Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]([CH3:27])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[C:33](O)=[O:34].S(Cl)(Cl)=O>C(N(CC)CC)C>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][N:17]([CH2:18][C:19]([CH3:27])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33](=[O:34])[C:32]2[CH:31]=[C:30]([O:29][CH3:28])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=Cc1ccccc1)CNCCCN1CCN[C@@H](Cc2ccccc2)C1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)N(CCCN2CCN[C@@H](Cc3ccccc3)C2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 7 %

Procedure:
Experimental condition similar to Example 18 were used with [3-(S)-(3-benzyl-piperazin-1-yl)-propyl]-(2-methyl-3-phenyl-allyl)-amine (prepared from (S)-2-benzyl piperazine described on scheme 11) 0.08 g (0.24 mmol), 3,4,5-trimethoxy benzoic acid 0.05 g (0.24 mmol), thionyl chloride 0.02 ml (0.46 mmol) and triethylamine. The free amine after purification was transformed to HCl salt, yielding 45 mg of a brown, semi-solid salt. Yield: 7%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]([CH3:17])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[N-:23]=[N+:24]=[N-:25].[Na+].[CH:27](OCC)(OCC)OCC.O>C(O)(=O)C.C(OCC)(=O)C>[CH3:17][C:15]1[N:16]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([N:1]3[CH:27]=[N:25][N:24]=[N:23]3)[CH:3]=2)[S:13][C:14]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1sc(-c2ccc(OC(C)C)c(N)c2)nc1C
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(OC(C)C)c(-n3cnnn3)c2)nc1C
Temperature: 70 °C
Yield: 78.8 %

Procedure:
A suspension was prepared by suspending 1.23 g of ethyl 2-[3-amino-4-(propan-2-yloxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 20 mL of acetic acid. A reaction mixture solution prepared by adding 478 mg of sodium azide and 1.09 g of triethyl ortho formate to the suspension was heated at 70° C. for 2 hours under a nitrogen atmosphere. After cooling the reaction mixture solution to room temperature, water was added to the reaction mixture solution, and extraction was performed using ethyl acetate. The organic layer was washed with saline, dried and concentrated under reduced pressure and purified by a conventional method to obtain 1.13 g of ethyl 4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: [Cl-].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:10]=1)(=[O:4])[CH3:3].CC(C)([O-])C.[K+].[CH:37]([C:39]1[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=1)=O.O>CN(C)C=O>[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH:11]=[CH:37][C:39]2[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=2)[N:10]=1)(=[O:4])[CH3:3]
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: CC(=O)Nc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)s2)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
To a solution of {[2-(acetylamino)-1,3-thiazol-4-yl]methyl}(triphenyl)phosphonium chloride (3.771 g, 8.325 mmol) in anhydrous N,N-dimethylformamide (35 ml) was added potassium tert-butoxide (2.515 g, 22.41 mmol) at 0° C., and the mixture was stirred for 15 min. 5-Formylthiophene-2-carboxylic acid (1.000 g, 6.404 mmol) was added by small portions, and the mixture was stirred at 0° C. for 30 min. The mixture was warmed to room temperature, stirred for 2 hr, and poured into iced water (300 ml). After stirring for 30 min, the mixture was washed twice with ethyl acetate. The aqueous layer was cooled to 0° C., and adjusted to pH 3 by dropwise addition of 6M hydrochloric acid. After stirring at 0-5° C. for 2 hr, the precipitated crystals were collected by filtration, washed 3 times with water, and twice with diisopropyl ether and dried under reduced pressure to give 5-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}thiophene-2-carboxylic acid (1.104 g, 3.751 mmol, yield 58.6%) as a yellow ocher solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([Cl:10])=[CH:5][N:4]=1.[CH3:11][NH2:12].C1CCCCC1.C(OCC)(=O)C>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:12][CH3:11])[C:6]([Cl:10])=[CH:5][N:4]=1
Reactant: CSc1ncc(Cl)c(Cl)n1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CCO
Product: CNc1nc(SC)ncc1Cl

