Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5])C.[Br-].S(=O)(=O)(O)O.[CH2:17](OCC)[CH3:18]>>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]1([OH:5])[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1cccs1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Product: OC1(c2cccs2)CC1
Reaction time: 1.5 h

Procedure:
2.00 ml (14.88 mmol) ethylthiophene-2-carboxylate and 0.44 ml (1.45 mmol) titanium tetra-isopropyloxide are placed in 56 ml diethyl ether, 10.51 ml (31.54 mmol) ethylmagnesum bromide (Grignard reagent in tetrahydrofuran) in 28 ml diethyl ether are added dropwise within 1 hour, while the temperature should not rise above 20° C. The reaction mixture is stirred for 1.5 hours, then hydrolysed with 180 ml 10% sulphuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.300 g (14% of theoretical)
Reaction SMILES: F.[CH3:2][N:3]([CH3:27])[C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=3[N+:24]([O-:26])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[CH:6][N:5]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O>>[CH3:2][N:3]([CH3:27])[C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[CH:19][C:18]=3[N+:24]([O-:26])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[CH:6][N:5]=1
Reactant: CN(C)c1ncc(-c2cccc(Nc3ccc(I)cc3[N+](=O)[O-])c2)cn1
Reactant: OB(O)c1ccco1
Agent: F
Product: CN(C)c1ncc(-c2cccc(Nc3ccc(-c4ccco4)cc3[N+](=O)[O-])c2)cn1
Yield: 89 %

Procedure:
N-(3-(2-(Dimethylamino)pyrimid-5-yl)phenyl)-4-(2-furanyl)-2-nitroaniline (7m) was prepared analogously from 6h (Example 10) and 2-furanylboronic acid in 89% yield. Mp 160-161° C.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1.Cl.O>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C(=CNc1ccccc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
10 g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.1 g (118 mmol) of aniline were dissolved at 40° C. in 200 ml of isopropanol. The solution was admixed with 3.6 ml (43.5 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 10 min. 200 ml of deionized water were added, the suspension was cooled to 10° C. and the crystallized product was filtered off.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:13][NH:14][C:15]([NH2:17])=[S:16].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:13][NH:14][C:15]1[S:16][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:17]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CNc1nc(-c2ccc(C#N)cc2)cs1
Temperature: 40 °C
Yield: 102.2 %

Procedure:
Slurry 4-cyanophenacyl bromide (1.12 g, 5 mmol) in absolute ethanol (25 mL). Heat to 40° C. to dissolve, then add N-methyl-thiourea (0.45 g, 5 mmol) and sodium bicarbonate (0.42 g, 5 mmol), and heat to reflux for 5 h. Cool to room temperature, filter the resulting off-white solid and wash with hexane (10 mL). Partition aqueous/ethanolic filtrate between water/EtOAc (4:1) and extract aqueous phase with EtOAc (2×25 mL). Dry the combined organic extracts over Na2SO4, concentrate in vacuo and combine with filtered solid from crude reaction mixture to obtain the desired intermediate (1.1 g, 99%) as an off-white solid suitable for use without additional purification. MS (ES+) m/z: 216 (M+H)+.
Reaction SMILES: [Br-:1].[Na+].[CH:3](=[C:6]([C:11]([CH2:13]Cl)=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH3:5]>CN(C)C=O>[CH:3](=[C:6]([C:11]([CH2:13][Br:1])=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH3:5]
Reactant: [Br-]
Reactant: CCC=C(C(=O)CCl)C(=O)OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC=C(C(=O)CBr)C(=O)OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
In 10.23 g of N,N-dimethylformamide was dissolved 11.45 g of the concentrated solution (pure weight of methyl 2-propylidene-4-chloroacetoacetate: 4.57 g), and cooled to 10° C. To this mixture was added 6.17 g of sodium bromide, and thereafter heated to 22° C. and vigorously stirred at 22±2° C. for 2 hours. The resulting reaction solution was cooled to 5° C. and washed with 20 g of water, followed by being separated into an aqueous and organic layers. The high-performance liquid chromatography analysis of the organic layer indicated that this layer contained 4.66 g of methyl 2-propylidene-4-bromoacetoacetate (82.6% yield, E/Z ratio=52/48) and 9.7% of the starting material methyl 2-propylidene-4-chloroacetoacetate remained.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:13][C@H:14]([NH:34][C:35](=[O:37])[CH3:36])[C@H:15]([OH:33])[CH2:16][NH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)C1C=CC=CC=1.[H][H].Cl>C(O)C.[Pd]>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:13][C@H:14]([NH:34][C:35](=[O:37])[CH3:36])[C@H:15]([OH:33])[CH2:16][NH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(OCc2ccccc2)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reaction time: 21 h

