yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C@@H:23]([CH3:27])[C:24]([NH2:26])=[O:25])[C:16]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:15][C:14](Br)=[CH:13][NH:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C-:28]#[N:29].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.[Cu]I.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>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C@@H:23]([CH3:27])[C:24]([NH2:26])=[O:25])[C:16]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:15][C:14]([C:28]#[N:29])=[CH:13][NH:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: [C-]#N
Reactant: C[C@@H](C(N)=O)C1(c2ccc(S(C)(=O)=O)cc2)NC=C(Br)N=C1C1CCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: C[C@@H](C(N)=O)C1(c2ccc(S(C)(=O)=O)cc2)NC=C(C#N)N=C1C1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A solution of 2(R)-(4-methanesulfonyl-phenyl)-3-cyclopentyl-5-bromo-pyrazin-2-yl-propionamide (6.11 g, 13.5 mmol), potassium cyanide (2.27 g, 33.8 mmol), copper(I) iodide (6.43 g, 33.8 mmol), tetrakis(triphenylphosphine)palladium(0) (320 mg, 0.27 mmol), and 18-crown-6 (365 mg, 1.37 mmol) in anhydrous N,N-dimethylformamide (30 mL) was heated at 150° C. under argon. After 4 h, the mixture was allowed to cool to 25° C. The mixture was concentrated to about one-half volume and then chloroform (700 mL) was added to precipitate the copper salts. The mixture was filtered through a pad of celite, and the salts were washed with warm chloroform (2×100 mL). The filtrate was then concentrated in vacuo. Biotage chromatography (FLASH 75S, Silica, 0% to 35% gradient ethyl acetate/hexanes) afforded 2(R)-(4-methanesulfonyl-phenyl)-3-cyclopentyl-5-cyano-pyrazin-2-yl-propionamide (4.49 g, 83%) as a light yellow solid: mp 229–231° C.; (ES)+-HRMS m/e calcd for C20H23N4O3S2 (M+H)+ 399.1486, found 399.1488.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)NC(C(N1CCC(C)CC1)=O)CCC1C=CC=CC=1Cl)(C)(C)C>>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:18](=[O:20])[N:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Agent: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Product: CN(Cc1ccccc1)C(=O)[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
tert-Butyl{(1R)-1-[benzyl(methyl)carbamoyl]-3-phenylpropyl}carbamate is prepared from Boc-(D)-homophenylalanine and N-methylbenzylamine in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is synthesized.
Reaction SMILES: [CH3:1][O-:2].[Na+].[N+](CC)([O-])=O.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].Cl>CS(C)=O>[CH3:1][O:2][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC[N+](=O)[O-]
Product: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 16.5 °C
Reaction time: 8 h
Yield: 117.6 %

Procedure:
Sodium methoxide (1.35 g; 25 mmol; 2.5 equiv) was slurried in DMSO (10 mL) and cooled in a cool water bath. Nitroethane (0.79 mL; 11 mmol; 1.1 equiv.) and 4-chloro-3-nitrobenzotrifluoride (1; 1.49 mL; 10 mmol) were mixed and added slowly dropwise with cooling such that the temperature remained between 15 and 20° C. After the addition was complete, the reaction mixture was allowed to warm slowly over 3 h from 15 to 18° C. and then stirred overnight at 18° C. to completely consume 1 according to GC analysis. Toluene (10 mL) was added and the mixture was cooled in ice water and 3 N HCl (10 mL; 30 mmol; 3 equiv) was added dropwise such that the temperature remained below 20° C. After the addition the layers were separated, and the organic solution was dried (Na2SO4) and concentrated to afford 2.60 g of crude product. Analysis of this material by 1H NMR and GC indicated that the major product was 6 with 2 and 3 as minor products. 6: 1H NMR (CDCl3) δ 8.127 (d, 1H, J=1.8 Hz); 7.803 (dd, 1 H, J=2.1, 8.7 Hz); 7.203 (d, 1H, J=9.06 Hz); 4.028 (s, 3H). GC (30 m DB-17, 100° C., 3 min; 100-280° C., 15°/min); 280° C., 1 min): tR 9.35 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[C:27]([O:36][CH3:37])[CH:28]=1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)c(OC)c1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 1, step 6) was reacted with methyl 4-(bromomethyl)-3-methoxy-benzoate and potassium carbonate to give the title compound as a colorless waxy solid. MS (m/e, ISP neg. ion)=523.1 [M−H+].
