Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=2)[C:3]=1[C:22]#[N:23].[CH2:24]([O:26][CH:27](OCC)OCC)[CH3:25]>C(O)C>[C:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:22]#[N:23])=[C:2]([N:1]=[CH:27][O:26][CH2:24][CH3:25])[NH:6][N:5]=2)=[CH:13][CH:12]=1)([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2n[nH]c(N)c2C#N)cc1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CCOC=Nc1[nH]nc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)c1C#N
Temperature: 120 °C

Procedure:
With stirring, a mixture of 13.8 g (43.9 mmol) of 5-amino-3-[4-(N-BOC-amino)-phenylamino]-4-cyano-pyrazole and 138 ml of orthoformic acid triethyl ester is heated at 120° C. for 3 hours, care being taken to ensure that the ethanol formed in the course of the reaction is distilled off from the reaction mixture. Cooling to RT, filtering and washing the filter residue with ethanol yield the title compound; m.p. 180-182° C.
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([OH:26])=O)[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:24]([NH:45][CH2:44][C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([OH:31])=[CH:33][CH:34]=2)=[CH:43][CH:42]=1)=[O:26])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCc1ccc(-c2ccc(O)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(-c2ccc(O)cc2)cc1
Yield: 48 %

Procedure:
Prepared analogously to Example 5d) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-ornithine, 4'-hydroxy-[1,1'-biphenyl]-4-methanamine and TBTU in a yield of 48% of theory.
Reaction SMILES: [CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.[C:14]([CH2:18][C:19](Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH:13][C:19](=[O:20])[CH2:18][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCC3
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc2oc3c(c2c1)CCC3
Yield: 60.4 %

Procedure:
Following the procedure of Example 1, 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (0.87 g, 5.0 mmol) and t-butylacetyl chloride (0.77 mL, 5.5 mmol) in pyridine (10 mL) provided N-(2,3-dihydro-1 H-cyclopenta[b]benzofuran-7-yl)-3,3-dimethyl-butyramide (0.82 g). Mp 195.5-197.0 ° c; MS (El) m/z 272 ([M+H]+); Anal. Calcd. for C17H21NO2: C, 75.25; H, 7.80; N, 5.16; Found: C, 75.34; H, 7.82; N, 5.14.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:36](=[O:37])[CH2:35][CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: O=C(O)CC1CCOCC1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2c1OCC2
Agent: Cl
Product: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](NC(=O)CC4CCOCC4)CC3)CC2)c2c1OCC2

Procedure:
The title compound, white solid (52 mg, 74%), MS (ISP) m/z=471.6 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br)#[N:26].C1CCCCC1>C(OCC)(=O)C>[C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][O:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1)#[N:26]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@]12CCNC2=O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3C#N)cc2)CC[C@]12CCNC2=O
Yield: 90.4 %

Procedure:
The title compound (102 mg, 90%) was prepared using a similar procedure as set out earlier in Description 11 starting from 1,1-dimethylethyl (2R,5R)-2-(4-hydroxyphenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D25, 84 mg, 0.252 mmol) and 2-cyanobenzyl bromide (74 mg, 1.5 eq); Rt (HPLC): 5.37 min; Rf (cyclohexane:ethyl acetate=1:1): 0.07; MS: (ES/+) m/z: 470 [M+Na+]. C26H29N3O4 requires 447.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.OO.O.[Na].[ClH:14]>>[NH2:1][C:2]1[C:7]([Cl:14])=[N:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1
Reactant: CCc1ccc(N)cn1
Reactant: Cl
Agent: OO
Agent: [Na]
Solvent: O
Product: CCc1ccc(N)c(Cl)n1
Reaction time: 0.25 h

Procedure:
2 g (16.4 mmol) of 5-amino-2-ethylpyridine (for the preparation see G. H. Cooper and R. L. Rickard, J. Chem. Soc. C, 3257-60 (1971) are dissolved in 17.7 ml of concentrated HCl, and 2.2 ml (21.4 mol) of 30% strength H2O2 solution are then carefully added. An exothermic reaction starts. The temperature is kept at about 50° C. by cooling with an ice-bath, and when the reaction has subsided the mixture is subsequently stirred at this temperature for a further 15 minutes. For working up, the mixture is poured onto 200 ml of water, the pH is brought to 10 with 40% strength sodium hydroxidde solution and the mixture is extracted twice with 100 ml of methylene chloride each time. After drying with Na2SO4, the mixture is evaporated and the residue is stirred with petroleum ether and filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[O:11][N:10]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[O:11][N:10]=1
Reactant: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1N

