Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]([F:24])([F:23])[F:22])[N:3]=1.CC[N:27]([CH:31]([CH3:33])[CH3:32])C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:27][C@H:31]1[CH2:32][CH2:8][C@H:7]([CH2:2][NH:3][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][C:21]([F:24])([F:23])[F:22])[N:3]=2)[CH2:6][CH2:33]1
Reactant: FC(F)(F)Oc1ccccc1CNc1ncc(C(F)(F)F)c(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 109.9 %

Procedure:
To a solution of the above (4-chloro-5-trifluoromethyl-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine (80 mg, 0.22 mmol) in DMF (2 mL) was added the Boc-protected cyclohexyl amine (74 mg, 0.33 mmol) followed by DIPEA (37 μL, 0.22 mmol). The reaction mixture was stirred at 70° C. for 3 h. When the reaction was complete, the reaction mixture was diluted with EtOAc and washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent. The resulting residue was then re-dissolved in CH2Cl2 (10 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 h and treated with saturated NaHCO3. The product was extracted with CH2Cl2 and dried over anhydrous Na2SO4. Silica gel preparative TLC using CH2Cl2:MeOH:NH4OH 10:1:0.2 as an eluent afforded 56 mg (56%) of the title compound as a white solid, m/z 462.4 [M−1]+.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:32][C:33](=[N:77][C:78](=[O:85])[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]([C:64]2[CH:69]=[C:68]([O:70][CH3:71])[CH:67]=[C:66]([O:72][CH2:73][CH2:74]O)[C:65]=2[F:76])[C:42]2[N:43]=[C:44]([O:53][CH2:54][O:55][C:56](=[O:63])[C:57]([CH3:62])([CH3:61])[CH2:58][O:59][CH3:60])[N:45]([C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[N:46]=2)=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.ClCCl>[NH2:32][C:33](=[N:77][C:78](=[O:85])[C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]([C:42]2[N:43]=[C:44]([O:53][CH2:54][O:55][C:56](=[O:63])[C:57]([CH3:62])([CH3:61])[CH2:58][O:59][CH3:60])[N:45]([C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[N:46]=2)[C:64]2[C:65]([F:76])=[C:66]([CH:67]=[C:68]([O:70][CH3:71])[CH:69]=2)[O:72][CH2:73][CH2:74][O:15][C:14]([C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[O:16])=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccncc1
Reactant: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCOC(=O)c3ccncc3)c2F)nn1-c1ncccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen atmosphere, triethylamine (0.112 mL) was added under ice-cooling to a mixture of 4-pyridinecarboxylic acid [CAS No. 55-22-1] (19.6 mg), TFFH (42.4 mg), and dichloromethane (6 mL), and the resulting mixture was stirred for 1 hour. To the resulting mixture, 3-methoxy-2,2-dimethylpropionic acid 5-({4-[amino(benzoylimino)methyl]phenylamino}-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl)-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-ylox ymethyl ester (14.9 mg) and DMAP (0.27 mg) were added, and the resulting mixture was stirred overnight at room temperature. Under reduced pressure, the solvent in the mixture was distilled off. The residue obtained was purified by reverse phase high-performance liquid chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid) to obtain the captioned compound (10.4 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5])[CH3:2].[C:12](#[N:15])[CH:13]=[CH2:14].CC[O-].[Na+]>>[C:12]([CH2:13][CH2:14][P:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[O:3][CH2:1][CH3:2])#[N:15]
Reactant: CCOP(O)c1ccccc1
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Product: CCOP(=O)(CCC#N)c1ccccc1
Reaction time: 1 h