Procedure:
To a solution of compound 10 (0.70 g, 1.2 mmol) in 70 mL of ethanol in a Parr bottle is added 0.33 g of 10% palladium on carbon. The mixture is placed under 20 psi of hydrogen and shaken for 21 h. The mixture is filtered and the catalyst is washed with ethanol. Concentration in vacuo affords a colorless oil, which is treated with ethereal HCl to give a quantitiative yield of hydrochloride 11 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.44 (s, 1H), 7.37 (m, 2H), 7.28 (m, 1H), 6.59 (s, 1H), 6.40 (m, 1H), 6.31 (m, 1H), 4.0 (m, 1H), 3.79 (m, 1H), 2.95 (m, 2H), 2.63 (m, 4H), 2.44 (m, 1H), 2.05 (m, 2H), 1.90 (s, 3H), 1.79 (m, 2H), 1.59 (m, 1H), 1.5–1.3 (m, 3H), 1.26 (d, J=7 Hz, 6H); MS (CI) m/z 457.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](Cl)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[S-:17][C:18]#[N:19].[K+].C(OCC)C>CC(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([N:19]=[C:18]=[S:17])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(NC(N=C=S)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A solution of Example 41B (1.91 g, 6.31 mmol) in acetone (30 mL) at ambient temperature was treated with potassium thiocyanate (1.38 g, 14.1 mmol). The mixture was stirred for 6 hours and solids were removed by filtration. The filtrate was concentrated to provide a yellow residue. The residue was treated with diethyl ether, and the suspension was sonicated and filtered. Concentration of the residue and purification by recrystallization (25% ethyl acetate/hexanes) provided 1.85 mg of the desired product as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][S:14]([NH:17][CH3:18])(=[O:16])=[O:15])[CH:11]=2)[NH:6][CH:5]=1)#[N:2].[H-].[Na+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][S:14]([NH:17][CH3:18])(=[O:16])=[O:15])[CH:11]=2)[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=1)#[N:2]
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(CC#N)c2c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)Cc1ccc2c(c1)c(CC#N)cn2Cc1ccccc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
3-(Cyanomethyl)-N-methyl-1H-indole-5-methanesulphonamide (0.4 g) was dissolved in re-distilled dimethylformamide (10 ml) and treated with sodium hydride (0.132 g, 80% dispersion in oil). After 0.5 h the stirred suspension was cooled to -30° C. and treated with distilled benzyl chloride (0.19 g). The mixture was allowed to warm to 10°, stirred for 1 h and then poured onto ice (10 g). The suspension was filtered, and the solid collected and washed with water (20 ml) and cyclohexane (30 ml). The solid was purified by chromatography (M) and the appropriate fractions were combined and concentrated in vacuo to 20 ml, whereupon a solid crystallised out which was collected and dried to give the title compound (0.12 g), m.p. 133°-135°. T.l.c. (M), Rf 0.4, (KMnO4)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=[C:3]1[C:14]([O:16][CH3:17])=[O:15].[H-].[Na+].[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]N)=[CH:24][CH:23]=1)#[N:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:7]2[C:2](=[O:1])[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]2=3)=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(=O)c1cc2c([nH]c1=O)CCCCCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(n(Cc3ccc(C#N)cc3)c1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under the nitrogen gas atmosphere, methyl 2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylate (300 mg, 1.27 mmol) was dissolved in DMF (5 mL), sodium hydride (61 mg, 1.53 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After that, 4-cyanobenzylamine (274.9 mg, 1.40 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. Subsequently, water and 5% citric acid were added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was refined with silica gel (10 g) column chromatography (ethyl acetate-hexane of 1:1 in mixing ratio), and colorless solid of methyl 1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylate (AA04, 100 mg, 22%, mp: 72-75° C.) and colorless solid of methyl 2-(4-cyanophenoxy)-5,6,7,8,9,10-hexahydro-cycloocta[b]pyridine-3-carboxylate (123 mg, 28%, mp: 122-123° C.) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]1[CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[C:14](=[CH:19][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][C:11]2[CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[C:14](=[CH:19][CH:20]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: COC(=O)c1ccc(CBr)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(CSc2cccc(Br)c2)cc1C(=O)OC
Reaction time: 2 h
Yield: 97.3 %

Procedure:
