Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][C:11]1[C:20]([Br:21])=[C:19]2[C:14]([C:15](=[O:32])[C:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:17]([CH:22]([CH3:24])[CH3:23])[O:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40](Br)[CH:41]=[CH2:42]>CN(C)C=O.O>[CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:42][CH:41]=[CH2:40])[C:11]1[C:20]([Br:21])=[C:19]2[C:14]([C:15](=[O:32])[C:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:17]([CH:22]([CH3:24])[CH3:23])[O:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1oc2c(Br)c(NC(=O)OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)OCc1ccccc1)c1ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc2c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of [8-bromo-3-(4-chlorophenyl)-2-isopropyl-4-oxo-4H-chromen-7-yl]carbamic acid benzyl ester (0.231 g, 0.44 mmol) and cesium carbonate (0.228 g, 0.701 mmol, 1.6 eq.) in N,N-dimethylformamide (10 ml) is treated with allyl bromide (0.058 g, 0.042 ml, 0.48 mmol, 1.1 eq.), and the mixture is stirred at room temperature for 4 h. The mixture is diluted with water and washed twice with ethyl acetate. The aqueous phase is additionally washed with methylene chloride. The combined organic phases are dried (magnesium sulfate) and filtered and the solvent is removed by evaporation in vacuo to afford the title compound as a yellow solid. The product is used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH3:20])[CH2:9][CH3:10]>C1C=CC=CC=1>[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:3]([CH2:2][C:1]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([CH2:8][CH2:9][CH3:10])[C:12]=2[CH3:20])=[O:7])[C:4]([OH:6])=[O:5])=[C:12]1[CH3:20])[CH2:9][CH3:10]
Reactant: CCCn1c(C)cc2ccccc21
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: CCCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CCC)c3ccccc23)c2ccccc21
Temperature: 25 °C
Yield: 33.1 %

Procedure:
A stirred solution of 20.0 g (0.204 mole) of maleic anhydride and 70.0 g (0.408 mole) of 1-n-propyl-2-methylindole in 200 ml of benzene was heated at reflux for a period of approximately eighteen hours and then allowed to cool to ambient temperature. The solid which separated from the cooled solution was collected by filtration, washed with fresh chilled benzene and dried in vacuo at 60° C to obtain 30.0 g of 2,4-bis(1-n-propyl-2-methyl-3-indolyl)-4-oxobutanoic acid (Formula VII: R=CH3CH2CH2 ; R1 =CH3 ; Y=H) as a white solid melting over the range 210° to 215° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][SH:23])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:23][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: O=c1cc(Cl)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1cc(SCc2ccc(Cl)cc2)cc[nH]1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-chloropyridin-2(1H)-one (100 mg, 0.77 mmol), K2CO3 (320 mg, 2.32 mmol) and (4-chlorophenyl)methanethiol (612 mg, 3.86 mmol) was stirred at 100° C. for 18 hours. After cooling the reaction to RT and was dilution with CH2Cl2 (5 mL), the crude product was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, employing LC-MS to identify the fractions containing the desired product) to afford 4-(4-chlorobenzylthio)pyridin-2(1H)-one 8A (96 mg, 46.9% yield). 1H NMR (400 MHz, Chloroform-D) δ ppm 12.30 (1H, br. s.), 7.28-7.43 (4H, m), 7.15 (1H, d, J=7.03 Hz), 6.28 (1H, d, J=1.51 Hz), 6.11 (1H, dd, J=6.90, 1.88 Hz), 4.11 (2H, s).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][O:15][C:7]1[CH:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(OCCF)cc1O
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCCF)cc1OCC(C)(C)CNC(=O)OC(C)(C)C
Yield: 72 %

Procedure:
Using a procedure similar to that of Example 26-B, methyl 4-(2-fluoroethoxy)-2-hydroxybenzoate (3.6 g, 17.8 mmol) is alkylated with 3-tert-butoxycarbonylamino-2,2-dimethylpropanol (3.62 g, 17.8 mmol) to afford methyl 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-fluoroethoxy)benzoate (5.12 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7]S(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[O:24][CH:23]=[CH:22]2.O>CN(C=O)C>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[O:24][CH:23]=[CH:22]2
Reactant: O=c1occc2cc(O)ccc12
Reactant: CS(=O)(=O)OCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1occc2cc(OC[C@H]3CCCO3)ccc12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
Methanesulfonic acid tetrahydrofuran-2-ylmethyl ester (2.7 g) and cesium carbonate (12 g) were added to a solution of 6-hydroxyisochromen-1-one (2 g) in DMF (50 mL) and the mixture was stirred at 80° C. for 7 h. After addition of water, the mixture was extracted with dichloromethane, dried over magnesium sulfate and concentrated. The product with the molecular weight of 246.27 (C14H14O4) was obtained in this way; MS (ESI): 247 (M+H+). 6-[(R)-1-(Tetrahydrofuran-2-yl)methoxy]isochromen-1-one was synthesized analogously.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccncc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3ccncc3)C2=O)sc1C(=O)O