Procedure:
To 42.45 g of phenylphosphonous acid-ethylester and 16.45 ml of acrylonitrile are added with stirring 5 ml of sodium ethylate (1 molar). The reaction is exothermic. After 1 hour stirring at 20° the mixture is fractionally distilled. There is obtained ethyl 2-cyanoethyl(phenyl)phosphinate as a colorless oil, b.p. 134°-136°/7 Pa.
Reaction SMILES: [N:1]1([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[N:1]1([C:8]2[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCCCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(azepan-1-yl)-2-phenylquinoxaline-6-carboxylate (132.4 mg, 0.37 mmol, 1.00 equiv) in methanol (15 mL), a solution of sodium hydroxide (73.4 mg, 1.83 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 80 mg (61%) of 3-(azepan-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7]CC[CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[N:11][C:12]([C:28]([NH2:30])=[O:29])=[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][N:20]3[CH:25]([CH3:27])[CH3:26])[N:14]=1.[C:31]([O:35]C(=O)N[C@H]([C@H](N)C)COC)(C)(C)C.C(OC(=O)N[C@H]1CCCC[C@H]1N)(C)(C)C>>[NH2:1][C@@H:2]([CH2:7][O:35][CH3:31])[C@H:3]([NH:8][C:9]1[N:10]=[N:11][C:12]([C:28]([NH2:30])=[O:29])=[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][N:20]3[CH:25]([CH3:26])[CH3:27])[N:14]=1)[CH3:4]
Reactant: CC(C)n1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)cccc21
Reactant: COC[C@H](NC(=O)OC(C)(C)C)[C@@H](C)N
Agent: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Product: COC[C@H](N)[C@@H](C)Nc1nnc(C(N)=O)c(Nc2cccc3c2ccn3C(C)C)n1

Procedure:
In accordance with Example 3 (Steps 1 to 4), 1-isopropyl-1H-indol-4-amine obtained in Example 45 was used instead of 1-methyl-1H-indol-4-amine, and tert-butyl((2R,3R)-3-amino-1-methoxybutan-2-yl)carbamate obtained in the above-described Step 1 was used instead of tert-butyl((1S,2R)-2-aminocyclohexyl)carbamate to obtain the titled compound as a light yellow solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=1)[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:23]=[CH:22][C:21]([C:24](=[O:48])[NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[C:32]([O:39][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)[CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:28])=[O:27])=[CH:20][C:16]=2[C:17](O)=[O:18])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:58]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH2:61][C@@H:60]([CH2:68][OH:69])[NH:59]1>>[CH2:1]([N:5]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=1)[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:23]=[CH:22][C:21]([C:24](=[O:48])[NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[C:32]([O:39][CH2:40][CH2:41][N:42]5[CH2:43][CH2:44][O:45][CH2:46][CH2:47]5)[CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:28])=[O:27])=[CH:20][C:16]=2[C:17]([N:59]2[C@H:60]([CH2:68][OH:69])[CH2:61][C:62]3[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:58]2)=[O:18])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Yield: 71.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(3-(butyl(3,4-dichlorobenzyl)carbamoyl)-4-chloro-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy)naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 186B, 12 mg, 0.014 mmol) and (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (Aldrich, 9 mg, 0.056 mmol) were converted to the title compound (10 mg, 70%). 1H NMR (CD3OD, mixture of amide rotamers) δ 9.23-9.09 (m, 1H), 8.24 (dd, J=1.7, 8.0 Hz, 0.5H), 8.10-7.94 (m, 3.5H), 7.76-7.59 (m, 3H), 7.53-7.29 (m, 1.5H), 7.27-6.80 (m, 6H), 6.68 (d, J=7.5 Hz, 0.5H), 5.27-5.04 (m, 1H), 4.75-4.59 (m, 3H), 4.54-2.44 (m, 18H), 2.39-2.26 (m, 3H), 2.25-2.06 (m, 1H), 1.65-0.81 (m, 5.5H), 0.75-0.65 (m, 1H), 0.61-0.51 (m, 0.5H); MS(ESI+) m/z 1005.3 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][N:16]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=O)=[CH:39][C:38]=1[C:46]([F:49])([F:48])[F:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(O)C.CN(C=O)C.[Pd]>[F:21][C:18]([F:19])([F:20])[C:17]([N:16]([CH2:15][C:11]1([OH:14])[CH2:10][CH2:9][N:8]([C:41](=[O:43])[C:40]2[CH:44]=[CH:45][C:37]([O:36][CH3:35])=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[CH2:13][CH2:12]1)[CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)CCN(CC1(O)CCN(Cc2ccccc2)CC1)C(=O)C(F)(F)F
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: COc1ccc(C(=O)N2CCC(O)(CN(CCC(C)C)C(=O)C(F)(F)F)CC2)cc1C(F)(F)F
Reaction time: 16 h
Yield: 56.7 %

