Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:52][CH:51]=[CH:50][N:49]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56][C:24]2[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=2)[N:43]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: COc1nc(Cl)ccc1C#N
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1C#N

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-2-methoxypyridine-3-carbonitrile was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 6-chloro-2-methoxypyridine-3-carbonitrile in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][N:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH:6]1[O:8][CH2:7]1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCOCC1.[H-].[Na+]>O>[C:18]1([CH2:17][O:24][CH2:7][CH:6]2[CH2:5][N:4]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:3][CH:2]([CH2:16][OH:1])[O:8]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CN(CC2CO2)CC2CO2)cc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
5.48 G (0.025 mole) of N,N-bis(2,3-epoxypropyl)benzylamine is added to a mixture of 2.70 g (0.025 mole) of benzyl alcohol in 75 ml of dioxane containing 1 equivalent of sodium hydride. The reaction is allowed to cool below 40° with an ice-bath for approximately 1/2 hour and is then heated at reflux overnight. After cooling to room temperature, the entire mixture is poured slowly, with stirring, into 150 ml of water. The aqueous mixture is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined, washed with 200 ml of water and 200 ml of saturated NaCl solution. The CHCl3 layer is then dried over anhydrous NaSO4, evaporated in vacuo to yield 6.1 g (74%) of crude product as a pale yellow oil. The oil is chromatographed on 300 g of neutral Alumina III to give 5.6 g (68%) of 6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinemethanol.
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)=[O:5])=[N-].[ClH:11].CCOCC>C(O)C>[Cl:11][CH2:3][C:4]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)=[O:5]
Reactant: [N-]=[N+]=CC(=O)c1cscn1
Reactant: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C(CCl)c1cscn1

Procedure:
4-Thiazolyl diazomethyl ketone, 0.1 g, is treated in 1 ml ethanol at 0° with HCl gas for a few seconds. Dilution with ether and scratching produces a copious white ppt which is filtered and washed 3× with ether, taken up in water, the pH made to 7 with K2HPO4, and extracted 3× with ether. The ether solution is dried with MgSO4, filtered and evaporated, affording 77 mg 4-thiazolyl chloromethyl ketone. IR (CHCl3) 5.85μ. NMR (δ, CDCl3): 4.95d, J=1, CH2Cl; 8.4m, 8.95m, J=1, H-2 and H-5.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:14][CH2:13][NH:12][CH:11]([CH3:10])[CH2:16]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CN(Cc2ccc(Cl)cc2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
3.49 g (17.0 mmol) 4-Chlorobenzylbromide was added dropwise to a mixture of 2.04 g (20.4 mmol) 2-Methyl piperazine and 2.40 ml (17 mmol) triethylamine in 60 ml DMF at room temperature. The reaction mixture was stirred for 16 hours at room temperature, the poured onto aq. sodium bicarbonate solution and extracted with ethylacetate. Purification of the crude product by flash chromatography gave 2.26 g (10.1 mmol, 59%) of 1-(4-chloro-benzyl)-3-methyl-piperazine as colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:15][CH:16]([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[O:25][C:26]=1[CH3:27]>>[CH:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[O:25][C:26]=1[CH3:27])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:19])([CH3:18])[CH3:17]
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)OC(C)C
Product: Cc1ccccc1-c1nc(Cn2ccc3cc(CC(OC(C)C)C(=O)O)ccc32)c(C)o1

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-isopropoxy-propionic acid methyl ester (preparation 8) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole to give rac-2-isopropoxy-3-[1-(5-methyl-2-o-tolyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11]COC)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[OH:11][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[N:10][CH:9]=1
Reactant: COCOc1cnc(OC)cc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 0.17 mol) in THF (150 mL) was added HCl (3 N, 250 mL). The reaction was stirred at 50° C. for 1 h, cooled to RT and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with solid K2CO3. The pale yellow solid was collected, washed with water, and dried in vacuum oven (40° C.) overnight to give 5-hydroxy-2-methoxyisonicotinaldehyde (17.9 g, 74.6%). 1H NMR (400 MHz; DMSO) δ=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H); MS (ESI) m/z 154.0 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.F[B-](F)(F)F.C1(C([N+:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]1([CH:7]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)[n+]2ccccc2)cc1
Reactant: CCOC(=O)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccccc1)c1ccccn1
Temperature: 0 °C
Yield: 43.6 %

