Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].C(O[C:20](=O)/[CH:21]=[CH:22]/CC)C.C(O)(=O)C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:20]([CH2:21][CH3:22])[CH2:3][C:2](=[O:4])[NH:5]1)=[O:8])[CH3:11]
Reactant: CC/C=C/C(=O)OCC
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)NC(=O)CC1CC
Yield: 87.1 %

Procedure:
To 150 mg of sodium dissolved in 150 mL of absolute ethanol was added diethyl acetamidomalonate (5.3 g, 25 mmol) and ethyl-(2E)-pent-2-enoate (3.5 g, 27.3 mmol). The reaction mixture was then refluxed for 20 h. After this period of time, 2 mL of glacial acetic acid was added, volatiles were removed under pressure with the aid of a water aspirator and heating bath. On cooling the residue solidified. The residue was dissolved in 50 mL of toluene and to this was added 20 mL of petroleum ether. The product precipitated when the mixture was cooled. The crystals were collected and washed with water and further dried in vacuo to obtain a white solid (5.6 g, 79.77%). Mass Spectrum (+ESI): 258 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:10]=1>>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[C:11]([NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1)[N:10]=[C:9]2[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3c(C)cccc3c(Oc3ccccc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 321(MH+).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11][CH:10]=1)([OH:8])=[O:7].N>S(=O)(=O)(O)O>[C:6]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N+:1]([O-:4])=[O:2])[CH:12]=[N:11][CH:10]=1)([OH:8])=[O:7]
Reactant: O=C(O)c1cncc2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cncc2cccc([N+](=O)[O-])c12
Reaction time: 16 h
Yield: 77.9 %

Procedure:
A nitrating mixture obtained by dissolving potassium nitrate (94 g.) in concentrated sulphuric acid (d= 1.83) (750 cc.) is added dropwise, over the course of 1 hour, to a solution of 4-carboxy-isoquinoline (146.8 g.) in concentrated sulphuric acid (d= 1.83) (880 cc.). The solution obtained is kept at a temperature of about 20° C. for 16 hours and is then poured onto ice (18 kg.). Ammonia (11 N) (5.5 liters) is added gradually, whilst stirring and keeping the temperature of the mixture at between 15° and 20° C. The yellow precipitate which has appeared is filtered off, washed with water (800 cc. in total) and then dried. 4-Carboxy-5-nitro-isoquinoline (144 g.) melting at 285° is thus obtained.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:26]3[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=3[CH3:28])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: Cc1ccccc1C=O
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 57.4 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 2-methylbenzaldehyde (0.5 g, 4.2 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.072 g, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH2:11][CH2:12][C:13](O)=[O:14])=[O:5])[CH3:2].B>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCC(=O)O)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCCO)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Yield: 98.5 %

Procedure:
5-(2-Carboxy-ethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1e (9.75 g, 30 mmol) was dissolved in 90 ml of anhydrous tetrahydrofuran under stirring, and added dropwise slowly with a solution of borane in tetrahydrofuran (90 ml, 1 mol/L, 90 mmol) to the solution while maintaining the temperature at −10˜−5° C. in an ice-salt bath under an argon atmosphere. Upon completion of the addition, the ice-salt bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred for 2-3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to evaporate the solvent. The residue was added with 100 ml of saturated sodium bicarbonate solution and 100 ml of ethyl acetate, and stirred until dissolved. The resulting mixture was extracted with ethyl acetate (100 ml×3). The combined organic extracts were washed with 100 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(3-hydroxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1f (9.2 g, yield 98%) as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])[CH3:2].[N+](=[CH2:19])=[N-]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([CH:5]1[CH2:19][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(OC)cc1F
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1c1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
(E)-3-(2-Fluoro-4-methoxy-phenyl)-acrylic acid ethyl ester (0.3 g, 1.34 mmol) obtained in Step A was dissolved in THF (10 mL), and diazomethane solution (21.4 mL, 5.36 mmol, 0.25M ether) was added thereto. After the reactant was cooled to 0˜5° C., palladium(II) acetate (45 mg, 0.2 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 5 hours. After the termination of the reaction, the reactant was filtered by using celite, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/10) to obtain the title compound (0.16 g, 51%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[C:18]([NH:20][N:21]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH3:23])[N:17]=[C:16]([CH3:33])[N:15]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:15]=[C:16]([CH3:33])[N:17]=[C:18]([NH:20][N:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([N:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[CH3:23])[CH:19]=1
Reactant: CC(=NNc1cc(-c2ccccc2NC(=O)OC(C)(C)C)nc(C)n1)c1ccc(N(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=NNc1cc(-c2ccccc2N)nc(C)n1)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
[2-(6-{N′-[1-(4-dimethylamino-phenyl)-ethylidene]-hydrazino}-2-methyl-pyrimidin-4-yl)-phenyl]-carbamic acid tert-butyl ester was dissolved in 10 mL of 5% trifluoroacetic acid in dichloromethane. The resultant reaction mixture was stirred at room temperature for 2 hours before being concentrated in vacuo. The residue was dissolved in methanol and the pH was adjusted to 7 with potassium bicarbonate. After filtration the methanol was concentrated in vacuo and the residue was purified by Si gel chromatography (1:1 ethyl acetate:hexanes) yielding 140 mg (60%) of the title compound as a brown solid. HPLC Purity: 95%.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)=[O:9])([CH3:6])[C:3]([O-])=[O:4]>Cl.O1CCOCC1>[CH3:1][C:2]1([CH3:6])[NH:7][C:8](=[O:9])[N:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:3]1=[O:4]
Reactant: CC(C)(NC(=O)Nc1ccc(SC(F)(F)F)cc1)C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)cc2)C1=O
Temperature: 4 °C

