Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:24]=1)[C:19]([OH:21])=[O:20].[C:44](=O)(O)[O-].[Na+].CI>CN(C=O)C>[CH3:44][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:24]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=2[OH:1])[CH:17]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)OC)c1
Reaction time: 144 h
Yield: 67.9 %

Procedure:
A mixture of 0.15 g (0.25 mmol) of 3-[[6-(2,3-dihydroxyphenyl) hexyl]oxy]-5-(octadecyloxy)benzoic acid, 0.05 g (0.6 mmol) of sodium bicarbonate and 0.64 ml (10 mmol) of methyl iodide in 3 ml of DMF was stirred and heated at 40° for 5 days. An additional 0.32 ml of methyl iodide and 0.05 g of sodium bicarbonate were added and heating at 40° was continued for 6 days. The solvent was removed at reduced pressure, the residue was extracted with ethyl acetate and the extract was washed with water. The dried extract was concentrated to an oil which was purified by chromatography on 4 g of silica gel using 25% ethyl acetate-hexane to give 0.104 g (68% yield, mp 82°-84°) of 3-[[6-(2,3-dihydroxyphenyl)hexyl]oxy]-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[S:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(c2ccc(CO)s2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ccc(CCl)s2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)thiophen-2-yl]-methanol (5.00 g, 25.0 mmol) in dry CH2Cl2 (46 mL) was treated at 0° C. with Et3N (4.5 mL, 32.5 mmol) followed by DMAP (305 mg, 2.5 mmol) and Ms-Cl (2.3 mL, 30.0 mmol). After stirring at rt for 2 h, the reaction was quenched with water (50 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(5-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane as a yellow oil. Part of this crude material (953 mg, 4.36 mmol) was dissolved in dry DMF (15 mL) and treated with NaN3 (859 mg, 13.08 mmol) at 80° C. for 24 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 2-azidomethyl-5-(2-methyl-[1,3]dioxolan-2-yl)thiophene as a yellow oil. LC-MS-conditions 02: tR=0.97 min; [M+H]+=226.50.
Reaction SMILES: Cl[C:2]1[C:3]([S:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])([N+]([O-])=O)[CH2:6][CH:7]=1.[NH2:22][CH2:23][CH2:24][NH2:25]>C(O)(C)C>[NH2:22][CH2:23][CH2:24][NH:25][C:2]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[S:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15]
Reactant: O=C(O)CCS(=O)(=O)C1=CC([N+](=O)[O-])([N+](=O)[O-])CC=C1Cl
Reactant: NCCN
Solvent: CC(C)O
Product: NCCNc1ccc([N+](=O)[O-])cc1S(=O)(=O)CCC(=O)O
Temperature: 0 °C

Procedure:
29.5 g of 3-(2-chloro-5-nitro-5-nitrophenylsulphonyl)propionic acid and 15 g of 1,2-diaminoethane are refluxed in 150 ml of isopropanol for two hours. The reaction mixture is cooled down to 0° C. and filtered with suction. The isolation is suspended in 100 ml of water, the suspension is brought to pH 3.5, and 15 g of sodium chloride are added for salting out. The precipitated betaine is filtered off with suction and dried. The yield of 3-[2-(-aminoethyl)amino-5-nitrophenylsulphonyl]-propionic acid is 28.5 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15](C(OC(C)(C)C)=O)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:27]=[C:28]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:27]=[C:28]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c(OCc3ccccc3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(NS(C)(=O)=O)c(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Ethyl 5-(benzyloxy)-6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.32 g, 0.54 mmol, 1 eq) was dissolved in dichloromethane and cooled to 0° C. Then added trifluoroacetic acid (3.2 ml). The above mixture was stirred at room temperature for 12 h. The solution was concentrated and the pH was brought to 8 and extracted with dichloromethane. The organic layer was concentrated yielding the desired product and was taken to the next step without further purification. Yield: 0.23 g (88%). 1HNMR (400 MHz, DMSO-d6): δ 1.21-1.24 (t, 3H), 3.33 (s, 3H), 4.1-4.23 (q, 2H), 5.39 (s, 2H), 7.27 (t, J=5 Hz, 2H), 7.38 (d, J=2 Hz, 1H), 7.43 (m, 2H), 7.53 (s, 1H), 7.61 (d, J=2 Hz, 2H), 7.78 (t, J=6 Hz, 2H), 8.73 (s, 1H), 9.58 (s, 1H). LCMS: (ES+) m/z=484.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>CN(C=O)C>[OH:43][CH:44]1[CH2:49][CH2:48][N:47]([C:11](=[O:13])[CH2:10][O:9][C:6]2[C:7](=[O:8])[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:46][CH2:45]1
