Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[O:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][CH2:11]1>CO>[CH3:1][O:2][C:3]([CH2:4][CH2:5][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:8][CH2:9][CH:10]1[O:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][CH2:11]1)=[O:6]
Reactant: NCCC1COc2ccccc2O1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CCC1COc2ccccc2O1
Reaction time: 6 h
Yield: 91.5 %

Procedure:
34.1 g (0.396 mol) of acrylic acid methyl ester are added at room temperature to a solution of 32.25 g (0.18 mol) of 2-(2-aminoethyl)-benzo-1,4-dioxan [J. Augustin et al., J. Med. Chem. 8, 446 (1965)] in 250 ml of methanol. The reaction mixture is stirred for 6 hours at 50° and, after cooling, is concentrated by evaporation in vacuo. 57.9 g (91.5%) of N,N-bis(2-methoxycarbonylethyl)-N-[2-(benzo-1,4-dioxan-2-yl)ethyl]-amine are obtained in the form of a red oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(OC)(C)(C)C>[C:18]([O:17][C:16](=[O:22])[NH:15][O:14][S:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:12])=[O:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Reaction time: 2 h

Procedure:
2,4,6-trimethylbenzenesulfonyl chloride (5 g, 0.022 mol) was added to a solution of methyl tertiary-butyl ether (50 mL) under nitrogen atmosphere at 0° C., followed by the addition of tert-butyl hydroxycarbamate (3.04 g, 0.22 mol) at 0° C. Next, triethylamine (3.24 mL, 0.023 mol) was added drop wise to the reaction mixture, which was then it was allowed to stir for 2 h. The reaction product was filtered through sintered funnel and the filtrate was concentrated under vacuum up to ¾ volume. Hexane (50 mL) was added to the concentrated filtrate, which was then stirred for 20 min wherein a precipitate formed. The participate was collected by filtration and the solid dried to afford tert-butyl(mesitylsulfonyl)oxycarbamate. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.31 (s, 1H), 2.38 (s, 9H). MS (M+1): 316.3.
Reaction SMILES: C(O[C:4](=[NH:19])[C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH:10]=1)C.O.[NH2:21][NH2:22]>C(O)C>[NH:21]([C:4](=[NH:19])[C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH:10]=1)[NH2:22]
Reactant: NN
Reactant: CCOC(=N)c1ccc2nc(C(=O)OCC)cn2c1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn2cc(C(=N)NN)ccc2n1
Reaction time: 2 h

Procedure:
To a solution of 625 mg of ethyl 6-[ethoxy(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate in 12 mL of ethanol is added dropwise at 0-5° C. 0.2 mL of hydrazine hydrate. The reaction mixture is stirred for 2 hours, a further 73 μL of hydrazine hydrate are added and the mixture is stirred for a further 2 hours while allowing the temperature to rise to 25° C. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dried to give 600 mg of ethyl 6-[hydrazino(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate, which is used without further purification in the rest of the synthesis.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:18]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCBr
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCON=C(C(C)=O)C(=O)OCC
Yield: 99.5 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformaide (200 ml.), potassium carbonate (52 g.) and n-hexyl bromide (41.4 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g.), oil.
Reaction SMILES: C[Si](C)(C)CCOC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([C:24]3[CH:28]=[C:27]([C:29]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[NH:30])[S:26][C:25]=3[S:39][CH3:40])(=[O:23])=[O:22])[CH:16]=2)=[C:10]([NH2:41])[CH:9]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:35]([O:34][C:32](=[O:33])[NH:31][C:29]([C:27]1[S:26][C:25]([S:39][CH3:40])=[C:24]([S:21]([C:17]2[CH:16]=[C:15]([C:11]3[C:12]([CH3:14])=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=3[NH2:41])[CH:20]=[CH:19][CH:18]=2)(=[O:22])=[O:23])[CH:28]=1)=[NH:30])([CH3:37])([CH3:38])[CH3:36]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2N)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
{2-Amino-3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-4-yl}-carbamic acid 2-trimethylsilanyl-ethyl ester (1000 mg, 1.48 mmol, Example 294, step f) was dissolved into THF (25 mL). To this was added TBAF (1M, 1.62 mL, 1.62 mmol) and the reaction was warmed to 40° C. with stirring for 3 hours. Additional TBAF (1.48 mL, 1.48 mmol) was added and the reaction was stirred at rt overnight. The solvents were removed in vacuo, the residue was dissolved into EtOAc and washed with water several times (5 washes). The combined organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in the title compound as a yellow solid (800 mg, 100%). 1H-NMR (CDCl3): δ: 8.03 (s, 1H), 7.95–7.93 (m, 1H), 7.89–7.88 (m, 1H), 7.59–7.53 (m, 2H), 6.08 (m, 1H), 5.99 (m, 1H), 2.55 (s, 3H), 1.85 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of the alcohol (72.3 g, 0.31 moles) produced in Example 20 and pyridine (37.3 ml, 0.46 moles) in 300 ml of methylene chloride was added dropwise under nitrogen over two hours to a solution of 4-nitrophenyl chloroformate (92.8 g, 0.46 moles) in 600 ml of methylene chloride at room temperature. After the addition the reaction was stirred for two days at room temperature. The reaction was then extracted two times with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure. Recrystallization of the crude product from methylene chloride-diisopropyl ether gave the tide compound as a crystalline solid, mp 118-120° C.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].Cl[CH:5]([C:11]([CH3:13])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[Mg+2]>O1CCOCC1>[CH3:13][C:11]1[N:3]=[CH:1][S:2][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC=S
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: CCOC(=O)c1scnc1C
Temperature: 110 °C

