Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[OH:22][S:23]([OH:26])(=[O:25])=[O:24]>C(O)C>[S:23]([O-:26])([OH:25])(=[O:24])=[O:22].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([C:16]3[CH:17]=[CH:18][NH+:19]=[CH:20][CH:21]=3)([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Reactant: O=S(=O)(O)O
Solvent: CCO
Product: CC(O)(c1cc[nH+]cc1)c1cnc(-c2ccc(F)cc2)s1
Product: O=S(=O)([O-])O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a suspension of 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (1 g, 3.3 mmol) in ethanol (25 mL) was added H2SO4 (0.18 mL, 3.3 mmol) slowly at 0° C., and then the mixture was stirred for 1 hour at room temperature. The solid that formed was filtered and washed with hexane (10 mL) to afford 4-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-hydroxyethyl)pyridin-1-ium hydrogen sulfate as an off-white solid (500 mg, 38% yield), HPLC purity 99.3%, mp 193-196° C. 1H NMR (400 MHz, DMSO-d6): 8.82 (d, 2H), 8.05 (d, 2H), 7.93-7.89 (m, 3H), 7.29 (t, 2H), 7.13 (br s, 1H), 2.00 (s, 3H); LC-MS m/z calculated for [M+H]+ 301.07. found 301.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[C:14]([OH:21])[CH:13]=1.O>C(OCC)(=O)C>[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:10][C:4]3[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=3[N:9]=2)=[C:14]([OH:21])[CH:13]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2nc(-c3ccc(N)cc3O)[nH]c2cc1C
Temperature: 130 °C
Yield: 28 %

Procedure:
To polyphosphoric acid at 130° C. were added 4,5-dimethylbenzene-1,2-diamine (500 mg, 3.67 mmol) and 4-amino-2-hydroxybenzoic acid (562 mg, 3.67 mmol), and the resulting mixture was then heated to 130° C. for 16 h. The solution was then poured into water and the resulting precipitate was dissolved in ethyl acetate and washed with Na2CO3. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 260 mg (28%) of the title compound (LCMS RT=6.14 min, MH+ 254.1)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][C:12](=C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:24]>>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][C:12](=[O:24])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1C[C@H](COCc2ccccc2)[C@H](c2cccc(F)c2)C1
Reactant: CO
Product: O=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(S)-(benzyloxymethyl)-4-(R)-(3-fluorophenyl)-1-methylenecyclopentane (0.77 g, 2.75 mmol) from Step A in methanol (30 mL) was cooled to −70° C. and ozone was bubbled through the solution until a blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethyl sulfide (5 mL) was added and the reaction was allowed to warm to rt over 16 h. Several drops of 2N HCl were added and the solution was stirred for 15 min to convert any methyl ketal to the desired ketone. The methanol was removed in vacuo and the was residue diluted with water, aq. sodium bicarbonate and ether.). The layers were separated and the aqueous was extracted with ether. The organic layers were washed with water, then brine, dried over sodium sulfate and concentrated. The residue was purified by FC using 10% ethyl acetate in hexanes to afford the title compound (0.88 g).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)([N:18]1C=CN=C1)=O.C(=O)=O.N[C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[C:35]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH:36]=[CH:37][CH:38]=2)[CH2:33]1>CN(C)C=O>[CH3:48][N:45]1[CH2:44][CH2:43][N:42]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]3[C:34]=2[CH2:33][C@H:32]([C:9]2[CH:8]=[C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:15]=[CH:14][C:10]=2[C:11]([NH2:18])=[O:13])[CH2:41][CH2:40]3)[CH2:47][CH2:46]1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](c2cc(N4CCCCC4)ccc2C(N)=O)CC3)CC1
Temperature: 75 °C
Reaction time: 17 h
Yield: 42.3 %