Procedure:
30 g of 2-methyl-2-[3-(4-trifluoromethylsulfanylphenyl)ureido]propionate 3 are dissolved in a mixture of 225 ml of 3 N HCl and 230 ml of dioxane, refluxed for 6 hours and, after cooling to 4° C., the product 5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione is isolated in the form of white crystals (24.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([O:22]CC4C=CC=CC=4)[CH:16]=[CH:15][C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([OH:22])[CH:16]=[CH:15][C:12]=3[C:13]=2[CH3:14])=[CH:30][CH:31]=1
Reactant: CCCc1c(OCc2ccccc2)ccc2c(C)c(C(=O)c3ccc(OC)cc3)oc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc2c(C)c(Cc3ccc(OC)cc3)oc12
Yield: 14.2 %

Procedure:
A solution of 2-(p-methoxybenzoyl)-3-methyl-6-benzyloxy-7-propylbenzofuran (1.04 gm, 2.5 mmoles) in ethanol (100 mL) was hydrogenated in a Parr hydrogenator in the presence of 10% palladium on charcoal for a period of 24 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel and eluted with 25% ethylacetate in hexane to yield 110 mg of 2-(p-methoxybenzyl)-3-methyl-6-hydroxy-7-propylbenzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[N:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:21]=[N:20][CH:19]=[CH:18][C:3]=1[C:4]1[O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Br)nc2c1
Temperature: 50 °C
Yield: 87.1 %

Procedure:
To a mixture of 0.29 g of 3-bromo-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 4 ml of tetrahydrofuran and 0.25 g of triphenylphosphine, 0.42 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.24 g of 2-(3-bromopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 27”).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccccc1OCCCCCl
Product: COc1ccccc1OCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(4-chlorobutoxy)-2-methoxybenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[OH:1][C:2]([CH2:14][C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(=O)c1ccncc1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Product: CCOC(=O)C(O)(CC(=O)c1ccncc1)C(=O)OCC

Procedure:
Diethyl ketomalonate (17.4 g, 0.1 mol) was heated with 4-acetylpyridine (12.1 g, 0.1 mol) at 120° C. for 15 h under nitrogen to provide diethyl 2-hydroxy-2-(4-pyridyl)cabonylmethyl-malonate as a crystalline solid. The diester was refluxed in ethanol with a slight excess of hydrazine hydrate hydrochloride for 15 h to provide 3-hydroxy-6-(4-pyridyl)-4-carbethoxy-pyridazine (4, Scheme 1). The above ester was recrystallized from ethanol, hydrolyzed with aqueous sodium hydroxide followed by careful neutralization with hydrochloric acid to afford 3-hydroxy-6-(4-pyridyl)-pyridazine-4-carboxylic acid (5, Scheme 1). The acid was dissolved in phosphorous oxychloride containing a catalytic amount of DMF and the mixture was allowed to react at 80° C. for 4 h to provide 3-chloro-4-chlorocarbonyl-6-(4-pyridyl)pyridazine (6, Scheme 1) as a dark oil The above dichloride was treated with gaseous ammonia in acetonitrile to afford the title compound as a tan solid. The above dichloride was treated with excess gaseous ammonia to afford the title compound as a tan solid: 1H NMR (DMSO-d6) δ 8.80 (d, J=6 Hz, 2H), 8.59 (s, 1H), 8.20 (s, 1H), 8.17 (d, 6 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C@@H:7]([NH:11][C:12]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)=[CH:21][C:20]=2[O:34][CH3:35])=[C:16]([CH3:36])[N:15]=[C:14]([NH2:37])[N:13]=1)[CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:39]>>[C:1]([O:4][CH2:5][CH2:6][C@@H:7]([NH:11][C:12]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:40]([CH2:38][CH3:39])[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:21][C:20]=2[O:34][CH3:35])=[C:16]([CH3:36])[N:15]=[C:14]([NH2:37])[N:13]=1)[CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCNCC(=O)OCC
Reactant: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCOS(C)(=O)=O)cc1OC
Product: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN(CC)CC(=O)OCC)cc1OC

