Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][NH:31]C(OC(C)(C)C)=O)[CH:26]=[CH:27][C:28]=1[F:29].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:30]([C:25]3[CH:26]=[CH:27][C:28]([F:29])=[C:23]([Cl:22])[CH:24]=3)[N:31]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cc(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 46.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.300 g), tert-butyl 2-(3-chloro-4-fluorophenyl)hydrazinecarboxylate (Intermediate-85, 0.300 g), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.200 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](O)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.CCCCCC.S(Cl)([Cl:28])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([Cl:28])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCCCCC
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5.0 g of 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid in 5.0 ml of thionyl chloride is heated on a steam bath under Argon for 1 hour and hexane added. The resulting solid is collected and dried to give 5.36 g of the desired product as a colorless oil. M+ =280 as methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].[C:20](#N)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:20]=[CH:14][N:15]([CH3:17])[CH3:16])[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: CC#N
Product: CC(=O)C(C=CN(C)C)c1ccc(F)cc1
Reaction time: 12 h

Procedure:
A mixture of 4-fluorophenyl acetone (50 grams) and 162.5 ml of N,N-dimethylformamide dimethyl acetal in 75 ml of acetonitrile is stirred for 12 hours and then the reaction mixture is concentrated on a rotary evaporator. The residual solid is suspended in 100 ml of hexane and filtered to give 59.6 grams of 1-(4-fluorophenyl)-2-(dimethylamino)ethenyl-2-propanone.
Reaction SMILES: [Cl-:1].[NH4+].O.C(O)C.[N+:7]([C:10]1[CH:34]=[CH:33][C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([O-])=O>CN1C(=O)CCC1.[Zn]>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:13]3[CH:33]=[CH:34][C:10]([NH2:7])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(NCc2ccc(CNc3ccc([N+](=O)[O-])cc3)cc2)cc1
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: Cl
Product: Nc1ccc(NCc2ccc(CNc3ccc(N)cc3)cc2)cc1

Procedure:
The mixture of powdered zinc (22.2 g), ammonium chloride (2.5 g), water (4 ml) and absolute ethanol (20 ml) were brought to reflux with the oil bath. The 4-nitro-N-(4-{[(4-nitrophenyl)amino]methyl}benzyl)aniline (3.4 g) was dissolved in 20 ml of NMP and introduced dropwise until there was decoloration of the reaction medium, while at the same time the reflux was maintained.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]([C:11]1[C:12](=[O:31])[CH2:13][CH:14]([C:18]2[CH:23]=CC=C[C:19]=2C2C=CC(O)=CC=2)[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:8][CH3:9].F[C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1.O>CS(C)=O>[C:7]([C:11]1[C:12](=[O:31])[CH2:13][CH:14]([C:18]2[CH:19]=[CH:5][C:2]([O:4][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[CH:3][CH:23]=2)[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)C1=C(O)CC(c2ccccc2-c2ccc(O)cc2)CC1=O
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2ccc(Oc3ccc(S(C)(=O)=O)cc3)cc2)CC1=O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.7 g (15.0 mmol) of potassium t-butoxide in 15 mL of methyl sulfoxide at room temperature was treated with 2.0 g (11 mmol) of 2-propionyl-3-hydroxy-5-((4-hydroxyphenyl)-phenyl)cyclohex-2-en-1-one. After 20 minutes of stirring, 2.0 g (11 mmol) of (4-fluorophenyl)methyl sulfone was added thereto and the solution was heated, under nitrogen, at 100° C. for 2.5 hours. The mixture was cooled to room temperature, poured into 100 mL of cold water and washed with 30 mL of diether ether and acidified with 1N HCl to pH 4 and extracted thrice with 20 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and passed through a short column of silica gel. Evaporation of the solvent afforded the above named product as a solid residue which was recrystallized from absolute alcohol. The product was recovered in a yield of 2.4 g (75 percent of theoretical) and melted at 157-158° C. 1H NMR (CDCl3) δ1.18 (t, J=7 Hz, 3H, --CH2CH3), 2.70-3.58 (m includes s at 3.03 for CH3SO 2 --, 10H), 7.00-7.38 (m, 6H, aromatics), 7.89 (d, J=9 Hz, 2H, aromatics), 18.17 (s, 1H, enol H).
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:16]=[C:17]([Br:23])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([Br:23])=[CH:16][C:15]=1[O:14][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7]
Reactant: COc1ccc(Br)cc1O
Reactant: O=C1CCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC1CCCC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
17.7 g (0.15 mol) of 2-chlorocyclopentanone and 41.4 g (0.3 mol) of potassium carbonate are added to a solution of 20 g (0.1 mol) of 3-hydroxy-4-methoxy-bromobenzene in 300 ml of absolute DMF and the mixture is stirred at RT for 12 h. After filtering off the solids, the filtrate is concentrated, the residue is taken up in 500 ml of ethyl acetate and the solution is extracted by shaking with 3×200 ml of distilled water. Column chromatography affords 21.1 g of the title compound as a brown oil. TLC (petroleum ether/ethyl acetate 6:4), Rf =0.47.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[OH2:16]>C[C@H](O)CC.CN(C=O)C>[C@@H:5]([O:16][C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)([CH2:6][CH3:7])[CH3:4]
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Reactant: O
Agent: CC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)Oc1nn2c(N)nnc2c(C)c1C
Temperature: 0 °C