Reaction SMILES: C(O)(=O)C.FC1C(OCCF)=CC(OC)=CC=1C(NC1C=CC(C(N)=N)=CC=1)C1NC(=O)N(C2N=CC=CN=2)N=1.[CH2:41]([C:44]1[CH:49]=[C:48]([Br:50])[CH:47]=[C:46]([O:51][CH3:52])[C:45]=1[OH:53])[CH:42]=[CH2:43].N1C=CN=C1.Cl[Si:60]([CH:67]([CH3:69])[CH3:68])([CH:64]([CH3:66])[CH3:65])[CH:61]([CH3:63])[CH3:62].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([C:44]1[CH:49]=[C:48]([Br:50])[CH:47]=[C:46]([O:51][CH3:52])[C:45]=1[O:53][Si:60]([CH:67]([CH3:69])[CH3:68])([CH:64]([CH3:66])[CH3:65])[CH:61]([CH3:63])[CH3:62])[CH:42]=[CH2:43]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=CCc1cc(Br)cc(OC)c1O
Agent: COc1cc(OCCF)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=CCc1cc(Br)cc(OC)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
After dissolving 3g of 2-allyl-4-bromo-6-methoxy-phenol [CAS No. 352019-92-2] in 10 ml of DMF, 1.3 g of imidazole and 2g of chlorotriisopropylsilane were added and the mixture was stirred at 50° C. for 4 hours. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-allyl-4-bromo-6-methoxyphenoxy)triisopropylsilane.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)[CH:12]=1.O.CN([CH:28]=[O:29])C>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[C:21]=2[CH:28]=[O:29])[CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1-c1cn2ccccc2n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Br)cc1-c1nc2ccccn2c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
POCl3 (0.39 g, 2.5 mmol) was added to DMF (0.43 g, 6 mmol) by dropwise at 0° C. Then 2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine (0.1 g, 0.33 mmol) in DMF (3 mL) was added. Then warmed to 25° C. and heated to 120° C. and stirred for 30 minutes and at 80° C. for 2 hours and then cooled to 25° C. H2O (20 mL) was added and extracted with EtOAc (3*50 mL), washed by aq NaHCO3 (3*50 mL) and brine (50 mL). After concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=3:1) to provide 2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (100 mg, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 9.85 (s, 1H), 9.60 (s, 1H), 7.77˜7.81 (m, 2H), 7.54˜7.58 (m, 2H), 7.12˜7.15 (m, 1H), 6.92˜6.94 (m, 1H), 3.82 (s, 3H). MS (M+H)+: 331/333.
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[Br:6][C:7]1[C:8]([C:24]#[N:25])=[C:9]([C:16]2[S:17][C:18]([Cl:23])=[C:19]([Cl:22])[C:20]=2[Cl:21])[NH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O.CCCCCC>[Br:6][C:7]1[C:8]([C:24]#[N:25])=[C:9]([C:16]2[S:17][C:18]([Cl:23])=[C:19]([Cl:22])[C:20]=2[Cl:21])[N:10]([CH2:4][O:3][CH2:1][CH3:2])[C:11]=1[C:12]([F:13])([F:15])[F:14]
Reactant: CCOCCl
Reactant: N#Cc1c(-c2sc(Cl)c(Cl)c2Cl)[nH]c(C(F)(F)F)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCOCn1c(-c2sc(Cl)c(Cl)c2Cl)c(C#N)c(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Chloromethyl ethyl ether (0.20 g, 2.13 mmol) is added to a mixture of 4-bromo-2-(3,4,5-trichloro-2-thienyl)-5-(trifluoromethyl) pyrrole-3-carbonitrile (0.30 g, 0.71 mmol) and potassium carbonate (0.29 g, 2.13 mmol) in N,N-dimethylformamide. The reation mixture is stirred at room temperature for 30 minutes, diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to obtain a clear oil. Flash chromatography of the oil using silica gel and a 15% ethyl acetate in hexane solution gives the title product as white crystals (0.24 g, 71%, mp 85°-87° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[C:12](Br)(Br)([Br:14])[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:13][C:12]([Br:14])=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(C=O)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C=C(Br)Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