Procedure:
The sub-title compound was synthesized by the method of example 9 step (vi) from the product of example 9 step (v) (75 mg) and the product of example 1 step (vi). The sub-title compound (60 mg) was obtained as a pale yellow oil; 1H NMR (300 MHz, CDCl3); 6.81 (1H, d), 6.44 (1H, d), 6.38 (1H, dd), 4.95 (2H, br s), 4.28-4.05 (3H, m), 4.00-3.85 (4H, m), 3.85 (3H, s), 3.57 (2H, s), 3.32 (2H, s), 2.77-2.62 (4H, m), 2.36 (3H, s), 1.97 (3H, s), 1.95-1.72 (3H, m), 1.63-1.50 (1H, m), 1.48-1.33 (1H, m), 1.30-1.15 (2H, m), 1.24 (3H, t), 1.11-0.98 (2H, m), 1.03 (3H, t), 0.77 (3H, t); LC-MS: m/z 574.
Reaction SMILES: C1([C:14]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:16][C:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:18][CH:19]=2)C=CC(C(OCCCC)=O)=CC=1.IC1C=C(C=CC=1)[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:38]>>[C:27]1([C:15]2[CH:14]=[CH:19][CH:18]=[C:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[C:16]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:32]=[CH:31][CH:30]=[C:29]([C:37]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:38])[CH:28]=1
Reactant: CCCCOC(=O)c1cccc(I)c1
Reactant: CCCCOC(=O)c1ccc(-c2ccc(C(=O)OCCCC)cc2-c2ccccc2)cc1
Product: CCCCOC(=O)c1cccc(-c2cccc(C(=O)OCCCC)c2-c2ccccc2)c1

Procedure:
This compound was prepared by the procedure for dibutyl 4,4′-terphenyl dicarboxylate (CS-13). The intermediate, butyl 3-iodobenzoate, was prepared and purified by vacuum distillation, collecting the fraction bp 104-108° C./0.2 mm. A colorless oil was obtained, mass: 26.17 g (85% of theory). 1H NMR (CDCl3): δ 0.98 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 4.32 (q, 2H), 7.18 (t, 1H), 7.88 (d, 1H), 8.00 (d, 1H), 8.36 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH2:43][CH2:44][S:45][CH3:46])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH2:43][CH2:44][S:45][CH3:46])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CSCCNC(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCNCCSC)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 6.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methylsulfanylethyl)acetamide (16 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (1.8 mg) was obtained.
Reaction SMILES: C([O:5][CH2:6][C:7]1[N:11]=[C:10]([NH2:12])[NH:9][N:8]=1)(=O)CO.[CH3:13][C:14]([CH2:16][C:17]([CH3:19])=O)=O>CCO.CC(O)=O>[CH3:13][C:14]1[CH:16]=[C:17]([CH3:19])[N:9]2[N:8]=[C:7]([CH2:6][OH:5])[N:11]=[C:10]2[N:12]=1
Reactant: Nc1nc(COC(=O)CO)n[nH]1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared by a slight modification of a reported procedure (Lippman, E.; Becker, V., Z. Chem., 1974, 14, 405): A solution of (5-amino-1H-1,2,4-triazol-3-yl)methanol glycolate (30.7 g, 0.161 mol, from Step 1, above) and 2,4-pentadione (32.3 g, 0.323 mol, 2 equiv) in a mixture of EtOH (750 mL) and AcOH (250 mL) was refluxed 20 h. At the beginning the reaction mixture was clear solution, then gradually turned yellow towards the end of the heating period. The solvent was removed under reduced pressure, and the resulting yellow paste triturated with EtOH (100 mL) and stirred for 15 min. The slurry was chilled to 5° C. (ice bath) with stirring for 30 min, filtered, and washed with cold (0-5° C.) EtOH. The product was dried in vacuo at 25-30° C. to give 24 g (83.7%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].N1C=CN=C1>C(Cl)Cl>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCBr
Temperature: 25 °C

