Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([C:19]2[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:26][CH2:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH:20]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(N2CCCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(N4CCCC4)c3)ccc12
Yield: 4 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (200 mg, 0.770 mmol), (3-pyrrolidin-1-ylphenyl)methylamine (149 mg, 0.848 mmol), Pd2(dba)3 (71 mg, 0.077 mmol), rac-BINAP (153 mg, 0.246 mmol) and NaOtBu (200 mg, 2.081 mmol) in DMA (6 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-(3-pyrrolidin-1-yl-benzylamino)-2H-phthalazin-1-one (11 mg) as a white solid. 1H (400 MHz, d6-DMSO) δ: 1.94 (m, 4H), 3.20 (m, 4H), 4.32 (d, 2H), 6.41 (d, 1H), 6.57 (s, 1H), 6.60 (d, 1H), 6.85 (s, 1H), 7.11 (t, 1H), 7.15 (dd, 1H), 7.62 (t, 1H), 7.01 (d, 1H), 12.33 (s, 1H) ppm; m/z (M+1) 355.31.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br-].O>CN(C)C=O.CC(C)N(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Agent: CC(C)N(C)C=O
Agent: [Br-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Sc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.11 g of 2-mercaptopyridine and 0.48 g of 50% sodium hydride were dissolved in 25 ml of dimethyl formamide, and the mixture was stirred at room temperature for 1 hour. A solution of 6.5 g of polyprenyl bromide of general formula (II) in which n is 15 and A2 is Br in 5 ml of dimethyl N,N-dimethylformamide was added dropwise. After the addition, the mixture was stirred overnight at room temperature. The reaction mixture was poured into about 50 ml of water, and extracted with diethyl ether. Then, the diethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The ether was distilled off to give a yellow liquid. The liquid was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent to give 3.9 g of a slightly yellow liquid. The NMR analysis of this liquid showed that the signal (doublet, δ=3.91) assigned to --CH2Br of the starting polyprenyl bromide disappeared, and a signal (doublet, δ=3.78) assigned to --CH2S and a signal (multiplet, δ=6.75-8.35) assigned to --S--C5H4N newly appeared. The FD-MASS analysis of this liquid gave m/e=1335.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22]C2CCCCO2)=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][CH2:31][O:32][CH2:33]COC>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][CH2:30][CH2:31][O:32][CH3:33])=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCOCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Product: COCCOCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as that described in example 1 except that (i) 2-fluoro-4-iodoaniline was used in place of 4-bromoaniline in step 2, and (ii) (R)-tert-butoxycarbonylamino-[4-(2-{2-methoxy-ethoxy}-ethoxy)-phenyl]-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-methoxy-phenyl]-acetic acid in step 4. (R)-tert-Butoxycarbonylamino-[4-(2-{2-methoxy-ethoxy}-ethoxy)-phenyl]-acetic acid was prepared as described in example 48 except that 1-(2-bromo-ethoxy)-2-methoxy-ethane was used in place of 2-(2-bromo-ethoxy)-tetrahydropyran.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[CH3:11][O:9][C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H](O)CC1
Reaction time: 2 h

Procedure:
To a solution of trans-4-hydroxycyclohexanecarboxylic acid (14.7 mmol, 2.12 g), K2CO3 (17.6 mmol, 2.44 g) in DMF (15 mL) is added iodomethane (17.6 mmol, 1.10 mL). After stirring for 2 hours, the mixture is diluted with EtOAc. The mixture is washed with H2O and brine, dried over Na2SO4 and concentrated. The obtained residue is used to next reaction without further purification (1.62 g, 70%); 1H-NMR (400 MHz, CDCl3): 1.24-1.33 (m, 2H), 1.45-1.53 (m, 2H), 1.98-2.28 (m, 4H), 2.21-2.29 (m, 1H), 3.57-3.64 (m, 1H), 3.67 (s, 3H).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccccc1
Yield: 91 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 3.96 g (6.50 mmol, 0.65 equivalent (equivalent relative to a carbonyl compound as a starting raw material; the same, hereinafter)) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.06 g (10 mmol) of benzaldehyde in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.76 g of the desired product (yield 91%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](=[O:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9]I>>[Cl:1][C:2]1[N:3]([CH3:9])[C:4](=[O:8])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=c1cccc(Cl)[nH]1
Product: Cn1c(Cl)cccc1=O
Reaction time: 5 h

