Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(C)(C)C.[F-:27].[CH2:28]([N+:32]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>O1CCCC1.C(OCC)C>[F:22][C:21]([S:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]2)=[CH:19][CH:18]=1)([F:24])[F:23].[F-:27].[CH2:41]([N+:32]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:42][CH2:43][CH3:44]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ccc(SC(F)(F)F)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O[C@H]1CC[C@H](Nc2ccc(SC(F)(F)F)cc2)CC1
Temperature: 40 °C

Procedure:
[Trans-4-(tert-butyl-dimethyl-silyloxy)-cyclohexyl]-(4-trifluoromethylsulfanyl-phenyl)-amine (180 mg, 0.44 mmol, prepared in accordance with Example 28) was dissolved in tetrahydrofuran (3 mL). A molar solution of tetrabutylammonium fluoride (500 μL, 5 mmol) was then added. The resulting mixture was heated to 40° C. and then maintained at that temperature for 4 hr. After cooling to room temperature, the mixture was diluted with diethylether (20 mL), washed with water (10 mL), and washed with saturated aqueous hydrogencarbonate (10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The oily residue obtained was purified by column chromatography on silica gel (dichloromethane and then dichloromethane/methanol, 95:5). The desired product was isolated as a colorless oil with traces of tetrabutylammonium fluoride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH2:8][N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C(=O)=O.CC(C)=O.[Na]>N>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(C)cc1)CC2
Agent: N
Agent: O=C=O
Agent: [Na]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-Methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.9 g/11.8 mmol) was placed in a round bottom flask and cooled to −78 C (external CO2/acetone bath). Ammonia (ca. 20 mL) was condensed into the flask and freshly cut sodium (3 g) was carefully added in small pieces (dark blue color observed) and the reaction allowed to stir for one hour. The reaction was quenched by the addition of solid ammonium chloride followed by careful addition of diethyl ether (30 mL). The reaction was then allowed to warm to room temperature and the ammonia allowed to boil off. Water was then carefully added (50 mL) and the layers separated. The organic layer was extracted with 1 N hydrochloric acid (2×50 mL). The aqueous extracts were basified with 33% aqueous sodium hydroxide and extracted with 10% methanol/methylene chloride (3×50 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated to afford 7-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (1.7 g/81%). 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J=8.0 Hz, 1H), 6.68-6.61 (m, 2H), 3.81 (s, 3H), 2.99-2.82 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:19](O)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([N:44](CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:28]([N:29]1[CH2:30][CH2:31][N:32]([NH:44][C:19]([C@@H:9]2[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:20])[CH2:33][CH2:34]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)[C@H]1C(=O)O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)[C@H]1C(=O)NN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(tert-Butoxycarbonyl)-3-phenyl-[(2S)-2-pyrrolidinecarboxylic acid] (14) (1.50 g; 5.1 mmol) prepared according to Chung, J. Y. et al., J. Org Chem. 55:270-5 (1990) is dissolved in methylene chloride (55 mL) at ambient temperature. 1-(Diphenylmethyl)piperazine (1.62 g; 6.4 mmol), N,N-diisopropylethylamine (1.50 g; 2.25 mmol) and PyBOP (3.35 g; 6.4 mmol) are added sequentially. The reaction is stirred for 18 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (33%→50% ethyl acetate in hexanes) affording the desired product as a white solid. CIMS: MH+ 526
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[CH2:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[C:11]=1[NH:17]C(=O)OCCCC)[CH3:9].CCOCC>C(#N)C>[NH2:17][C:11]1[C:12]([F:16])=[N:13][CH:14]=[CH:15][C:10]=1[CH2:8][CH3:9]
Reactant: CCCCOC(=O)Nc1c(CC)ccnc1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCc1ccnc(F)c1N
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (2.2 g, (0.18 mmol) and sodium iodide (2.7 g, 0.18 mmol) were added to a solution of 3.6 g (0.15 mmol) of [-butyl N-(4-ethyl-2-fluoro-3-pyridyl)carbamate in 50 mL of dry acetonitrile with stirring at ambient temperature. After 2 hours the mixture was poured into ether and and the resulting solution was washed with dilute aqueous sodium bisulfite, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain an oil. This oil was purified by column chromatography to obtain 1.6 g (76 percent of theory) of the title compound as a gold oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1])[CH3:20]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 2-fluoro-4-nitro-benzoic acid (1.0 g, 5.4 mmol) in ethanol (10 ml) was treated with concentrated sulphuric acid (0.3 ml) and stirred at reflux overnight. Upon cooling to room temperature, a crystalline precipitate started to form. Precipitation was completed at 0° C., the solid was filtered, washing with ethanol/water 2:1, and dried under high vacuum, yielding 750 mg (65% yield) 2-fluoro-4-nitro-benzoic acid ethyl ester as a white solid. This was used as such in the following reaction.