Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.O.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:18]([O:17][C:15]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=2)[CH2:2]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.5 %

Procedure:
A solution of 8.00 g (49 mmol) of 6-Methoxy-1,2,3,4-tetrahydro-isoquinoline in 196 mL of 48% hydrobromic acid was refluxed for 3 h. The mixture was then concentrated and coevaporated several times with ethanol. The resulting slurry was filtered and dried under vacuum to give 7.43 g of 1,2,3,4-Tetrahydro-isoquinolin-6-ol hydrobromide as a solid. To 7.38 g of the crude hydrobromide dissolved in 117 mL each of dioxane and water was added 6.34 g (35.3 mmol) of benzyl chloroformate with ice bath cooling. A 1 M solution of potassium carbonate was slowly added until a pH of 10 was maintained. The mixture was stirred overnight at room temperature. Excess dioxane was removed by evaporation, and the resulting aqueous mixture was acidified with 1 N HCl and the product extracted with ethyl acetate. The organic portion was washed with water and brine, dried over Na2SO4 and concentrated to give 10.4 g of an oil which was crystallized from ether/hexane to give 7.05 g of 7D as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH:10](Br)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CN(C)C=O>C(N(CC)CC)C>[CH2:1]([O:8][C:9](=[O:16])[CH:10]([O:25][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(Br)C(=O)OCc1ccccc1
Reactant: O=C(O)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(OC(=O)c1ccncc1)C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
A total of 29.5 g of benzyl-(RS)-α-bromo-isocaproate was added dropwise at 60° with stirring over a period of 15 minutes to a solution of 12.8 g of isonicotinic acid in a mixture of 60 ml. of dimethylformamide and 14.8 ml of triethylamine. The reaction mixture was stirred for 5 hours at 90°. The triethylamine hydrobromide was then filtered off by suction and the filtrate evaporated under reduced pressure at 60°. The residue was dissolved in 100 ml of ethyl acetate and filtered and the filtrate washed three times with 15 ml portions of 1-N potassium bicarbonate solution and twice with 20 ml portions of water. The ethyl acetate solution was dried with magnesium sulphate and evaporated under reduced pressure at 45°. Benzyl-(RS)-2-(isonicotinoyloxy)-isocaproate was obtained as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C(O)C>[CH2:13]([O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]2[NH:28][C:27]1[CH:29]=[CH:30][C:24]([O:23][CH2:22][CH:21]([OH:20])[CH2:31][OH:32])=[CH:25][CH:26]=1)[CH3:14]
Reactant: Nc1ccc(OCC(O)CO)cc1
Reactant: CCOC(=O)c1cnc2ccc(OCC)nc2c1Cl
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(OCC)nc2c1Nc1ccc(OCC(O)CO)cc1

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-1,5-naphthyridine-3-carboxylate (2.0 g), absolute ethanol (30 ml) and 4-(2,3-dihydroxypropoxy)aniline (1.38 g) was boiled under reflux for 1 hour. The reaction mixture was hot filtered and the filtrate evaporated to dryness. The residue was triturated with dichloromethane and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography on silica using ethyl acetate as the mobile phase to give ethyl 6-ethoxy-4-[4-(2,3-dihydroxypropoxy)anilino]-1,5-naphthyridine-3-carboxylate, m.p. 143°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([CH:11]=[CH2:12])[CH:4]=1.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:11]=[CH2:12]
Reactant: BrP(Br)Br
Reactant: C=Cc1cc(OC)ccc1CO
Solvent: O
Solvent: CCOCC
Product: C=Cc1cc(OC)ccc1CBr

Procedure:
To a solution of (4-methoxy-2-vinylphenyl)-methanol (7.90 g, 48.2 mmol) in diethyl ether (100 mL) at 0° C. is added PBr3 (5.0 mL, 53 mmol) over 1 min. Water is added carefully to destroy excess PBr3. The mixture is partitioned carefully between EtOAc and NaHCO3 (plus a small amount of KOH to adjust pH to 7˜8). The organic extract is dried with MgSO4 and concentrated to give the title compound and it is used directly in the next step: 1H NMR (CDCl3) δ 3.83 (s, 3H), 4.57 (s, 2H), 5.44 (dd, J=1, 11 Hz, 1H), 5.74 (dd, J=1, 17 Hz, 1H), 6.81 (dd, J=3, 8 Hz, 1H), 7.03 (d, J=2 Hz, 1H), 7.06 (dd, J=11, 17 Hz, 1H), 7.25 (d, J=8 Hz, 1H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][C:9]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:24][CH2:25][CH2:26][N:27]5C(=O)C6=CC=CC=C6C5=O)[CH:17]=4)[C:12](=[O:38])[C:11]=3[CH:10]=2)C(=O)C2=CC=CC=C12.O.NN.Cl>CO.O>[NH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19](=[O:23])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:24][CH2:25][CH2:26][NH2:27])[CH:17]=3)[C:12](=[O:38])[C:11]=2[CH:10]=1
Reactant: O=C1c2ccc(OCCN3C(=O)c4ccccc4C3=O)cc2C(=O)c2ccc(OCCN3C(=O)c4ccccc4C3=O)cc21
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: NCCOc1ccc2c(c1)C(=O)c1ccc(OCCN)cc1C2=O
Temperature: 0 °C