Reactant: OC1CCNCC1
Reactant: Cn1nccc(OCC(=O)O)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1nccc(OCC(=O)N2CCC(O)CC2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
11.1 g (60.2 mmoles) of intermediate 4i are placed in 250 mL of DMF under nitrogen. At 0° C., 21.3 g (66.3 mmoles) of TBTU then 16.8 mL (120 mmoles) of Et3N then 6.1 g (60.2 mmoles) of 4-hydroxypiperidine are added. The reaction medium is agitated for 20 h at ambient temperature then concentrated to dryness. The residue obtained is purified by silica gel flash chromatography (CH2Cl2-MeOH, gradient 100:0 to 90:10 in 40 min). 10.14 g of intermediate 5c are thus obtained in the form of a yellow solid (yield 63%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH: 80:20, Rf=0.59.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:12].[Cl:14]CCl>CN(C=O)C.Cl[Cu]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:14])=[CH:6][C:5]=1[Cl:12]
Reactant: ClCCl
Reactant: COC(=O)c1c(C)cc(Br)cc1Cl
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(Cl)cc1Cl
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A solution of the 4-bromo-2-chloro-6-methyl-benzoic acid methyl ester (1.31 g, 5 mmol) in DMF was treated with CuCl (1.96 g, 20 mmol) and stirred at 140° C. for 1-2 h. After this time, the reaction mixture was diluted with dichloromethane (15 mL) and the solids removed by filtration. The filtrate was concentrated. Silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded 2,4-dichloro-6-methyl-benzoic acid methyl ester (0.72 g, 65%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])[CH2:10][CH:9]=2)=[CH:4][C:3]=1[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.[O:34]1CCOCC1.Cl>O>[CH3:25][C:17]1([CH3:26])[O:16][C:15](=[O:27])[N:14]([CH:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:4]=[C:3]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:2](=[O:34])[NH:7][CH:6]=3)=[CH:9][CH2:10]2)[C@H:18]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1COCCO1
Reactant: CC1(C)OC(=O)N(C2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)[C@H]1c1ccccc1
Agent: Cl
Solvent: O
Product: CC1(C)OC(=O)N(C2CC=C(c3c[nH]c(=O)c(-c4ncccn4)c3)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A resealable tube was charged with (4S)-3-(4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (See Step 1 in the synthesis of Examples 72 and 73)(50 mg, 0.112 mmol, 50% ee), dioxane (2.647 mL), and water (882 μL). Concentrated HCl (37%) (221 μL) was added, the system was flushed with argon, and the tube was sealed. The reaction mixture was then stirred at 100° C. for 2 hours. LC-MS indicated a clean and complete reaction. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc. The organic phase was concentrated under reduced pressure. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% MeOH in DCM. The resulting product was then washed with 10% ammonium hydroxide in MeOH. The solution was concentrated under reduced pressure providing (4S)-5,5-dimethyl-3-(4-(6-oxo-5-(pyrimidin-2-yl)-1,6-dihydropyridin-3-yl)cyclohex-3-en-1-yl)-4-phenyloxazolidin-2-one (44 mg, 0.099 mmol, 88% yield, 50% ee) as yellow solid. m/z (ESI) 443.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:32]2[CH:33]=[CH:34][C:35](B(O)O)=[CH:36][C:31]=2[N:30]=[CH:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:35]5[CH:34]=[CH:33][C:32]6[N:28]([CH3:27])[CH:29]=[N:30][C:31]=6[CH:36]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cn1cnc2cc(B(O)O)ccc21