Procedure:
51.82 g of 2-chloro-pyrid-6-one (400 mmol) and 12.7. g of 83% sodium-hydride dispersion in mineral oil (440 mmol) are reacted in 400 ml absolute dimnethylfomamide at room temperature under argon for 15 minutes. 32.4 ml methyl-iodide (520 mmol) are added dropwise and stirring is continued at 50° for 5 hours. The reaction mixture is evaporated on a rotary evaporator until the solvent starts to distill from a bath of 60°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[N:10]=[C:9]([O:11]C)[C:8]([Cl:13])=[C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:6]=1.O1CCOCC1>C(OCC)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([Cl:13])=[C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:6]=1
Reactant: COC(=O)Cc1nc(OC)c(Cl)c(N2CCOCC2)n1
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Yield: 86.8 %

Procedure:
500 mg of (5-chloro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetic acid methyl ester and 5 ml of 4N hydrochloric dioxane are placed in a microwave tube. After microwave irradiation for 30 minutes at a temperature of 110° C., the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in ethyl ether. The solid formed is filtered off so as to give 414 mg of (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid methyl ester, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:25](#N)C.[H-].[Na+]>IC>[Cl:1][C:2]1[N:24]=[C:5]2[C:6]([N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:25])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(Cc1ccccc1N(C)S(C)(=O)=O)c1cccn2nc(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (250.0 mg, 0.6834 mmol) in acetonitrile (1 mL, 20 mmol) at room temperature was added sodium hydride, 60% disp. in mineral oil (33.0 mg, 0.825 mmol) followed by iodomethane (46.80 uL, 0.7517 mmol). The mixture was stirred at room temperature for 2 hours then additional iodomethane (10 uL) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a tan resin. The recovered material was purified via chromatography using an ISCO automated purification apparatus (silica gel column 24 g 20%→80% ethyl acetate:hexane solvent gradient). N-(2-{[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino}-methyl]-phenyl)-N-methyl-methanesulfonamide was isolated as tan foam (0.207 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.6 Hz, 1H), 7.35-7.27 (m, 4H), 6.89-6.84 (m, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.54-5.40 (br m, 1H), 5.06-4.90 (br m, 1H), 3.32 (s, 3H), 3.24 (s, 3H), 3.01 (s, 3H). MS=380, 382 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:31])([F:33])[F:32])[CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)c(C(F)(F)F)c2)CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of N-tert-butyloxycarbonyl-4-piperidinol (1.0 g, 5.0 mmol) in THF (20 mL) at 0° C. was added potassium tert-butoxide (5.0 mL of a 1.0 M solution in THF, 5.0 mmol). The mixture was stirred for 10 min and 4-fluoro-2-trifluoromethyl-benzonitrile (1.04 g, 5.5 mmol) was added. The mixture was stirred at 0° C. for 1 h and then at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:2 EtOAc:hexanes as eluant to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-trifluoromethylbenzonitrile as a colorless gum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]([CH2:15][CH3:16])[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22])[CH3:2].S1(CCCC1)(=O)=[O:24].[Se](=O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH:14]=[O:24])[N:10]([CH2:15][CH3:16])[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc(C)c(OCC)cc2c1=O
Reactant: O=S1(=O)CCCC1
Agent: O=[Se]=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2nc(C=O)c(OCC)cc2c1=O

Procedure:
A mixture of 30.4 g of ethyl 1,4-dihydro-6-ethoxy-1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate (Compound VIII where R1 =R2 =R3 =C2H5) and 100 ml of sulfolane was stirred at 140°-145° C. and 22 g of selenium dioxide in limited amounts was added thereto. After reacting the mixture under the same conditions for 5 hours and then allowing it to cool, chloroform was added thereto. The insoluble materials were removed by filtration. The filtrate was washed successively with 3% sodium carbonate solution, water, dried over anhydrous sodium sulfate and evaporated. To the residue was added isopropanol and the precipitated crystals were collected by filtration to obtain 22.0 g of ethyl 1,4-dihydro-6-ethoxy-1-ethyl-7-formyl-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 169°-170° C.
Reaction SMILES: [OH-].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(C)C>[C:7]1([O-:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: Oc1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CC(C)O
Product: [O-]c1ccccc1