Procedure:
(S)-Butan-2-ol (1.7 ml) was initially charged at RT with stirring and cooled almost to 0° C. with an ice bath. Subsequently, the mixture was admixed with portions of sodium hydride (85 mg). The suspension formed was heated to 55° C. for 1.5 h and then admixed with portions of 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 100 mg), suspended in (S)-butan-2-ol (2 ml) and DMF (2 ml). After stirring at 55° C. for 1 h, the mixture was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 105 mg of the title compound were isolated in sufficient purity. LC-MS rt: 0.81 min [M+H]+: 236.2 (met. b)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH3:26][NH2:27]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH3:26])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)ccc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(5-Amino-2-fluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) was added to a mixed liquid of a 40% aqueous solution (103 mg) of methylamine and pyridine (1 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and ethanol was added to the residue. Solids formed were collected by filtration and washed with hexane to obtain the title compound (85 mg) as a pale yellow powder.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.CO.[OH2:18].Cl.[NH2:20]O.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:18][N:20]=[CH:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: NO
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C=NO)CC1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of tert-Butyl 4-formylpiperidine-1-carboxylate (30.0 g, 140 mmol), MeOH (150 mL, 3700 mmol) and water (150 mL, 8330 mmol) was cooled in an ice-water bath. Hydroxylamine hydrochloride (11.7 g, 160 mmol) and sodium carbonate (7.45 g, 70 mmol) were added and the resulting mixture was stirred in the ice bath, then allowed to warm to ambient temperature overnight. The reaction was concentrated to an aqueous suspension and was extracted with ethyl acetate. The organic extract was washed with brine, dried, and concentrated to afford the title compound as a white solid (31.3 g, 98%).
Reaction SMILES: C(NC(C)C)(C)C.CS(O[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)(=O)=O.[NH2:33][C@@H:34]([CH3:44])[C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[OH:36]>CN(C)C=O>[OH:36][C@H:35]([C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)[C@@H:34]([NH:33][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[CH3:44]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCOS(C)(=O)=O)cc2)cc1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 57.5 %

Procedure:
Diisopropylamine (0.40 mL) was added to a mixture of ethyl 4′-(2-methanesulfonyloxyethoxy)biphenyl-4-carboxylate (0.32 g) and 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.32 g) in N,N-dimethylformamide (6 mL), and the mixture was stirred for 14 hrs at 80° C. After being cooled to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=15/1) to afford ethyl 4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl-amino]ethoxy}biphenyl-4-carboxylate (0.22 g).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:24][NH:25][CH:26]([CH2:28][CH3:29])[CH3:27]>N1C=CC=CC=1>[CH3:24][N:25]([CH:26]([CH3:27])[CH2:28][CH3:29])[C:17]([C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:18]
Reactant: O=C(O)c1cc(-c2ccccc2)c2ccccc2c1
Reactant: CCC(C)NC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2)c2ccccc2c1
Yield: 54.9 %

