Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[C:23]([F:40])=[CH:24][C:25]([F:39])=[C:26]([NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=5)=[O:30])[CH:27]=4)[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=CC=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH2:19]([N:16]1[C:17]2[C:12](=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=2)[CH:13]=[C:14]([C:22]2[C:23]([F:40])=[CH:24][C:25]([F:39])=[C:26]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[O:30])[CH:27]=2)[C:15]1=[O:21])[CH3:20]
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2F)cc2cnc(NC)cc21
Yield: 42.2 %

Procedure:
A solution of 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (267 mg, 0.421 mmol) in TFA (3 mL) was stirred at RT for 40 min. The mixture was evaporated at reduced pressure, dissolved in EtOAc, washed with satd. NaHCO3, then brine, dried (Na2SO4), concentrated in vacuo, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and partially concentrated to give an aqueous solution. The aqueous solution was diluted with satd. NaHCO3 and allowed to precipitate. The white solid was collected by filtration, washed with water and dried in vacuo to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (83 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.50 (br s, 1H), 8.80 (br s, 1H), 8.42 (s, 1H), 8.10-8.00 (m, 1H), 7.82 (s, 1H), 7.48 (d, 1H), 7.40-7.30 (m, 2H), 7.15-7.05 (m, 2H), 6.80-6.70 (m, 1H), 5.99 (s, 1H), 4.13 (m, 2H), 2.85 (s, 3H), 1.21 (m, 3H); MS (ES-API) m/z: 468.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([C:12]2[NH:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[O:11][C:10]([C:12]3[NH:13][CH:14]=[CH:15][CH:16]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(NNC(=O)c1ccc[nH]1)c1ccc(Br)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1ccc(-c2nnc(-c3ccc[nH]3)o2)cc1
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
To 1.2 g of N′-(4-bromobenzoyl)-1H-pyrrole-2-carbohydrazide (3.89 mmol) was added 5 ml phosphoryl trichloride (1.65 mmol). The reaction was stirred for 25 minutes at 120° C. The reaction was cooled to 0° C., and ice was added. The resulting solid was filtered, and washed with water, NH4OH, dichloromethane and ethyl acetate. Purification by silica gel chromatography (dichloromethane:methanol=9:1) resulted in the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.05-8.00 (m, 2H), 7.89-7.83 (m, 2H), 7.18 (td, J=1.5, 2.6, 1H), 6.97 (ddd, J=1.5, 2.4, 3.7, 1H), 6.33 (dt, J=2.4, 3.6, 1H). 13C NMR (400 MHz, DMSO-d6) δ 110.16, 112.49, 115.12, 122.71, 123.96, 125.23, 128.26, 132.49, 159.37, 161.57.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([N:10]1C(=O)C2C(=CC=CC=2)C1=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.NN>CO>[F:1][CH2:2][C@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:10]
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CF)c1ccccc1
Agent: NN
Solvent: CO
Product: N[C@H](CF)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-(2-fluoro-1-phenylethyl)isoindoline-1,3-dione (290 mg, 1.077 mmol) in MeOH (3.59 mL) was added hydrazine (0.507 mL, 16.15 mmol). The reaction mixture was stirred at 80° C. for 3 h. The white precipitate was filtered off. The filtrate was concentrated to yield the crude (S)-2-fluoro-1-phenylethanamine, which was used in next step without further purification. LCMS (m/z): 140.1 (MH+), 0.28 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.43-7.34 (m, 4H), 7.34-7.27 (m, 1H), 4.57 (dd, J=3.7, 8.8 Hz, 1H), 4.49-4.38 (m, 1H), 4.38-4.32 (m, 1H), 4.32-4.25 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])O.[Na+].Br[CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][Br:23])[C:16](Br)=[O:17]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:15]1[C:16](=[O:17])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: O=C(Br)C(Br)CCCCBr
Reactant: Nc1ccccc1S
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2SC1CCCCBr
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
9.25 g (=0.07 m) of 2-aminothiophenol, 27.9 g of benzyltrimethylammonium chloride, and 25 g of sodium hydrogen carbonate were introduced into 150 ml of chloroform with stirring. The resulting suspension was cooled to -5° C., and a solution of 25.3 g of 2,6-dibromocaproic acid bromide in 70 ml of chloroform was added slowly with stirring to the cooled suspension. The addition took 30 minutes, and the temperature varied between -5° C. and +5° C. The mixture was maintained in this temperature range for a further hour. The mixture was then heated under reflux for 7 hours. Afterward it was cooled, filtered and the chloroform was distilled off from the filtrate. The remaining residue was treated with water and toluene. The organic phase was separated, dried, and fractionated by column chromatography. The fraction containing 2-(4-bromobutyl)-2H-1,4-benzothiazine-3(4H)-one was separated. After crystallization in the presence of diethyl ether, 5.9 g of 2 -(4-bromobutyl)-2H-1,4-benzothiazine-3(4H)-one were obtained from this fraction as slightly beige-colored crystals having a melting point of 100° C.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+].CCCCCC>CO.C(OCC)(=O)C>[C:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccc(C2=NCCN=C2c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(Cc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Yield: 91.3 %