Procedure:
Ethyl phenylacetate (3.13 g, 19 mmol, 1.0 equiv) was added in a dropwise manner to a solution of LDA (19 mmol, 1 equiv) in THF (30 mL) at −78° C. The resultant solution was maintained at to −78° C. for 25 minutes, and then warmed to 0° C. for 10 minutes. Triphenylmethylpyridinium tetrafluoroborate (7.8 g, 19 mmol, 1.0 equiv) was added in one portion. The reaction mixture was allowed to warm to 23° C. overnight and then concentrated. The residue was partitioned between saturated aqueous ammonium chloride (50 mL) and ethyl acetate (50 mL). The layers were separated, and the aqueous layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (25% THF/hexanes) to afford ethyl α-phenylpyridylacetate (2.0 g).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:5]12[O:22][CH:4]1[CH2:3][CH2:2][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate (617 g, 3.37 mol) in anhydrous DCM (10 L) was added m-CPBA (989 g, 5.73 mol) in portions at 0° C. The mixture was stirred at room temperature for 1 hour. Saturated Na2S2O3 (1 L) was added and the organic layer was separated. The organic layer was washed with 5% aqueous K2CO3 (5 L×2), brine (4 L), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=100:1-20:1) to obtain pure tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7].O1CCOCC1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>O>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][CH:5]([C:4](=[O:9])[CH3:3])[C:6](=[O:8])[CH3:7])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC(C(C)=O)C(C)=O
Reaction time: 0.33 h

Procedure:
28 g of potassium hydroxide dissolved in 28 ml of water was added to a mixture of 50 g of 2,4-pentandione, and 100 ml and 115 ml of dioxane at 0 to 10° C. After 20 minutes of stirring, 125 g of bromoacetic acid ethyl ester was added dropwise and the mixture was stirred for 19 hours. The layers were separated and washed with water and diethyl ether. The organic layer was dried and 3-acetyl-4-oxo-pentanoic acid ethyl ester was isolated by fractional distillation.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,4-dichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[N:5]=[CH:4][N:3]=1.[NH3:14]>C(O)(C)C>[CH3:13][C:11]1[N:10]=[CH:9][N:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:14])[CH:7]=2)[CH:12]=1
Reactant: N
Reactant: Cc1cn(-c2cc(Cl)ncn2)cn1
Solvent: CC(C)O
Product: Cc1cn(-c2cc(N)ncn2)cn1
Yield: 68.6 %

Procedure:
A solution of 4-chloro-6-(4-methyl-1H-imidazol-1-yl)pyrimidine (1.18 g, 6.1 mmol) in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at 80° C. in a sealed vial for 18 h. After cooling the solid precipitate was filtered and dried to give 6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-amine (733 mg, 69.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (1H, d, J=1.26 Hz), 8.28 (1H, d, J=0.76 Hz), 7.49 (1H, t, J=1.13 Hz), 7.16 (2H, s), 6.50 (1H, d, J=0.76 Hz), 2.15 (3H, d, J=0.76 Hz). LCMS: RT=0.39 min, MH+=176.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[N:11][C:4]=2[NH:3]1.[OH:14]OS([O-])=O.[K+]>CN(C=O)C>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[N:11][C:4]=2[NH:3]1
Reactant: O=S([O-])OO
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2ccc(C(=O)O)nc2N1
Reaction time: 1.5 h
Yield: 70 %

Procedure:
This acid was prepared from 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (900 mg) by oxidation with Oxone (potassium peroxymonosulphate) (3.7 g) in a DMF solution (50 mL). After 1.5 hours at room temperature, dilution with water (50 mL) filtration and drying in vacuo afforded the acid as an off-white solid (687 mg, 70%): LCMS (ES) m/e 195 (M+H)+; 1H NMR δ 7.81 (d, J=8.1 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 4.77 (s, 2H).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:22][CH:21]([CH3:23])[CH:20]=[C:19]([C:11]1[NH:10][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1)[C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 65.5 %

