Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Cl:11][C:12]1[CH:28]=[C:16]([C:17]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:18])[C:15]([OH:29])=[C:14]([C:30](=[O:33])[CH2:31][CH3:32])[CH:13]=1.[C:34](Cl)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15](=[C:16]([C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:18])[CH:28]=1)[O:29][C:32]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:31]([CH3:34])[C:30]2=[O:33]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C([O-])c1ccccc1
Reactant: CCC(=O)c1cc(Cl)cc(C(=O)OCCN2CCCCC2)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCN3CCCCC3)cc(Cl)cc2c1=O
Yield: 83 %

Procedure:
A 14.4 g (0.1 mole) quantity of sodium benzoate was added with stirring to a mixture of 10.2 g (0.03 mole) of β-piperidinoethyl 5-chloro-3-propionylsalicylate and 12.6 g (0.09 mole) of benzoyl chloride. The resulting mixture was heated in an oil bath at 180° to 190° C. for 8 hours to undergo reaction. After cooling, a 5% aqueous solution of sodium carbonate was added to the reaction mixture. The solids formed were purified with alcohol to provide 10.6 g (83.0%) of white crystals which were treated with a hydrochloric acid-alcohol mixture and were recrystallized from alcohol. The hydrochloride of the compound was found to have a melting point of 196.1° to 198.3° C.
Reaction SMILES: CO[C:3]1[CH:4]([CH3:11])[CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][N:9]=1.[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH3:11][CH:4]1[CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][NH:9][C:3]1=[NH:13]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1=NCC(C)CCC1C
Solvent: CO
Product: CC1CCC(C)C(=N)NC1
Product: Cl

Procedure:
The product of EXAMPLE 129 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=[O:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][N:65]([CH:63]=[O:64])[CH2:66][CH2:67]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=CN1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCN(C=O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-formyl-piperazine in DMSO at ambient temperature.
Reaction SMILES: P(CC1N=CC=CN=1)(=O)=O.[P:11]([O:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[C:39]3[N:38]=[CH:37][N:36]=[C:34]([NH2:35])[C:33]=3[N:32]=[CH:31]2)[C@H:27]([OH:40])[C@@H:26]1[OH:41])([O:14][P:15]([O:18]P(O)(O)=O)([OH:17])=[O:16])(=[O:13])[OH:12].[NH2:42][C:43]1[C:48]([CH2:49][P:50](=[O:52])=[O:51])=[CH:47][N:46]=[C:45]([CH3:53])[N:44]=1>>[P:11]([O:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[C:39]3[N:38]=[CH:37][N:36]=[C:34]([NH2:35])[C:33]=3[N:32]=[CH:31]2)[C@H:27]([OH:40])[C@@H:26]1[OH:41])([O:14][P:15]([OH:17])([OH:18])=[O:16])(=[O:12])[OH:13].[NH2:42][C:43]1[C:48]([CH2:49][P:50]([O:13][P:11]([OH:23])([OH:14])=[O:12])([OH:52])=[O:51])=[CH:47][N:46]=[C:45]([CH3:53])[N:44]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: Cc1ncc(CP(=O)=O)c(N)n1
Agent: O=P(=O)Cc1ncccn1
Product: Cc1ncc(CP(=O)(O)OP(=O)(O)O)c(N)n1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
As noted above, in bacteria and fungi, phosphomethylpyrimidine kinase; (EC 2.7.4.7) catalyzes the reaction of ATP+4-amino-2-methyl-5-phosphomethylpyrimidine to produce ADP+4-amino-2-methyl-5-diphosphomethylpyrimidine; thiamine-phosphate diphosphorylase; (EC 2.5.1.3) catalyzes the reaction of 2-methyl-4-amino-5-hydroxymethylpyrimidine diphosphate+4-methyl-5-(2-phosphono-oxyethyl)thiazole to produce diphosphate+thiamine monophosphate; (EC 3.1.3.-) catalyzes the reaction of thiamine monophosphate to produce thiamine. The present inventor has first recognized the importance of this distinction in providing a target for inhibition of pathogenic microorganisms.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[N:12]=1>CN(C)C=O>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Brc1cccc(Br)n1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(Oc2ccccc2)n1
Yield: 79 %