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(pyridin-4-ylmethyl) imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 319.2 (M+1).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.COC1C(OC)=C(OC)C=C(/[CH:46]=[CH:47]/[C:48]([N:50]2[C:55](=[O:56])[CH:54]=[CH:53][CH2:52]C2)=[O:49])C=1.CN(C)CCO>C1(C)C=CC=CC=1.C1COCC1>[C:48]([NH:50][C:55](=[O:56])/[CH:54]=[CH:53]/[CH3:52])(=[O:49])[C:47]([CH3:46])=[CH2:1]
Reactant: COc1cc(/C=C/C(=O)N2CCC=CC2=O)cc(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CN(C)CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Experimental Procedure: Triphenylphosphine (92.0 mg, 0.35 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (DIAD, 71.0 mg, 0.35 mmol) were dissolved to a 1:1 mixture of THF and toluene (4 mL); then mono-demethylated piperlongumine (50.0 mg, 0.18 mmol) was added. After 10 min, 2-(dimethylamino) ethanol (31.0 mg, 0.35 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 h. At the end, the solvent was evaporated under vacuum, and the crude product was subjected to flash chromatography (hexane/ethyl acetate=100/0 to 50:50), to afford the desired product in 90% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:32])[CH:10]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:12]3[C:13]([F:15])=[CH:14][C:9]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]4=[O:7])=[CH:10][C:11]=3[F:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCCCC4=O)cc3F)CC2)c(C)c1
Yield: 48.4 %

Procedure:
Using piperidin-2-one (51 mg) and (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 111 and by the reaction and treatment in the same manner as in Example 1, the title compound (101 mg) was obtained.
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C:15]1[CH:16]=[C:17]([S:26][C@H:27]([CH3:31])[C:28](Cl)=[O:29])[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:22]([C:19]1[CH:18]=[C:17]([S:26][C@H:27]([CH3:31])[C:28]([N:9]2[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]2=[O:10])=[O:29])[CH:16]=[C:15]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:20]=1[OH:21])([CH3:23])([CH3:24])[CH3:25]
Reactant: C[C@@H](Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)Cl
Reactant: C=CC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of 60% sodium hydride (665 mg, 19.0 mmol) and toluene (40 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (2.0 g, 18.0 mmol) in toluene (20 mL) over a 30 min period. The cooling bath was removed and the solution was allowed to warm to room temperature and stir there for a 30 min period to ensure complete anion generation. To the anion at 25° C. was added dropwise a solution of (2R)-2-(3,5-di-t-butyl-4-hydroxyphenyl)thiopropanoyl chloride (29, 6.21 g, 19.0 mmol) in toluene (20 mL) over a 20 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 2:1). Water (100 mL) was added to the reaction and the phases were separated. The aqueous phase was extracted with t-butyl methyl ether (2×100 mL). The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution (1×250 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×24 cm length) using hexane and ethyl acetate (10:1) afforded 2.32 g (32%) of (5S)-N-((2R)-2-(3,5-di-t-butyl-4-hydroxyphenyl)thiopropanoyl)-5-ethenylpyrrolidin-2-one (33a) as a white crystalline material: mp 105°-106° C.; 1H NMR (CDCl3) δ1.37-1.42 (m, 21 H), 1.79-1.86 (m, 1 H), 1.97-2.05 (m, 1 H), 2.32-2.41 (m, 1 H), 2.57-2.67 (m, 1 H), 4.71-4.75 (t, J=6.8 Hz, 1 H), 5.03-5.17 (m, 3 H), 5.33 (s, --OH, 1 H), 5.78-5.87 (m, 1 H), 7.23 (s, 2 H); 13C NMR (CDCl3) δ174.7, 172.6, 154.7, 136.3, 135.7, 132.7, 120.9, 115.3, 58.8, 44.1, 34.3, 31.9, 30.2, 23.9, 16.4; IR (KBr) 3581 (s), 2964 (s), 1748 (vs), 1684 (vs), 1426 (s), 1345 (s), 1227 (vs), 1198 (s), 917 (w), 885 (w) cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:17]=[C:18]([CH3:20])[CH3:19].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([C:14]([O:16][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:15])[CH3:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 95 h