Procedure:
A solution of 1-benzenesulfonyl-2-(3-methyl-1-m-tolyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (2.99 g) in ethanol (50 mL) and tetrahydrofuran (100 mL) was treated with 10% aqueous sodium hydroxide solution (20 mL). The reaction was stirred at 85° C. for 14 h. The reaction mixture was cooled to 25° C. and concentrated in vacuo. Water (100 mL) was added to the residue, and the solution was extracted with ethyl acetate (2×100 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. A light yellow solid was obtained and washed with ethanol (20 mL), then dried to afford 2-(3-methyl-1-m-tolylbut-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.30 g, 77.8%) as a white solid: 1H NMR (300 MHz, CDCl3): δ ppm 9.50 (s, 1H), 7.98-7.89 (m, 2H), 7.23-7.01 (m, 5H), 6.50 (s, 1H), 5.64 (d, 1H, J=10.2 Hz), 2.98-2.90 (m, 1H), 2.32 (s, 3H), 1.12 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[F:15])[CH3:2].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29]O)[C:22](=[O:28])[NH:23]2>>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:29]=[C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])[NH:23][C:22]2=[O:28])=[CH:10][C:9]=1[F:15])[CH3:17]
Reactant: O=C1Nc2cccc(F)c2C1=CO
Reactant: CCN(CC)CCCOc1ccc(N)cc1F
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3cccc(F)c32)cc1F
Yield: 67.4 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-Diethylamino-propoxy)-3-fluoro-phenylamine (720 mg, 1.5 equiv.) and 4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (358 mg, 2.00 mmol) are reacted to give the named compound as a yellow solid (541 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH3:21])[C:10]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH3:21])[C:10]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3F)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Yield: 164.2 %

Procedure:
Compound 25 (130 mg, 0.29 mmol, 1 equiv) was dissolved in EtOH (5 mL) and THF (5 mL). A solution of 1 N NaOH (2.9 mL, 2.85 mmol, 10 equiv)) was added and the solution refluxed for 1.5 h. The reaction was cooled to RT and then acidified to pH 2 with 1 N HCl. The product was extracted with EtOAc (100 mL) and the organic layer was washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered and concentrated to provide the title compound (26) (204 mg, 100%), as a pale yellow solid. 1HNMR (400 MHz, DMSO-d6): δ 7.74 (s, 1H), 7.58 (m, 2), 7.38 (m, 2H), 7.32-7.16 (m, 6H), 7.11 (m, 1H), 6.36 (m, 2H), 3.87 (s, 3H), 2.18 (s, 3H). LRMS m/z 429.4 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]=[C:11]2[C:20]3[C:15](=[N:16][NH:17][C:18]=3[N:19]=1)[CH2:14][CH2:13][N:12]2CC1C=CC(OC)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([NH:8][C:9]1[N:10]=[C:11]2[C:20]3[C:15](=[N:16][NH:17][C:18]=3[N:19]=1)[CH2:14][CH2:13][NH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCc3n[nH]c4nc(NCc5ccccc5)nc2c34)cc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CNc2nc3c4c(n[nH]c4n2)CCN3)cc1
Temperature: 65 °C