Procedure:
Tert-butyl-dimethylsilyl chloride (28.16 g, 186.8 mmol) was added in portions to a solution of 9-bromo-nonan-1-ol (27.8 g, 124.6 mmol) and imidazole (25.4 g, 373 mmol) in dry DCM (400 mL) at −10° C. under a nitrogen atmosphere. The reaction mixture was allowed to warm to RT overnight. The solids were removed by filtration and the filtrate was washed with 10% citric acid (aq), then brine, dried (MgSO4), filtered, and concentrated to dryness to afford the title compound as a yellow oil.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[C:8]([F:12])[CH:7]=[CH:6][C:5]=1[F:13].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH2:10]([C:9]1[C:8]([F:12])=[CH:7][CH:6]=[C:5]([F:13])[C:4]=1[CH2:3][C:2]1[NH:17][CH2:16][CH2:15][N:18]=1)[CH3:11]
Reactant: CCc1c(F)ccc(F)c1C=C(Br)Br
Reactant: NCCN
Product: CCc1c(F)ccc(F)c1CC1=NCCN1

Procedure:
2-(2-Ethyl-3,6-difluoro-benzyl)-4,5-dihydro-1H-imidazole was prepared from 2-(2,2-dibromo-vinyl)-3-ethyl-1,4-difluoro-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 225.3 ([M+H]+, 100%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6](F)[N:5]=1.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(F)cc(OCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1.14 g (0.0382 mol) of 80% sodium hydride were added at 25° C. under nitrogen to 70 ml of benzyl alcohol, and this mixture was stirred at 100° C. for 30 minutes. After it had been cooled to 40° C., 5.0 g (0.0382 mol) of 2-amino-4,6-difluoropyrimidine were added, and the mixture was then stirred at 100° C. for 5 hours. After the reaction was complete, a little precipitate was filtered off, and the filtrate was concentrated under 1 mbar at a bath temperature of 150° C. The viscous residue obtained in this way was induced to crystallize by trituration with cyclohexane. 6.3 g (75.2% of theory) of the title compound of melting point 96°-98° C. were obtained after filtering off, washing with water and drying.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:17]([N+]([O-])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][N:4]=1.[F-:23].[K+]>>[F:23][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:22])[CH3:1])=[N:4][CH:5]=2)[CH:18]=1
Reactant: CN(C)c1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cn1
Reactant: [F-]
Agent: [K+]
Product: CN(C)c1ccc(-c2cc(F)c3ccccc3n2)cn1
Yield: 37.4 %

Procedure:
5-(4-Fluoroquinolin-2-yl)-N,N-dimethylpyridin-2-amine T480 was prepared using general procedure M from N,N-dimethyl-5-(4-nitroquinolin-2-yl)pyridin-2-amine (4 mg, 0.014 mmol) and KF (16 mg, 0.28 mmol). The crude product was purified by silica chromatography to afford 5-(4-fluoroquinolin-2-yl)-N,N-dimethylpyridin-2-amine as a light-brown solid (1.4 mg, 37%). 1H NMR (400 MHz, CDCl3): δ 8.89 (d, J=2.8 Hz, 1H), 8.36 (dd, J=11.6 Hz, 1H), 8.09 (m, 1H), 8.04 (m, 1H), 7.73 (m, 1H), 7.51 (m, 1H), 7.47 (d, J=11.6 Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 3.19 (s, 6H); MS (ESI): 268 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[C:17]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:23]=4)=[O:21])[CH:16]=[CH:15][C:14]=3[CH3:34])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:35][CH3:36].C1(C)C=CC(S(O[CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>O>[CH3:36][O:35][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:34]
Reactant: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 100 °C
Yield: 12.2 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (250 mg), 3-methylsulphonylpropyl 4-toluenesulphonate (150 mg), cesium carbonate (501 mg) and N,N-dimethylacetamide (5 ml) was stirred and heated to 100° C. for 1 hour. After cooling the reaction mixture to ambient temperature, water was added and the precipitated solid was isolated and dried under vacuum. The material so obtained was purified by column chromatography on silica using a 10:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (38 mg); NMR: 2.14 (s, 3H), 2.13 (m, 2H), 3.02 (s, 3H), 3.24 (m, 2H), 3.49 (m, 4H), 3.68 (m, 4H), 3.93 (s, 3H), 4.29 (t, 2H), 7.08 (d, 1H), 7.16 (s, 1H), 7.21 (s, 1H), 7.27 (d, 1H), 7.58 (d, 1H), 7.76 (s, 1H), 7.83 (s, 1H), 8.25 (d, 1H), 8.27 (s, 1H), 9.4 (s, 1H), 10.28 (s, 1H); m/s: M+H+ 607.