Procedure:
Thioformamide (7.5 g, 122.72 mmol), ethyl 2-chloroacetoacetate (16.4 g, 99.52 mmol) and magnesium carbonate (20 g, 237.22 mmoL) were taken dioxane (100 mL) and heated at 110° C. for 4 hrs. The reaction mixture was cooled to room temperature and filtered to remove magnesium carbonate. The solvent was evaporated to dryness and the residue was taken in ether (200 mL) and washed successively with 0.5 M NaOH solution (200 mL×2) and saturated brine solution (100 mL) and dried over Na2SO4. It was filtered and evaporated to give 4-methyl-5-(ethoxycarbonyl)thiazole as an oil which was purified by silica gel column chromatography using hexanes:EtOAc (8:2, v/v) as a eluent; yield: 3.28 g (17%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([O:38][CH2:39][O:40][CH3:41])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH:17]=O)[CH:15]=3)[N:8]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:53][NH:54][CH3:55].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([O:38][CH2:39][O:40][CH3:41])[CH2:35][CH2:36][CH2:37]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:54]([CH3:55])[CH3:53])[CH:15]=3)[N:8]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CC=O)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CCN(C)C)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetaldehyde (14C) (300 mg, 0.490 mmol) in tetrahydrofuran (3.267 mL) was added sequentially acetic acid (0.056 mL, 0.980 mmol), sodium sulfate (139 mg, 0.980 mmol) and dimethylamine (0.368 mL, 0.735 mmol). The reaction was stirred for 0.5 hours at ambient temperature, and sodium triacetoxyborohydride (208 mg, 0.980 mmol) was added in a single portion. The reaction was stirred overnight and then quenched by the addition of saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated, and the aqueous layer was extracted with addition ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS ESI(+) m/z 641.2 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:32]=[CH:31][C:8]([C:9]([C:11]2[CH:30]=[CH:29][C:14]([CH2:15][S:16][C:17]3[N:18]([CH3:28])[C:19](=[O:27])[C:20]4[C:25]([CH3:26])=[CH:24][S:23][C:21]=4[N:22]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O>O1CCCC1>[CH3:28][N:18]1[C:19](=[O:27])[C:20]2[C:25]([CH3:26])=[CH:24][S:23][C:21]=2[N:22]=[C:17]1[S:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:32][CH:31]=2)=[CH:30][CH:29]=1
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(CSc3nc4scc(C)c4c(=O)n3C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Yield: 60.9 %