Procedure:
To a solution of 6.5 g (0.135 mol) of 50% sodium hydride in 75 ml of dimethylformamide at 0° C. and under N2 was added a solution of 11.9 g (0.127 mol) of phenol in 75 ml of dimethylformamide. Once dropwise addition was complete, 30.0 g (0.127 mol) of 2,6-dibromopyridine was added in one portion and the mixture was heated at 60° to 65° C. for 18 hours. The mixture was then cooled and partitioned between ether and 1N aqueous NaOH. The ether extracts were washed two times with aqueous NaHCO3, dried over MgSO4, filtered and concentrated under vacuum. The solid residue was slurried in hexane, filtered and dried to afford 25.1 g (79%) of the title compound as a white powder: m.p. 83° to 86° C.; 1H NMR (CDCl3) δ 6.70 (d, 1H), 7.0-7.5 (m, 7 H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([CH2:6]NC2C3C(=CC=CC=3)N=C(C)C=2C(=O)C)=[CH:4][CH:3]=1.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([CH3:35])[C:29]([C:36]([O:38][CH3:39])=[O:37])=[C:28]2[NH2:40].BrC1C=CC(CBr)=CC=1>>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([CH3:35])[C:29]([C:36]([O:38][CH3:39])=[O:37])=[C:28]2[NH:40][CH2:6][C:5]1[CH:22]=[CH:23][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1c(C)nc2ccc(Br)cc2c1N
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Agent: BrCc1ccc(Br)cc1
Product: COC(=O)c1c(C)nc2ccc(Br)cc2c1NCc1ccccc1

Procedure:
Methyl 6-bromo-4-benzylamino-2-methylquinoline-3-carboxylate was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from methyl 6-bromo4-amino-2-methylquinoline-3-carboxylate and 4-bromobenzyl bromide. Melting point: 89° C.; MS(ES+): 385/387.
Reaction SMILES: C[N:2]1C=CN=C1.P(Cl)(Cl)(Cl)=O.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH3:35])[O:23][C@H:22]1[N:36]1[CH:43]=[C:42]([F:44])[C:40](=O)[NH:39][C:37]1=[O:38])(=O)C1C=CC=CC=1.[OH-].[NH4+]>C(#N)C>[F:44][C:42]1[C:40]([NH2:2])=[N:39][C:37](=[O:38])[N:36]([CH:43]=1)[C@@H:22]1[O:23][C@H:24]([CH3:35])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: Cn1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-methylimidazole (0.8 ml) and phosphoryl chloride (0.28 ml) in acetonitrile (20 ml) was added 2',3'-di-O-benzoyl-5'-deoxy-5-fluorouridine (500 mg) obtained above at 0° C. After stirring of the reaction mixture for 1.5 hours at room temperature 28% ammonium hydroxide (2.5 ml) was added to the mixture at 0° C., and the mixture was stirred for 1 hour at room temperature. Acetonitrile and ammonia were removed under reduced pressure. The residue was acidified with 1N-HCl and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 155 mg of 2',3'-di-O-benxoyl- 5'-deoxy-5-fluorocytidine, mp 192°~194° C.; MS 476 ((M+Na)+).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([O:28][CH3:29])=[O:27])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:35](=O)(O)[O-].[Na+].CI>O.CO>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[C:17]([S:34][CH3:35])=[N:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([O:28][CH3:29])=[O:27])[CH:21]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(SC)nc2=O)c1
Temperature: 40 °C