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6c(c5)ncn6C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (1-methyl-1H-benzimidazol-5-yl)boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 7): tR=0.36 min; Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:24][N:25]([CH3:29])[C:26]([S:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])=[O:27]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1c(NC(=O)C(CS)Cc2ccccc2)cccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(NC(=O)C(CSC(=O)N(C)C)Cc2ccccc2)cccc1C(=O)O
Yield: 28.7 %

Procedure:
3-[(2-Mercaptomethyl-3-phenylpropionyl)amino]-2methylbenzoic acid (compound of Example 7) (0.66 g) is dissolved in pyridine (2 ml), and thereto is added dimethylaminocarbonyl chloride (0.26 g) with stirring under ice cooling, and the mixture is stirred under ice cooling for 2 hours and further at room temperature for 2 hours. To the reaction mixture is added ethyl acetate (50 ml) and the mixture is washed with saturated aqueous citric acid solution and water, dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and the precipitates are separated by filtration to give the title compound (0.23 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:3][CH:2]=1.S(Cl)(Cl)=O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1Nc1ccncc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1Nc1ccncc1)N1CCCCC1
Reaction time: 3 h
Yield: 103.5 %

Procedure:
2-(4-Pyridinylamino)benzoic acid (244 g, 1.14 moles) was added with stirring at room temperature to 1.4 liters of thionyl chloride containing a catalytic amount (about 1.4 ml) of N,N-dimethylformamide. A mildly exothermic reaction ensued. The reaction was stirred at room temperature for 3 hours when the excess thionyl chloride was removed in vacuo. The residual oil was azeotroped twice with toluene. The yellowish gummy acid chloride was suspended in 1.5 liters of acetonitrile and 556 ml of piperidine was added with cooling (15°-20° C.) and stirring. Stirring was continued for 3 hours. The precipitated white solid was filtered and washed with a little cold acetonitrile. It was slurried once in about 2 liters of water while adjusting the pH to 9 by addition of potassium carbonate. The solid was dried and recrystallized from 2.7 liters of ethyl acetate to afford 166 g (51.6%) of 1-[2-(4-pyridinylamino)benzoyl]piperidine, m.p. 153°-156° C.
Reaction SMILES: C(C1C=CC(C2C=CC(CCN(C[C@H:26]([OH:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)C(=O)OC(C)(C)C)=CC=2)=CC=1N(C(C)C)C)=O.OO.Cl([O-])=[O:42].[Na+]>C(#N)C.C(OCC)(=O)C>[C:26]([OH:33])(=[O:42])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: [O-][Cl+][O-]
Reactant: CC(C)N(C)c1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C=O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)c1ccccc1
Temperature: 20 °C
Reaction time: 10 h
Yield: 47.8 %

Procedure:
To a solution of tert-butyl [2-[4′-formyl-3′-[isopropyl(methyl)amino]-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (310 mg) in acetonitrile (3.5 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1.6 ml) were added 30% hydrogen peroxide solution (60 μl) and 80% sodium chlorite (110 mg) below 10° C. The reaction mixture was stirred at 20° C. for 10 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=15/1) to give a benzoic acid product (35 mg). To a solution of the product in ethyl acetate (0.5 ml) was added 4N hydrogen chloride in ethyl acetate (0.5 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-[isopropyl(methyl)amino]-4-biphenylcarboxylic acid dihydrochloride (23 mg).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][C@H:40]([C:44]([OH:46])=[O:45])[CH:41]([CH3:43])[CH3:42]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:44]([OH:46])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Yield: 62.6 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (10.8 g) prepared by the method described in Preparation 2 and L-valine (5.85 g), N-(3-hexadecanoyloxyoctadecanoyl)-L-valine (8 g) was obtained as crystals according to a similar manner to that of Example 6.