Procedure:
A solution of 2-[4-(4-acetoxybenzoyl)benzylthio]-3,5-dimethylthieno [2,3-d]pyrimidin-4(3H)-one (1.40 g) and 1N-sodium hydroxide/water (6.7 ml) in tetrahydrofuran (20 ml) was stirred at room temperature for 10 minutes. This reaction mixture was concentrated and the residue was dissolved in water and acidified with 1N-HCl. The resulting precipitate was extracted with ethyl acetate, washed with water, dried, and concentrated. The residue was recrystallized from methanol-ethyl acetate to provide the title compound as colorless solid (775 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>CN(C)C=O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10][C:11]1[N:15]=[CH:14][N:13]([C:24](=[O:25])[N:23]([CH3:27])[CH3:22])[N:12]=1
Reactant: Cc1cc(C)c(Sc2nc[nH]n2)c(C)c1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(Sc2ncn(C(=O)N(C)C)n2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-(2,4,6-trimethylphenyl)thio-1H-1,2,4-triazole (220 mg), anhydrous potassium carbonate (280 mg) and N,N-dimethylformamide (1 ml) was added N,N-dimethylcarbamoyl chloride (0.14 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to a silica-gel column chromatography with 10 to 15% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (276 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([Br:10])[C:3]=1[CH3:11].CS(C)=O.CC(C)([O-])C.[K+].[Cl:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1Cl>C1(C)C=CC=CC=1>[Br:10][C:4]1[C:3]([CH3:11])=[C:2]([CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][C:28]1[CH:27]=[CH:26][C:25]([N+:30]([O-:32])=[O:31])=[CH:24][C:23]=1[Cl:22])[NH2:1]
Reactant: Cc1cc(N)c(C)c(Br)c1O
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(N)c(C)c(Br)c1Oc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
Into a dry 250 milliliter round bottom flask equipped with a magnetic stirrer and nitrogen inlet was added 4-amino-2-bromo-3,6-dimethylphenol (11.94 grams, 55.3 mmol) prepared in Part B and dry dimethylsulfoxide (118 milliliters). Potassium t-butoxide (7.26 grams, 64.65 mmol) was added portionwise under nitrogen and the mixture was stirred at room temperature for 0.5 hours. Solid 3,4-dichloronitrobenzene (13.33 grams, 70.52 mmol) was then added and the reaction mixture was heated at 50° C. for 48 hours. After cooling the mixture was diluted with toluene and washed successively with saturated NH4Cl solution (3x) and with 5% NaOH solution until the aqueous washes remained colorless. This was followed by washes with water and brine, drying over Na2SO4 and solvent removal under reduced pressure to afford the crude product (9.4 grams) as a dark red-brown oil. Flash column chromatography on 650 grams of silica gel (3:1 hexane:ethyl acetate) afforded pure 3-bromo-4-(2 -chloro-4-nitrophenoxy)-2,5-dimethylaniline (4.7 grams, 12.6 mmol, 23%) as a yellow-brown solid. H'-NMR (CDCl3) 8.42 (d, J=2 Hz, 1H), 8.01 (d,d; J=2, 9 Hz; 1H), 6.55 (d, J=9 Hz, 1H), 6.58 (S, 1H), 3.73 (brS, 2H), 2.28 (S, 3H), 2.06 (S, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: COc1ccc(N)cc1C(F)(F)F
Product: COc1ccc(NC(=O)c2cc(Cl)ccc2O)cc1C(F)(F)F
Yield: 79.1 %

Procedure:
Using 5-chlorosalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].Cl[CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([O:13][CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Oc1cc(OC)c(OC)c(OC)c1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4,5-Trimethoxyphenol (5,83 g) was dissolved in DMF (60 mL), and potassium tert-butoxide (3.55 g) was added to the solution under ice cooling. Ethyl 2-chloroaceto-acetate (4.46 mL) was then added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was heated to 80° C. and stirred for 2 hours. After allowing the reaction mixture to cool, water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane 1:3) to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:24][NH:25][CH:26]([CH2:28][CH3:29])[CH3:27]>N1C=CC=CC=1>[CH3:24][N:25]([CH:26]([CH3:27])[CH2:28][CH3:29])[C:17]([C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:18]
Reactant: O=C(O)c1cc(-c2ccccc2)c2ccccc2c1
Reactant: CCC(C)NC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2)c2ccccc2c1
Yield: 54.9 %

Procedure:
Operations are carried out as for Example 1, starting from 4.3 g of 4-phenyl naphthalene 2-carboxylic acid, 20 ml of thionyl chloride and then 1.5 g of N-methyl 2-butanamine in 20 ml of pyridine. 3 g of N-methyl N(1-methyl propyl) 4-phenyl naphthalene 2-carboxamide, melting at 108° C., are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[OH:24])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:44]1[O:46][C@H:45]1[CH2:47]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:21]([C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:23])[C:4]([O:24][CH2:47][C@H:45]4[CH2:44][O:46]4)=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:13]=2)[CH:19]=[C:18]([CH3:20])[N:17]=1)[CH3:22]
Reactant: OC[C@H]1CO1
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cc(C)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H]4CO4)c(CC)c3)no2)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.2 %

