Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CO)c(Cl)c1
Reaction time: 0.08 h
Yield: 51 %

Procedure:
The triflate compound (638 mg, 2 mmol) obtained in Step 1-2, palladium acetate (14 mg), 1,3-diphenylphosphinopropane (25 mg), methanol (4 ml) and triethylamine (0.6 ml) were dissolved in dimethylformamide (5 ml), and the obtained solution was stirred at 80° C. in carbon monoxide atmosphere for 16 hours. After leaving the reaction mixture to cool followed by the extraction with ethyl acetate/hexane and the purification by the silica gel column chromatography, methyl 2-chloro-4-t-butylbenzoate was obtained. The ester thus obtained was dissolved in dichloromethane (2 ml). 1 M solution (2.5 ml) of diisobutylaluminum hydride in toluene was added dropwise to the obtained solution at −78° C. in argon atmosphere, and the resulting solution was stirred at that temperature for 5 minutes. 0.5 M hydrochloric acid (20 ml) was added to the reaction mixture, and the temperature was elevated to room temperature. After the extraction with ethyl acetate followed by the purification by the silica gel column chromatography, 2-chloro-4-t-butylbenzyl alcohol (yield: 204 mg, 51%) was obtained.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.Cl.[SH:44][C@@H:45]1[CH2:49][N:48]([C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=2)=[O:51])[C@H:47]([CH:63]2[CH2:66][N:65]([CH3:67])[CH2:64]2)[CH2:46]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:18]([S:44][C@@H:45]3[CH2:49][N:48]([C:50]([O:52][CH2:53][C:54]4[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=4)=[O:51])[C@H:47]([CH:63]4[CH2:64][N:65]([CH3:67])[CH2:66]4)[CH2:46]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: CN1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Agent: Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CN(C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 80.5 %

Procedure:
The same procedure as in Example 49-1) was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (300 mg, 0.50 mmol) and (2S,4S)-4-mercapto-2-(N-methylazetidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride (195 mg, 0.50 mmol, compound of Reference Example 42) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(N-methylazetidin-3-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (280 mg, yield: 80% ).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[O:18][CH2:19][CH:20]([O:32][Si](C(C)(C)C)(C)C)[CH2:21][O:22][CH2:23][P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([O:40][CH3:41])[N:10]=1)=O)(C)(C)C>C(O)(=O)C>[NH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[O:18][CH2:19][CH:20]([OH:32])[CH2:21][O:22][CH2:23][P:24]([O:26][CH2:27][CH3:28])([O:29][CH2:30][CH3:31])=[O:25])=[C:11]([O:40][CH3:41])[N:10]=1
Reactant: CCOP(=O)(COCC(COn1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)O[Si](C)(C)C(C)(C)C)OCC
Solvent: CC(=O)O
Product: CCOP(=O)(COCC(O)COn1cnc2c(OC)nc(N)nc21)OCC
Yield: 74.6 %

