Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][C:7]1[C:14]([OH:15])=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])(=[O:5])[CH3:4].Cl>CO>[C:3]([NH:6][C:7]1[C:14]([OH:15])=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][C:8]=1[CH2:9][OH:10])(=[O:5])[CH3:4]
Reactant: COc1ccc(C=O)c(NC(C)=O)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)c(NC(C)=O)c1O
Reaction time: 0.17 h
Yield: 72.6 %

Procedure:
NaBH4 (550 mg, 14.53 mmol) is slowly added to a solution of 2-acetamido-3-hydroxy-4-methoxybenzaldehyde (3.0 g, 14.34 mmol) [M. Grossa, F. Wessely Monatsh. Chem. 1966, 97, 1384-1390] in methanol (80 ml). After stirring for 10 minutes, the suspension is poured onto a 0.1 N aqueous HCl solution (50 ml) and then extracted with CH2Cl2 (3 times). The organic phases are combined, dried over MgSO4, filtered off and concentrated in vacuo. The residue obtained is purified by means of chromatography with pure ethyl acetate and yields the title compound as a colorless solid (2.2 g). TLC, silica gel (glass plates), ethyl acetate, Rf=0.19.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:4][N:3]=1.[N+](C1C=CC=CC=1)([O-])=O.Cl[Sn](Cl)(Cl)Cl>O=P(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2[N:7]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:5]=2[NH:4][N:3]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Temperature: 185 °C
Reaction time: 1 h

Procedure:
To a mixture of 565 mg of N-(3-Methyl-5-phenyl-1H-pyrazol-4-yl)-benzamide was added 5 mL of nitrobenzene followed by 270 μL of POCl3 and the resulting mixture was heated at 185° C. After 1 h, 0.4 mL of a SnCl4 solution (1.0 M solution in heptane) was added and the mixture was heated for an additional 2 h, then concentrated under reduced pressure and purified by means of MPLC (12 g SiO2, 35% ethyl acetate:heptane) to give the title compound as a tan solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[C:12](=[C:14]([C:18]([NH2:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[C:12](=[C:14]([C:18]([NH2:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3c(C(N)=O)cccc3s2)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: NC(=O)c1cccc2sc(-c3ccc(O)cc3)nc12

Procedure:
A mixture of EXAMPLE 1E (0.55 g) and a 1M solution of boron tribromide in dichloromethane (25.1 mL) were stirred at ambient temperature for 3 hours. The mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The precipitate that formed in the aqueous phase was filtered to afford the title compound. 1H NMR (DMSO-d6) δ 10.35 (s, 1H), 9.27 (s, 1H), 8.30 (d, J=6.7 Hz, 1H), 8.17 (d, J=6.7 Hz, 1H), 8.00-8.03 (m, 2H), 8.92 (s, 1H), 7.53 (t, J=7.9 Hz, 1H), 6.95-6.99 (m, 2H).
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])C(C)C.[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][Al:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)C[Al](CC(C)C)Oc1ccccc1-c1ccccc1

Procedure:
In a manner analogous to that described in Example 1, 16 g of triisobutylaluminum and 13.72 g of 2-phenyl-phenol are reacted in absolute toluene to afford (2-biphenylyloxy)diisobutylaluminum and this is then reacted with 20.52 g of pyridine-N-oxide-2-thiol to yield the title compound. The isolation of the product is carried out in an analogous manner. The yield of (2-biphenylyloxy)bis(2-pyridinethiolato)aluminum N,N'-dioxide, an almost white powder, is 33.4 g, about 92.5% of theory. Upon heating it sinters from about 174° C. and melts at 236°-238° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)(=[O:22])=[O:21]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])=[CH:6][CH:5]=[C:4]([NH:29][CH:26]2[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]2)[N:3]=1
Reactant: Nc1nc(Cl)ccc1C(=O)c1c(F)cccc1F
Reactant: CS(=O)(=O)N1CCC(N)CC1
Product: CS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3c(F)cccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2,6-difluoro-phenyl)-methanone (Example 51) and 1-methanesulfonyl-piperidin-4-ylamine (Step A. Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 411.1298, Calcd for (M+H)+: 411.1297.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[N+:29]([O-:31])=[O:30].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]4[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=4[CH2:8][O:7][C:6]=3[CH:20]=2)=[C:23]([N+:29]([O-:31])=[O:30])[CH:24]=1
Reactant: Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(Nc3ccc(F)cc3[N+](=O)[O-])ccc21
Temperature: 100 °C