Procedure:
A commercially available 10% solution of tetramethylammonium hydroxide in methanol (manufactured by TOKYO KASEI CO.) was subjected to solvent exchange with isopropanol to produce a solution of tetramethylammonium hydroxide in isopropanol. To a 3.83 ml portion of the solution (2.24 mmoles of tetramethylammonium hydroxide) was added 0.211 g of phenol (2.24 mmoles) to produce a solution of tetramethylammonium phenolate in isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@@H:14](O)[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:16])[F:17])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@@H](O)C(F)(F)F)c1=O
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Reaction time: 18 h

Procedure:
At RT, 5.0 g (13.12 mmol) of the compound from Example 8A together with 1.93 g (15.8 mmol) of 4-N,N-dimethylaminopyridine were initially charged in 70 ml of pyridine, 5.54 ml (32.92 mmol) of trifluoromethanesulfonic anhydride were added a little at a time and the mixture was stirred for 18 h. For work-up, 5 ml of 1 N hydrochloric acid were added and the pyridine was removed on a rotary evaporator. The residue was taken up in 50 ml of ethyl acetate and washed with 25 ml of water. The aqueous phase was re-extracted twice with in each case 25 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 4:1). This gave 3.50 g (73% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35]1[NH:44][C:43](=[O:45])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][C:35]3[NH:44][C:43](=[O:45])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: O=c1[nH]c(CS(=O)(=O)c2ccccc2Br)nc2ccccc12
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)Cc3nc4ccccc4c(=O)[nH]3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine and 2-(((2-bromophenyl)sulfonyl)methyl)quinazolin-4(3H)-one. MS (ESI): mass calcd. for C25H18FN5O3S, 487.11; m/z found, 487.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.60-8.43 (d, J=1.4, 2H), 8.12-8.02 (dd, J=8.0, 1.5, 1H), 7.96-7.89 (dd, J=8.0, 1.3, 1H), 7.84-7.71 (m, 2H), 7.66-7.42 (m, 4H), 7.42-7.22 (m, 3H), 6.91 (s, 2H), 4.37 (s, 2H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]([CH2:13][N:14]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[N:15]3)[C:9](=[O:23])[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.O1CCOCC1>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][N:10]([CH2:13][N:14]4[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[N:15]4)[C:9](=[O:23])[N:8]=3)[CH2:2][CH2:3]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(Br)c1
Reactant: O=c1nc(N2CCNCC2)ncn1Cn1ccc(C(F)(F)F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(N2CCN(c3ncn(Cn4ccc(C(F)(F)F)n4)c(=O)n3)CC2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 30.8 %

Procedure:
A 1,4-dioxane solution (1.0 mL) of 4-(piperazin-1-yl)-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,5-triazin-2(1H)-one (50 mg, 0.07 mmol) synthesized in Reference Synthesis Example 17, 1-bromo-3-methoxybenzene (8.6 μL, 0.07 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.2 mg, 0.007 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (6.5 mg, 0.01 mmol), and cesium carbonate (44 mg, 0.14 mmol) was stirred in a nitrogen atmosphere at 80° C. for 1 day. After the completion of the reaction, water was added to the reaction solution and extraction with ethyl acetate from the resultant reaction solution was performed three times. The organic layer was washed with brine, was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The resultant residue was purified by preparative thin-layer chromatography (hexane/ethyl acetate=1/1 (v/v)) to obtain the title compound (9.4 mg, yield: 32%).
Reaction SMILES: C([Mg]CCCC)CCC.C(NC(C)C)(C)C.[CH2:17]([N:24]1[C:28]2[C:29]([N:35]([CH3:37])[CH3:36])=[N:30][N:31]([CH3:34])[C:32](=[O:33])[C:27]=2[N:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:38]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1>[CH2:17]([N:24]1[C:28]2[C:29]([N:35]([CH3:37])[CH3:36])=[N:30][N:31]([CH3:34])[C:32](=[O:33])[C:27]=2[N:26]=[C:25]1[Cl:38])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)c1nn(C)c(=O)c2ncn(Cc3ccccc3)c12
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CCCC[Mg]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)c1nn(C)c(=O)c2nc(Cl)n(Cc3ccccc3)c12
Reaction time: 8 h
Yield: 51.7 %