Procedure:
In 20 ml of methanol were dissolved 2.570 g of 2,3-diphenyl-5,6-dihydropyrazine, 1.060 g of benzaldehyde and 0.672 g of potassium hydroxide. The solution was heated under reflux for 1 hour. Methanol was removed from the reaction solution by distillation under reduced pressure, and to the residue was added 50 ml of water. The resulting mixture was extracted three times with ethyl acetate. The organic layer from the extraction was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to column chromatography on silica gel. A crude product was obtained from the eluates with an 8:1 hexane : ethyl acetate mixture. The crude product was recrystallized from hexane to give 2.940 g of 2,3-diphenyl-5-benzylpyrazine as colorless prisms. M.P. 118°-119° C. Physical properties of the product support a chemical structure of the below formula (VII).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Br:21][C:22]1[C:23]([CH3:34])=[C:24]([Cl:33])[CH:25]=[C:26]([CH:30](Cl)[CH3:31])[C:27]=1[O:28][CH3:29]>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:30]([C:26]3[CH:25]=[C:24]([Cl:33])[C:23]([CH3:34])=[C:22]([Br:21])[C:27]=3[O:28][CH3:29])[CH3:31])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.80 g, 4.9 mmol), cesium carbonate (2.4 g, 7.3 mmol) and potassium iodide (82 mg, 0.49 mmol) in N,N-dimethylformamide (20 mL) was added 3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (1.47 g, 4.93 mmol) and the mixture was stirred at 140° C. for 1 hour. The mixture was diluted with water and ethyl acetate. The precipitate was collected and dried to give the desired compound. LCMS calculated for C17H17BrClN4O2 (M+H)+: m/z=423.0; Found: 423.0.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[C:48]1[NH:52][N:51]=[C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH:49]=1>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:51]2[C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:49][C:48]([C:44]3[O:43][CH:47]=[CH:46][CH:45]=3)=[N:52]2)=[CH:37][CH:38]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CCOC(=O)c1cc(-c2ccco2)[nH]n1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccco2)nn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and ethyl 5-(furan-2-yl)-1H-pyrazole-3-carboxylate. The regioisomers were separated silica gel chromatography. Compound 30: M/e+ 447 for C24H20ClN4O3 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8 7.93 (d, J=6.2 Hz, 1H), 7.67 (d, J=7.7 Hz, 2H), 7.56 (d, J=9.1 Hz, 1H), 7.34 (d, J=7.7 Hz, 2H), 7.25 (d, J=2.9 Hz, 1H), 7.17 (m, 1H), 6.98 (s, 1H), 6.81 (t, J=6.6 Hz, 1H), 6.62 (s, 1H), 6.09 (s, 1H), 4.40 (m, 4H), 1.39 (t, J=6.9 Hz, 3H) ppm; Compound 31: M/e+ 447 for C24H20ClN4O3 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.37 (d, J=6.9 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.65 (d, J=9.1 Hz, 1H), 7.42 (m, 3H), 7.24 (m, 1H), 7.09 (s, 1H), 6.84 (td, J=6.6, 1.1 Hz, 1H), 6.58 (d, J=3.3 Hz, 1H), 6.40 (dd, J=3.3, 1.8 Hz, 1H), 6.15 (s, 2H), 4.36 (q, J=7.3 Hz, 2H), 1.39 (t, J=7.3 Hz, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.[N:14]([O-])=O.[Na+].Cl.C([O-])(O)=O.[Na+]>>[Cl:8][C:7]1[C:2]2[N:1]=[N:14][N:10]3[N:11]=[N:12][N:13]=[C:9]3[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(Cl)cccc1-c1nnn[nH]1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1cccc2c1nnn1nnnc21
Yield: 80.5 %