Procedure:
A mixture of 17.4 g (0.03 mole) of the intermediate 2,6-bis-(2-phthalimidoethoxy)anthraquinone, prepared in (A) above, 200 ml. of methanol, and 3.6 g. (0.06 mole) of hydrazine hydrate (85%) is heated to reflux for four hours. Water (100 ml.) is added and the methanol boiled out of the mixture. Then, 75 ml. of 37% hydrochloric acid is added and the resulting mixture heated to reflux for another hour. The mixture is allowed to cool, then chilled at 0° C., and the precipitate of phthalhydrazide removed by filtration with suction. The filtrate is evaporated to dryness, made alkaline with 10% sodium hydroxide, and the base is extracted into chloroform. The chloroform layer is washed with water, dried with anhydrous magnesium sulfate, filtered, and the chloroform evaporated. The 2,6-bis-(2-aminoethoxy)anthraquinone base is converted to the dihydrochloride salt as described in Example 1, and recrystallized from a solvent or solvent mixture such as isopropanol, ethanol/ether, or butanone/methanol. In a similar manner, 2,7-bis(2-aminoethoxy)anthraquinone can be prepared from 2,7-bis(2-chloroethoxy)anthraquinone.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[N:14]=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>CCOCC>[CH2:20]([O:19][C:15]1[N:14]=[C:13]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][CH:16]=1)[CH3:21]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCOc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(OCC)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (4.5 ml, 11.3 mmol) was added to a stirred solution of 2-bromo-6-ethoxypyridine (Rec. Trav. chim., 1965, 84, 53; 2.1 g, 11.3 mmol) in anhydrous ether (25 ml), under nitrogen, at about −40° C. After about 20 minutes, tri-n-butyltin chloride (3.1 ml, 11.4 mmol) was slowly added and, after a further 15 minutes, the reaction mixture was allowed to warm to room temperature. The resulting mixture was quenched by the addition of aqueous ammonium chloride solution, then the organic phase separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using an elution gradient of pentane:dichloromethane (100:0 to 80:20), to give the title compound (1.6 g, 34%) as a colourless oil. δ(CDCl3): 0.90 (t,9H), 1.08 (t,6H), 1.30-1.42 (m,9H), 1.58 (m,6H), 4.40 (q,2H), 6.53 (d,1H), 6.97 (d,1H), 7.39 (dd,1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O>[CH:21]1([O:1][C:2]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[N:13][N:12]=[N:11]3)=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: O=Cc1cc(-n2cnnn2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(-n2cnnn2)ccc1OC1CCCC1

Procedure:
A mixture of 2-hydroxy-5tetrazol-1-yl-benzaldehyde (500 mg) and potassium carbonate (431 mg) in dimethylformamide (5 ml) at 20° was treated with cyclopentyl bromide (0.33 ml). After 24 h water (20 ml) was added and the mixture extracted with ethyl acetate (2×25 ml). The organics were washed with water (25 ml) and brine (25 ml) and dried (Na2SO4). Evaporation gave a yellow solid which was purified by FCC (ethyl acetate/cyclohexane (2:1)) to give the title compound, as a yellow solid (334 mg).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([O-:3])=[O:2].C([O:11][CH:12](O)[C:13]([F:16])([F:15])[F:14])C.C(=O)([O-])[O-].[K+].[K+]>CC(=O)OCC>[N+:1]([CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH:12]([OH:11])[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2]
Reactant: CCCCC[N+](=O)[O-]
Reactant: CCOC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCC(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a stirred solution of 1-nitropentane (1.0 g, 8.5 mmol) and trifluoroacetaldehyde ethyl hemiacetal (1.2 mL, 8.5 mL) was added potassium carbonate (K2CO3 ) (0.06 g, 0.43 mmol). The reaction mixture was heated at 60° C. under Ar for 3 h. The mixture was cooled to R.T., then taken up in EA (50 mL). The organic layer was washed with 1 N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated to give (2SR)-(3SR)-3-nitro-1,1,1-trifluoro-2-heptanol as a crude oil (1.7 g, 93%): 1H NMR (CDCl3, 300 MHz) δ 0.91 (t, 3H, J=7.2 Hz), 1.24-1.43 (m, 4H), 2.04-2.11 (m, 2H), 4.08-4.77 (m, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[K+].[CH3:15]I>CC(C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1ccc2cc([N+](=O)[O-])ccc21
Yield: 92.3 %