Procedure:
To a solution of 2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (150 mg, 0.464 mmol) in THF (10 mL), PPh3 (146 mg, 0.557 mmol) and (S)-glycidol (52 mg, 0.696 mmol) is added. The mixture is cooled to 0° C. before DEAD (303 mg, 0.696 mmol, 320 μL of a 40% solution in toluene) is added. The mixture is warmed to rt and stirred for 1 h. The solvent is evaporated and the residue is purified by chromatography on prep. TLC plates with heptane:EA 1:1 to give (R)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (201 mg) as a white solid; LC-MS*: tR=1.10* min; [M+1]+=380.42.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C:4]1[C:5]([Cl:33])=[N:6][C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]([NH2:32])=[O:31])[CH:21]=2)=[N:8][C:9]=1[N:10]([CH3:12])[CH3:11].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Cl:33][C:5]1[C:4]([CH2:3][C:2]#[N:1])=[C:9]([N:10]([CH3:12])[CH3:11])[N:8]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]([NH2:32])=[O:31])[CH:21]=2)[N:6]=1
Reactant: CN(C)c1nc(Cc2ccccc2-c2cc(C(N)=O)cc3ccccc23)nc(Cl)c1CC(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CN(C)c1nc(Cc2ccccc2-c2cc(C(N)=O)cc3ccccc23)nc(Cl)c1CC#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
To a solution of N-(4-{([5-(2-amino-2-oxoethyl)-4-chloro-6-(dimethylamino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide (0.360 g, 0.76 mmol) in pyridine (15 mL) at rt was added trifluoroacetic anhydride (0.161 mL, 1.14 mmol) dropwise and the resulting reaction mixture was stirred at room temperature for 15 hours. The volatiles were removed in vacuo and the remaining residue was partitioned between EtOAc and saturated aqueous ammonium chloride solution. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the resulting crude product by silica gel chromatography eluting with 20% EtOH in CHCl3 gave N-(4-{([4-chloro-5-(cyanomethyl)-6-(dimethylamino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide as an amorphous solid (0.345 g, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Li]C(C)(C)C.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[O:34][C:33]([C:35]([O:37]C)=O)=[N:32][N:31]=1>C1COCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[O:34][C:33]([C:35](=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:32][N:31]=1
Reactant: CCCCCCCC/C=C\CCCCCCCBr
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCCCCCC=CCCCCCCCC(=O)c1nnc(-c2ccccn2)o1
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
A solution of cis-1-bromo-heptadec-8-ene (60 mg, 0.2 mmol) in THF (1 mL) was treated with t-BuLi (1.5 M in pentane, 270 μL, 0.4 mmol) at −40° C. After stirring for 30 min, the resulting alkyl lithium reagent was added to a solution of methyl 5-(pyridin-2-yl)-[1,3,4]-oxadiazole-2-carboxylate (20 mg, 0.1 mmol) in THF (2 mL) at −40° C. The reaction mixture was stirred for 4 h before it was quenched with the addition of brine. The mixture was extracted with EtOAc, concentrated, and purified by flash chromatography (SiO2, 1×3 cm, 30% EtOAc-hexanes) to provide the title compound (8.5 mg, 23%) as white solid. 1H NMR (400 MHz, CDCl3) 8.85 (dd, J=5, 1.2 Hz, 1H), 8.30 (dd, J=7.9, 1.2 Hz, 1H), 7.94 (td, J=7.6, 1.5 Hz, 1H), 7.54 (ddd, J=7.6, 4.7, 1.2 Hz, 1H), 5.34-5.37 (m, 2H), 3.22 (t, J=7.3 Hz, 2H), 2.02 (m, 4H), 1.82 (m, 2H), 1.27-1.41 (m, 20H), 0.88 (t, J=6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 187.2, 165.1, 161.2, 150.8, 142.6, 150.8, 142.6, 137.3, 130.0, 129.7, 126.7, 124.0, 40.1, 31.9, 29.8, 29.7, 29.5, 29.3, 29.2, 29.1, 29.0, 27.2, 27.1, 23.6, 22.7, 14.1; MALDI-FTMS m/z 412.2955 (C25H37N3O2+H+ requires 412.2958).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[O:42])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[C:43]([Mg]Br)#[CH:44]>O1CCCC1>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]([OH:42])[CH:43]=[CH2:44])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: C#C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Solvent: C1CCOC1
Product: C=CC(O)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 71-(a) except for using 1.02 g (1.64 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 15-(a), and using 4 ml of tetrahydrofuran solution containing 1M ethynyl magnesium bromide in place of tetrahydrofuran solution containing ethynyl magnesium bromide, whereby 1.01 g of the title compound was obtained as a yellowish oil substantially quantitatively.