Procedure:
A solution of N-[(4-fluorophenyl)sulfonyl]-D-alanine from Example 3a (8.00 g, 32.4 mmol), isobutene (120 mL), and concentrated sulfuric acid (0.5 mL) in 1,4-dioxane (20 mL) and CH2Cl2 (60 mL) was added to a 500 mL high pressure bottle and sealed. The mixture was shaken at room temperature for 95 hours at a pressure of 18 psi. The mixture was poured into an aqueous solution containing 20 g of sodium bicarbonate, which was cooled by an ice bath. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed successively with water and brine, dried with MgSO4, and concentrated to a clear, yellow oil (6.06 g). Chromatography on silica gel (20% ethyl acetate in hexane) afforded N-[(4-fluorophenyl)sulfonyl]-D-alanine, 1,1-dimethylethyl ester, as a white solid (5.00 g, 51% yield): Anal. calc'd for C13H18NO4FS: C, 51.47; H, 5.98; N, 4.62. Found: C, 51.39; H, 5.82; N, 4.53.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[CH2:9][C:10]#[N:11].S(=O)(=O)(O)[OH:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[CH2:9][C:10]([NH2:11])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: N#CCC(=O)c1ccccc1Cl
Product: NC(=O)CC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 17.0 g (94.65 mmole) of 3-(2-chloro-phenyl)-3-oxo-propionitrile and 50 mL of sulfuric acid was stirred at room temperature for 18 hours. The mixture was poured into ice-water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 20:80-70:30) to give 14.12 g of 3-(2-chloro-phenyl)-3-oxo-propionamide.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:17])[CH:11]=[CH:12][O:13][C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH3:24][CH:25]([CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[CH2:26][CH2:27][O:28][C:29](=[O:35])[CH2:30]CC(Cl)=O>C1COCC1.CCOCC>[CH:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:17])[CH:11]=[CH:12][O:13][C:14](=[O:16])[CH2:15][CH2:30][C:29]([O:28][CH2:27][CH2:26][CH:25]([CH3:24])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])=[O:35])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC=CC(C)c1cccc(C(C)C)c1
Reactant: CC(C)=CCCC(C)CCOC(=O)CCC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)=CCCC(C)CCOC(=O)CCC(=O)OC=CC(C)c1cccc(C(C)C)c1
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A solution of 7.60 g acetic acid 3-(3-isopropyl-phenyl)-but-1-enyl ester in 50 ml of THF was cooled to −70° C. A solution of 5.00 g potassium-tert-butoxide in 50 ml of THF was added at 70° C. and the resulting reaction mixture was stirred for 2 hours at the same temperature. 11.20 g 3-chlorocarbonyl-propionic acid 3,7-dimethyl-oct-6-enyl ester was then dropped in and the reaction mixture was stirred for another 2 hours at −70° C. Then the reaction mixture was diluted with ether, washed with saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The residue was purified by chromatography to yield 7.10 g of a yellow oil.
Reaction SMILES: [CH:1]1([C:4](=[O:21])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH3:16])[C:9]=2[S:17]([CH3:20])(=[O:19])=[O:18])=[O:7])[CH2:3][CH2:2]1.[CH2:22]([O:24][CH:25](OCC)OCC)[CH3:23]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:21])[C:5](=[CH:25][O:24][CH2:22][CH3:23])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH3:16])[C:9]=2[S:17]([CH3:20])(=[O:19])=[O:18])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1c(F)ccc(C(=O)CC(=O)C2CC2)c1S(C)(=O)=O
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(F)c(OC)c1S(C)(=O)=O)C(=O)C1CC1
Yield: 95.9 %

Procedure:
A mixture of 3-cyclopropyl-1-(4-fluoro-3-methoxy-2-methylsulphonylphenyl)propane-1,3-dione (5.4 g) and triethylorthoformate (4.8 g) in acetic anhydride (4.5 g) was heated under reflux for 4 hours. The mixture was evaporated to give 3-cyclopropyl-2-ethoxymethylene-1-(4-fluoro-3-methoxy-2-methylsulphonylphenyl)propane-1,3-dione (6.1 g) as a red oil, which was used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][CH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH2:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]4[NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1CN
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Reaction time: 1.3 h

Procedure:
A mixture of 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 15a, (0.42 g, 0.90 mmol) and tert-butyl trans-2-(aminomethyl)cyclohexylcarbamate (0.24 g, 1.06 mmol) were heated in THF (10 mL) to 70° C. After 1.3 hours, the mixture was concentrated in vacuo. Flash chromatography (SiO2, 0-60% EA/Hex, gradient elution) provided the desired intermediate, tert-butyl trans-2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexylcarbamate, 14e, as a racemic mixture of trans isomers, which was taken into the next reaction without further purification (0.52 g, 92% yield).
Reaction SMILES: [C:1]([NH2:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)Br.[P:14]([OH:17])([OH:16])[OH:15]>O1CCOCC1.O>[C:2]1([C:1]([NH2:9])([P:14]([OH:17])(=[O:15])[OH:16])[P:14]([OH:17])(=[O:16])[OH:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: OP(O)O
Agent: BrP(Br)Br
Solvent: O
Solvent: C1COCCO1
Product: NC(c1ccccc1)(P(=O)(O)O)P(=O)(O)O