Procedure:
To a solution of 5-nitro-1H-indole (2.0 g, 12.3 mmol) in acetone (20 ml), powdered potassium hydroxide (3.4 g, 60.7 mmol, 5 eq) was added followed by the addition methyl iodide (2.61 g, 18.5 mmol, 1.5 eq) at 0° C. The reaction mixture was heated to reflux for 10 hr. The solvent was evaporated and water was added. The compound was extracted with ethyl acetate, dried over anhydrous sodium sulphate, filtered and the organic layer was concentrated to dryness to yield 1-methyl-5-nitro-1H-indole (2.0 g, 92%). The crude compound was used in the next stage without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]=O)=[CH:5][CH:4]=1)#[N:2].O.[CH3:15]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH:12]=[CH2:15]
Reactant: COC(C)(C)C
Reactant: N#Cc1ccc(CCCC=O)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=CCCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A suspension of 6.5 g of methyl-triphenylphosphonium bromide in 50 ml of t-butyl methyl ether was treated with 2.1 g of potassium t-butylate at -5° C. and the mixture was then stirred at room temperature for 40 minutes. Subsequently, the mixture was treated at 0° C. with a solution of 2.6 g of 4-(p-cyanophenyl)butyraldehyde in 30 ml of t-butyl methyl ether and the resulting mixture was stirred for 1 hour at room temperature. Thereafter, the reaction mixture was treated with water and extracted three times with diethyl ether. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and concentrated. The crystalline residue was dissolved in hot ethyl acetate, the solution was treated with petroleum ether and the precipitated triphenylphosphine was filtered off. The oil obtained after concentrating the filtrate was purified by chromatography on silica gel with ethyl acetate/petroleum ether (vol. 5:95), whereby 1.92 g of p-(4-pentenyl)benzonitrile were isolated as a light yellowish liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([OH:12])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:30]3[C@H:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([N:28]1[CH2:27][C@H:26]2[C@H:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:12]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CC(C(=O)O)c1ccccc1N(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1N(C)C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
N,N'-carbonyldiimidazole (0.85 g) is added to a solution, cooled to 5° C., of (RS)-2-(2-dimethylaminophenyl)propionic acid (1 g) in dichloromethane (30 cc), and the mixture is stirred for 30 minutes at this temperature. A solution of (3aR, 7aR)-7,7-diphenylperhydro-4-isoindolone hydrochloride (1.7 g) and triethylamine (1.4 cc) in dichloromethane (30 cc) is added. The reaction mixture is stirred at 20° C. for 16 hours, washed with water (2×100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 3 cm, height 50 cm), eluting under a nitrogen pressure of 0.5 bar with ethyl acetate and collecting 125-cc fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR, 7aR)-2-[(RS)-2-(2-dimethylaminophenyl)propionyl]-7,7-diphenylperhydro-4-isoindolone (1.4 g) in the form of white meringue-like product;
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CBr)[CH:20]([C:36]1[CH:41]=[CH:40][C:39]([O:42]C)=[CH:38][CH:37]=1)[CH2:19]2>CN(C)C=O.O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:3][CH2:2][C:1]([OH:9])=[O:8])[CH:20]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[CH2:19]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C2Cc3cc(OC)ccc3C2CCCCCCCCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CC(c1ccc(O)cc1)C2CCCCCCCCCCCC(=O)O
Temperature: 50 °C