Procedure:
To N-benzyl-5-(4-methoxybenzyl)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylen-7-amine from step-2 was added neat trifluoroacetic acid(1 mL). The reaction mixture was heated at 65° C. for 4-16 h. The reaction mixture was evaporated and the crude reside was dissolved into DMSO. The crude product in DMSO was purified using reverse phase column chromatography using a Maccel AQ C18 column and a gradient of 1-95% ACN/water containing 0.05% trifluoroacetic acid, to yield the desired N-benzyl-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylen-7-amine in acceptable purities by LC/MS. LC-Mass: m/e 387 (M+1).
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[NH:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].[N:43]1(C(N2C=CN=C2)=N)C=CN=[CH:44]1>CN(C=O)C>[C:37]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]5[N:30]=[C:29]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[NH:28][N:27]=5)[CH2:24][CH2:25]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][N:12]4[C:44]([NH2:43])=[N:2][N:1]=[C:3]4[C:4]=3[CH:5]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: N=C(n1ccnc1)n1ccnc1
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Solvent: CN(C)C=O
Product: Nc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CN5CCC(c6n[nH]c(-c7ccccn7)n6)CC5)cc4)nc3ccn12
Temperature: 85 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To 5-hydrazino-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridine (I-3) (70 mg, 0.126 mmol) in DMF (1.5 mL) was added literature known 1,1-di-1H-imidazol-1-ylmethanimine (102 mg, 0.633 mmol). The reaction mixture was stirred at 85° C. for 4 hours, concentrated in vacuo, and chromatographed to furnish the desired 9-phenyl-8-(4-{[40(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl}[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine (1-4) (46 mg) as its trifluoroacetic acid salt. 1H NMR: (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.74 (d, J=4.3 Hz, 1H), 8.29-8.27 (m, 2H), 8.19 (m, 1H), 7.67 (m, 1H), 7.54-7.53 (m, 2H), 7.48-7.46 (m, 2H), 7.47 (d, J=7.7 Hz, 1H), 7.34-7.26 (m, 5H), 4.43 (s, 2H), 3.65 (br d, J=10.9 Hz, 2H), 3.46 (br s, 1H), 3.27-3.19 (m, 2H), 2.50-2.42 (m, 2H), 2.10-2.06 (m, 2H).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Al](C)C.C(O[C:17]([C:19]1[C:23]([Cl:24])=[C:22]([CH3:25])[NH:21][N:20]=1)=[O:18])C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>ClCCl>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:17]([C:19]1[C:23]([Cl:24])=[C:22]([CH3:25])[NH:21][N:20]=1)=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a stirred solution of dibutylamine (13 mL, 76 mmol) in dichloromethane (250 mL) under nitrogen atmosphere was added trimethylaluminium (38 mL, 2M in toluene, 76 mmol). The mixture was stirred at ambient temperature for 30 minutes. (4-Chloro-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (4.8 g, 25 mmol) in dichloromethane (30 mL) was added dropwise to the mixture. The reaction was stirred for 12 hours under a nitrogen atmosphere. The mixture was poured into saturated Rochelle salt solution slowly and stirred at ambient temperature for 2 hours. The organic layer was collected. The aqueous layer was extracted with dichloromethane and combined with the organic layer. The organic phase was brine-washed, dried over sodium sulfate, filtered, concentrated down, and dried. The residue was purified by eluting through a silica gel column with a 0 to 100% ethyl acetate/heptane gradient to afford the title compound (4.7 g, 68% yield) as a clear oil. MS (ESI) [m/e, (M+H)+]=272.4. 1H NMR (400 MHz, chloroform-d) δ ppm 3.50 (t, J=7.5 Hz, 2H), 3.37 (t, J=7.5 Hz, 2H), 2.28 (s, 3H), 1.64 (quin, J=7.5 Hz, 2H), 1.44-1.55 (m, 2H), 1.30-1.43 (m, 2H), 1.10-1.22 (m, 2H), 0.97 (t, J=8.0 Hz, 3H), 0.82 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:37][CH3:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.[CH3:48][O:49][CH2:50][CH2:51]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.[Cl-].[Na+].O>[F:47][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:37][CH3:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:51][CH2:50][O:49][CH3:48])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCOC)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 6-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-hexanoate (120 mg) is dissolved in tetrahydrofuran (1 ml), and thereto are added 2-methoxyethanol (21 μl) and triphenylphosphine (69 mg), and thereto is added dropwise 40% diethyl azodicarboxylate in toluene (115 μl) under water-cooling, and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=6:1) to give ethyl 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoate (120 mg). MS (m/z): 739 [M+H]+