Procedure:
In accordance with general method Z, 0.85 g (3.14 mmol) of (6), 0.70 g (3.19 mmol) of 1-bromo-4-fluoro-2-nitrobenzene, 2 spatula tips of Pd(OAc)2, 0.10 g of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphine ligand), 0.70 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out and dissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at 100° C. under an argon atmosphere for 4 h. The crude product is purified by chromatography over silica gel with MC/EtOH (98/2). Yield: 0.10 g (7.8%); melting point 210.7° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[O:13]2)=[CH:7][CH:6]=1)(=O)C.Cl>[OH-].[Na+]>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[O:13]2)=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(C=C2Oc3ccccc3NC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccccc2OC1=Cc1ccc(O)cc1

Procedure:
A mixture of 2-[(4-acetoxyphenyl)methylene]-2H-1,4-benzoxazin-3(4H)-one (0.49 g, 0.0016 mol) and NaOH 10% (30 ml) was refluxed for 1 h. The reaction mixture was cooled and acidified with 6N HCl. The precipitated was collected by filtration, then washed with water and dried. The crude product was purified by recrystalization from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=2)=[N:6][CH:7]=1.C([O:36][C:37](=[O:40])[CH2:38]Br)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:38][C:37]([OH:40])=[O:36])=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=2)=[N:6][CH:7]=1
Reactant: CCCc1cc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C)cn2)ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C)cn2)ccc1OCC(=O)O

Procedure:
Alkylation of 4-(2-{(5-methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-propylphenol with tert-butyl-bromo-acetate, followed by standard TFA hydrolysis (as described in previous examples) provided after chromatography the title compound as a white foam.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:14]1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]1[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc([N+](=O)[O-])c(N=C2NC3(CCCC3)CS2)c1C
Reactant: BrC1CCCC1
Product: Cc1ccc([N+](=O)[O-])c(N=C2SCC3(CCCC3)N2C2CCCC2)c1C

Procedure:
2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, step 1. The acetamide was converted to 2,3-dimethyl-6-nitroaniline, then deprotected according to Method A2a, step 2. The aniline was converted to 2,-dimethyl-6-nitrophenyl isothiocyanate according to Method A2a, step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method C1e to give 2-(2,3-dimethyl-6-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2,3-dimethyl-6-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([C:25]1[S:26][C:27]([O:30][CH2:31][CH3:32])=[N:28][N:29]=1)[CH3:24]>CC(C)=O>[CH2:31]([O:30][C:27]1[S:26][C:25]([CH:23]([O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)[CH3:24])=[N:29][N:28]=1)[CH3:32]
Reactant: CCOc1nnc(C(C)Br)s1
Reactant: Cc1ccc(Oc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1nnc(C(C)Oc2ccc(Oc3ccc(C)cc3)cc2)s1
Yield: 73.6 %

Procedure:
0.84 g of 4-(4-methylphenoxy)phenol was dissolved in 5 ml of acetone followed by adding 0.87 g of anhydrous potassium carbonate and 1.0 g of 2-(1-bromoethyl)-5-ethoxy-1,3,4-thiadiazole. The resulting mixture was refluxed with stirring and heating for 2 hours. After cooling, insoluble salts were filtered off, and acetone was distilled off under reduced pressure. The residue was purified by chromatography on silica gel to obtain 1.1 g of the compound No. 10 described in Table 1.
Reaction SMILES: [CH:1]1([CH:6]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:6]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCC2)oc2ccc(F)cc12
Yield: 94.2 %