Procedure:
A solution of diethyl malonate (0.64 g.) in dimethylformamide (10 ml.) was added to a stirred suspension of sodium hydride (0.14 g. of a 50% suspension in mineral oil) in dimethylformamide (10 ml.) which was maintained under an atmosphere of argon, and the mixture was stirred and heated to 50° C. for 5 minutes and then cooled to laboratory temperature. 10-[(1RS, 2RS)-5-Methoxy-2-p-methoxyphenylindan-1-yl]decyl bromide (1.2 g.) was added and the mixture was stirred at laboratory temperature for 16 hours and then diluted with water and extracted with diethyl ether. The extract was dried and evaporated to dryness and a solution of the residue (1.47 g.) in ethanol (10 ml.) was added dropwise to a stirred solution of potassium hydroxide (1.4 g.) in water (10 ml.) which was heated under reflux. The mixture was stirred and heated under reflux for 10 minutes, diluted with water and extracted with diethyl ether. The aqueous solution was acidified with concentrated aqueous hydrochloric acid and extracted with diethyl ether, and the extract was dried and evaporated to dryness. There was thus obtained as residue 12-[(1RS, 2RS)-5-methoxy-2-p-hydroxyphenylindan-1-yl]dodecanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>CN(C=O)C>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:48](=[O:50])[CH3:49])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(C)=O)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (0.0551 g, 0.097 mmol) and pyridine (0.05 mL, 0.618 mmol) in DMF (2 mL) was treated dropwise with acetic anhydride (Aldrich) (10.0 μl, 0.107 mmol) at 0° C. The orange solution was stirred at rt overnight. The mixture was concentrated in vacuo to reduce the solvent volume to about 1 mL. Water (2 mL) and brine (20 mL) were added and the aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give N-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)acetamide (0.060 g, 100% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 11.88 (s, 1H); 8.75 (d, J=2.19 Hz, 1H); 8.47 (s, 1H); 8.24 (d, J=2.34 Hz, 1H); 8.06-8.16 (m, 1H); 7.86-7.95 (m, 1H); 7.83 (br. s., 1H); 7.19 (t, J=8.48 Hz, 4H); 6.87 (d, J=6.58 Hz, 4H); 4.84 (d, J=10.96 Hz, 4H); 3.80 (d, J=4.09 Hz, 6H); 2.59 (s, 3H); 2.20 (s, 3H). m/z (ESI, +ve ion) 611.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:2]3[C:3]4[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:24]=2)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2cccc(-c3ccc(F)cc3C#N)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: N#Cc1cc(F)ccc1-c1cccc(-c2ccnc3nc(C(F)(F)F)ccc23)c1
Yield: 25.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (91 mg, 0.28 mmol) as described in Example 7 part g), affording 4-fluoro-3′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile (22 mg, 26%). δH (360 MHz, CDCl3) 7.39-7.45 (1H, m), 7.51-7.76 (7H, m), 7.87 (1H, d, J 8.4), 8.71 (1H, d, J 8.4), 9.29 (1H, d, J 4.6). m/z (ES+) 394 [MH]+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])C.[NH2:20][C:21]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:29][C:27]1[CH:28]=[C:21]2[C:22]([CH:23]=[C:5]([N:6]3[C:7](=[O:16])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14]3=[O:15])[CH:4]=[N:20]2)=[CH:25][CH:26]=1
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Reactant: Nc1cc(Br)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cnc2cc(Br)ccc2c1
Yield: 45.3 %

Procedure:
A mixture of 2-(2,2-diethoxyethyl)isoindoline-1,3-dione (3.16 g, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (1.902 g, 10.00 mmol) in toluene (60 mL) was heated under reflux using Dean-Stark apparatus overnight. A very dark/black solid precipitated overnight and was collected, washed with toluene and hexanes, then dissolved in chloroform fortified with DMF. The mixture was washed with aq. NaHCO3 solution (×2), ensuring any precipitate was dissolved in additional chloroform during separation. The organic layer was dried (sodium sulfate) and evaporated onto silica gel. Purification by flash chromatography (0-2% methanol in dichloromethane) afforded the title compound (1.6 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (d, 1 H), 8.57 (d, J=2.3 Hz, 1 H), 8.35 (d, J=1.8 Hz, 1 H), 8.11 (d, J=8.6 Hz, 1 H), 8.09-8.02 (m, 2 H), 8.02-7.93 (m, 2 H), 7.87 (dd, J=1.9, 8.7 Hz, 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]([CH3:79])[CH:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1>CN1C(=O)CCC1>[CH3:71][N:72]([CH3:79])[CH:73]1[CH2:78][CH2:77][N:76]([C:32]([C:31]2[CH:35]=[CH:36][C:28]([NH:27][C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([C:9]4[N:10]=[C:11]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[N:12]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[N:8]=4)=[CH:24][CH:23]=3)=[O:37])=[CH:29][CH:30]=2)=[O:33])[CH2:75][CH2:74]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)nc(N5CCOCC5)n4)cc3)cc2)CC1
Yield: 50.2 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with N,N-dimethylpiperidin-4-amine (51 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (30.6 mg, 52% yield); MS (ESI) m/z=616.7