3-Fluoro-4-methoxy benzaldehyde (0.5 g, 0.00324 mol) was dissolved in DCM (30 mL). Carbon tetrabromide (2.15 g, 0.0064 mol) and triphenylphosphine (3.4 g, 0.013 mol) were added to the solution followed by stirring at RT for 3 h. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh) to provide the desired compound as a yellow colored oil (0.6 g, 60% yield).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:35]=[CH:34][C:18]2/[C:19](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:20]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:27]1[C:20]2/[C:19](=[C:30](\[CH3:33])/[C:31]#[N:32])/[C:18]3[CH:34]=[CH:35][C:15]([CH2:14][N:8]4[C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=5[N:5]=[C:4]4[CH2:1][CH2:2][CH3:3])=[CH:16][C:17]=3[CH2:23][O:22][C:21]=2[CH:24]=[C:25]([F:29])[CH:26]=1
Reactant: CCCc1nc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)cc(F)c21
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)cc(F)c1/C2=C(\C)C#N
Yield: 96.2 %

Procedure:
Using 2-propyl-1H-benzo[d]imidazole (Synthetic Communication, 2002, vol. 32, p 3703; 67 mg, 0.42 mmol) and (E)-2-[8-(bromomethyl)-1,3-difluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (160 mg, 0.43 mmol) obtained in Reference Example 2, and in the same manner as in Reference Example 1A, the title compound (184 mg, 97%) was obtained.
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:45]([NH:47][C@H:48]([C:53](O)=[O:54])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([C@@H:7]1[C:8](=[O:25])[O:9][C@H:10]1[CH2:11][C@@H:12]([O:24][C:53](=[O:54])[C@H:48]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:47][CH:45]=[O:46])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)C[C@H](NC=O)C(=O)O
Reactant: CCCCCCCCCCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(C)C)NC=O
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution of 100 mg of rac-3-hexyl -4-(2-hydroxy-tridecyl)-2-oxetanone(2R,3S,4S:2S,3R,4R) or of 100 mg of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 74 mg of triphenylphosphine and 45 mg of N-formyl-L-leucine in 2 ml of THF are added dropwise while stirring 44.3 μl of diethyl azodicarboxylate. After stirring overnight the organic phase is evaporated in vacuo and the residue is purified by chromatography on silica gel with toluene-ethyl acetate (9:1). There are obtained 20 or 37 mg of N-formyl-L-leucine (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, [α]D20 =-33° C. (c=0.36, CHCL3).
Reaction SMILES: [CH2:1]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][C@H:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[N+:45]([O-])=O)[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][CH:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[N+:23]([O-])=O.O.O.Cl[Sn]Cl.C(Cl)(Cl)Cl.CO>CO>[CH2:3]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[NH2:23])[CH2:2][CH2:1][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][CH:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[NH2:45]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3[N+](=O)[O-])cc2OC)C1
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: C=C1CC(CO)N(C(=O)c2cc(N)c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3N)cc2OC)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
A mixture of the diol 76 (0.98 g, 1.49 mmol) and SnCl2.2H2O (3.36 g, 14.9 mmol) in MeOH (35 mL) was heated at reflux and the progress of the reaction monitored by TLC (90% CHCl3/MeOH). After 45 minutes, the MeOH was evaporated in vacuo and the resulting residue was cooled (ice), and treated carefully with saturated NaHCO3 (120 mL). The mixture was diluted with EtOAc (120 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give a brown solid. Flash chromatography (95% CHCl3/MeOH) afforded the pure bis-amine 77 as an orange solid (0.54 g, 61%): [α]19D=−31.8° (c=0.30, CHCl3); 1H NMR (270 MHz, CDCl3) δ 6.74 (s, 2Harom), 6.32 (s, 2Harom), 5.00 (br s, 2H, NCH2C═CH2), 4.93 (br s, 2H, NCH2C═CH2), 4.54 (br s, 2H, NCHCH2OH), 4.24-4.14 (m, 4H, OCH3CHCH2O), 3.98-3.50 (m, 