Procedure:
Palladium (50.8 mg, 0.48 mmol) 10% on activated carbon and N-[(1-benzyl-4-hydroxy-4-piperidyl)methyl]-2,2,2-trifluoro-N-isopentyl-acetamide (112 mg, 0.29 mmol) in propan-2-ol (3 mL) was stirred under an atmosphere of hydrogen for 18 hours. The catalyst was filtered through Celite® and washed with MeOH. The organics were concentrated in vacuo to provide a clear oil. To the oil was added DMF (2 mL) and triethylamine (40 μL, 0.29 mmol) and this solution was added dropwise to a solution 4-methoxy-3-(trifluoromethyl)benzoic acid (64 mg, 0.29 mmol) and HATU (110 mg, 0.29 mmol) in DMF (1 mL). The reaction mixture was stirred for 16 hours. The solution was partitioned between water and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in MeOH and purified by reverse phase HPLC (Gilson 20-99% water/MeOH) to give 2,2,2-trifluoro-N-[[4-hydroxy-1-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-piperidyl]methyl]-N-isopentyl-acetamide (82 mg, 56%). ESI-MS m/z calc. 498.5. found 499.5 (M+1)+; Retention time: 1.86 minutes (3 min run).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:7]([NH:9][NH2:10])=[O:8]
Reactant: Cc1ccc(C(CCCCl)C(=O)NNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(CCCCl)C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (10 mL) was added to tert-butyl N′-(5-chloro-2-p-tolylpentanoyl)hydrazinecarboxylate (600 mg), and the reaction solution was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of 5-chloro-2-p-tolylpentanoic acid hydrazide hydrochloride. A solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (2.03 g) and triethylamine (1 mL) in ethanol (8 mL) was added to a solution of the resulting crude product of 5-chloro-2-p-tolylpentanoic acid hydrazide 2hydrochloride and triethylamine (0.87 mL) in ethanol (8 mL), and the reaction solution was stirred at 80° C. in a nitrogen atmosphere for 19.5 hours. The reaction solution was cooled to room temperature, and then the solvent was evaporated from the reaction solution under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=9:1) and further purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=9:1) to obtain 221 mg of a racemate of the title compound. The resulting racemate (100 mg) was separated by CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the title optically active compound with a retention time of 17 minutes and positive optical rotation (48.6 mg) and the title optically active compound with a retention time of 23 minutes and negative optical rotation (48 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)[OH:16].O.C(Cl)Cl>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[C:12]([OH:16])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
190 mg of α-(p-isobutylphenyl)-propionaldehyd are dissolved in 15 ml of acetone, and the solution cooled to -25° C is added to 220 ml of a solution containing 30 g chromiumtrioxide, 25 ml of concentrated sulfuric acid and water per 100 ml. The whole stirred for one hour at -25° C, the temperature was allowed to rise to about 0° C while stirring and then the reaction mixture was poured into a mixture of 20 ml water and 60 ml of methylene chloride. The two phases are separated and the watery phase washed two times with 30 ml of methylene chloride each time. The organic layers are dryed over magnesiumsulfat and evaporated. These were obtained 157 mg of α-(p-isobutylphenyl)-propionic acid, which melted after recrystallisation from few hexane at 74°-75.5°. This compound is known as "IBUPROFEN" and is used as antiinflammatory agent (cf. Brit. Pat. No. 971,700 and French Pat. No. 1,545,270).
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=CC(Cl)=CC=2)[C:6](=[O:15])[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[CH2:22]([NH:29]CCN)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCCO)C>>[CH2:22]([N:29]1[C:2]2=[CH:3][C:4]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:5][C:6](=[O:15])[N:7]2[CH2:8][CH2:13]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCNCc1ccccc1
Reactant: O=c1cc(-c2ccccc2)cc(Cl)n1-c1ccc(Cl)cc1
Solvent: CCOCCO
Product: O=c1cc(-c2ccccc2)cc2n1CCN2Cc1ccccc1

Procedure:
A mixture of 2 g. of 6-chloro-1-(4-chlorophenyl)-4-phenyl-2-pyridone, 2 g. of N-benzylethylenediamine, and 5 ml. of 2-ethoxyethanol was refluxed for 50 hours. Then, by treating the reaction mixture obtained as in Example 5, 0.5 g. of 1-benzyl-5-oxo-7-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5].C(OC(=O)[NH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(C)(C)C>>[ClH:1].[NH2:40][CH:41]1[CH2:46][CH2:45][N:44]([C:24](=[O:26])[CH2:23][NH:22][C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([S:13](=[O:15])(=[O:14])[NH:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:4](=[O:5])[C:3]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:2]=3[Cl:1])=[CH:28][CH:27]=2)[CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1
Product: Cl
Product: NC1CCN(C(=O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccccc3C(=O)c3ccc(Cl)cc3Cl)cc2)CC1