Procedure:
A mixture of the product from example 2 step (iv) (1 g), sodium bicarbonate (0.22 g) and methyl iodide (0.7 ml) in water (4 ml) and methanol (30 ml) was heated at 40° C. for 4 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Used directly in the next step.
Reaction SMILES: O.[Na].[CH:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([C:15]=2[CH2:17][OH:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])[CH3:20].CCCCCC>O1CCCC1>[CH2:19]([N:21]([CH2:25][CH3:26])[C:22](=[O:23])[O:18][CH2:17][C:15]1[C:14]2[C:9]([CH:8]=[C:7]3[C:16]=1[CH:3]=[CH:4][CH:5]=[CH:6]3)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:20]
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: CCN(CC)C(=O)Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCN(CC)C(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To the solution containing 1.6 g of 50% sodium hydrate (33 mmol) and 4 mL of dehydrated tetrahydrofuran (dehydrated THF), the solution dissolved 6.3 g of 9-anthracenemethanol (30 mmol; produced by Wako Pure Chemical Industries, Ltd.) into 26 mL of dehydrated tetrahydrofuran (dehydrated THF) was dropped. Then, after this solution of 4.5 g of N,N-diethylcarbamoyl chloride (33 mmol; produced by Sigma-Aldrich Japan Co.) in 4 mL of dehydrated tetrahydrofuran (dehydrated THF) was added, the solution was reacted by stirring for 2 hours at 60° C. After completing reaction, reaction solution was cooled, and n-hexane was poured into the cooled solution, then, the solution was washed with water, and organic layer after washing was condensed. The resultant condensed residue was purified with column chromatography (Filler: Silica-Gel (Wako-Gel C-200; produced by Wako Pure Chemical Industries, Ltd.), Developing solvent: n-heptane) to obtain 5.7 g of 9-anthrylmethyl N,N-diethylcarbamate (yield: 61%) represented by the above-described formula [7] as yellow crystal. Measurement results of 1H-NMR and melting point are shown as the follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14].[OH:17]O.[Na+].[Cl-]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[N+:10]([C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14])[O-:17]
Reactant: COCC(C)(C)NCc1ccc(F)cc1F
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COCC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
A solution of N-(2,4-difluorophenylmethyl)-N-[dimethyl(methoxymethyl)methyl]amine obtained in Example 14 (378.8 mg, 1.65 mmol) and Na2WO4 2H2O (84.3 mg, 0.256 mmol) in methanol (5 ml) was cooled to 0° C. in ice-water bath. To the mixture was added dropwise 31% H2O2 aqueous solution (439.3 mg, 4.00 mmol). After addition the mixture was gradually warmed to room temperature and stirred for 15 hours. The mixture was added to sat. NaCl aqueous solution and extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (toluene/ethyl acetate=5/1) to give the title compound (204.8 mg; 51%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)#[CH:36]>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:6]=[CH:7][C:2]([C:36]#[C:35][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:3][CH:4]=2)/[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccccn3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (370 mg, 0.636 mmol; example 4) in a mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed and 2-ethynylpyridine (118 mg, 1.144 mmol) was added under argon atmosphere. The solution was cooled; tetrakis(triphenylphosphine)palladium (59.0 mg, 0.051 mmol) and copper(I) iodide (19.3 mg, 0.102 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h. The mixture was evaporated in vacuo and the residue was dissolved in dichloromethane (60 mL). The solution was washed with water (2×20 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-[4-(pyridin-2-ylethynyl)phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([F:14])[CH:3]=1.Cl[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>CN(C)C=O.FC(F)(F)C(O)=O.[Mn]>[F:14][C:4]1[CH:3]=[C:2]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:12][C:5]=1[CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CCOC(=O)C(C)Cl
Reactant: CS(=O)(=O)NCc1ccc(Br)cc1F
Agent: [Mn]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(CNS(C)(=O)=O)c(F)c1
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To a stirred solution of N-(4-bromo-2-fluorobenzyl)methanesulfonamide (2.94 g, 10.421 mmol) in dimethylformamide were added ethyl 2-chloropropionate (1.725 mL), manganese (1.145 g) and (2,2′-bipyridine)nickel(II)-dibromide (273 mg, mmol). Trifluoroacetic acid (2 drops) was added. The reaction mixture was stirred for 36 h at 60° C. After cooling down to room temperature, the mixture was hydrolysed by 1N HCl and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to obtain ethyl 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoate (218 mg).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH3:25])[C:8]([C:21]([F:24])([F:23])[F:22])([O:16][Si](C)(C)C)[C:9]=1[NH:10]2.[OH-].[K+].CCO>C1COCC1.O>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH3:25])[C:8]([C:21]([F:22])([F:23])[F:24])([OH:16])[C:9]=1[NH:10]2
Reactant: CC1CCc2c([nH]c3ccc(Cl)c(Cl)c23)C1(O[Si](C)(C)C)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC1CCc2c([nH]c3ccc(Cl)c(Cl)c23)C1(O)C(F)(F)F
Temperature: 60 °C
Yield: 19.7 %