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:11]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][C:32]([CH3:58])([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@@H:42]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:45])[NH2:43])=[O:36])[CH3:33].C(O)C.C([BH3-])#N.[Na+]>O1CCCC1>[C:1]([NH:9][C@@H:10]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:11]([S:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH2:12][NH:43][C@H:42]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])=[O:45])[CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:35]([O:34][C:32]([CH3:58])([CH3:31])[CH3:33])=[O:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CS[C@H](C=O)C(Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CSC(CN[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A mixture of (S)-β-(benzoylamino)-α-[[(4-methoxyphenyl)methyl]thio]-benzenebutanal (isomer A) (0.59 g. 1.40 mmole), 1-[N6 -[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester (1.55 g., 3.88 mmole), and crushed 3 A° molecular sieves (2.0 g.) in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After stirring for 2 hours, sodium cyanoborohydride (0.27 g., 3 eq.) is added and stirring continued for 18 hours. The reaction mixture is filtered through Celite to remove the sieves. The filtrate is then diluted with ethyl acetate and washed with water, 1N hydrochloric acid (twice), 1N sodium bicarbonate, and brine. After drying over anhydrous MgSO4, the solvent is removed at reduced pressure to give the desired product, a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone 4:1) isomer A at Rf =0.31, and isomer B at Rf =0.15. Repeated chromatography (flash, silica gel LPS-1; chloroform:methanol, 98:2; hexane-acetone, 65:35; benzene:acetone, 4:1; ethyl acetate:hexane, 6:4; ethyl acetate:hexane, 6:4) gives 0.41 g. of 1-[N-[(3S)-3-(benzoylamino)-2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-N6 -[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester (isomer A) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[C:15]([C:38]#[C:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Nc2nc(Cl)cc(-c3ccccc3)n2)cc1Cl
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(C#Cc3ccccc3)cc(-c3ccccc3)n2)cc1Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of compound (3-chloro-4-methoxy-phenyl)-(4-chloro-6-phenyl-pyrimidin-2-yl)-amine (0.4 g, 1.15 mmol), (PPh3)4Pd (53 mg, 0.05 mmol), copper iodide (11 mg, 0.06 mmol) and triethylamine (0.93 g, 9.23 mmol) in dimethylformamide (10 mL) was stirred at 80° C. for 0.5 hour under nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C. and phenylacetylene (0.24 g, 2.30 mmol) was added to it. The mixture was stirred at 80° C. for 12 hours under nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C., diluted with water (20 mL) and extracted with ethyl acetate (3×15 mL). The organic layers were collected, combined, washed with water (10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by column chromatography using ethyl acetate-petroleum ether to give the desired product.
Reaction SMILES: [NH2:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:15][N:16]([CH3:29])[C:17]1([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:48]CCCl>>[ClH:48].[ClH:48].[CH:13]1[C:14]2[CH:2]([NH:1][CH:20]3[CH2:21][CH2:22][C:17]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)([N:16]([CH3:29])[CH3:15])[CH2:18][CH2:19]3)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C1(c2cccs2)CCC(=O)CC1
Reactant: ClCCCl
Reactant: NC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C1(c2cccs2)CCC(NC2c3ccccc3-c3ccccc32)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
362 mg 9-Aminofluorene and 434 mg 4-dimethylamino-4-thiophen-2-yl-cyclohexanone were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (5×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 440 mg of a cis/trans mixture of N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine were obtained as a white solid, from which the corresponding dihydrochloride was precipitated with 1.85 Methanolic hydrochloric acid (1.55 ml) in 2-butanone (10 ml) (460 mg; m.p. 202-205° C.).
Reaction SMILES: [N:1]([Sn](C)(C)C)=[N+:2]=[N-:3].[C:8]1([C:14]2([C:21]3[CH:28]=[C:27]([O:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[CH:26]=[CH:25][C:22]=3[C:23]#[N:24])[CH2:19][CH:18]3[CH2:20][CH:15]2[CH2:16][CH2:17]3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[C:8]1([C:14]2([C:21]3[CH:28]=[C:27]([CH:26]=[CH:25][C:22]=3[C:23]3[NH:24][N:3]=[N:2][N:1]=3)[O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:19][CH:18]3[CH2:20][CH:15]2[CH2:16][CH2:17]3)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: c1ccc(C2(c3cc(OCc4ccc5ccccc5n4)ccc3-c3nnn[nH]3)CC3CCC2C3)cc1
Temperature: 140 °C
Reaction time: 72 h