Procedure:
The title compound was prepared from {4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acid (Example 6.1/c)) and piperidin-4-yl-carbamic acid tert-butyl ester (Aldrich) according to the method described in Example 11.1. MS (EI) 589.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH3:13])[C:14](=[O:16])[O:15][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Benzyloxycarbonyl-L-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g) were suspended in toluene (190 mL), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the reaction mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and then saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, the resulting crystals were filtrated to give the title compound (19.0 g) as white crystals in an yield of 93%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][CH:12]1OC(C)OC(C)O1>>[CH3:11][CH:12]1[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[O:1]1
Reactant: CC1OC(C)OC(C)O1
Reactant: NC(=O)c1ccccc1O
Product: CC1NC(=O)c2ccccc2O1

Procedure:
2-Hydroxybenzamide was transformed by Method G (using paraldehyde). M.p. 124–126° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]#[CH:23])[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].C1(C=O)CCCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH2:11]([C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]#[C:23][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[CH2:20][CH2:21]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C#CC1CCC(CCCCC)CC1
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=CC1CCCCC1
Solvent: CCN(CC)CC
Product: CCCCC[C@H]1CC[C@H](C#Cc2ccc(C#N)c(F)c2)CC1
Reaction time: 12 h

Procedure:
0.2 mmol of bis-(triphenylphosphine)-palladium(II) chloride and 0.1 mmol of copper(I) iodide are added to a mixture of 0.01 mol of 2-fluoro-4-bromobenzonitrile, 0.01 mol of 4-pentylcyclohexylacetylene (which can be prepared, for example, from the corresponding cyclohexanecarbaldehyde by the method of Corey, Fuchs in Tetrahedron Letters (1972) 3769) and 40 ml of triethylamine at room temperature and the mixture is stirred for 12 hours. The reaction can be monitored with the aid of thin layer chromatography. When the reaction has ended, the suspension is filtered and the filtrate is evaporated. Purification by chromatography and/or crystallization gives 1-(trans-4-pentylcyclohexyl)-2-(3-fluoro-4-cyano- phenyl)-acetylene of M.=38° and C.=40.3°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([O:9]CC)=O.[OH-].[NH4+:13]>>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([NH2:13])=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)c1ocnc1C
Agent: [OH-]
Product: Cc1ncoc1C(N)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 4-methyloxazole-5-carboxylate (7.8 g, 50 mmoles) and ammonium hydroxide in a seal tube was stirred at rt for 12 hours. After completion of the reaction, solid was filtered and washed with water. The aqueous was extracted with ethyl acetate. The organic extract was dried and concentrated and combined with the filtered solid. Yield: 4.1 g (47%) 1H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H), 7.92 (s, 1H). LCMS: (ES+) m/z=126.7 (M)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([N+:22]([O-])=O)[CH:14]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(N(CC)CC)C.[CH3:32][CH:33](N)[CH2:34][OH:35].C(OCC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([NH:22][CH:33]([CH3:32])[CH2:34][OH:35])[CH:14]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: CC(N)CO
Reactant: Cn1nc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Cl)c1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(CO)Nc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
The dinitrobenzene obtained in Step A (10.0 g, 27.3 mmol) was dissolved in dimethylformamide (40 cm3). Triethylamine (4.6 cm3, 32.7 mmol) and DL 2-aminopropanol (2.6 cm3, 32.7 mmol) were added, and the mixture stirred at room temperature for 17 hours, then at 50° C. for 4 hours. The mixture was cooled to room temperature, poured into diethyl ether (200 cm3) and washed with water (3×200 cm3). The ether layer was collected, dried (MgSO4), filtered and the solvent removed under reduced pressure to give a waxy yellow solid. Recrystallisation (ethyl acetate/hexane) gave DL-2-[5-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol -3-yloxy)-2-nitrophenylamino]-propane-1-ol (8.71 g) as an orange solid. m.p. 118°-120° C.