Procedure:
5,6-Dichloro-2-methyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.15 g, 0.3 mmol) was dissolved in THF (5 mL) and a solution of KOH (0.068 g, 1.2 mmol) in water (5 mL) was added followed by EtOH (2 mL). The reaction mixture was heated at 60° C. for 6 h, diluted with water (10 mL) and extracted into EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude residue which was purified by column chromatography [EtOAc-hexane (1:4) as eluant] to provide the title compound (0.02 g, 20%). 1H NMR (500 MHz, CDCl3, δ in ppm) (mixture of two diastereomers) 8.35 (br s, 1H), 8.28 (br s, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 3.26-2.98 (m, 4H), 2.51 (s, 1H), 2.46-2.42 (m, 1H), 2.35 (s, 1H), 2.26 (m, 1H), 2.12-1.97 (m, 3H), 1.84-1.78 (m, 1H), 1.21-1.18 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH3:10][NH:11][CH3:12].[CH2:13]=O.Cl>C(O)C.O>[CH3:10][N:11]([CH2:13][C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=1)[CH3:12]
Reactant: C=O
Reactant: CNC
Reactant: Cc1cccc(C)c1O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(CN(C)C)cc(C)c1O
Temperature: 0 °C
Yield: 46 %

Procedure:
A solution of 2,6-dimethyl phenol (20 g, 0.163 mol) in ethanol (100 mL) at room temperature was treated with dimethylamine (19 mL of a 40% solution of dimethylamine in water, 0.163 mol) followed by formaldehyde (13.5 mL of a 37% solution of formaldehyde in water, 0.163 mol). The reaction was heated to reflux for 12 h. The reaction mixture was cooled to 0° C. in an ice bath, diluted with water (100 mL) and brought to pH=5 with a 1N aqueous hydrochloric acid solution. The water layer was extracted with diethyl ether (2×150 mL). The aqueous layer was brought to pH=8 by the addition of a 1N aqueous sodium hydroxide solution, cooled to 0° C. in an ice bath and was extracted with diethyl ether (3×200 mL). The organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting oil was dried under high vacuum overnight to afford 4-dimethylaminomethyl-2,6-dimethyl-phenol as an off-white solid (13.42 g, 46%); EI(+)-HRMS m/z calcd for C11H17NO (M+) 179.1310, found 179.1308. Molecular Weight=179.2642; Exact Mass=179.1310
Reaction SMILES: [Cl-].[O:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH3+:5].C(Cl)Cl.[C:15](OC(=O)C)(=[O:17])[CH3:16].CCN(C(C)C)C(C)C>CCOC(C)=O>[O:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH:5][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: [NH3+]CC(=O)c1ccccc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
2-oxo-2-phenylethanaminium chloride (5) (1.7 g, 10.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by CH2Cl2 (50 mL). The resulting solution was cooled to 0° C. via an ice bath. Next, acetic anhydride (1.4 mL, 15.0 mmol, 15.0 equiv.) and DIEA (5.3 mL, 30.0 mmol, 30.0 equiv.) were added to the reaction flask. The reaction solution stirred for 2 h at 0° C. and was allowed to warm to rt. The solution was stirred at rt for 1 h. The solution was transferred to a separatory funnel with CH2Cl2 (90 mL). The resulting organic layer was washed with 1% HCl (2×50 mL) and sat. NaCl (2×50 mL). The organic layer was dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give a yellowish solid. The solid was dissolved in EtOAc (15 mL) and precipitated during the slow addition of hexanes (30 mL). The precipitate that formed was dried under vacuum to give 1.3 g (74%) of 10 as a white solid. Rf=0.31 (100% EtOAc); mp=85-87° C.; IR (KBr) 3319, 3059, 2936, 2900, 1683, 1649, 1597, 1556, 1370, 1011 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J=7.5 Hz, 2H, Ph-H), 7.63 (t, J=7.5 Hz, 1H, Ph-H), 7.50 (t, J=7.5 Hz, 2H, Ph-H), 6.69 (br s, 1H, Ac—NH), 4.78 (d, J=4.5 Hz, 2H, Ac—NH—CH2), 2.12 (s, 3H, NH—COCH3); 13C NMR (125 MHz, CDCl3) δ 194.4, 170.5, 134.5, 134.3, 129.1, 128.1, 46.7, 23.2; LRMS (ESI-MS m/z): Mass calcd for C10H11NO2 [M]+, 177.20. Found 178. Anal. calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.63; H, 6.29; N, 7.87. Spectroscopic data were consistent with the literature data for this compound.
Reaction SMILES: [CH2:1](C(C(OCC)=O)C(OCC)=O)CCC.[CH3:16][O:17][CH2:18][C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]23[O:34][CH2:33][C:30]([CH2:35][CH2:36][CH3:37])([CH2:31][O:32]2)[CH:29]([C:38]([F:41])([F:40])[F:39])[O:28]3)=[CH:23][CH:22]=1>>[CH2:35]([C:30]12[CH2:33][O:34][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]#[C:19][CH2:18][O:17][CH3:16])=[CH:26][CH:25]=3)([O:32][CH2:31]1)[O:28][CH:29]2[C:38]([F:41])([F:39])[F:40])[CH2:36][CH2:37][CH3:1]
Reactant: CCCC12COC(c3ccc(C#CCOC)cc3)(OC1)OC2C(F)(F)F
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Product: CCCCC12COC(c3ccc(C#CCOC)cc3)(OC1)OC2C(F)(F)F

Procedure:
4-n-Butyl-1-[4-(3-methoxyprop-1-ynyl)phenyl]-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane was prepared from diethyl n-butyl-malonate in a manner analogous to the synthesis of 1-[4-(3-methoxyprop-1-ynyl)phenyl]-4-n-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:8][CH:9]=1)[CH3:3].[CH3:15][I:16]>O1CCCC1.C(Cl)Cl>[I-:16].[CH2:13]([O:12][C:10]([C:7]1[NH:8][CH:9]=[C:5]([CH2:4][N+:2]([CH3:15])([CH3:1])[CH3:3])[CH:6]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1cc(CN(C)C)c[nH]1
Reactant: CI
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C[N+](C)(C)C)c[nH]1
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product obtained in Step D (0.3 g) in a mixture of tetrahydrofuran (2.2 ml) and CH2Cl2 (2.2 ml) there is added methyl iodide (0.350 ml). A precipitate appears. The reaction mixture is stirred for one hour at ambient temperature and is then left at 4° C. overnight. The reaction mixture is evaporated to dryness and the residue obtained is used directly in the next Step.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[N:11][OH:12])=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([C:8]1[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[CH:10]=[N:11][OH:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C=NO)c([N+](=O)[O-])cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(C=NO)c(Cc2ccccc2)c1OC
Reaction time: 4 h

Procedure:
6-Nitroveratraldoxime (113 g, 0.5 mole) was dissolved in 2500 ml of dimethylformamide. To this solution was added sodium methoxide (27 g, 0.5 mole). The suspension was treated with benzyl chloride (63 g, 0.5 mole) and stirring was continued for an additional 4 hr. The orange suspension was diluted with 3 l. of water and the solid was filtered, m.p. 109°-113°, yield: 110 g (78%). A small amount of the material was recrystallized from toluene to give an analytical sample melting at 116°-117°.