Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH3:23])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[S:14]1[CH:15]=[C:11]([CH2:10][C@@H:9]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[CH3:23])=[O:17])[NH2:8])[N:12]=[CH:13]1
Reactant: C[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1C(=O)[C@@H](N)Cc1cscn1
Reaction time: 0.75 h
Yield: 62 %

Procedure:
Compound (3) (33.77 g, 99.48 mmol) and p-toluenesulfonic acid hydrate (37.85 g, 199 mmol) were dissolved in ethyl acetate (101 ml) and the solution was cooled with ice. To the mixture, 4 mol/L solution of hydrogen chloride-ethyl acetate (125 ml) was added, and the mixture was stirred for 2 hours 45 minutes. After the mixture was concentrated under reduced pressure, methanol was added to the residue. The mixture was concentrated. Methanol-toluene (1:1) was added to the residue and concentrated under reduced pressure to give crystalline residue. The residue was washed with acetone and filtered to give compound (4) as crystals (36 g, 62%). After the mother liquor was concentrated under reduced pressure, methanol and toluene were added to the residue and concentrated. Obtained crystalline residue was washed with acetone to give compound (4) (10.67 g, 18.4%).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][N:31]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[OH2:69]>CS(C)=O.C(OCC)(=O)C>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:30]1[N:31]=[CH:32][C:33]([OH:69])=[CH:34][CH:35]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Br)cn1
Reactant: O
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(O)cn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (475 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (55 mg), potassium acetate (198 mg) and bis(pinacolato)diboron (256 mg) are dissolved in dimethylsulfoxide (2 ml), and the mixture is heated to 80° C. under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (10 ml), and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (0.75 ml) under ice-cooling. The reaction solution is stirred at room temperature overnight, and thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, followed by an addition of water and diethylether, and the mixture is separated. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 6-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-ol (141 mg). MS (m/z): 643 [M+H]+
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1>>[N:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:40][CH:41]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(Cc2ccncc2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cc2ccncc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(pyridin-4-yl-methyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol/ammonia=5:1:0.01) C29H23N3O3
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH:20]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[CH:20]1([C:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)[OH:7])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C3CCCC3)ccc2c1

Procedure:
In a similar manner to that described in Example 1-(iv), the reaction of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.60 g) with cyclopentylmagnesium bromide in THF (1.0 M, 10 ml) was carried out to give the titled compound (0.80 g) as a colorless solid.
Reaction SMILES: CS[C:3](=[NH:5])[NH2:4].Cl[C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[Na+].N[C:15]1[C:20]([NH2:21])=[CH:19][C:18]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][C:16]=1[C:28](=[O:31])[CH2:29][CH3:30]>O.CCOC(C)=O.CC(O)=O>[CH2:10]([O:9][C:7](=[O:8])[NH:4][C:3]1[NH:5][C:15]2[C:16]([C:28](=[O:31])[CH2:29][CH3:30])=[CH:17][C:18]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][C:20]=2[N:21]=1)[CH3:11]
Reactant: CCC(=O)c1cc(-c2cccnc2)cc(N)c1N
Reactant: CSC(=N)N
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)CC)c2[nH]1
Temperature: 90 °C

Procedure:
To a mixture of 2-methyl-2-thiopseudourea (109 mg, 0.39 mmol) and ethyl chloroformate (75 μL, 0.78 mmol) in water (2 mL) at 5° C. was added over 40 minutes a 6N aqueous NaOH solution until pH stabilized to 8. The pH was then adjusted to 5 with glacial AcOH. A suspension of 1-(2,3-diamino-5-pyridin-3-yl-phenyl)-propan-1-one (0.30 mmol) in water (5 mL) was subsequently added to the reaction mixture. The reaction was heated at 90° C. for 18 hours, cooled to ambient temperature, and diluted with water (10 mL) and EtOAc (20 mL). The phases were separated and the aqueous layer extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo. The crude residue was taken up in DMSO, purified by preparative HPLC, and by flash column chromatography (SiO2; CH2Cl2:MeOH, 1:0 to 19:1). The residue was then converted to the bis-HCl salt to afford the title compound as an off white solid (5.0 mg): HPLC (10 to 90% CH3CN, 8 min.): Rt=3.90 minutes; 1H NMR (CD3OD, 500 MHz) δ 9.39 (d, 1H), 9.07 (d, 1H), 8.93 (d, 1H), 8.48 (d, 1H), 8.28 (d, 1H), 8.25 (dd, 1H), 4.46 (q, 2H), 3.35 (q, 2H), 1.43 (t, 3H), 1.29 (t, 3H); MS (ES+) m/z (M++1) 339.1.
Reaction SMILES: [CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[O:28][CH3:29])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:34].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[O:28][CH3:29])[C:8](=[O:12])[N:9]([CH2:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[O:34])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3OC)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3OC)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-methoxybiphenyl-2-carbonitrile (1.9 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.3 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.28 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as pale-yellow crystals (1.2 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[Br:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1>CC(C)=O>[BrH:9].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[N:5]=1)[CH3:8]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1nnc(N)s1
Solvent: CC(C)=O
Product: Br
Product: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Yield: 111.6 %