Procedure:
Prepared from 2-methylsulphenyl-4,5-dichloro-pyrimidine by reacting with methylamine in ethanol at 90° C., melting point: 241° C., Rf value: 0.59 (silica gel; cyclohexane/ethyl acetate=2:1)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]([OH:25])=O)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH2:26]([NH:33][CH2:34][CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:22][C:23]([N:33]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:34][CH3:35])=[O:25])=[CH:4][CH:3]=1
Reactant: CCNCc1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc(N)nc2)cc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(6-amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[N:41][CH:42]=1.[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([CH2:57]O)[CH:53]([C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)[CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([CH2:57][O:43][C:40]2[CH:39]=[CH:38][C:37]([Cl:36])=[CH:42][N:41]=2)[CH:53]([C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)[CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: OCC1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(C2CN(Cc3ccccc3)CCC2COc2ccc(Cl)cn2)cc1
Reaction time: 0.33 h

Procedure:
In a 100 mL four necked round bottom flask with a magnetic stirrer and inert atmosphere 1.3 g polymer bound triphenylphosphine was stirred in 15 mL THF. At 0-5° C. a solution of 514 mg (2.23 mmol) di-tert-butyl azodicarboxylate in 8 mL THF and a solution of 271 mg (2.1 mmol) 5-chloro-2-hydroxypyridine in 10 mL THF was added. The mixture was stirred for 20 min at 0° C.-5° C. 441 mg (1.4 mmol) [(3RS, 4RS)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-methanol in 8 mL THF was added. The ice bath was removed and the brownish mixture was stirred for 2 h at room temperature. The mixture was filtrated over decalite and washed with ethyl acetate. The solvents were evaporated and the residue purified by column chromatography on silica gel eluting with ethyl acetate/toluene to yield after evaporation of the product containing fractions 0.3 g (50%) of the title compounds as white solid. MS (m/e): 298.3/427.1 [(M+H)+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8].Br[CH2:18][C:19]#[CH:20]>CC(C)=O>[C:7]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:20][C:19]#[CH:18])[CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCC(C(C)(C)C)CC1
Temperature: 0 °C
Yield: 83.6 %

Procedure:
Anhydrous potassium carbonate (196 g) was added to a solution of 4-tert-butylpiperidine (98.9 g) in anhydrous acetone (1.2 liters) and the resulting suspension was cooled to 0° C., with stirring under an inert atmosphere. A solution of 1-bromoprop-2-yne (87.5 g) in anhydrous acetone (100 ml) was then added dropwise, the temperature being maintained below 5° C. The reaction mixture was then stirred at ambient temperature for 24 hours, filtered and the filtrate was evaporated under reduced pressure (water-pump). The residual oil thus obtained was extracted with petroleum spirit (b.p. 40°-60° C.). The resulting solution was treated with decolourizing charcoal, filtered and the filtrate was evaporated to give 4-tert-butyl-1-(prop-2-ynyl)piperidine (105 g), m.p. 48°-49° C., which may be further purified by distillation under reduced pressure (water-pump) (b.p. 108°-110° C./15 mm Hg) or by sublimation under reduced pressure (water-pump) at 80° C./20 mm Hg.
Reaction SMILES: N#CN.C(O)(=O)C.[NH2:8][C:9]1[N:10]=[C:11]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=2)[S:12][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](F)[CH:17]=1)=[O:15].BrCC(C1C=CC=C([C:48]([F:51])([F:50])[F:49])C=1)=O>>[NH2:8][C:9]1[N:10]=[C:11]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:26][CH:25]=2)[S:12][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:48]([F:51])([F:50])[F:49])[CH:17]=1)=[O:15]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: Nc1nc(Nc2ccc(OCCN3CCCC3)cc2)sc1C(=O)c1cccc(F)c1
Agent: N#CN
Solvent: CC(=O)O
Product: Nc1nc(Nc2ccc(OCCN3CCCC3)cc2)sc1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
This compound was prepared from cyanamide, 1-[2-(isothiocyanato-phenoxy)-ethyl]-pyrrolidine of Example 118 and 2-bromo-1-(3-trifluoromethyl-phenyl)-ethanone of Example 127 following a procedure similar to Example 123. Mass spectrum (ES) MH+=477.
Reaction SMILES: [CH2:1]([CH:8]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH:9]([OH:14])[CH2:10][N+]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+].S(=O)(=O)(O)O.C(Cl)Cl.[CH3:37][OH:38]>>[CH2:1]([C@H:8]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[C@H:9]([OH:14])[CH:10]([O:38][CH3:37])[O:27][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1ccccc1)C(O)C[N+](=O)[O-]
Reactant: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 49 %