5 g (26 mmol) of 3-bromothiophenol and 9.2 g (32 mmol) of dimethyl 4-bromomethylphthalate are dissolved in 150 mL of 2-butanone. 4 g (29 mmol) of potassium carbonate are added and the mixture is brought to reflux and stirred for 2 h. The reaction medium is then filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica. A yellow oil (10 g) is obtained in a yield of 100%.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:7]=1.[C-:18]#[N:19].[Na+]>C(O)C>[C:18]([C:7]1[N:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:5](=[O:16])[NH:4][C:3](=[O:17])[CH:2]=1)#[N:19]
Reactant: [C-]#N
Reactant: Cc1ccccc1Nn1cc(Br)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1Nn1c(C#N)cc(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
To 1.35 mmol of 5-bromo-1-(2-methylanilino)-2,4-pyrimidinedione in 5 ml of 50% aqueous ethanol is added 1.41 mmol of sodium cyanide. The mixture is heated to reflux for 4 hours, after which it is cooled to RT, filtered and recrystallized from ethanol to give 6-cyano-1-(2-methylanilino)-2,4-pyrimidinedione.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:13]=[C:9]2[O:10][CH2:11][CH2:12][N:8]2[N:7]=1)=O)C.[BH4-].[Li+].CO>C1COCC1>[O:10]1[CH2:11][CH2:12][N:8]2[N:7]=[C:6]([CH2:4][OH:3])[CH:13]=[C:9]12
Reactant: CCOC(=O)c1cc2n(n1)CCO2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2n(n1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To the stirred solution of ethyl2,3-dihydropyrazolo[5,1-b][1,3]oxazole-6-carboxylate (5.47 g, 35 mmol) of in 100 ml of THF was added 1.05 g of lithium borohydride and 1.54 g of methanol. The solution was heated at 40 C for 2.5 hour. The reaction was quenched by 1N HCl, and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture was adjusted pH to 8 with k2CO3. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated to an oil and column chromatographed to give 2.68 g of the desired product (65%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].[CH2:24](Br)[C:25]#[CH:26].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:26][C:25]#[CH:24])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Reactant: C#CCBr
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCn1c(C(=O)OCC)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (70.0 mg, 0.164 mmol), propargyl bromide (80% in xylene, 45.5 μL, 0.41 mmol, 2.5 eq), DBU (3.2 mL), and anhydrous THF (3.2 mL) was stirred at 50° C. under N2 for 1 h, and then at ambient temperature for 17 h. The solvent was evaporated and the resultant residue was diluted with ethyl acetate (75 mL). The organic layer was washed with water (20 mL), followed by brine (20 mL), dried (Na2SO4), filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography (silica, ISCO, 45 mL/min, Hexane:EtOAc, gradient 100:1 to 1:100). Crystallization from EtOAc-hexane gave the desired compound as a yellow solid (34.5 mg, 45.3%). 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.44 (d, J=5.87 Hz, 1H), 7.60 (s, 1H), 7.45 (dd, J=10.26 Hz, 2.0 Hz, 1H), 7.37-7.27 (m, 2H), 6.87 (t, J=9.20 Hz, 1H), 5.29 (s, 2H), 4.46 (q, J=7.14 Hz, 2H), 2.29 (t, J=2.47 Hz, 1H), 1.49-1.40 (t, J=7.20 Hz, 3H); LC-MS (method D): [M+H]+=464.0, RT=2.40 min.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(OC(F)(F)F)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-trifluoromethoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.96 (d, J=13 Hz, 2H), 2.12 (s, 1H), 2.31 (d, J=13 Hz, 2H), 2.40 (s, 2 H), 3.50 (s, 2H), 3.60 (s, 4H), 4.40 (s, 1H), 7.45-7.51 (m, 1H), 7.56-7.62 (m, 1H), 7.74 (s, 1H), 7.82-7.87 (m, 1H); MS (APCI/NH3) m/z 341 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:27]([F:29])[F:28])=[N:24][CH:25]=1>>[F:29][CH:27]([F:28])[O:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][N:15]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH:13]([CH3:17])[C:14]2=[O:16])=[CH:21][CH:22]=1
Reactant: FC(F)Oc1ccc(CBr)cn1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)F)nc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with 5-(bromomethyl)-2-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.82 min.; [M+H]+: 393.28 g/mol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([C:20]5[CH:28]=[CH:27][CH:26]=[C:25]6[C:21]=5[CH:22]=[CH:23][N:24]6C(OC(C)(C)C)=O)[CH2:15][C@@H:14]5[CH2:36][O:37][CH2:38][CH2:39][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[C:42]([OH:44])([C:41]([F:46])([F:45])[F:40])=[O:43].[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([C:20]5[CH:28]=[CH:27][CH:26]=[C:25]6[C:21]=5[CH:22]=[CH:23][NH:24]6)[CH2:15][C@@H:14]5[CH2:36][O:37][CH2:38][CH2:39][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3C[C@@H]4COCCN4c4nc(-c5cccc6[nH]ccc56)ncc43)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2ncc3c(n2)N2CCOC[C@H]2CN3c2cccc3[nH]ccc23)c2cc[nH]c2c1
Yield: 28 %

Procedure:
(R)-tert-Butyl 4-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-1H-indole-1-carboxylate (PREPARATION x65, 9 mg, 0.017 mmol) was dissolved in CH2Cl2 (1 mL) and trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 30 minutes. The material was then concentrated in vacuo and the product was purified by LC/MS using a 20-45% CH3CN gradient in H2O (with 0.035% TFA). The pure fractions were combined and lyophilized to afford a TFA salt of the title compound as a yellow solid (2 mg, 28%). 1H NMR (400 MHz, CD3CN) δ ppm 3.36-3.61 (m, 3H), 3.68-3.87 (m, 2H), 3.97-4.07 (m, 1H), 4.07-4.20 (m, 2H), 4.91-5.00 (m, 1H), 6.28-6.38 (m, 1H), 6.98-7.09 (m, 2H), 7.12-7.17 (m, 1H), 7.22-7.35 (m, 3H), 7.44-7.51 (m, 2H), 7.65-7.75 (m, 2H), 9.57-9.67 (m, 1H), 9.67-9.81 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C25H22N6O, 423.19. found 423.3.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]=[CH:9][C:10](=[CH2:12])[CH3:11]>O1CCCC1>[CH3:11][C:10]1[CH2:12][CH:2]2[CH:3]([CH2:8][CH:9]=1)[C:4](=[O:5])[O:6][C:1]2=[O:7]
Reactant: C=CC(=C)C
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: CC1=CCC2C(=O)OC(=O)C2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5-L round bottom reaction flask fitted with a condenser was charged with maleic anhydride (C2H2(CO)2O) (500 g) and tetrahydrofuran (THF) (3 L) and isoprene (CH2═C(CH3)CH═CH2) (400 g) was then added at room temperature. The reaction was mildly exothermic. The reaction mixture was stirred at room temperature for about 2 hours till the Gas Chromatography (“GC”) analysis showed the consumption of maleic anhydride. The resulting mixture containing crude 5-methyl-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione was used directly in the next step.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[OH:10].C(O[C:14]([S-])=[S:15])C.[K+]>N1C=CC=CC=1>[SH:15][C:14]1[O:10][C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[N:2]=1
Reactant: Nc1cc(O)ccc1O
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: Oc1ccc2oc(S)nc2c1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a solution of 2-aminobenzene-1,4-diol hydrochloride (3.58 g) in pyridine (40 mL) was added potassium ethylxanthate (3.91 g), and the mixture was stirred with heating under reflux for 3 hr. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in water, and the solution was acidified with 1M hydrochloric acid. The precipitated solid was collected, and washed with water to give the title compound (2.08 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=1)=O>C(O)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: Cn1cc(C(=O)CBr)cn1
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(Br)cn1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
In a 25 mL flask 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 6, 478 mg, 1.58 mmol) and 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethanone (Intermediate 96, 352 mg, 1.73 mmol) were suspended in ethanol (10 mL). The reaction mixture was heated at 80° C. for 12 h, cooled to room temperature and concentrated to one half the volume under reduced pressure. The resulting solids were filtered and washed with acetonitrile. Isolation gave 640 mg of the title compound as an off-white solid.
Reaction SMILES: CC(C)=[O:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH2:27][C:28]#[N:29])=[C:14]([CH2:25][OH:26])[CH:15]=[C:16]3[C:24]=2[C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=[CH:17]3)=[CH:8][CH:7]=1.[Mn]([O-])(=O)(=O)=O.[K+]>O>[C:28]([CH2:27][C:13]1[C:12]([C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)=[C:24]2[C:16]([CH:17]=[CH:18][C:19]3[O:23][CH2:22][O:21][C:20]=32)=[CH:15][C:14]=1[C:25]([OH:3])=[O:26])#[N:29]
Reactant: CC(C)=O
Reactant: N#CCc1c(CO)cc2ccc3c(c2c1-c1ccc(F)cc1)OCO3
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: N#CCc1c(C(=O)O)cc2ccc3c(c2c1-c1ccc(F)cc1)OCO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of acetone (5 ml) and water (2 ml) was dissolved 9-(4-fluorophenyl)-7-hydroxymethylnaphtho[1,2-d]-1,3-dioxole-8-acetonitrile (200 mg), and potassium permanganate (400 mg) was gradually added thereto. The mixture was stirred for 1 hour at room temperature and potassium permanganate (200 mg) was gradually added thereto. The insoluble substances were filtered off and 1N hydrochloric acid was added to the filtrate. The resultant precipitates were collected by suction and recrystallized from methanol to give the entitled compound (23 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([N:3](C(=O)C1C=CC(O)=CC=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].[N:38]1([C:46](=O)[CH2:47]Cl)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:46][CH2:47][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 127.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 1-azocan-1-yl-2-chloroethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (20 mg) was obtained.