Procedure:
This compound was prepared from 1 g of 5-(2-amino-3-chlorophenyl)tetrazole, 0.45 g of NaNO2, and concentrated HCl by the procedure described in Example 1. The reaction mixture was made basic with aqueous NaHCO3 and extracted with chloroform as before. The combined and dried extracts were concentrated under a stream of nitrogen at room temperature. The residue was washed with hexane and air dried to yield 0.85 g of a cream colored solid identified by thin layer chromatographic analysis and infrared absorption analyses as the essentially pure compound 7-chlorotetrazolo[4,5-C][1,2,3]benzotriazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:15]I>O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:15])[N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1ccc(I)nc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
2-Chloro-3-pyridinol (60 g, 0.46 mole) is dissolved in 700 ml water containing potassium carbonate (220 g, 1.6 mole) in a 21 one neck round bottom flask. The solution is treated with iodine (141 g, 0.56 mole) and the reaction is stirred 4 h at room temperature. The excess iodine is quenched with saturated sodium thiosulfate and the pH of the mixture is adjusted to 2 with 12 N hydrochloric acid. The mixture is extracted with 3×250 ml ethyl acetate. The combined organics are dried over magnesium sulfate and are concentrated in vacuo to a yellow solid. The crude solid is recrystallized from 150 ml ethyl acetate and 700 ml heptane to give 69 g (58%) of 2-chloro-3-hydroxy-6-iodo-pyridine. The mother liquor is concentrated to a yellow solid which is recrystallized from 60 ml ethyl acetate and 370 ml heptane to provide 15.5 g (13%).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:21])(=O)[CH3:2].Cl.[CH2:23]([O:25][NH2:26])[CH3:24].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:23]([O:25][NH:26][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:21])[CH3:2])[CH3:24]
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(Cl)cc2)CC1=O
Reactant: CCON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCONC(C)=C1C(=O)CC(CCSc2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.8 Gram of 2-acetyl-5-[2-(4-chlorophenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 80 ml of ethanol, and after adding 0.31 g of ethoxyamine hydrochloride and 0.32 g of triethylamine, the resulting solution was stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. After removing chloroform, the product obtained was purified by thin layer chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 0.43 g of 2-(1-ethoxyaminoethylidene)-5-[2-(4-chlorophenylthio)ethyl]cyclohexane-1,3-dione [Compound (1)].
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[N:12]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[CH:13]=[N:14][CH:15]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>CC1C=CC(C)=CC=1>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([N:12]2[C:11]3[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1][C:15]=3[N:14]=[CH:13]2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(=Cc1cncn1-c1ccc(Br)cc1)N=[N+]=[N-]
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)c1cc2c(ncn2-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C

Procedure:
A suspension of ethyl 2-azido-3-[3-(4-bromophenyl)-3H-imidazol-4-yl]acrylate (7) (240 mg) in p-xylene (10 mL) was heated at reflux under nitrogen for 30 min. The mixture was then cooled to rt, and the resulting white solid was collected by filtration, washed with hexane, and dried in air to yield ethyl 1-(4-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate EXAMPLE 1. LC-MS (ES+): m/z 334/336 (1/1) [MH+]. 1H NMR (CDCl3, 400 MHz): δ=1.40 (t, J=7.1 Hz, 3H), 4.38 (q, J=7.1 Hz, 2H), 6.94 (d, J=1.6 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.93 (s, 1H), 8.99 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([CH:18]=[N:19][OH:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=O)CCC1=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][NH2:43].C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:19][OH:20])=[N:43][CH2:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Reactant: NCc1ccccn1
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=NCc1ccccn1)NO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde-oxime ((i.e. the product of Example 1 Step 2, 177 mg, 0.42 mmol) in DMF (4 mL) was added N-chlorosuccinimide (67 mg, 0.50 mmol) and the mixture was stirred at 70° C. bath temperature for 30 min. After cooling to 0° C., picolylamine (85 mg, 0.79 mmol) and triethylamine (145 mg, 1.44 mmol) was added. The mixture was allowed to war to room temperature over night and was then poured on ice water. The pH was adjusted to 7 by addition of NH4Cl and the resulting precipitate was filtered off. The crude product was then purified by column chromatography on SiO2 (CH2Cl2: MeOH=96:4) to give the title compound (75 mg, 42%).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:19])[C:17]=1[F:18])[N:14]([NH:20][CH3:21])[CH:13]=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]2=[O:27].[C:28]([O:32][C:33]([C:35](=[CH2:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:19])[C:17]=1[F:18])[N:14]([N:20]([CH3:21])[CH2:43][CH:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:13]=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]2=[O:27]
Reactant: C=C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(N(C)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Yield: 38.3 %