Reaction SMILES: [C:1]([O:7][CH:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2]C(C)=O.C(N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C(#N)C>[N+:34](=[CH:2][C:1]([O:7][CH:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])=[O:6])=[N-:35]
Reactant: CC(=O)CC(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)=CC(OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3-methyl-1-trichloromethyl-2-butenyl acetoacetate (5.75 g, 0.02 mole) and triethylamine (2.02 g, 0.02 mole) in 50 ml of acetonitrile was added a solution of tosyl azide (3.94 g, 0.02 mole, prepared according to the method of Organic Synthesis Collective Volume V, page 179 A) in acetonitrile dropwise over a period of 10 minutes. The resultant mixture, containing the thus produced 3-methyl-1-trichloromethyl-2-butenyl-2-diazoacetoacetate, was stirred at room temperature for two hours and then poured into 60 ml (0.06 mole) of 1 N aqueous sodium hydroxide. The resulting mixture was stirred at room temperature for 30 minutes and then extracted with about 100 ml of ether. After phase separation, the aqueous layer was extracted with an additional 150 ml portion of ether, and the ether extracts were combined. The ethereal solution was then washed ten times with 50 ml portions of 3% aqueous potassium hydroxide containing sodium chloride and then three times with 50 ml portions of saturated aqueous sodium chloride. The washed ethereal solution was dried over magnesium sulfate, and the ether was removed by evaporation, affording a brown oily residue. The residue was purified by column chromatography on silica gel using benzene as the eluant, to give 3-methyl-1-trichloromethyl-2-butenyl diazoacetate (4.63 g, 85% yield).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:23][CH:24]=2)[N:14]=1.O>CC(N(C)C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[S:23][CH:24]=3)[N:14]=2)[CH:7]=1
Reactant: Fc1cccc(Oc2csc(C(F)(F)F)c2)n1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cnn(-c2cccc(Oc3csc(C(F)(F)F)c3)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
0.114 g of 4-trifluoromethylpyrazole is introduced in 5 ml of dimethylacetamide under nitrogen and at 0° C. 0.028 g of NaH is added. The mixture is allowed to come to RT over 30 min and then 0.2 g of 2-fluoro-6-(2-trifluormethyl-4-thienyloxy)pyridine is added and the mixture is heated at 80° C. for 9 h, cooled to RT and poured into water. After threefold extraction with ethyl acetate the product is washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.043 g of 2-(4-trifluoromethylpyrazol-1-yl)-6-(2-trifluoromethyl-4-thienyloxy)pyridine as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1[N:12]=[N:13][CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH:3]=2)[C:23]#[N:24])[N:10]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(-c2cnnc(-c3ccc(F)cc3F)n2)ccc1F
Temperature: 150 °C

Procedure:
A mixture of 5-(3-bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine (0.1 g, 0.27 mmol), zinc cyanide (0.032 g, 0.27 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.01 mmol) in N,N-dimethylformamide (4 ml) was heated to 150° C. Fog 600 s in a Smith Synthesiser microwave reactor (Personal Chemistry, Uppsala, Sweden). The reaction was partitioned between ethyl acetate (80 ml) and water (40 ml). The organic layer was washed with water (40 ml) and the combined organics dried over Mg2SO4, filtered and the solvent removed at reduced pressure. The crude product was chromatographed on silica gel, eluent 50% ethyl acetate in isohexane, to give 5-[3-(2,4-difluorophenyl)-[1,2,4]triazin-5-yl]-2-fluorobenzonitrile as a yellow solid (0.054 g): δH (400 MHz, CDCl3) 7.02-7.14 (2H, m), 7.48 (1H, t, J 8.6 Hz), 8.33-8.39 (1H, m), 8.49-8.53 (1H, m), 8.62 (1H, dd, J 2.2, 6.1 Hz), 9.65 (1H, s); m/z(ES+) 313.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:8]=1[NH:9][C:10]1[C:11]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][S:13][CH:14]=1.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:4][C:14]1[S:13][CH:12]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10]=1[NH:9][C:8]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:7]=1[Cl:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)Cc1cscc1Nc1c(Cl)cccc1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)Cc1csc(Cl)c1Nc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
1.35 g (10 mmoles) of sulfuryl chloride in 20 ml of methylene chloride are added dropwise to a solution of 3.02 g (10 mmoles) of 4-(2,6-dichloroanilino)-3-thiophenacetic acid in 15 ml of methylene chloride at -15°. After 10 minutes, 10 ml each of 2 N NaOH and 10 percent strength (aq) sodium dithionite solution are added. The aqueous phase is separated off, acidified and extracted with ethyl acetate, and the product phase is dried and concentrated. Recrystallization of the residue from cyclohexane yields pure 5-chloro-4-(2,6-dichloroanilino)-3-thiophenacetic acid (d. 141° to 142°).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][O:28][C:29]1[O:33][C:32]([C:34](O)=[O:35])=[N:31][CH:30]=1>>[CH3:27][O:28][C:29]1[O:33][C:32]([C:34]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:35])=[N:31][CH:30]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: COc1cnc(C(=O)O)o1
Product: COc1cnc(C(=O)Nc2cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c2)o1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5-(methyloxy)-1,3-oxazole-2-carboxylic acid.