Procedure:
A solution of 2-[bis(t-butoxycarbonyl)amino]-9-[2-(t-butyldimethylsilyloxy)-3-(diethoxyphosphorylmethoxy) propoxy]-6-methoxypurine (0.66 g, 0.91 mmol) in 80% acetic acid (25 ml) was stirred at 85° C. for 4 h. The solution was evaporated in vacuo and the residue chromatographed on silica, eluting with chloroformmethanol 25:1, affording 2-amino-9-[3-(diethoxyphosphorylmethoxy)-2-hydroxypropoxy)-6-methoxypurine (275mg, 75%) as a clear gum. νmax (film) 3460, 3340, 1640, 1580, 1460 and 1390 cm-1 ; δH (CDCl3) 1.34 (6H, t, J6.9 Hz, 2×CH3CH2), 3.75 (2H, m, CH2OCH2P), 3 89 (2H, d, J7.7 Hz, CH2P), 4.04 (1H, m, CHOH), 4.09 (3H, s, OCH3), 4.17 (4H, m, 2×CH3CH 2), 4.34 (2H, m, CH2ON), 5.09 (2H, br.s, D2O exchangeable, NH2), 7.78 (1H, s, H-8). Found: C, 40.67; H, 6.18, N, 16.54%; M+ 405.1413. C14H24N5O7P.0.5H2O requires C, 40.58; H, 6.08; N, 16.90%; M+ 405.1413.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[N:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: Cc1cccnc1Oc1cccc(C=C2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccnc1Oc1cccc(C=C2CCN(C(=O)Nc3cccnn3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
3-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Example 42, Step 5), phenyl pyridazin-3-ylcarbamate (335 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4CH):CH2Cl2) to afford the title compound (380 mg) as a white foam. MS (APCI 10V) AP+ 402.0, 281.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.33 (s, 3H) 2.46 (td, J=5.86, 0.80 Hz, 2H) 2.59 (td, J=5.71, 0.82 Hz, 2H) 3.52-3.62 (m, 2H) 3.64-3.71 (m, 2H) 6.44 (s, 1H) 6.84-6.94 (m, 2H) 7.03 (d, J=7.24 Hz, 1H) 7.05 (d, J=7.33 Hz, 1H) 7.34 (dd, J=8.78, 7.66 Hz, 1H) 7.59 (dd, J=9.15, 4.67 Hz, 1H) 7.66-7.73 (m, 1H) 7.87-7.96 (m, J=4.96, 1.22, 0.55, 0.55 Hz, 1H) 8.12 (d, J=8.97 Hz, 1H) 8.78 (d, J=4.26 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([O:24]CC)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+].C(O)COCCO.Cl>O>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(OCC)cn3)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Yield: 89.1 %

Procedure:
0.5 g (1.42 mM) of 2-octyl-5-(5-ethoxypyrimidine-2-yl)indan, 1.0 g (25 mM) of NaOH and 10 ml of diethylene glycol were mixed and refluxed for 3 hours under stirring. After the reaction, the reaction mixture was poured into water and acidified with HCl to precipitate a crystal. The crystal was recovered by filtration and washed with water. The resultant crystal was dissolved in toluene and washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=1/10) to obtain 0.41 g of 2-octyl-5-(5-hydroxypyrimidine-2-yl)indan (Yield: 89.0%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(#N)C.[Cu]I.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:4][N:3]=1
Reactant: Cc1c(I)cnc(N)c1C#N
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: Cc1c(C#C[Si](C)(C)C)cnc(N)c1C#N

Procedure:
In another variation in the method to the 2,4-diamino-5,6-disubstituted-5-deazapteridines described above, 2-amino-3-cyano-5-iodo-4-methylpyridine is reacted with trimethylsilylacetylene in the presence of copper(I) iodide and bis(triphenylphosphine)palladium(II) chloride under basic conditions in acetonitrile, affording 2-amino-3-cyano-4-methyl-5-(trimethylsilylethynyl)pyridine. The 5-(trimethylsilylethynyl)pyridine is in turn treated with potassium carbonate in methanol, yielding the corresponding 2-amino-3-cyano-4-methyl-5-ethynylpyridine. The 5-ethynylpyridine is then reacted with an appropriately substituted halide, for example, 4-trifluoromethylphenyl iodide, again in the presence of copper(I)iodide and bis(triphenylphosphine)palladium(II) chloride under basic conditions in acetonitrile, yielding a 2-amino-3-cyano-4-methyl-5-(substituted-ethynyl)pyridine, for example, 2-amino-3-cyano-4-methyl-5-[(4-trifluoromethylphenyl)ethynyl]pyridine. The so-prepared pyridine is then cyclized and hydrohalogenated with chloroformamidine hydrochloride in diglyme, affording the corresponding 2,4-diamino-5-methyl-6-[1-chloro-2-substituted-ethenyl]-5-deazapteridine, for example, 2,4-diamino-5-methyl-6-[1-chloro-2-(4-trifluoromethylphenyl)ethenyl]-5-deazapteridine. Cyclizations with an appropriately substituted 2-amino-3-cyanopyridine and chloroformamidine hydrochloride in diglyme are taught by N. V. Harris et al (J. Med. Chem. 1990, 33, 434-444). Example 10 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C[Li].[CH2:18](OCC)C.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH:12]([OH:13])[CH3:18])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)nc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(Br)cc2)nc1
Reaction time: 1 h
Yield: 60 %