Procedure:
Solid potassium tert-butoxide (823 mg) was added to tetrahydrofuran (40 ml) solution of ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.0 g) and tert-butyl 2-tert-butoxycarbonylacrylate (1.67 g), with stirring and suspending under ice-cooling, and the suspension was stirred for 0.5 hour with ice-cooling and then 1.5 hours at room temperature. The reaction solution was poured into a mixed liquid of ethyl acetate ice-water (150 ml/150 ml) and was adjusted to have pH of 3.0 with 1N hydrochloric acid. The organic layer was separated out, washed with water and saline solution, and dried over magnesium sulfate. This was concentrated under reduced pressure to obtain an amorphous product. The amorphous product was subjected to column chromatography with silica gel and eluted with a mixed solvent of methylene chloride ethyl acetate (20/1 to 10/1). The fractions containing the object product were collected, and the solvent was removed by distillation under reduced pressure. The residue was tritulated with n-hexane, and the precipitates were filtered out to obtain ethyl 6,7,8-trifluoro-1 -[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4 -dihydro-4-oxoquinoline-3-carboxylate (1.35 g) as an almost white powder.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[O:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-oxazolylmethoxy]benzyl]-3-pyrrolyl]propionate (532 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(2-phenyl-4-oxazolylmethoxy]benzyl]-3-pyrrolyl]propionic acid (428 mg, yield: 85%). This was recrystallized from ethanol-hexane. Melting point: 139–140° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@H:10]([O:14][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(C)(=O)=O
Product: CCCCCCCC/C=C\CCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCC/C=C\CCCCCCCC

Procedure:
Compound VI-4 (507 mg, 56.4%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 250 mg, 1.29 mmol) and (Z)-octadec-9-enyl methanesulfonate (Nu-Chek Prep, Inc; 1.79 g, 5.17 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]([C:34](Cl)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>N1C=CC=CC=1>[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]([C:34]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([N:14]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[CH2:18][N:17]5[CH:25]=[CH:26][CH:27]=[C:16]5[CH2:15]4)=[O:13])=[CH:8][CH:7]=3)=[N:2]2)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccn(C(=O)c3ccccc3-c3ccccc3)n2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 45.8 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (20 ml) and 2-biphenylcarbonyl chloride (0.65 g), the title compound (0.49 g) was obtained as an amorphous solid, MS, Hz: 534 (M)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][C:10]([N:13]([CH3:15])[CH3:14])=[N:11][CH:12]=1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[F-].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:7]1[CH:8]=[N:9][C:10]([N:13]([CH3:15])[CH3:14])=[N:11][CH:12]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CN(C)c1ncc(Br)cn1
Agent: [F-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C)C)nc1
Reaction time: 2 h
Yield: 74 %

Procedure:
n-Butyl lithium (1.5 M n-hexane solution; 6.06 ml, 9.09 mmol) was added dropwise to a solution of 5-bromo-2-dimethylaminopyrimidine (1.75 g, 8.66 mmol) in tetrahydrofuran (18 ml) at −78° C. under argon atmosphere in 15 min. The mixture was stirred at the same temperature for 2 hrs. and then tri-n-butyltin chloride (2.5 ml) was added dropwise thereto. The mixture was stirred at the same temperature for 0.5 hrs. and then at room temperature for 1 hr. To the reaction mixture were added 10% aqueous potassium fluoride (50 ml) and ethyl acetate (50 ml) in turn and the mixture was stirred at room temperature for 0.5 hrs. The organic layer was separated and washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography on amine silica gel (Chromatolex (trademark) NH) (n-hexane) to give 5-tri-n-butylstannyl-2-dimethylaminopyrimidine (2.65 g, 74%) as a colorless oil.