Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:21]([O:23]C)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][C:16]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)O)CCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclopentane carboxylate (5.5 g, 15.6 mmol) in methanol:THF (4:1, 100 ml) 10 N sodium hydroxide (15 ml) was added at room temperature. It was stirred for 16 h and evaporated to dryness in vacuo, the residue was dissolved in 100 mL water, pH adjusted to 7 with 5N hydrochloric acid solution. It was extracted with chloroform;methanol (3:1) washed with water, dried and concentrated to give 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclopentane carboxylic acid. Yield 4.5 g (86%); White solid, mp. 108-110° C. Electrospray Mass Spec 336 (M−H)−.
Reaction SMILES: [O:1]([C:8]1[CH:19]=[CH:18][C:11]([O:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][N:15]1[CH2:16][CH2:17][C@@H:13]([O:12][C:11]2[CH:18]=[CH:19][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:14]1
Reactant: c1ccc(Oc2ccc(O[C@@H]3CCNC3)cc2)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCN1CC[C@@H](Oc2ccc(Oc3ccccc3)cc2)C1
Temperature: 60 °C
Yield: 59.2 %

Procedure:
(R)-3-(4-Phenoxy-phenoxy)-pyrrolidine (1.24 g, 4.25 mmol) was taken into anhydrous DMF (10 mL) in a nitrogen flushed 100 mL, 1-neck round bottom flask. Methyl-4-bromobutyrate (846 mg, 4.68 mmol) was added to the mixture followed by potassium carbonate (1.18 g, 8.5 mmol). The reaction was heated at 60° C. for 24 h. The mixture was then cooled to room temperature and partitioned between ethyl acetate and water. The water layer was washed with ethyl acetate (3×). The combined ethyl acetate layers were then washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was then purified by silica gel flash chromatography (20:1 silica ratio, eluted with 1:1 ethyl acetate and hexane) to obtain the title product (894.4 mg, 59%) LCMS; m/z 356 (M+1); 1H NMR (400 MHz, DMSO) δ 1.65-1.78 (m, 3H), 2.21-2.26 (m, 1H), 2.32-2.35 (m, 2H), 2.37-2.42 (m, 3H), 2.58-2.61 (m, 1H), 2.63-2.69 (m, 1H), 2.80-2.84 (m, 1H), 3.58 (s, 3H), 4.80 (s, 1H), 6.89-6.98 (m, 6H), 7.07-7.09 (m, 1H), 7.32-7.36 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C(C)=[N:48][O:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:45]([CH3:44])=[N:46][O:47][N:48]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cc1nonc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nonc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as light-yellow gum. MS(m/e): 379.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2O)=[CH:5][CH:4]=1.[ClH:14]>>[Cl:14][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)C(O)CCC2
Reactant: Cl
Product: COc1ccc2c(c1)C(Cl)CCC2

Procedure:
35.6 g (0.2 mol) of 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol (D. G. Thomas, A. H. Nathan J. Am. Chem. Soc. 79, 331, 1948) are stirred at ambient temperature for 3 hours in a liter of concentrated hydrochloric acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:14]([CH:18]([O:20][C:21](=[O:23])[CH3:22])[CH3:19])[CH2:15][S:16](=O)[C@H:11]12)=[O:8].P(Cl)(Cl)Cl>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:25])=[C:14]([CH:18]([O:20][C:21](=[O:23])[CH3:22])[CH3:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a cooled solution of 0.514 g. of benzhydryl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylate 1-oxide (isomer II from the previous example) in 15 ml. of dimethylformamide was added 0.190 ml. of phosphorous trichloride. The reaction mixture was removed from the ice-bath and allowed to warm to room temperature at which temperature it was stirred for one hour. The reaction mixture was then transferred with the aid of ethyl acetate to a separatory funnel and was then washed with aqueous sodium bicarbonate solution (2X), and brine (2X) and then dried over anhydrous sodium sulfate. Evaporation in vacuo provided a product which was chromatographed on a silica gel column using a toluene-ethyl acetate gradient to give 0.328 g. (65.5 percent) of the title product as a froth:
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([CH:17]([CH2:23][C:24]#[CH:25])[C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.C1(C)C=CC=CC=1>[CH3:3][C:2]1[NH:5][C:18](=[O:19])[C:17]([CH2:23][C:24]#[CH:25])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: CC(=N)N
Reactant: C#CCC(C(=O)OCC)C(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C#CCc1c(-c2ccccc2)nc(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.2 %