Procedure:
To 10 ml of acetone, 2.7 g of 2-amino-5-ethyl-1,3,4-thiadiazole and 1.3 g of 4'-bromomethyl-2-cyanobiphenyl were added, followed by heating under reflux for 2 hours. After the reaction mixture was cooled, the crystals so precipitated were collected by filtration, washed successively with acetone and diethyl ether and then dried, whereby 2.14 g of the title compound was obtained.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]>CS(C)=O>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:14]([N+:27]([O-:29])=[O:28])[CH:15]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(-c2ccccc2OC)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Dimethyl malonate (14 mL) was added dropwise to 2.9 g of sodium hydride suspended in 50 mL of dimethylsulfoxide. The mixture was heated at 100° C. for 15 minutes and cooled to room temperature. Crude 4-fluoro-2′-methoxy-3-nitrobiphenyl in 60 mL of dimethylsulfoxide was added and the mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled and quenched with 300 mL of saturated sodium chloride solution and extracted twice with ethyl acetate. The extracts were combined, washed with saturated ammonium chloride, water, and brine, dried over anhydrous sodium sulfate and concentrated to give crude dimethyl 2′-methoxy-3-nitrobiphenyl-4-malonate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[NH2:33][C:34]1[NH:39][C:38]2=[N:40][CH:41]=[C:42]([CH3:43])[C:37]2=[C:36]([Cl:44])[N:35]=1.C(#N)C>C(Cl)Cl>[NH2:33][C:34]1[N:35]=[C:36]([Cl:44])[C:37]2[C:42]([CH3:43])=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:38]=2[N:39]=1
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Reactant: Cc1cnc2[nH]c(N)nc(Cl)c1-2
Agent: Br
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2nc(N)nc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product from Step C of Example 2 (1.57 g, 3.16 mmol) in CH2Cl2 (50 mL) was added HBr (5.7 M in acetic acid; 3.3 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h, concentrated in vacuo and co-evaporated with toluene (2×20 mL). The resulting oil was dissolved in MeCN (20 mL) and added dropwise to a solution of the sodium salt of 2-amino-4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine in acetonitrile [generated in situ from 2-amino-4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see Liebigs Ann. Chem. 1984: 708-721] (1.13 g, 6.2 mmol) in anhydrous acetonitrile (150 mL), and NaH (60% in mineral oil, 248 mg, 6.2 mmol), after 2 h of vigorous stirring at room temperature]. The combined mixture was stirred at room temperature for 24 h and then evaporated to dryness. The residue was suspended in water (100 mL) and extracted with EtOAc (300+150 mL). The combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (5×7 cm) using ethyl acetate/hexane (0 to 30% EtOAc in 5% step gradient) as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (0.96 g) as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][N:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.[CH2:22]([SH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH2:22]([S:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][N:6]=[CH:5]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1nncc2cc(SCc3ccccc3)ccc12
Reaction time: 0.08 h
Yield: 76 %

Procedure:
A two-neck round-bottom flask was charged with 6-bromo-1-chlorophthalazine (Pharmablock, Nanjing Hi-Tech Zone, China, 4.44 g, 18.24 mmol), Xantphos (0.528 g, 0.912 mmol), and Pd2(dba)3 (0.417 g, 0.456 mmol). 1,4-dioxane (36.5 ml) and N,N-diisopropylethylamine (6.37 ml, 36.5 mmol) were added. The flask was fitted with a reflux condenser and placed in an 80° C. heating bath. After 5 min, benzyl mercaptan (2.265 ml, 19.15 mmol) was added drop wise. After 20 min. the mixture was cooled, then concentrated under a vacuum. EtOAc (about 25 mL) was added to the residue, and the flask was rotated on the rotovap in a 40° C. bath for 1.5 h. This removed most of the solid from the sides of the flask. The flask was sonicated for 30 s, then the mixture was concentrated under a vacuum. The residue was taken up in EtOAc to form a thick slurry. The flask was sonicated for 30 s, then the mixture was filtered. The collected solid was washed with several large volumes of EtOAc (until the filtrates were essentially colorless). The filtrate was concentrated, and the residue was purified by chromatography on silica gel (80-g column with a 25-g silica gel loading column, 0 to 50% EtOAc/Heptane, then 50 to 100% EtOAc/Heptane). The resulting solid was taken up in heptane, sonicated for 30 s, then filtered. The collected solid was washed with heptane (3×, which removed some of the yellow color), and dried under a stream of N2 (g) for 20 min to give 6-(benzylthio)-1-chlorophthalazine (3.975 g, 13.86 mmol, 76% yield) as a light-orange powder: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=9.28 (d, J=0.7 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.82 (dd, J=1.9, 8.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.45-7.28 (m, 5H), 4.35 (s, 2H); m/z (ESI) 287.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[N:32]=1.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([NH:20][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[N:32]=2)[CH:21]=[CH:22][CH:23]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)C(=O)OC(C)(C)C
Reactant: COc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(Nc2cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)n1
Yield: 81.8 %