Procedure:
A suspension of 1.02 g of an 87:13 mixture of the (1S,2R) and (1S,2S) isomers of 2-(1-benzyl-2-hydroxy-3-nitropropyl)-2,3-dihydro-1H-isoindole-1,3-dione in 2 ml of methanol is treated at 0° with 5.7 ml of a 7% solution of sodium methylate in methanol and the resulting yellow solution is added dropwise over a period of 20 minutes to a solution, cooled to -350°, of 7.2 ml of sulfuric acid in 27.6 ml of methanol. The reaction mixture is subsequently added to a stirred mixture of 150 ml of methylene chloride and 70 ml of ice-water and the aqueous phase is extracted with methylene chloride. The combined methylene chloride phases were dried, filtered and concentrated, and the residue was purified on silica gel with hexane/ethyl acetate (3:1). After evaporation and drying there is obtained 0.52 g (49%) of pure (1S,2S)-2-(1-benzyl-2-hydroxy-3,3-dimethoxypropyl)-2,3-dihydro-1H-isoindole-1,3-dione as a colourless oil, IR (film): 3465 m (OH), 1772 s and 1708 s (C=O of imide), 1071 s (C--O--C).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([O-:37])=[O:36].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][CH2:22][C:23]([O:25][CH2:42][C:41]2[CH:44]=[CH:45][C:38]([N+:35]([O-:37])=[O:36])=[CH:39][CH:40]=2)=[O:24])=[O:11])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)S[C@H]1C[C@@H](CCC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-(2-carboxyethyl)-4-acetylthiopyrrolidine (323 mg) was dissolved in 3.3 ml of dry dimethylformamide, and 150 mg of triethylamine and 324 mg of p-nitrobenzyl bromide were added thereto, followed by stirring at room temperature for 3.5 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate, washed successively with a saturated sodium bicarbonate solution, water, dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and distilled off to remove the solvent. The residue was purified by silica gel column chromatography to obtain (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(2-p-nitrobenzyloxycarbonylethyl)-4-acetylthiopyrrolidine.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][NH:10][CH3:11])[N:8]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH:29]([CH3:31])[CH3:30])[NH:16][C:17]([O:19]C1C=CC([N+]([O-])=O)=CC=1)=O.C(N(CC)CC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH:29]([CH3:30])[CH3:31])[NH:16][C:17]([N:10]([CH3:11])[CH2:9][C:7]1[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[S:5][CH:6]=1)=[O:19]
Reactant: CNCc1csc(C(C)C)n1
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Yield: 72.1 %

Procedure:
A solution of 15.7 g (92 mmol) of 2-isopropyl-4-(((N-methyl)amino)methyl)thiazole in 200 ml of THF was combined with a solution of 20.5 g (69 mmol) of N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester. The resulting solution was treated with 1.6 g of 4-dimethylaminopyridine and 12.9 ml (92 mmol) of triethylamine, heated at reflux for 2 h, allowed to cool, and concentrated in vacuo. The residue was taken up in CH2Cl2, washed extensively with 5% aqueous K2CO3, dried over Na2SO4, and concentrated in vacuo. The resulting product mixture was purified by silica gel chromatography using chloroform as an eluent to provide 16.3 g (54%) of the desired compound. 1H NMR (DMSO-d6) δ 0.88 (d, J=7 Hz, 3 H), 0.92 (d, J=7 Hz, 3 H), 1.32 (d, J=7 Hz, 3 H), 2.05 (octet, J=7 Hz, 1 H), 2.86 (s, 3 H), 3.25 (heptet, J=7 Hz, 1 H), 3.61 (s, 3 H), 3.96 (dd, J=8, 7 Hz, 1 H), 4.44 (AA', 2 H), 6.58 (d, J=8 Hz, 1 H), 7.24 (s, 1 H). Mass spectrum: (M+H)+ =328.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.CO.[NH3:14]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([O-:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[NH4+:14]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: N
Solvent: CO
Product: Nc1ccc(Cl)cc1C(=O)[O-]
Product: [NH4+]
Reaction time: 2 h
Yield: 95 %