Procedure:
To a stirred suspension of 8.00 g (84.6 mmol) of acetamidine hydrochloride in 100 mL of methanol was added 4.56 g (84.4 mmol) of solid sodium methoxide. The mixture was stirred for 40 min at room temperature and rotovaped to remove the methanol. The residue was suspended in 75 mL of ethanol and a solution of 6.19 g (26.9 mmol) of ethyl 2-benzoyl-pent-4-ynoate in 75 mL of toluene was added. The mixture was heated to reflux with a Dean Stark trap and the first 80 mL of distillate was collected and discarded. An 80 mL portion of toluene was added and the mixture was heated at reflux for two weeks. The mixture was allowed to cool, diluted with 70 mL of ether and extracted with two 50 mL portions of 5% aqueous sodium hydroxide. The aqueous extracts were acidified to pH 1 and washed with two 75 mL portions of ethyl acetate. The pH of the aqueous phase was adjusted to 10 and the white precipitate that formed was collected by filtration. Drying furnished 1.76 g (29%) of 2-methyl-6-phenyl-5-propargyl-4(3H)-pyrimidinone, mp 220°-225° C., 1H-NMR (d6-DMSO) δ 2.3 (3H,s), 2.68(1H,t,J=4), 3.20(2H, d,J=4), 7.45(3H,m), 7.65(2H,m).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)[C:10]=1[C:11]([N:13]1[CH2:17][CH:16]2[CH2:18][N:19]([C:21](=[NH:23])[NH2:22])[CH2:20][CH:15]2[CH2:14]1)=[O:12].C[O-].[Na+].[F:36][C:37]([F:48])([F:47])[C:38](=O)[CH2:39][C:40](=O)[C:41]([F:44])([F:43])[F:42]>C(O)CCC>[F:36][C:37]([F:47])([F:48])[C:38]1[CH:39]=[C:40]([C:41]([F:42])([F:43])[F:44])[N:22]=[C:21]([N:19]2[CH2:18][CH:16]3[CH:15]([CH2:14][N:13]([C:11]([C:10]4[C:24]([N:28]5[N:32]=[CH:31][CH:30]=[N:29]5)=[CH:25][CH:26]=[CH:27][C:9]=4[F:8])=[O:12])[CH2:17]3)[CH2:20]2)[N:23]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: N=C(N)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC2CN(c3nc(C(F)(F)F)cc(C(F)(F)F)n3)CC2C1
Yield: 6.2 %

Procedure:
Crude 5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboximidamide—TFA salt (66 mg) was diluted with n-butanol (4 mL) and treated with sodium methoxide (51.9 mg, 0.961 mmol). The reaction is heated to reflux for 1 hour, then cooled and 1,1,1,5,5,5-hexafluoropentane-2,4-dione (400 mg, 1.92 mmol) is added prior to re-heating the reaction to reflux for 19 hours. The mixture was then cooled and concentrated, then diluted with DCM and saturated sodium bicarbonate. Extract with DCM and concentrate. Reverse phase HPLC gave the title compound (4.6 mg). MS (ESI): mass calculated for C21H16F7N7O, 515.39; m/z found 416.2 [M+H]+. Rotamers observed in 1H NMR.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[O:1]([CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCOc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCOc1ccccc1
Temperature: 0 °C
Yield: 95 %

Procedure:
3-Phenoxypropionic acid (10.0 g, 60 mmol) was dissolved in methanol (100 mL). The reaction mixture was allowed to cool to 0° C. and SOCl2 was slowly added over a 15 min period. The reaction mixture was slowly allowed to warm to room temperature over a 2 h period. The reaction mixture was concentrated in vacuo, then redissolved in ethyl acetate (100 mL). The organic layer was washed with water (2×150 mL), dried (MgSO4), concentrated in vacuo to provide crude product in 95% yield. 1H NMR (CDCl3)δ2.84 (t, J=6.4 Hz, 2H), 3.76 (s, 3H), 4.28 (t, J=6.4 Hz, 2H), 6.95 (m, 3H), 7.31 (m, 2H).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CCCCCC[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CO[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH2:41][CH2:40][CH2:39][CH2:38]2.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1>>[CH3:32][C:31]1[CH:26]=[CH:27][C:28]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:29][CH:30]=1
Reactant: COc1ccc2c(c1)CCCC2
Reactant: CCCCCCCCCCCCC
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1ccccc1-c1ccccc1C
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 60 °C
Yield: 76 %