Procedure:
Operations are carried out as for Example 1, starting from 4.3 g of 4-phenyl naphthalene 2-carboxylic acid, 20 ml of thionyl chloride and then 1.5 g of N-methyl 2-butanamine in 20 ml of pyridine. 3 g of N-methyl N(1-methyl propyl) 4-phenyl naphthalene 2-carboxamide, melting at 108° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[N:4][C:3]=1[N:15]1[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]1.C(N(CC)CC)C.[F:29][C:30]1([F:45])[CH2:35][CH2:34][CH:33]([NH:36][C:37](=O)[O:38]CC(Cl)(Cl)[Cl:41])[CH2:32][CH2:31]1.O>CS(C)=O>[ClH:41].[F:29][C:30]1([F:45])[CH2:31][CH2:32][CH:33]([NH:36][C:37]([N:18]2[CH2:19][CH2:20][N:15]([C:3]3[N:4]=[N:5][C:6]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:16][C@@H:17]2[CH3:21])=[O:38])[CH2:34][CH2:35]1
Reactant: Cc1c(-c2ccccc2)nnc(N2CCN[C@@H](C)C2)c1C
Reactant: O=C(NC1CCC(F)(F)CC1)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)nnc(N2CCN(C(=O)NC3CCC(F)(F)CC3)[C@@H](C)C2)c1C
Product: Cl
Yield: 76.2 %

Procedure:
Treat a mixture of (S)-4,5-dimethyl-3-(3-methylpiperazin-1-yl)-6-phenylpyridazine (199 mg, 0.70 mmol) and triethylamine (0.30 ml, 2.15 mmol) in DMSO (5 ml) with 2,2,2-trichloroethyl 4,4-difluorocyclohexylcarbamate (341 mg, 1.10 mmol). Heat the reaction at 100° C. for 4 d. Pour the reaction mixture into H2O, rinsing with EtOAc. Extract the mixture with EtOAc. Wash the organic layer twice with H2O, then brine. Dry over Na2SO4 and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 0 to 10% MeOH in CH2Cl2). Dissolve the purified free base in MeOH (1 mL) and treat with 1 M HCl in Et2O (1 mL). Concentrate the mixture to provide the title compound as a yellow foam (256 mg, 76%). ES/MS m/z 444.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:16]I>C1OCCOCCOCCOCCOC1.CN(C)C=O>[CH3:1][O:2][C:3]([CH3:16])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CI
Reactant: CCOC(=O)C(OC)C(=O)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(OC)C(=O)OCC
Yield: 50 %

Procedure:
Diethyl methoxymalonate (31.0 grams, 0.2 mole), prepared in Example LIII Part A, sodium hydride (3.91 grams of 60% reagent, 0.2 mole), methyl iodide (46.27 grams, 0.3 mole) and 15-crown-5 (2 drops) were reacted in 300 milliliters of N,N-dimethylformamide in a manner similar to that described in Example LII Part A to give 23.77 grams (0.1 mole) of diethyl methoxy(methyl)malonate. NMR analysis of the product indicated the following:
Reaction SMILES: N[C:2]1[C:3]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:4][C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH2:32]=O.[C:34]([BH3-])#[N:35].[Na+].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[CH3:32][N:35]([CH3:34])[C:2]1[C:3]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:4][C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: [BH3-]C#N
Reactant: Nc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)c1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. To a solution of 5-amino-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (425 mg, 1.0 mmol) in acetonitrile (10 ml), formalin (0.8 ml, 10 mmol), sodium cyanotrihydridoborate (188 mg, 3.0 mmol), and acetic acid (0.1 ml) was added and this was agitated for 1 hour. 2N NaOH solution was added, and extraction was carried out 2 times with dichloromethane. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=2:1), and 260 mg of 5-dimethylamino-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (yield 57%) was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 141 are shown below.
Reaction SMILES: [F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.[C:23]([CH:25]([C:33]#[N:34])[C:26]([CH3:32])([CH3:31])[C:27](OC)=[O:28])#[N:24].CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[NH2:24][C:23]1[C:25]2[C:26]([CH3:32])([CH3:31])[C:27](=[O:28])[NH:34][C:33]=2[N:17]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][C:11]([CH3:14])=[N:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:2]=3[F:1])[N:6]=2)[N:16]=1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3cccc(F)c3F)c2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1