Procedure:
6-(4-Bromophenyl)nicotinaldehyde (3.2 g, 12 mmol) was dissolved in tetrahydrofuran (50 mL), and a solution of methyllithium in diethyl ether (1.0 M, 15 mL, 15 mmol) was added dropwise at −78° C. under a nitrogen atmosphere, followed by stirring at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.30 (hexane/ethyl acetate=2/1) by thin layer chromatography was concentrated under reduced pressure to afford 1-[6-(4-bromophenyl)pyridin-3-yl]ethanol (2.0 g, 7.2 mmol) as a white solid (yield 59%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:5](=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:3]#[N:4].[C-]#N.[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[O:28][CH3:29].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([C:24](=[O:25])[CH:7]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH2:6][C:5](=[O:14])[C:2]([CH3:15])([CH3:1])[C:3]#[N:4])=[CH:22][C:21]=1[O:28][CH3:29]
Reactant: COc1cc(C=O)ccc1Cl
Reactant: CC(C)(C#N)C(=O)C=Cc1ccncc1
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)C(CC(=O)C(C)(C)C#N)c2ccncc2)ccc1Cl
Reaction time: 0.25 h
Yield: 222.9 %

Procedure:
A solution of the product of Example 1 Step 1 (4.0 g, 20.0 mmol) in DMF (7 ml) was added to a solution of sodium cyanide (300 mg, 6.12 mmol) in DMF (7 ml) over 15 minutes at room temperature. After stirring for a further 15 minutes, a solution of 4-chloro-3-methoxy-benzaldehyde (F. Claudi et al., J. Med. Chem., 1992, 35, 4408) (640 mg, 3.75 mmol) in DMF (6 ml) was added dropwise. The mixture was stirred at room temperature for 18 hours and then diluted with water and the pH of the solution adjusted to 9 with aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform and the organic phase washed with water and brine, dried and concentrated in vacuo. The residue was chromatographed on silica gel eluting with chloroform/ethanol/0.880 ammonia solution (90:9:1) to give the title compound (3.1 g, 42%); MS (ES+) m/e 371, 373 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][CH:12]=2)[C:8]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: C#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 56.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-ethynyl-phenyl)-propionic acid (121 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 24 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-ethynyl-phenyl)-N-thiazol-2-yl-propionamide (92 mg, 56.8%) as a white solid: mp 181-183° C.; EI-HRMS m/e calcd for C19H20N2OS (M+) 324.1296, found 324.1295.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:16]I>C(Cl)Cl>[I:16][C:13]1[CH:14]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=[CH:11][C:12]=1[OH:15]
Reactant: II
Reactant: CCCCCCCCc1ccc(O)cc1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(O)c(I)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A mixture of 4-octyl phenol (0.15 g, 0.73 mmol), CF3CO2Ag (0.25 g, 1 mmol) and I2 (0.185 g, 0.73 mmol) in CH2Cl2 (10 ml) was stirred for 0.5 h at 0° C., then for 0.5 h at room temperature. The solution was filtered through Celite bead and washed with CH2Cl2 (30 ml). The filtrates were evaporated to dryness to give the title compound (0.21 g, 87%) as fawn oil. 1H NMR (CDCl3) 7.32 (d, 1H, J=8.34 Hz); 7.28 (d, 1H, J=1.26 Hz); 6.98 (dd, 1H, 8.37, 1.71 Hz); 6.62 (s, 1H); 4.69 (t, 2H, J=5.88 Hz); 3.62-3.38 (m, 4H); 2.59 (t, 2H, J=7.29 Hz); 1.56-1.51 (m, 2H); 1.34-1.2 (m, 10H); 0.81 (t, 3H, J=6.48 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH2:22]([O:25][C:26]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:30][C:29]2[CH:28]=[C:27]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:26]([O:25][CH2:22][CH2:23][CH3:24])=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: CCCOc1c(-c2ccccc2)cc(N)cc1-c1ccccc1
Solvent: Cc1ccccc1
Product: CCCOc1c(-c2ccccc2)cc(N=C(C)c2cccc(C(C)=Nc3c(C)cc(C)cc3C)n2)cc1-c1ccccc1
Reaction time: 24 h