Procedure:
1.15 ml of a 1 M tetrahydrofuran solution of dibutylmagnesium was added to a 2 ml tetrahydrofuran solution of 0.320 ml of diisopropylamine at room temperature under a nitrogen atmosphere, and the mixture was stirred for 8 hours. This solution was added to a 4 ml tetrahydrofuran solution of 0.162 g of 1-benzyl-7-dimethylamino-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 15 hours. Then, a 5 ml tetrahydrofuran solution of 0.540 g of hexachloroethane was added dropwise to the solution. After the mixture had been stirred for 4 hours, 30 ml of a 5% aqueous ammonium chloride solution was added thereto. The mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 30 ml of water and 30 ml of a saturated sodium chloride solution, and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.094 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([NH:25][C:26]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[O:27])[C:21]([O:23]C)=[O:22])[CH:15]=2)[N:10]=1.[OH-].[Na+].O.Cl>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([NH:25][C:26]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[O:27])[C:21]([OH:23])=[O:22])[CH:15]=2)[N:10]=1
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCCC[C@H]2C(=O)NC(Cc2ccc3nc(-c4c(Cl)cccc4Cl)ccc3c2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 455 mg of methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-[({(2S)-1-[(4-methylphenyl)sulfonyl]piperidinyl}carbonyl)amino]propanoate 46 in CH3OH (5 ml) are added 0.8 ml of 1 N NaOH and 1 ml of water. The solution is stirred at RT overnight, and 1 N HCl (0.8 ml) is added to obtain a weakly acidic pH. Methanol is then evaporated, and the solid obtained is filtered, washed with water and dried to give 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-[({(2S)-1-[(4-methylphenyl)sulfonyl]piperidinyl}carbonyl)amino]propanoic acid 90.
Reaction SMILES: [CH2:1]([CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH:21]([S:42][C:43](=[S:59])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[O:22]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[S:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CCOCC.Cl>[CH2:1]([CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH:21]([S:42][C:43](=[S:59])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[OH:22])=[S:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCCC(=S)NCCC(OC(c1ccccc1)(c1ccccc1)c1ccccc1)SC(=S)CCCCCCCCCCCCCCC
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=S)NCCC(O)SC(=S)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
3-tetradecylthioacetylamino-2-tetradecylthioacetylthio-1-triphenylmethyloxy-propane (example 20d) (187 mg, 0.21 mmol) was dissolved in ether saturated with gaseous hydrochloric acid (12 ml). The reaction medium was stirred at room temperature for 20 hours. The precipitate which formed was filtered and washed with diethyl ether to give the desired compound in the form of a white powder.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[CH:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[Cl-].[Ca+2].[Cl-].[OH-].[Na+].[BH4-].[Na+]>C(O)(C)C.CO.CC(C)=O.O>[CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccnc(C(=O)NC2CC2)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CC1)c1cc(CO)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.45 g (23.27 mmol) of ethyl 2-(cyclopropylcarbamoyl)pyridine-4-carboxylate (Example 51A) and 1.55 g (13.96 mmol) of calcium chloride were dissolved in 56.6 ml of isopropanol and 5.7 ml of methanol. At RT, a solution of 4.6 ml of water, 0.1 g (1.16 mmol) of 45% strength sodium hydroxide solution and 1.06 g (27.92 mmol) of sodium borohydride were slowly added dropwise, and the reaction mixture was stirred at RT overnight. 10 ml of acetone were added, and the reaction mixture was stirred at RT for 2 h. The precipitate was filtered off and washed with isopropanol, and the filtrate was evaporated.