Procedure:
Azidotrimethyltin (82.0 mg, 0.40 mmol) was added to a stirred solution of 6a (40.0 mg, 0.09 mmol) in toluene (0.6 mL) at room temperature and the resulting mixture heated to 140° C. After 72 h, the reaction mixture was cooled to room temperature, and the volatiles were removed in vacuo. The residue was taken up in cold hydrogen chloride/MeOH (1 mL; saturated solution) and stirred for 20 min at room temperature. The reaction mixture was concentrated in vacuo, and the crude residue was purified by flash chromatography on silica gel (gradient elution, 0-10% methanol/methylene chloride as eluent) to furnish the title compound as an off-white foam. Rf: 0.15 (1:2 hexane:EtOAc). m/z (ES) 474 (MH)+. 1H NMR (500 M, CDCl3): δ 0.89-0.93 (m, 1H), 1.19-1.26 (m, 1H), 1.26-1.40 (m, 2H), 1.46-1.55 (m, 1H), 1.72 (br d, 1H), 1.88 (td, J=2.8, 13.6 Hz, 1H), 2.03 (dd, J=2.3, 13.7 Hz, 1H), 2.34 (br s, 1H), 3.01 (br d, J=3.6 Hz, 1H), 5.55 (s, 2H), 6.94 (dd, J=2.3, 8.4 Hz, 1H), 7.0-7.22 (m, 3H), 7.22-7.32 (m, 3H), 7.62-7.68 (m, 2H), 7.78-7.86 (m, 2H), 7.90-7.96 (m, 1H), 8.20 (m, 1H), 8.37 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)#[N:2].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:1]([C:3]1[C:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])=[CH:14][CH:15]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cnc(Nc2ccc(OCCO)cc2)nc1-c1cccs1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Nc3ncc(C#N)c(-c4cccs4)n3)cc2)cc1

Procedure:
5cyano-N-[4-(2-p-toluenesulphonyloxyethoxy)phenyl]-4-thien-2-ylpyrimidin-2-amine was prepared from 5-cyano-N-[4-(2-hydroxyethoxy)-phenyl]-4-thien-2-ylpyrimidine-2-amine (8.02 g, 23.7 mmol) and 4-toluene-sulphonylchloride (9.0 g, 47.4 mmol) to give a yellow solid (4.97 g), m.p. 160°. δH (d6 DMSO) 10.32 (1H, s), 8.84 (1H, s), 8.26 (1H, d, J 3.9 Hz), 7.99 (1H, d, J 5.0 Hz), 7.80 (2H, d, J 8.3 Hz), 7.64 (2H, m), 7.47 (2H, d, J 8.3hz), 7.33 (1H, t, J 4.5 Hz), 6.85 (2H, d, J 9.0 Hz), 4.33 (2H, t, J 4.0 Hz), 4.15 (2H, m) and 2.41 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][CH3:39]>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:5]1[CH:6]=[N:7][C:2]([N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH3:40])[CH3:33])[CH3:39])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1ccnc(N2CCOCC2)c1
Reactant: CNCCCN(C)C
Product: CN(C)CCCN(C)c1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2Cl)cn1
Yield: 73 %