Procedure:
2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-acetylpyridine (387 mg, 1.38 mmol) and 4-propoxy-3,5-diphenylaniline (440 mg, 1.45 mmol) were dissolved in 50 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 1 day the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from cold ethanol. The product was isolated as a yellow treacle (700 mg) and used as such.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([C:20]([F:21])([F:22])[F:23])[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=1[C:9]([NH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[N:1]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26]
Reactant: BrCCCCCBr
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCCCC1

Procedure:
The title compound, white solid, MS: m/e=453.2 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1,5-dibromopentane.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C([Li])CCC.[CH3:13][O:14][C:15](=[O:43])[C:16]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)=[CH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1>C1COCC1>[CH3:13][O:14][C:15](=[O:43])[C:16]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH:5]3[S:1][C:2](=[O:7])[NH:3][C:4]3=[O:6])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)=[CH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CBr)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,4-Thiazolidinedione (2.83 g, 24.2 mmol) was dissolved in dry THF (170 mL) and cooled to 0° C. under argon. Butyllithium (1.6 M in hexanes, 30 mL, 48.0 mmol) was added dropwise. Stirring continued for 0.5 h at 0° C. Under argon, 13 (5.7 g, 11.8 mmol) was dissolved in dry THF (30 mL) and was added rapidly via syringe to the above suspension with rapid stirring. The temperature was maintained at 0° C. for 45 min before quenching with aqueous HCl (5%, 40 mL). Additional H2O (40 mL) was added and extracted with ethyl acetate (3×30 mL). Organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. Flash chromatography over silica gel using hexanes-ethyl acetate (3:2) as eluting solvent yielded the title compound, 11, (0.93 g, 15%). The melting point and 1H NMR of compound 11 made by this method were identical to those for compound 11 produced by the synthetic route starting from compound 10 described above.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.[OH-].[Li+]>C1COCC1.O>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)Cn1ccc2ccc(C(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1ccc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Methyl 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetate (120 mg, 0.467 mmol) was dissolved in a mixture (1/1) of THF/H2O (4 ml), and lithium hydroxide (112 mg, 4.67 mmol) was added. The mixture was stirred at room temperature for 2 hours. The organic solvent was evaporated and 2N HCl was added to the resulting mixture (pH=5). The precipitate was collected by filtration affording 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetic acid (90 mg, 0.370 mmol, 79% yield). MS/ESI+ 244.0 [MH]+.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH:24]1[O:28][C:27](=[O:29])[N:26]([CH3:30])[CH2:25]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:8])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH:24]3[O:28][C:27](=[O:29])[N:26]([CH3:30])[CH2:25]3)[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C(O)C(=O)O
Product: CN1CC(CCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)OC1=O

Procedure:
Following the procedure of Example 1, α,α-diphenyl-4-piperidinemethanol and 5-(2-chloroethyl)-3-methyl-2-oxazolidinone are reacted and the product thereof is reacted with oxalic acid to give the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1.O>C(Cl)Cl>[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([N:9]([CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][CH2:11][CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:36])[CH:29]=1
Reactant: c1ccc(C(CCNCCC2CCCCC2)c2ccccc2)cc1
Reactant: COC(=O)c1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(NC(=O)N(CCC2CCCCC2)CCC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
46 mg of (2-cyclohexyl-ethyl)-(3,3-diphenyl-propyl)-amine (0.147 mmol, 1 eq) were diluted in 1 mL of DCM. 30 mg (0.172 mmol, 1.2 eq) of 3-isocyanato-benzoic acid methyl ester were then added to the mixture. The reaction mixture was stirred at room temperature for 90 min before adding water, then the aqueous phase was extracted with DCM. The organic phase was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel (eluant: gradient Hept/EtOAc 5/1). 63 mg of the desired urea were obtained. MS (ES+): 499.5+ (M+H)+. TLC: Rf: 0.57 (eluant: heptane/EtOAc: 1/1).