Procedure:
To a solution of 4-piperidinobenzoic acid (88 mg, 0.43 mmol; described in: Weringa, W. D.; Janssen, M. J. Recl. Trav. Chim. Pays-Bas 1968, 87(12), 1372-1380) in anhydrous N,N-dimethylformamide (5 mL) was added 1,1′-carbonyldiimidazole (73 mg, 0.45 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 17 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent gave 75 mg (42% yield) of the title compound as white crystals: mp 196-198° C.; [α]21D '63° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 432 (2, M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][CH:6]=[CH:5]2.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc2ncccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4cc3OC)c2cc1OC
Temperature: 155 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
6-Hydroxy-7-methoxyquinoline (65 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (148 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 155° C. overnight. The reaction solution was cooled to room temperature. Water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (134 mg, yield 100%).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:15]([OH:17])=O)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:23]([NH:31][C:15]([C:7]1[C:6](=[O:18])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)=[O:17])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCn1c2c(cc(C(=O)O)c1=O)CCCC2
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCn1c2c(cc(C(=O)NCCc3ccccc3)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
1-Butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (4-002-01) (100 mg, 0.38 mmol) was dissolved in toluene (10 mL), and to the reaction mixture were added thionyl chloride (83 μL, 1.14 mmol) and catalytic amount of DMF, and the reaction mixture was reacted at 75° C. for 30 min. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in methylene chloride (5 mL). To the reaction mixture was added phenethylamine (143 μL, 1.14 mmol) and the reaction mixture was stirred at room temperature for 10 min. To the reaction mixture was added diluted hydrochloric acid (1 mol/L, 10 mL) and the reaction mixture was extracted with ethyl acetate (30 mL), washed with brine (10 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene/ethyl acetate), followed by recrystallization from diethyl ether to give 1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid phenethylamide (4-002) (100 mg, 74%) as white crystal.
Reaction SMILES: CC(C)(OC([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)=[O:15])[N:12]=1)=O)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)=[O:15])[N:12]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)Cc2csc(NC(=O)OC(C)(C)C)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1csc(NC(=O)Cc2csc(N)n2)n1

Procedure:
The product from step (i) (0.8 g) in dry dichloromethane (15 ml) was treated with trifluoroacetic acid (5 ml). After 6 hours at room temperature the mixture was azeotroped with toluene. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The organic solution was dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with ethyl acetate/isohexanes and filtered. Yield 0.53 g.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:17][N:18]([CH:20](OC)OC)[CH3:19]>>[CH3:17][N:18]([CH3:20])/[CH:19]=[C:10](\[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)/[C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=1)=[O:16]
Reactant: CCc1ccc(C(=O)Cc2ncc[nH]2)cc1
Reactant: COC(OC)N(C)C
Product: CCc1ccc(C(=O)/C(=C/N(C)C)c2ncc[nH]2)cc1

Procedure:
1 mmol of 1-(4-ethylphenyl)-2-imidazolylethan-1-one was heated to 80° C. in N,N-dimethylformamidedimethyl acetal for six hours and concentrated in vacuo to obtain (2E)-3-(dimethylamino)-1-(4-ethylphenyl)-2-imidazolylprop-2-en-1-one.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][NH:7][C:8](=[O:51])[CH2:9][CH2:10][NH:11][C:12](=[O:50])[C@H:13]([OH:49])[C:14]([CH3:48])([CH3:47])[CH2:15][O:16][P:17]([OH:46])(=[O:45])[O:18][P:19]([OH:44])(=[O:43])[O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[C:36]3[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=3[N:29]=[CH:28]2)[C@H:24]([OH:37])[C@@H:23]1[O:38][P:39]([OH:42])([OH:41])=[O:40])(=[O:3])[CH3:2].[C:52]([O-])(=O)C>>[C:1]([S:4][CH2:5][CH2:6][NH:7][C:8](=[O:51])[CH2:9][CH2:10][NH:11][C:12](=[O:50])[C@H:13]([OH:49])[C:14]([CH3:47])([CH3:48])[CH2:15][O:16][P:17]([OH:46])(=[O:45])[O:18][P:19]([OH:44])(=[O:43])[O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[C:36]3[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=3[N:29]=[CH:28]2)[C@H:24]([OH:37])[C@@H:23]1[O:38][P:39]([OH:42])([OH:41])=[O:40])(=[O:3])[CH:2]=[CH2:52]
Reactant: CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Reactant: CC(=O)[O-]
Product: C=CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Reaction time: 0 h