Procedure:
To a mixture of methyl 4-{[cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}benzoate (1.19 g) synthesized above, tetrahydrofuran (6 mL) and ethanol (6 mL) was added 1N aqueous sodium hydroxide solution (6 mL), and the mixture was stirred with heating under reflux for 3.5 hr. 1N Aqueous sodium hydroxide solution (6 mL) was additionally added to the mixture, and the mixture was stirred with heating under reflux for 14 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (11 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.08 g, 94%) as a colorless amorphous form.
Reaction SMILES: [CH:1]12[CH:12]=[CH:11][CH:7]([CH:8]3[CH:10]1[CH2:9]3)[CH:6]1[CH:2]2[C:3](=[O:14])[O:4][C:5]1=[O:13].[CH3:15][OH:16]>>[CH3:15][O:16][C:3]([CH:2]1[CH:1]2[CH:12]=[CH:11][CH:7]([CH:8]3[CH:10]2[CH2:9]3)[CH:6]1[C:5]([OH:4])=[O:13])=[O:14]
Reactant: O=C1OC(=O)C2C3C=CC(C4CC34)C12
Reactant: CO
Product: COC(=O)C1C2C=CC(C3CC23)C1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
rac-(1R,2R,6S,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (1.00 g, 5.26 mmol) was dissolved in methanol (20 mL). The reaction was stirred at 25° C. for 72 h. The mixture was concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 60% ethyl acetate in hexanes) afforded the desired product, rac-(1S,2S,4R,5R,6R,7S)-7-(Methoxycarbonyl)tricyclo[3.2.2.02,4]non-8-ene-6-carboxylic acid (1.11 g, 5.00 mmol, 95%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.01-0.10 (2H, m), 0.93-1.02 (2H, m), 2.98-3.05 (4H, m), 3.45 (3H, s), 5.68-5.77 (2H, m), 11.94 (1H, s). LC-MS (ESI) calcd for C12H14O4 222.24. found 223.2 [M+H+].
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].B(F)(F)F>C(O)(CC)C.CCOCC>[C:1]([O:16][CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC#CCCCCCC(=O)O
Agent: FB(F)F
Solvent: CCC(C)O
Solvent: CCOCC
Product: CCCCCCC#CCCCCCC(=O)OC(C)CC
Yield: 170.5 %

Procedure:
A solution of 7-tetradecynoic acid (1.22 g) and BF3 -etherate (1 ml) in 20 ml of sec-butyl alcohol was refluxed for 18 hours. The solution was diluted with ether and washed with saturated Na2CO3 solution, water, 2N NaOH, water, and saturated NH4Cl solution. The ether layer was dried (MgSO4) and the solvent removed under reduced pressure to give 1.30 g of sec-butyl 7-tetradecynoate as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CCOC(C)=O>CC#N.O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C

Procedure:
To a suspension of 1H-indole-3-carboxylic acid ethyl ester (800 mg, 4.23 mmol) and potassium carbonate (1.34 g, 9.72 mmol) in CH3CN (21 mL) under nitrogen was added tert-butyl bromoacetate (875 μL, 5.92 mmol) and the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool to RT, EtOAc and water were added and the layers were separated, the aqueous one being re-extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography (c-hexane to c-hexane/EtOAc 1:1) to afford the desired compound. TLC, Rf (EtOAc)=0.77; MS (LC/MS): 304.1 [M+H]+, 302.0 [M−H]−; tR (HPLC conditions a): 4.01 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]([CH3:42])[C:13](=[O:41])/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][C:19]3[NH:20][C:21](=[O:40])[CH:22]([N:26]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:23][C:24]=3[CH:25]=2)=[CH:3]1.Cl.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]([CH3:42])[C:13](=[O:41])/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][C:19]3[NH:20][C:21](=[O:40])[CH:22]([NH2:26])[CH2:23][C:24]=3[CH:25]=2)=[CH:3]1
Reactant: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CC(N=C(c1ccccc1)c1ccccc1)C(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CC(N)C(=O)N2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.8 %

Procedure:
To a suspension of (E)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methyl-3-[6-(benzhydrylideneamino)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylamide (0.5 g, 0.9 mmole) in dioxane (15 mL) was added 1 N HCl (10 mL) with stirring at RT. After approximately 5 min the suspension cleared up then gradually reformed. After stirring for 1 h the reaction was neutralized with 1 N NaOH (10 mL) and concentrated to near dryness under vacuum. The resulting suspension was diluted with H2O (20 mL) and filtered, and the solid was rinsed with cold H2O and dried under vacuum. The slightly pinkish solid was triturated with Et2O, filtered, and dried under vacuum to give the title compound (248 mg, 71%) as an off-white solid: MS (ES) m/e 390.4 (M+H)+.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1.[Cl:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22]>CN(C=O)C>[Cl:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][O:22][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1
Reactant: CC(C)(CO)CCl
Reactant: ClCc1cccc(Oc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CCl)COCc1cccc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.6 %