Procedure:
A solution of 3-(2,6-dichlorophenyl)-5-isopropyl-4-[(3-methyl-4-nitrophenoxy)methyl]isoxazole (0.36 g, 0.86 mmol) in ethanol (3 mL) was treated with tni(II)chloride (0.71 g, 3.2 mmol) and refluxed overnight. Water (15 mL) was added and the pH adjusted to 10-11 with solid sodium carbonate. The product was then extracted with chloroform; the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and condensed to a residue which was chromatographed on silica gel using 50% ethyl acetateihexane. Yield=0.24 g. (72%) of 4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)=[CH:5][C:4]=1[NH2:16].[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:16][C:4]1[CH:5]=[C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1N
Solvent: CC(C)=O
Product: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1NC(=S)NC(=O)c1ccccc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a stirred solution of 4.20 g (19.1 mmol) 2-methoxy-5-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-phenylamine in 200 ml acetone was added dropwise 2.88 ml (21.0 mmol) benzoyl isothiocyanate and stirring continued for 1 h at room temperature. The mixture was then concentrated in vacuo to afford 7.30 g (100%) 1-benzoyl-3-[2-methoxy-5-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-phenyl]-thiourea as a yellow solid. ES-MS m/e (%): 406 (M+Na+, 13), 384 (M+H+, 100).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:13]([Cl:14])=[C:12]([O:15]C)[C:11]([O:17]C)=[CH:10][C:7]=1[CH:8]=[O:9].O>C(Cl)Cl>[Cl:5][C:6]1[C:13]([Cl:14])=[C:12]([OH:15])[C:11]([OH:17])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1cc(C=O)c(Cl)c(Cl)c1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(Cl)c1Cl
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A solution of 2.51 g of boron tribromide in methylene chloride is added to dropwise to a solution of 0.47 g of 2,3-dichloro-4,5-dimethoxybenzaldehyde in methylene chloride at -50° to -60° C. and the mixture is stirred at -50° C. to room temperature for 1 hour. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is evaporated to remove solvent. Methanol and 10% hydrochloric acid are added to the residue and the mixture is stirred at room temperature for 1 hour. To the reaction mixture are added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is washed with n-hexane and dried to give 0.38 g of 2,3-dichloro-4,5-dihydroxybenzaldehyde.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:14](#[N:17])[CH:15]=[CH2:16]>C(O)(C)(C)C>[C:1]([CH:5]1[CH2:6][C:7]([CH2:16][CH2:15][C:14]#[N:17])([CH2:16][CH2:15][C:14]#[N:17])[C:8](=[O:11])[C:9]([CH2:16][CH2:15][C:14]#[N:17])([CH2:16][CH2:15][C:14]#[N:17])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)C1CC(CCC#N)(CCC#N)C(=O)C(CCC#N)(CCC#N)C1
Yield: 75.2 %

Procedure:
A solution of 4-t-butylcyclohexanone (15.4g) and crushed KOH (0.5g) in tert.butanol (62.4g) was stirred and kept at or below 30° C. while acrylonitrile (21.2g) was added dropwise. During the addition a solid began to precipitate. When addition was complete the thick slurry was stirred for a further hour before the solid was collected by filtration. The solid was washed with water, then crystallised from 2-ethoxyethanol to yield 27.5g of 4-t-butyl-2,2,6,6-tetra(β-cyanoethyl)cyclohexanone, m.p. 175°-178° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][OH:13])[N:5]=1)(=[O:3])[CH3:2].[F:14][C:15]([F:31])([F:30])[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[C:25]([CH3:27])[C:24](O)=[C:23]([CH3:29])[CH:22]=2)[N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C.O>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][O:13][C:24]2[C:23]([CH3:29])=[CH:22][C:21]([C:18]3[N:17]=[C:16]([C:15]([F:14])([F:31])[F:30])[O:20][N:19]=3)=[CH:26][C:25]=2[CH3:27])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(CCCO)n1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(CCCOc2c(C)cc(-c3noc(C(F)(F)F)n3)cc2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 0.1 g (0.55 mmol) of 2-acetyl-6-(3-hydroxypropyl)-pyridine, 0.14 g of 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 0.175 g (1.2 eq) of triphenylphosphine in DMF under nitrogen at 0° C. was added dropwise a solution of 0.097 g (1.2 eq) of DEAD in DMF. The bright red solution was stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and the residue was purifed by MPLC to afford 2-acetyl-6-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[OH:28])[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[OH:28])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O
Agent: [Pd]
Product: CCOC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O

Procedure:
3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester (4.0 g, 10.1 mmol) was hydrogenated over 10% palladium on carbon under an atmosphere of hydrogen. Filtration and evaporation provided the title compound in quantitative yield. MS m/z 396 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:20]([NH:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2NCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18 %