Procedure:
Using an analogous procedure to that described in Example 21, 6-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 73% yield; NMR Spectrum: (DMSOd6) 1.67 (m, 2H), 2.12 (s, 6H), 2.21 (t, 2H), 3.07 (s, 3H), 3.51 (m, 4H), 3.58 (m, 2H), 3.71 (m, 4H), 6.69 (d, 1H), 7.1 (d, 1H), 7.23 (s, 1H), 7.5 (d, 1H), 8.04 (m, 2H), 8.28 (d, 1H), 8.72 (s, 1H), 9.7 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M+H+ 552 and 554.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH:7]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:5][OH:6].[H-].[Na+].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Br>CN(C=O)C>[CH3:1][O:2][N:3]=[C:4]([CH:7]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:5][O:6][CH2:36][C:35]1[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:34]=1[F:33]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CON=C(CO)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C(COCc1ccc(F)cc1F)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Treat a solution of the hydroxy-oxime (200 mg, 0.44 mmol) of Step 4 in DMF at 0° C. with NaH (12 mg, 0.48 mmol). Stir the resulting mixture for 30 mins at 0° C. Add 2,4-difluorobenzylbromide (60 μL, 0.465 mmol) in one portion and remove cooling bath. Stir the reaction for 12-18 hours at room temperature. Quench the reaction with H2O and extract with EtOAC (3×30 mL). Dry the combined organic layers over MgSO4, filter and concentrate under reduced pressure to give the crude compound as a yellow oil. Purify by silica gel chromatography (column: 2.5 cm×15 cm; pack column in 50% EtOAc/Hexane and elute using a gradient of 50-100% EtOAc/Hexane) to obtain 128 mg (0.22 mmol, 50% ) of the title compound as a pale oil. HRMS (FAB, M+H+): m/e cal'd for [C30H33N2O3Cl2F2 ]+ : 577.1836, found 577.1832.
Reaction SMILES: C(OC(=O)CC(C)=O)C.N1CCCCC1.[CH2:16]([O:18][C:19](=[O:30])[C:20]([C:27](=[O:29])[CH3:28])=[CH:21][CH:22]([CH3:26])[CH2:23][CH2:24][CH3:25])[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:19]([C:20]1[CH2:21][C:22]([CH3:26])([CH2:23][CH2:24][CH3:25])[O:29][C:27]=1[CH3:28])([O:18][CH2:16][CH3:17])=[O:30]
Reactant: CCCC(C)C=C(C(C)=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCCC1(C)CC(C(=O)OCC)=C(C)O1
Temperature: 120 °C

Procedure:
4-Carbethoxy-2,5-dimethyl-2-propyl-2,3-dihydrofuran was prepared by the acid-catalyzed rearrangement of ethyl-2-acetyl-4-methyl-2-heptenoate. The ethyl-2-acetyl-4-methyl-2-heptenoate was obtained by reacting 390 grams (3 moles) ethylacetoacetate with 300 grams (3 moles) 2-methylvaleradehyde in the presence of a small amount (10.2 grams; 0.12 mole) piperidine. For the rearrangement, 100 grams (0.47 mole) of the ethyl-2-acetyl-4-methyl-2-heptenoate was combined with 4.4 grams (0.023 mole) p-toluenesulfonic acid and 100 mls toluene. The mixture was heated at reflux (120° C.) for about 2 hours and worked up in accordance with the procedure of Example XXIV. Short path distillation of the crude product yielded 4-carbethoxy-2,5-dimethyl-2-propyl-2,3-dihydrofuran (B.P. 98°-100° C. at 2.5 mm Hg). The product had a pleasing cis-jasmine-like (jasmone, celery, jasmine absolute) odor. The structure ##STR25## was confirmed by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [O-]O.[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:13].CC(C1C=CC=CC=1)=C>>[CH3:10][C:9]([CH3:11])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:13]
Reactant: O=S(=O)(O)O
Reactant: CC(C)c1ccccc1
Agent: C=C(C)c1ccccc1
Agent: [O-]O
Product: CC(C)(O)c1ccccc1

Procedure:
cleaving cumene hydroperoxide in a first stage back mixing reactor in the presence of sulfuric acid and controlling the yield of α-methylstyrene as produced from dimethylphenylcarbinol to no more than 35%, by weight of the reaction mixture output from the first stage,
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.O[CH:28]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)[CH:29]1[CH2:31][CH:30]1[C:32]#[N:33]>ClCCCl.ClCCl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:28]([C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1)[CH:29]1[CH2:31][CH:30]1[C:32]#[N:33]
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: Cc1ccc(C(O)C2CC2C#N)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cc(F)cc23)C2CC2C#N)cc1

Procedure:
3.63 g (16.4 mmol) of indium(III) chloride and 1.9 ml (24.6 mmol) of trifluoroacetic acid were added to 4.23 g (16.4 mmol) of the compound from Example 87A and 2.56 g (13.7 mmol) of the compound from Example 158A under argon in 300 ml of 1,2-dichloroethane, and the mixture was stirred under reflux for 4 h. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 3.16 g (49% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[O:10]=[C:2]1[N:3]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)oc2ccccc21
Reaction time: 1 h
Yield: 103.1 %

Procedure:
A solution of 1,3-benzoxazol-2(3H)-one (676 mg, 5.0 mmol) in (5 mL) was added to a suspension of NaH (220 mg, 5.5 mmol) in DMF (5 mL) at room temperature, and the resulting solution was stirred for 1 h. Ethyl bromoacetate (0.55 mL, 5.0 mmol) was added to the reaction mixture, and stirring was continued for 2 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined and washed with water, brine, and dried (Na2SO4). The solvent was removed under reduced pressure to give the title compound (1.14 g, >100%) as a brown solid. MS (ES) m/e 222 [M+H]+.