Procedure:
In a reaction flask was placed NiCl2(PCy3)2 (61.2 mg, 0.0886 mmol), PCy3 (49.0 mg, 0.175 mmol), tridecane (255 mg, 1.386 mmol, as an internal standard), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (273 mg, 1.683 mmol). The Grignard reagent (1 M in THF, 5.0 mmol) was added to this mixture under a nitrogen atmosphere at room temperature. The resulting solution was warmed to 60° C. for 15 hours. A sample was withdrawn and quenched with an aqueous sodium citrate solution (1 M). The aqueous solution was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (1.272 mmol, 76% yield), bitoluene (0.50 mmol), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (0.357 mmol) in the reaction mixture.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:15].Br[CH2:17][C:18]([OH:20])=[O:19]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([O:14][CH2:17][C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]=1[F:15]
Reactant: O=C(O)CBr
Reactant: OC1(c2ccc(Cl)c(F)c2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COC1(c2ccc(Cl)c(F)c2)CCC1
Reaction time: 0.5 h

Procedure:
To an ambient suspension of NaH (0.341 g, 8.52 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (7 mL) was added a solution of Example 56A (0.342 g, 1.71 mmol) in N,N-dimethylformamide (1 mL) dropwise. The reaction was stirred for 0.5 h, and 2-bromoacetic acid (0.474 g, 3.41 mmol) was added as a solution in N,N-dimethylformamide (2 mL) dropwise. The reaction was stirred at room temperature for 24 h and was then quenched by the slow addition of H2O (10 mL) and diethyl ether (15 mL). The layers were separated, and the organic discarded. The aqueous was acidified to pH ˜4-5 with 10% HCl and was extracted with diethyl ether (3×15 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil, which was used without further purification in the subsequent step, MS (ESI) m/z 259[M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C@H:11]12[CH2:17][C@H:14]([NH:15][CH2:16]1)[CH2:13][N:12]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:15]2[CH2:16][C@@H:11]3[CH2:17][C@H:14]2[CH2:13][N:12]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc([N+](=O)[O-])nc1

Procedure:
5-Bromo-2-nitropyridine, prepared as described in (J. Am. Chem. Soc., (1945) 67, 668), and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), were coupled according to the procedure of Example 2A to provide the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=[CH:14][C:13]([CH:16]([N:18]([CH2:26][C:27](O)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:58][C:59]1[CH:60]=[CH:61][C:62]([C:73]([F:76])([F:75])[F:74])=[C:63]([C:65]([N:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)=[O:66])[CH:64]=1>CN(C=O)C.O>[C:22]([O:21][C:19](=[O:20])[N:18]([CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:11][CH:12]=1)[CH3:17])[CH2:26][C:27]([N:70]1[CH2:71][CH2:72][N:67]([C:65](=[O:66])[C:63]2[CH:64]=[C:59]([F:58])[CH:60]=[CH:61][C:62]=2[C:73]([F:76])([F:74])[F:75])[CH2:68][CH2:69]1)=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(c1ccc(-c2ccccc2)cc1)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(-c2ccccc2)cc1)N(CC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 25 %

Procedure:
DIPEA (182 mg, 0.24 mL, 1.4 mmol) was added to a stirred solution of [(1-biphenyl-4-yl-ethyl)-tert-butoxycarbonyl-amino]-acetic acid (100 mg, 0.28 mmol) in DMF (5 mL). HOBT (42 mg, 0.31 mmol) and EDCI (135 mg, 0.7 mmol) were then added at room temperature. After 2 minutes, (5-Fluoro-2-trifluoromethyl-phenyl)-piperazin-1-yl-methanone hydrochloride salt (105 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (using 60-120 silica gel and 30-50% EtOAc in hexane as eluent) to afford 43 mg (27.56% yield) of (1-biphenyl-4-yl-ethyl)-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester, LCMS Purity: 96.02%. 1H NMR (CDCl3): δ 7.78 (t 1H), 7.64-7.5 (s, 4H), 7.5-7.3 (m, 5H), 7.24 (d, 1H), 7.04 (m, 1H), 5.8-5.2 (bd, 2H), 4.0 (s, 1H), 3.8 (s, 3H), 3.6-3.2 (m, 5H), 3.1 (s, 3H), 1.5 (s, 9H).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:18][CH:19]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:34]([NH:41][C:42]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46](O)=[O:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N1CCC[C@H]1C(O)=O.C(N=C=O)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(N(CC)CC)C>[OH:18][CH:19]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:46]([C@@H:45]1[CH2:49][CH2:50][CH2:51][N:44]1[C:42]([NH:41][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:43])=[O:47])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Reactant: OC(COCc1ccccc1)[C@@H]1CCCN1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diphenylphosphoryl azide (259.2 g), triethylamine (80.8 g) and (S)-2-[1-hydroxy-2-(phenylmethyloxy)ethyl]pyrrolidine (176.6 g) were added to a solution of N-(benzylaminocarbonyl)-L-proline obtained by stirring L-proline (91.9 g), benzyl isocyanate (90.3 g) and triethylamine (80.8 g) in DMF (900 ml) at room temperature for 1 hour, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a 7% aqueous solution of citric acid and extracted with ethyl acetate. The extract was washed with water, saturated sodium hydrogenbicarbonate and water in order, dried over sodium sulfate, and concentrated to give the title compound (330.9 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.ClCC(=O)CC(OC)=O.FC1C=CC(N=C=O)=CC=1.[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][N:45]=2)[C:40]([CH:47]=O)=[CH:39]1.N1CCC[C@H]1C(O)=O>CC(O)C>[NH:38]1[C:46]2=[N:45][CH:44]=[CH:43][CH:42]=[C:41]2[C:40]([CH:47]=[C:11]2[O:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]2=[O:18])=[CH:39]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Agent: COC(=O)CC(=O)CCl
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C=Nc1ccc(F)cc1
Solvent: CC(C)O
Product: COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.25 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.26 g, y. 68%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][C:22](=[O:28])[NH:23]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(C)C>[N:11]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][C:22](=[O:28])[NH:23]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=C1CCc2c(cccc2OCCCN2CCN(Cc3ccccc3)CC2)N1
Solvent: CC(C)O
Product: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Yield: 107.5 %