Procedure:
A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)aniline (50 mg), tetrakistriphenylphosphine palladium (18 mg), potassium carbonate (24 mg), 2-chloro-6-methoxypyridine (25 mg) and toluene (3 ml) was heated under reflux under nitrogen atmosphere for 16 h and, thereafter, ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=1:4) to give 54.5 mg of the titled compound (yield, 82%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(C)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc(C)cc3)cc12
Yield: 31.3 %

Procedure:
11.4 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 870 mg of N-[6-chloro-5-(4-methylphenyl)-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran. The medium is then refluxed for 20 hours and the mixture is then allowed to return to room temperature and 20 cm3 of ethyl acetate are added; the organic phase is washed with 2×20 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 2×20 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is taken up in 10 cm3 of diethyl ether, filtered off on a sinter funnel and then dried under reduced pressure (90 Pa; 50° C.) to give 195 mg of N-[6-chloro-5-(4-methylphenyl)-1H-indazol-3-yl]butanamide in the form of a beige-coloured powder.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl-].[Ca+2].[Cl-].S(Cl)(Cl)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][C:21]=1[O:31][CH3:32]>O.CN(C)C=O>[CH3:32][O:31][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=1[O:19][CH3:18])[CH:26]=[CH:27][C:28]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])=[O:29]
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Into 15 ml of dimethylformamide were dissolved with heating 2.0 g of anthranilic acid and 2.3 g of anhydrous calcium chloride. To 10 ml of dimethylformamide were added in order 0.78 ml of thionyl chloride and 2.08 g of 3',4'-dimethoxycinnamic acid, during which the reaction system was stirred and cooled with ice and water. The resulting mixture was added dropwise to the above solution, during which the reaction system was stirred and cooled with ice and water. After the completion of the dropping, the reaction mixture was stirred for 30 minutes at the same temperature and then for 1 hour at room temperature. After the completion of the reaction, 80 ml of ice-water mixture was added thereto. Then, air was introduced thereinto for 30 minutes, and crystals deposited were collected by filtration and recrystallized from ethanol-water (1:2) to give 2.35 g (yield: 71.8%) of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid. Melting point: 209°-211° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[N:7]=1.[C:12]([O:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>C(O)C.CN(C)C=O>[C:12]([O:15][CH2:16][C:17]1[NH:11][C:9](=[O:10])[C:3]2[C:2](=[N:7][C:6]([OH:8])=[CH:5][N:4]=2)[N:1]=1)(=[O:14])[CH3:13]
Reactant: NC(=O)c1ncc(O)nc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2nc(O)cnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 5.0 g (0.0324 mole) of 3-amino-5-hydroxy-2-pyrazinecarboxamide, 29.5 g (0.134 mole) of triethyl orthoacetoxyacetate and 9.5 ml of acetic anhydride. Refluxing time: 1 hour 45 minutes. Yld: 3.8 g (50%), m.p.>300° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29]([O:31]CC)=O)[NH:23][C:22]2=[O:34])#[N:18].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:78]2[CH:82]=[N:81][C:80]([O:83][CH2:84][CH2:85][O:86][C:87]3[CH:88]=[C:89]([CH2:93][NH2:94])[CH:90]=[CH:91][CH:92]=3)=[N:79]2)C=CC=CC=1>>[C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29]([NH:94][CH2:93][C:89]1[CH:90]=[CH:91][CH:92]=[C:87]([O:86][CH2:85][CH2:84][O:83][C:80]3[N:81]=[CH:82][NH:78][N:79]=3)[CH:88]=1)=[O:31])[NH:23][C:22]2=[O:34])#[N:18]
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(OCCOc4nc[nH]n4)c3)[nH]c(=O)c2c1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 51 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a yellow powder (31.7 mg, 12%).