Procedure:
Under a nitrogen atmosphere, 0.65 g of sodium hydride (60% oily suspension) was suspended in 10 ml of dry DMF, and a solution of 3.23 g of 2-chloromethyl-6-phenoxypyridine and 2.00 g of 3-chloro-2,2-dimethylpropanol in 10 ml of dry DMF was added dropwise with ice-cooling. After stirring for 12 hours at room temperature, the reaction solution was poured into dilute hydrochloric acid-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel (developing solvent, hexane:ethyl acetate=50:1) to obtain 0.52 g of desired 6-phenoxy-2-pyridylmethyl 3-chloro-2,2-dimethylpropyl ether [present compound (1)] as a colorless oily product.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:10][N:11]([CH3:30])CCCC#CC1C=CC(NC(=O)C(F)(F)F)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=1>>[OH:41][C:38]1[CH:39]=[CH:40][C:31]([C@H:9]([CH2:10][NH:11][CH2:30][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=2)[O:8][Si:1]([CH3:3])([CH3:2])[C:4]([CH3:6])([CH3:7])[CH3:5])=[C:32]2[C:37]=1[NH:36][C:35](=[O:42])[CH:34]=[CH:33]2
Reactant: CN(CCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCCCCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 102, using Intermediate 52 in place of Intermediate 45. ES/MS calcd. for C33H50N3O6Si+ 612.4. Found m/z=612.5 (M+H)+.
Reaction SMILES: C(O)CCCCCC/C=C/C=C/C.[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26])(=[O:16])[CH3:15].C(OCCCCC=CCCCCOC(=O)C)(=O)C.ClCCC=CCCCl>>[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][Cl:26])(=[O:16])[CH3:15]
Reactant: CC(=O)OCCCCCCCCCl
Agent: C/C=C/C=C/CCCCCCCO
Agent: CC(=O)OCCCCC=CCCCCOC(C)=O
Agent: ClCCC=CCCCl
Product: CC(=O)OCCCCC=CCCCl

Procedure:
FIGS. 24A and 24B show another synthesis of E,E-8,10-dodecadienol. With reference to FIG. 24A, 8-chlorooctan-1-yl acetate was synthesized from the cross metathesis of 1,10-diacetoxy-5-decene and 1,6-dichloro-3-hexene with Catalyst 801 to yield 8-chloro-5-octen-1-yl acetate, which was reduced and deacetylated. With reference to FIG. 24B, 8-chlorooctan-1-yl acetate was refluxed with two equivalents of triethyl phosphite in toluene for four hours to yield the octanol phosphonate intermediate. The mixture was cooled to −40° C. under argon. Lithium diisopropyl amine was added (2.3 mol equivalents to the phosphonate) and slowly warmed to room temp. Freshly distilled crotonaldehyde (2 mol equivalents) was added and stirred at room temp for 4 hours. The mixture was worked up to yield 8,10-dodecadienol.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@@H:4]([C:15]([O:17][CH3:18])=[O:16])[NH:3]1.Cl.COC(=O)C(CC1C2C(=CC=CC=2)NC=1)N>>[CH2:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH:4]([C:15]([O:17][CH3:18])=[O:16])[NH:3]1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Agent: COC(=O)C(N)Cc1c[nH]c2ccccc12
Agent: Cl
Product: COC(=O)C1Cc2c([nH]c3ccccc23)CN1
Yield: 75 %

Procedure:
In the same manner as described above (1) using DL-tryptophan methyl ester hydrochloride, there is obtained the title compound (75%) as colorless needles, m.p. 185°-187° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH2:20])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(F)ccc2[N+](=O)[O-])C1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Nc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.6 %

Procedure:
A mixture of 3-(5-fluoro-2-nitrophenylamino)azetidine-1-carboxylic acid tert-butyl ester (4.84 g, 15.54 mmol) in EtOAc (100 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (500 mg) and was stirred at RT under a hydrogen atmosphere for 16 h. Additional 10% Pd/C (500 mg) was added and stirring under a hydrogen atmosphere continued for 6 h. The mixture was filtered and the filtrate concentrated in vacuo to afford the title compound as a brown foam (4.4 g, quantitative). LCMS (Method J): RT 2.39 and 2.60 min [M+H]+ 282.1.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:34][Si](C)(C)C>CC(CC)=O>[ClH:34].[CH3:33][N:2]([CH3:1])[C:3]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-[5-(1H-indol-3-yl)pentyl]acetamide (81 mg, 0.182 mmol) was dissolved in ethyl methyl ketone (3 ml), and chlorotrimethylsilane (0.035 ml, 0.27 mmol) was added. After 1.5 h the hydrochloride was isolated as a colourless solid with an m.p. of 174-183° C. in a yield of 71% (62 mg).