Procedure:
(a)-2 5 grams of 5-[3-(4-benzylpiperazinyl)propoxy]-3,4-dihydrocarbostyril and 0.8 g of 5%-Pd charcoal are added into 150 ml of isopropanol and catalytically reduced at 60° C. for 5 hours under 3 atm. of hydrogen gas pressure. The catalyst is removed by filtration and the mother liquor thus obtained is concentrated under reduced pressure. The residue is recrystallized from ligroin-benzene to obtain 4.1 g of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril in the form of colorless prism-like crystals having a melting point of 195°-196° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].[CH:11](OCC)(OCC)OCC>OS(O)(=O)=O>[Cl:10][C:3]1[C:2]2[N:1]=[CH:9][N:8]([CH3:11])[C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(OCC)OCC
Reactant: CNc1ccnc(Cl)c1N
Agent: O=S(=O)(O)O
Product: Cn1cnc2c(Cl)nccc21
Reaction time: 0.38 h
Yield: 91.1 %

Procedure:
To a heterogeneous mixture of 3-amino-2-chloro-4-methylaminopyridine (5.9 g, 37 mmol) and triethyl orthoformate (12.92 mL, 87.2 mmol) was added 5 drops of conc. H2SO4. A short path distillation apparatus was attached. The reaction flask was lowered into a hot oil bath and stirred at 110° C. to 190° C. The time spent heating was 20-25 minutes. On cooling, the thick residue was dissolved in CH2Cl2 (40 mL) and was allowed to stir overnight with a little CaO. The solid was removed by filtration and the filtrate was concentrated. Flash chromatography on silica gel eluting with (CH2Cl2 /CH3OH, 95:5) gave 5.65 g (91%) of 4-chloro-1-methyl-1H-imidazo[4,5-c]pyridine as a light yellow solid: mp 127°-131° C.; MS 167 (M+).
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=O.[CH:15]([C:17]([CH2:19][CH3:20])=[O:18])=[CH2:16].Cl>CO>[CH3:16][C:15]1[C:17](=[O:18])[CH2:19][CH2:20][C:4]2([CH3:3])[C:5]=1[CH2:6][CH2:7][C:8]1[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)CC
Reactant: CC1C(=O)CCc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1=C2CCc3ccccc3C2(C)CCC1=O
Temperature: -15 °C
Reaction time: 4 h
Yield: 103.6 %

Procedure:
Potassium hydroxide in the amount of 2.24 g (40 mmol) was dissolved in 50 ml of 90 % methanol in 100-ml three-necked flask, and the obtained solution was then cooled with ice under agitation in a stream of nitrogen gas. A methanol solution (8 ml) containing 5.17 g (32 mmol) of 1-methyl-2-tetralone was added dropwisely to the above obtained solution over a period of 10 minutes. The reaction vessel was then cooled to -15° C., and 2.67 g (31 mmol) of ethyl vinyl ketone was added dropwisely to the reaction vessel. The temperature of the resulted mixture was brought to room temperature over a period of 4 hours under agitation in a stream of nitrogen gas. The mixture had been allowed to stand over night, and then the mixture was refluxed under heating for 3 hours in an atmosphere of nitrogen gas. After the temperature of the mixture had been brought to room temperature, the mixture was made acidic with hydrochloric acid and then extracted with ether. The ether layer was removed and washed with water, and then dried with sodium sulfate. The ether was distilled off to obtain 7.27 g of oily yellow residue. This residue was allowed to stand to obtain 5.54 g of crystals. These crystals were recrystallized twice from cyclohexane to obtain 3.95 g of colorless needle-like crystals.