Procedure:
400 mg (1.11 mmol) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were admixed with 3 ml of tert-butanol, 277 mg (1.33 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 2 ml of tert-butanol and 175 mg (1.56 mmol) of potassium tert-butoxide, and the mixture was heated to reflux for 24 h. A little water was added and the reaction solution was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). The product-containing fractions were concentrated and the residue was stirred with water/isopropanol. The solids were filtered off and purified again by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 170 mg (35% of theory) of the target compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#N)=[C:4]([F:11])[C:3]=1[Br:12].C(O)=[O:14]>[Ni]>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:14])=[C:4]([F:11])[C:3]=1[Br:12]
Reactant: N#Cc1cc(F)c(N)c(Br)c1F
Reactant: O=CO
Agent: [Ni]
Product: Nc1c(F)cc(C=O)c(F)c1Br
Temperature: 85 °C
Yield: 83 %

Procedure:
Raney nickel (5.3 g, 50% slurry in water) was added to a solution of 4-amino-3-bromo-2,5-difluoro-benzonitrile (4.0 g, 17.2 mmol) in formic acid (60 mL). After heating for 1 h at 85° C., the reaction mixture was filtered through Celite, washed with DCM and evaporated to dryness. The residue was suspended in DCM and neutralized carefully with saturated sodium hydrogencarbonate. The aqueous phase was extracted with DCM and the combined organic phases were dried over sodium sulfate and evaporated to yield 4-amino-3-bromo-2,5-difluorobenzaldehyde (3.4 g, 14.3 mmol, 83%). 1H NMR (d6-DMSO) δ 9.91 (d, J=3.0 Hz, 1H), 7.45 (dd, J=11.0, 6.0 Hz, 1H), 6.96 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccc(Cl)cc3c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2

Procedure:
363 mg of methyl 10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate were hydrogenated at room temperature in 50 ml of ethyl acetate in the presence of 6 mg of 10 percent palladium/carbon. The catalyst was removed by filtration and the solvent was removed in vacuo. The-residue was purified by chromatography on silica gel and the product was crystallized from methanol. There was obtained methyl 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate of m.p. 138°-139°.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:46]=[C:17]2[N:18]([CH2:41][C:42]3([CH3:45])[CH2:44][CH2:43]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:46]=[C:17]2[N:18]([CH2:41][C:42]3([CH3:45])[CH2:44][CH2:43]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(C)CC2)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC2(C)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({2-methyl-4-[(1-methylcyclopropyl)methyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.36 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.16 g, 40%).
Reaction SMILES: [NH2:1][C:2](N)=[S:3].ClC1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8]N=1.[OH-].[K+].[OH-].[Na+]>C(O)C.O.C(Cl)Cl>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:2]([SH:3])=[N:1][CH:8]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: NC(N)=S
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(S)nc1
Temperature: 25 °C
Yield: 60 %

Procedure:
Thiourea (684 mg, 8.80 mmol) was added to a solution of 2-chloro-5-(trifluoromethyl)pyridine (1.45 g, 8.00 mmol) in ethanol (4 ml), and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, subsequently a solution of potassium hydroxide (792 mg, 12.0 mmol) in water (4 ml) was added thereto, and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled again to room temperature, and 1 N sodium hydroxide and methylene chloride were added thereto. After the aqueous layer was separated, acetic acid added to the aqueous layer, which was then extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was washed with a mixed solvent of to hexane and diethyl ether, and was collected by filtration to obtain the title compound (860 mg, 4.80 mmol, 60%) as a pale yellow solid.