Procedure:
To a solution of 0.090 g (0.35 mmol) of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one in 3.5 ml of dichloromethane was added 0.040 mL (0.36 mmol) of benzaldehyde, 0.184 g (0.87 mmol) of sodium triacetoxyborohydride and few drops of glacial acetic acid. The reaction mixture was stirred at room temperature for 15 hours. The residue was dissolved in dichloromethane and a saturated aqueous solution of sodium carbonate, extracted with dichloromethane and washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 95/5/0.5 to give 0.022 g (13%) of pure product.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.CN(C)C=O.[Cl:24][C:25]1[N:34]=[C:33](Cl)[C:32]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[N:26]=1>C(OCC)(=O)C>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:33]1[C:32]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[N:26]=[C:25]([Cl:24])[N:34]=1
Reactant: CC1NCCc2ccccc21
Reactant: Clc1nc(Cl)c2c(n1)CCCC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1c2ccccc2CCN1c1nc(Cl)nc2c1CCCC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A mixture solution of 1-methyl-1,2,3,4-tetrahydroisoquinoline(2.6 g, 17.4 mmol), triethylamine(2.8 mL), N,N-dimethylformamide (20 ml) and 2,4-dichloro-5,6,7,8-tetrahydroquinazoline(3.2 g, 15.8 mmol) prepared in the above Step 2 were stirred at 80° C. for 3 hours and cooled. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography to give 3.1 g of the titled compound. (Yield: 62.5%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1>CC(O)(C)C.C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:4][N:3]=4)=[CH:35][CH:36]=3)=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: COc1ccc2c(Cc3ccc(N)cc3)ccnc2c1
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1ccc2c(Cc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2c1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 1-chloro-4-phenylphthalazine (0.082 g, 0.34 mmol) and 4-((7-methoxyquinolin-4-yl)methyl)benzenamine (0.090 g, 0.34 mmol) in tBuOH (2.5 mL) was heated to 105° C. in a resealable tube. After 3 hrs, the mixture was cooled to RT, diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic fraction was dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography using 50-100% Hexanes:EtOAc to afford N-(4-((7-methoxyquinolin-4-yl)methyl)phenyl)-4-phenylphthalazin-1-amine as a light yellow solid. MH+=469.2@1.47 min
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:24]=[CH:23][C:22]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)=[CH:21][N:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(Br)cn2)cs1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Yield: 85 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyrimidin-2-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 110-1 and 4-trifluoromethoxyphenylboric acid (400 mg) were dissolved in dioxane (6 mL) and aqueous sodium carbonate solution (2 mol/L, 3 mL), tetrakis(triphenylphosphine)palladium (75 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (600 mg) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1)C.[H-].[Na+].Br[CH2:36][CH2:37][O:38][CH2:39][CH3:40]>>[CH2:37]([O:38][CH2:39][CH2:40][N:23]1[C:24]2[C:29](=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=3[C:4]([OH:3])=[O:32])[CH2:16][CH2:17]2)=[CH:22]1)[CH3:36]
Reactant: CCOCCBr
Reactant: CCOC(=O)c1cc(C)ccc1OCCN1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CCOCCn1cc(C2CCN(CCOc3ccc(C)cc3C(=O)O)CC2)c2cc(OC)ccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 1.4 g (3.2 mmol) of 2-{2-[4-(5-methoxy-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-5-methyl-benzoic acid ethyl ester (prepared as in Example 138, part A), 0.17 g (4.2 mmol) of NaH in 60% of mineral oil and 0.43 mL (3.8 mmol) of bromoethylethyl ether. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.470 g (35% of yield) of the desired product.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(C#N)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (1.0 g--see Preparation 3), 4-cyanophenethyl bromide (0.82 g), anhydrous potassium carbonate (2.0 g) and acetonitrile (30 ml) was heated under reflux for 10 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were dried (MgSO2) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was further purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.22 g.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1.[OH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[C:29]1(/[C:22](=[N:21]/[O:20][CH2:19][C:18]2[CH:35]=[CH:36][C:15]([O:14][CH2:2][C:3]3[O:7][N:6]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:4]=3)=[CH:16][CH:17]=2)/[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1cc(-c2ccccc2)no1
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)no2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 68.1 %

Procedure:
A mixture of 5-(chloromethyl)-3-phenylisoxazole (238 mg), methyl E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (350 mg), potassium carbonate (310 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-phenyl-4-[4-(3-phenyl-5-isoxazolylmethoxy)benzyloxyimino]butyrate (358 mg, yield 62%) as a colorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.