Procedure:
S-acetyl CoA synthetase (acetate thiokinase from bakers yeast, Sigma, Saint Louis, Mo., USA; catalogue No. 1765) (1.9 mg/ml) is added. Using the fed-batch approach meaning step-wise addition (feeding) of H-CoA, 15 μl aliquots of H-CoA are added after 5, 10, 15 and 20 minutes, raising the H-CoA concentration by 1 mM each time, and a further 5 mM ATP is added after 25 minutes. Samples are analysed for H-CoA by HPLC (Instrumentation: Agilent Technologies HP1090L with HP1100 Variable Wavelength UV Detector and Chemstation (rev. A.06.01) Data System; column: Luna C18 from Phenomenex, 25 cm×4.6 mm inner diameter, bead diameter 5 μm (No. 92); mobile phase: A: 25 mM ammonium formate (pH 7.0), B: methanol; gradient 5% B for 0 min, then to 30% B in 20 min; flow 1 ml/min (approximately 130 bar), oven temperature 40° C., Detector: UV at 210 nm; injection volume 5 μl, Run time 28 min; peaks are found at the following retention times: ATP approximately 3.710 min, Coenzyme A at approximately 10.554 min, acetyl CoA at approximately 14.457 min, acrylyl CoA at approximately 17.500 min, bisadduct at approximately 15.993 min). When no H-CoA is detected, further 15 μl aliquots of H-CoA are added after 80, 95, 110 and 120 minutes, again raising the H-CoA concentration by 1 mM each time. Further 15 μl aliquots of H-CoA are added after 145 and 155 minutes and sufficient ATP to raise the concentration by 5 mM is added after 150 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]O)=[C:7]([CH3:14])[C:6]([O:15][CH3:16])=[C:5]([O:17][CH3:18])[C:4]=1[O:19][CH3:20].C(N(CC)CC)C.CS(Cl)(=O)=O.[I-:33].[Na+]>C(Cl)Cl.CC(C)=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][I:33])=[C:7]([CH3:14])[C:6]([O:15][CH3:16])=[C:5]([O:17][CH3:18])[C:4]=1[O:19][CH3:20]
Reactant: COc1c(C)c(CCCCO)c(OC)c(OC)c1OC
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(CCCCI)c(OC)c(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
In anhydrous methylene chloride (300 ml) were 1,2,3,4-tetramethoxy-5-methyl-6-(4-hydroxybutyl)benzene (28.2 g, 0.1 mole) as obtained in Reference Example 59 and triethylamine (16 g, 0.15 mole), and the solution was cooled to 0° C. A solution of methanesulfonyl chloride (14.3 g, 0.12 mole) in methylene chloride (30 ml) was added dropwise to the solution, followed by stirring for 30 minutes. The reaction solution was washed with water, dilute aqueous phosphoric acid and water, successively, and the organic layer was dried (over MgSO4) and freed of the solvent. Acetone (300 ml) and sodium iodide (39.0 g, 0.26 mole) were added to the residue, and the mixture was warmed at 50° C. for 2 hours. After the completion of the reaction, acetone was distilled off under reduced pressure, and isopropyl ether (300 ml) and water (200 ml) were added to the residue for extraction of the product. The organic layer was washed with 5% aqueous sodium hydrosulfite and water, successively, and dried (over MgSO4), followed by distilling off the solvent under reduced pressure. The residue was chromatographed on a column of silica gel, and developing with isopropyl ether-hexane (1:1) yielded 1,2,3,4-tetramethoxy-5-methyl-6-(4-iodobutyl)benzene (37.0 g, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([OH:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:21][C:22]1[C:27]([CH2:28][CH2:29]O)=[CH:26][CH:25]=[C:24]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:23]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:29][CH2:28][C:27]2[C:22]([CH3:21])=[N:23][C:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=3)=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)c2ccccc2c1
Product: CCOC(=O)C(C)(C)Oc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc2c1

Procedure:
In analogy to the procedures described in example 4D] and 4E], 2-(4-hydroxy-naphthalen-2-yloxy)-2-methyl-propionic acid ethyl ester (example 17D]) was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 4K]) to give 2-methyl-2-(4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-naphthalen-2-yloxy)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([Cl:28])=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[ClH:28].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH:17][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CCN(C)CCCN)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C)CCCNC(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Product: Cl

Procedure:
800 mg (3.17 mmol) N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methyl-1,3-propanediamine (D2), 630 mg (3.33 mmol) 4-nitro benzoyl chloride and 0.35 g (3.49 mmol) triethylamine in 30 ml methylene chloride were stirred for 2 hours at room temperature. The mixture was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified twice by chromatography on silicagel using methylene chloride/methanol: 97/3 then 94/6 yielding 700 mg (55%) of the desired compound as a base. The compound was salified in methylene chloride by adding a solution of hydrochoric acid in diethyl ether yielding 594 mg (43%) of the desired compound as a yellow solid: mp =80-90° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[C@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]I.O>CN(C=O)C>[CH3:16][O:14][C:13](=[O:15])[C@H:9]([C@H:10]([CH3:12])[OH:11])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
To a solution of N-Boc-L-allo-threonine (500 mg, 2.28 mmol) in DMF (5 mL), KHCO3 (637 mg, 4.56 mmol) and MeI (227 μl, 3.65 mmol) were added and the reaction was stirred 5 h at rt. Water (20 mL) was added and the mixture was extracted with ether (3×20 mL), dried (Na2SO4) and evaporated to afford the methyl ester 106 (494 mg, 93%) that was used without purification in the next step. 1H-NMR (500 MHz, CDCl3): 1.19-1.25 (m, 3H), 1.48 (s, 9H), 3.78 (s, 3H), 4.05-4.10 (m, 1H), 4.32-4.40 (m, 1H), 4.45-4.54 (m, 1H).
Reaction SMILES: CO[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15](SC)[C:4]=1[C:5]([NH:7]C1CCCCC1=O)=[O:6].C(O)(=O)C.N1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[F:20][C:19]([F:21])([F:22])[C:17]1[CH:18]=[CH:3][C:4]([C:5]([NH2:7])=[O:6])=[CH:15][CH:16]=1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
2-Methoxy-6-methylsulfanyl-N-(2-oxo-cyclohexyl)-4-trifluoromethyl-benzamide (intermediate B, 380 mg, 1.05 mmol) was dissolved in 10 mL tetrahydrofurane. Acetic acid (145 mg, 2.4 mmol) and pyrrolidine (97 mg, 1.4 mmol) were added and the reaction mixture was stirred 1 h at room temperature. Sodium triacetoxyborohydride (290 mg, 1.4 mmol) was added and stirring was continued at room temperature overnight. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→140:10:1) yielded cis-2-methoxy-6-methylsulfanyl-N-2-pyrrolidin-1-yl-cyclohexyl)-4-trifluoromethyl-benzamide as a light yellow solid (125 mg, 28%), MS: m/e=417.3 [(M+H)+] and trans-2-methoxy-6-methylsulfanyl-N-2-pyrrolidin-1-yl-cyclohexyl)-4-trifluoromethyl-benzamide as a light yellow solid (28 mg, 6%), MS: m/e=417.3 [(M+H)+].
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[CH2:6][O:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[CH2:2][CH3:3].C1(C)C=CC=CC=1.CSC.B>CO>[Cl:14][C:13]1[CH:12]=[C:11]([Cl:15])[CH:10]=[C:9]([Cl:16])[C:8]=1[O:7][CH2:6][CH2:5][NH:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCNC(=O)COc1c(Cl)cc(Cl)cc1Cl
Agent: B
Solvent: CSC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCNCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C