14H, NCHCH2OH, NCH2C═CH3 and OCH3), 2.76 (dd, 2H, J=8.61, 15.91 Hz, NCH2C═CH2CH2), 2.46-2.41 (m, 2H, NCH2C═CH2CH2), 2.33-2.28 (m, 2H, OCH2CH2CH2O); 13C NMR (67.8 MHz, CDCl3) δ 171.0 (NC═O), 151.0 (Cquat), 143.5 (Cquat), 141.3 (Cquat), 140.6 (Cquat), 112.4 (C—Harom), 111.9 (Cquat), 107.8 (NCH2C═CH2), 102.4 (C—Harom), 65.2 (OCH2CH2CH2O), 65.0 (NCHCH2OH), 59.8 (NCHCH2OH), 57.1 (OCH3), 53.3 (NCH2C═CH2), 34.4 (NCH2C═CH2CH2), 29.0 (OCH2CH2CH2O); MS (FAB) (Relative Intensity) 596 (M+., 13), 484 (M-NCH2CCH2CH2CHCH2OH, 14), 389 (10), 371 (29), 345 (5), 224 (8), 206 (44), 166 (100), 149 (24), 112 (39), 96 (34), 81 (28); IR (NUJOL®) 3600-3000 (br. OH), 3349 (NH2), 2922, 2852, 2363, 1615, 1591 (NH2), 1514, 1464, 1401, 1359, 1263, 1216, 1187, 1169, 1114, 1043, 891, 832, 761 cm−1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=[CH:3]1.Cl.Cl.[NH2:22][OH:23].[OH-].[Na+]>>[CH3:1][CH:2]([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:4])[CH:3]=[N:22][OH:23]
Reactant: CC1C=NC(c2ccccc2)CC=CCCC=CC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C=NO)CC=CCCC=CCC(N)c1ccccc1
Yield: 100 %

Procedure:
502 g (1.98 mols) of 3-methyl-12-phenyl-1-aza-1,5,9-cyclododecatriene are added dropwise in the course of 1.5 hours to 220 g of 37% hydrochloric acid at a rate such that the temperature does not rise above 80° C. The mixture is then cooled to room temperature (20°-25° C.) and 140 g (2.02 mols) of hydroxylamine hydrochloride are added. About 185 g (4.6 mols) of solid sodium hydroxide are added in the course of one hour, the mixture being cooled with a waterbath, until the pH of the aqueous solution is 10-11. The organic phase which separates out is separated off and washed with water until neutral. 567 g (1.98 mols) of 2-methyl-11-phenyl-11-amino-undeca-4,8-dienal oxime are obtained in the form of a highly viscous liquid; yield 100% of theory.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=O)=[CH:12]1.[BH4-].[Na+].CO>C1(C)C=CC=CC=1.O>[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH2:20][NH:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:12]1
Reactant: Nc1ncccc1C(=O)O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)c1cccnc1NCc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Aminonicotinic acid (945 mg, 6.85 mmol) was added to a suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1 g, 6.85 mmol) in toluene (10 mL) under N2 atmosphere. A catalytic amount of tosyl acid was added to above and the mixture was heated to reflux for 3 h. The reaction was cooled to RT and NaBH4 was added. After stirring for 10 min., MeOH (2 ml) was added to above and the reaction was stirred for another 5 h at RT. The mixture was diluted with water and extracted with EtOAc. The aq layer was acidified using 1N HCl. The resultant precipitate was filtered and washed with AcCN affording compound as yellow solid.
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[CH3:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][N:12]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][N:12]=1
Reactant: Cc1nsc2ncccc12
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nsc2ncccc12

Procedure:
N-Bromosuccinamide (10.7 mmol) was added to a solution of 3-methylisothiazolo[5,4-b]pyridine (10.0 mmol) in carbontetrachloride (20 mL). Benzoyl peroxide (0.82 mmol) was added and the reaction mixture was heated at reflux for 48 h. The reaction mixture was filtered through Celite (ethyl acetate) and the eluent was concentrated to provide crude 3-(bromomethyl)isothiazolo[5,4-b]pyridine as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 67.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 82 mg of 5-methoxy-2-oxindole, and 2 drops piperidine in 2 mL of ethanol were heated to 95° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 110 mg (67%) of the title compound as a brown solid.