Procedure:
120 parts of benzamide were suspended in 300 parts of dioxan and reacted with 541 parts of phosphorus tribromide. Then 82 parts of phosphorous acid dissolved in dioxan were added at about 20°C, and the mixture was heated at 60° to 70° C for 3 to 4 hours. The reaction mixture was poured on ice and then concentrated. Subsequently, the mixture was extracted with acetone and then with ether. The residue was isolated, dissolved in water and precipitated again with ethyl acetate/acetone. The precipitate, the trihydrate of 1-phenyl-1-aminomethane-1,1-diphosphonic acid was isolated and dried in air. The yield amounts to 18%, based on PBr3.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:17]([N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH2:3][CH2:4]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1(c2ccc3c(c2)OCO3)CCNCC1
Reactant: BrCCc1ccccc1
Solvent: CC(C)=O
Product: OC1(c2ccc3c(c2)OCO3)CCN(CCc2ccccc2)CC1

Procedure:
2.2 g. 4-Hydroxy-4-(3.4-methylene dioxy phenyl)-piperidine are dissolved hot in 35 ml. acetone, the solution is mixed with 0.95 g β phenethyl bromide and the reaction mixture is refluxed.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.Cl.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:27]1([NH:33][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[N:15][C:7]=2[O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([S:2][CH3:1])[CH:4]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncccc2C(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]nicotinic acid (200 mg, 0.77 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (427 ul, 3.07 mmol) was added followed by cyclohexylamine hydrochloride (88 ug, 0.77 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (50 ml) and diethyl diethyl ether (50 ml). The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 35:65) as eluant to give a white solid which was recrystallised from diethyl diethyl ether/pentane to give N-cyclohexyl-2-[3-(methylsulfanyl)phenoxy]nicotinamide (134 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([O:15][CH3:16])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:18](N)=[NH:19]>C(N)=O>[CH2:13]([O:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:19][CH:18]=[N:1]2)=[CH:8][C:9]=1[O:15][CH3:16])[CH3:14]
Reactant: N=CN
Reactant: CCOc1cc(N)c(C(=O)OC)cc1OC
Agent: Cl
Solvent: NC=O
Product: CCOc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 130 °C
Yield: 69.8 %

Procedure:
A mixture of methyl 2-amino-4-ethoxy-5-methoxybenzoate (4.43 g, 19.7 mmol) and formamidine hydrochloride (2.255 g, 28 mmol) in formamide (20 mL) was heated at 130° C. for 8 hours. The reaction mixture was quenched with water, filtered, washed with water, and dried under vacuum with P2O5 to give 7-ethoxy-6-methoxyquinazolin-4(3H)-one as solid (3.029 g, 70%). 1H NMR (300 MHz, DMSO-d6) δ 12.1 (br, 1H), 7.97 (s, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 4.16 (q, 2H), 3.87 (s, 3H), 1.38 (t, 3H); LC-MS (ESI) m/z 221 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[CH3:2].Cl[C:26]1[C:35]2[C:30](=[CH:31][C:32]([C:36]([F:39])([F:38])[F:37])=[CH:33][CH:34]=2)[N:29]=[CH:28][CH:27]=1>>[CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:26]3[C:35]4[C:30](=[CH:31][C:32]([C:36]([F:39])([F:37])[F:38])=[CH:33][CH:34]=4)[N:29]=[CH:28][CH:27]=3)=[CH:22][CH:23]=2)[CH2:13][CH2:12]1)[CH3:2]
Reactant: CCc1cccc(N2CCN(Cc3ccc(N)cc3)CC2)c1CC
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: CCc1cccc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)c1CC

Procedure:
In the manner given in Example 1C, 1-(2,3-diethylphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(2,3-diethylphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1CNC(=O)C1.[Br:22][Br-]Br>O1CCCC1>[Br:22][CH2:14][C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: COc1cc(C(=O)CBr)cc(OC)c1OC
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
3',4',5'-Trimethoxyacetophenone (15.0 g) and pyrrolidone hydrotribromide (35.39 g) were dissolved in tetrahydrofuran (225 ml), followed by stirring at 40° C. for one hour. The reaction solution was cooled to room temperature, precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained crude crystals were washed with hexane (100 ml) to give 2-bromo-3',4',5'-trimethoxyacetophenone (Compound XIa, 12.20 g).