Procedure:
In a 50 mL volume glass vessel equipped with a stirrer and a thermometer were placed 5.0 g (29.1 mmol) of 5-chloroanthranilic acid and 20 mL (156 mmol) of 15 wt. % ammonia methanol solution. The reaction was carried out for 2 hours at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, to obtain 5.0 g (isolated yield: 95%) of ammonium 5-chloroanthranilate as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:38]=1[NH2:39].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:38]=1[NH:39][C:24]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:26]
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Yield: 90.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (56 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (66 mg) was added, and the admixture was refluxed with heat for 3 minutes. 2,5-Dimethoxyaniline (102 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 10 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 81 mg of the title compound (yield: 90%).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3]O.S(Cl)([Cl:14])=O>>[CH3:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][Cl:14]
Reactant: C[C@H](CO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: C[C@H](CCl)Cc1ccccc1

Procedure:
In accordance with the general procedure described in Example 8 (a), 22.5 g (0.15 mol) of (S)-2-methyl-3-phenylpropanol are reacted with 20.2 g (0.17 mol) of thionyl chloride, and the crude product is distilled under a high vacuum (18 torr) to give (b) (b.p. 110°-112° C.) as a colourless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.[CH3:10]O>>[CH3:10][O:8][C:7]([CH:5]1[CH2:4][CH2:3][C:2](=[O:1])[NH:6]1)=[O:9]
Reactant: CO
Reactant: O=C1CCC(C(=O)O)N1
Product: COC(=O)C1CCC(=O)N1
Yield: 90 %

Procedure:
A mixture of 5-oxo-pyrrolidine-2-carboxylic acid (5 g, 38.7 mmol) and Amberlyst® 15 (5 g) in MeOH (50 ml) was refluxed for 20 hours. After cooling, the reaction was filtered and the solvent removed under vacuum to afford the title compound (4.9 g, 90% yield) that was used without further purification in the next step.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.Cl.Cl.Cl.[N:52]1([CH2:56][CH2:57][N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C.O>CN(C)C=O>[N:52]1([CH2:56][CH2:57][N:58]2[CH2:59][CH2:60][N:61]([C:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][CH:27]=4)[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:62][CH2:63]2)[CH2:53][CH2:54][CH2:55]1
Reactant: C1CN(CCN2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCN(CCN2CCC2)CC1
Reaction time: 20 h
Yield: 51.2 %

Procedure:
[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 1-[2-(azetidin-1-yl)ethyl]piperazine trihydrochloride (64.6 mg), triethylamine (0.129 ml) and water (0.100 ml) were added thereto in this order, followed by stirring for 20 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (23.8 mg, 51.2%).
Reaction SMILES: [CH:1](=[N:10][OH:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C(=O)N([Cl:19])C(=O)C1>CN(C=O)C>[OH:11][N:10]=[C:1]([Cl:19])/[CH:2]=[CH:3]\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=CC=Cc1ccccc1
Solvent: CN(C)C=O
Product: ON=C(Cl)/C=C\c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cinnamaldoxime (10 g, 68 mmol) in DMF (100 mL) at room temperature was added solid NCS (9.08 g, 68 mmol). The suspension was stirred at room temperature overnight. The reaction mixture was poured into ice-water, extracted with a mixture of ethyl acetate and hexanes (7:3, 3×), dried with Na2SO4, concentrated and dried in vacuum to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[N:21][CH:22]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])=[N:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridylmethyl]-1H-pyrazol-4-yl]propionate (638 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (495 mg, yield: 82%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 143–144° C.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([N+:12]([O-])=O)[CH:5]=1>O.CO.[Zn]>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([CH:5]=1)[NH2:12]
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CCc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of ammonium chloride (12.5 g, 0.2 mol) in water (30 ml) is added to a mixture of zinc dust (35.7 g, 0.5 mol) and 4-bromo-1-ethyl-2-nitrobenzene (18 g, 0.07 mol) in methanol (720 ml) and water (180 ml). The reaction mixture is refluxed for one hour, then cooled to room temperature and filtered through a plug of diatomaceous earth. The filtrate is concentrated in vacuo, then diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo to yield 5-bromo-2-ethylaniline (14 g), used without further purification in the next step.