Procedure:
N-(n-propyl)-2,4,6-trichlorophenoxyacetamide, 44.0 gm, was added to 250 ml of toluene. 28 ml of borane methyl sulfide [BH3 (CH3)2S](2 equivalents) was then slowly added to the system. The system was heated at approximately 60° C. for 15 hours at which time reaction completion was checked by IR spectroscopy. 200 ml of methanol was then slowly added to the system. After addition of the methanol, the system was acidified by bubbling in HCl gas. Afterwards, the system was refluxed for 1 hour. The solvent was then removed by stripping. The resulting oil was dissolved in methanol which was then stripped. The oil was next dissolved in methylene chloride. The organic solution was washed with a sodium hydroxide solution and then with water. The methylene chloride was removed by stripping to give 36.3 gm of the N-(n-propyl) ethanolamine 2,4,6-trichlorophenylether, as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[O:9]
Reactant: NCCCSc1ccncc1
Reactant: O=C(O)Cc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(Cc1cccs1)NCCCSc1ccncc1
Yield: 86.3 %

Procedure:
To a solution of 913 mg (6.42 mmol) of 2-thienylacetic acid and 961 mg (8.35 mmol) of N-hydroxysuccinimide in 65 ml of methylene chloride, 1.48 g (7.70 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.08 g (6.42 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.62 g of the desired compound field: 86.3%, pale yellow powder).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][C:12]#[N:13])=[CH:9][C:4]=2[O:3][CH2:2]1.COC(OC)[N:18]([CH3:20])C.C(=O)(O)O.[NH2:27][C:28](N)=[NH:29].C[O-].[Na+]>CO>[NH2:29][C:28]1[N:27]=[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:11]([C:20]#[N:18])=[CH:12][N:13]=1
Reactant: COC(OC)N(C)C
Reactant: N=C(N)N
Reactant: N#CCC(=O)c1ccc2c(c1)OCO2
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 3-benzo[1,3]dioxol-5-yl-3-oxo-propionitrile and N,N-dimethylformamide dimethyl acetal. Then treatment with guanidine carbonate and sodium methylate in methanol. EI-MS m/e (%): 240 (M+, 100), 239 ([M—H]+, 62).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH3:10][OH:11].S(Cl)([Cl:14])=O>>[CH3:10][O:11][C:7]([C:2]1[CH:3]=[C:4]([Cl:14])[CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)c1cc(Cl)ccn1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Picolinic acid (1) (10 g, 81 mmol) was dissolved in thionyl chloride (40 ml). The reaction mixture was heated to 80° C. and was allowed to stir for 3 days. The reaction mixture was cooled in an ice bath and MeOH (20 ml) was added very slowly. The reaction mixture was allowed to stir for 1 hour, and all solvents were removed under vacuum. The crude product was taken up in ethyl acetate, washed twice with saturated sodium bicarbonate solution, washed with brine and dried over MgSO4. The crude product was purified on silica gel, eluted with 40% ethyl acetate/hexane to yield to the title product 2, a tan crystalline solid (8.1 g (57%), 46.5 mmol). 1H NMR (DMSO-d6): δ 8.72 (d, J=5.2 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.2 Hz, 2.1 Hz, 1H), 3.93 (s, 3H). MS (ESI-POS): [M+H]+=172.