Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][OH:21])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][O:21][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester, which was directly subjected to the following reaction.
Reaction SMILES: [NH2:1][C:2]1[N:3]([N:15]=CC2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:6]=1.O.NN.O>C(O)COCCO>[NH2:15][N:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:6]=[C:2]1[NH2:1]
Reactant: COc1ccccc1-c1cn(N=Cc2ccccc2)c(N)n1
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: COc1ccccc1-c1cn(N)c(N)n1

Procedure:
A solution of 23.2 g of 2-amino-1-benzylideneamino-4-(2-methoxyphenyl)-imidazole and 15.8 ml of hydrazine hydrate in 80 ml of diethylene glycol is stirred at 170° C. for 7 hours. After cooling, 400 ml of water are added to the reaction mixture. The product that has separated out is filtered off with suction, washed with water and recrystallized from 200 ml of ethanol. In that manner there is obtained the title compound, m.p. 195°-196° C., 1H-NMR (DMSO): δ=7.9 (d, 1H); 7.06 (m, 2H); 6.91 (m, 2H); 5.52 (s, 2H); 5.3 (s, 2H); 3.88 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:36]=[CH:35][C:25]([CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[CH2:32]([O:31][P:27]([CH2:26][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:13])[NH:21][C:22]2[CH:36]=[CH:35][C:25]([CH2:26][P:27]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:34])=[CH:24][CH:23]=2)=[CH:36][CH:35]=1)(=[O:34])[O:28][CH2:29][CH3:30])[CH3:33]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(CP(=O)(OCC)OCC)cc2)cc1)OCC
Temperature: 23 °C
Reaction time: 72 h
Yield: 59.2 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and diethyl 4-aminobenzylphosphonate (2.90 g, 11.6 mmol) in 23 mL of pyridine. The reaction mixture was stirred for 3 days at 23° C. under nitrogen atmosphere. The crude product was recrystallized from acetonitrile-DMF to yield 2.60 g of the title compound, mp 237°-238° C. (dec.).
Reaction SMILES: [SH:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][N:3]=1.[CH3:14]I>[OH-].[Na+].CO>[CH3:14][S:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][N:3]=1
Reactant: CC(C)(C)c1nnc(S)n(N)c1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(C(C)(C)C)c(=O)n1N
Temperature: 20 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
4 parts by weight of 3-mercapto-4-amino-6tert.-butyl-1,2,4-triazin-5-(4H)-one are dissolved in a mixture of 11 parts by weight of 2 normal sodium hydroxide solution and 4 parts by weight of methanol and the solution is treated at 0° C with 3.2 parts by weight of methyl iodide. The reaction mixture is then stirred at 20° C for a further 4 hours. The reaction product crystallizes out, is filtered off, dried and recrystallized from benzene. 3.52 parts by weight of 3-methylthio-4-amino-6-tert.-butyl-1,2,4-triazin-5(4H)-one (XV) of melting point 126°-127° are obtained. Yield: 82% of theory.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)CCCCC>>[C:2]1([N:15]2[C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:18][C:16]2=[O:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: O=C1CCCCC1O
Solvent: CCCCCCO
Product: O=c1[nH]c2c(n1-c1ccccc1)CCCC2
Yield: 29.6 %

Procedure:
A mixture of 4.5 g (39.4 mmol) of 2-hydroxycyclohexanone, 7.5 g (55 mmol) of phenylurea and 7 ml of hexanol is stirred under reflux for 20 hours. The mixture is concentrated under vacuum and the solid residue is recrystallized from acetone, and 2.5 g of product, m.p.=220° C., are recovered. Yield—29.6%.
Reaction SMILES: O1CCCCC1[O:7][C:8]([CH3:29])([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:9]=[CH:10]/[CH:11]1[CH2:13][C:12]1([C:19]([O:21]CC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:30](C(OCC)=O)([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[C:42]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C@@H:11]([CH:10]=[CH:9][C:8]([OH:7])([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][C@H:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]1=[O:21])([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CCOC(=O)CCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: CCCCCC(C)(/C=C/C1CC1(C(=O)OCC)C(=O)OCC)OC1CCCCO1
Product: CCCCCC(C)(O)C=C[C@H]1C[C@H](C(=O)OCC)C(=O)C1(CCCCCCC(=O)OCC)C(=O)OCC

Procedure:
For example, the use of the compound of formula 4, diethyl trans-2-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}cyclopropane-1,1-dicarboxylate, described in Example 41and the compound of formula 5, triethyl heptane-1,1,7-tricarboxylate, described in Example 42, in the procedure of Example 45 gives diethyl trans-3-(6-carboethoxyhexanyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, γmaxfilm 3500, 1725 cm-1, nmr (CDCl3) δ 0.88 (t, 3H), 4.17 (m, 6H), 5.64 (m, 2H), via the intermediate diethyl trans-3-(6-carboethoxyhexanyl)-4-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}-2-oxo-1,3-cyclopentanedicarboxylate, γmaxfilm 1730 cm-1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(O)C>O.[Pd]>[CH:6]1([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NCC(=O)O
Reactant: O=C1CCCCC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C(O)CNC1CCCCC1

Procedure:
338 g of glycine (4.5 mols) is dissolved in 1.5 liters of deionized water. The solution is put into a 1-gallon autoclave. 25 g of 10% Pd on C, 551 g of cyclohexanone (5.6 mols) and 500 ml of ethanol are added. Hydrogenation is carried out at 60° C. between 56.2 and 70.3 kg/cm2. In the course of three hours a pressure drop corresponding to 98.4 kg/cm2 is observed.
Reaction SMILES: Br[CH:2]([C:8]#[N:9])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C.O>[C:8]([CH:2]([S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])#[N:9]
Reactant: Sc1ccccc1
Reactant: CN(C)C(=O)C(Br)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)C(=O)C(C#N)Sc1ccccc1
Temperature: 50 °C

Procedure:
A suspension of 2-bromo-2-cyano-N,N-dimethylacetamide (3.80 g, 20 mmol), potassium carbonate (2.902 g, 21 mmol) and thiophenol (2.314 g, 21 mmol, 2.16 mL) in acetonitrile (20 mL) was heated to 50° C. for 3 days. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were combined and concentrated. The concentrate was purified by column chromatography on silica gel with 0-50% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 221 (M+H)+.
Reaction SMILES: C1(O)CCCCC1.[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[C:8]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCOC(=O)CCCCC
Solvent: OC1CCCCC1
Product: CCCCCC(=O)OC1CCCCC1
Yield: 95 %

Procedure:
Likewise, refluxing a toluene solution containing one equivalent of hexyl hexanoate, 2 equivalents of cyclohexanol and 1 mol % of the PNN complex 1 under argon atmosphere for 20 h resulted in 84% conversion of hexyl hexanoate as determined by GC analysis, with the exclusive formation of the ester cyclohexyl hexanoate in 83% yield (Table 8, entry 2). Notably, unlike the traditional transesterification methods, this reaction does not form an alcohol product; rather, an irreversible incorporation of both the acyl and alkoxo parts of the starting ester into the product ester takes place. While 2 equivalents of the alcohol with respect to the ester are sufficient, somewhat higher yields are obtained when 3 equivalents of alcohol were used. Thus, reaction of 3 equivalents of cyclohexanol with hexyl hexanoate resulted after 26 h in 96% conversion with 95% yield of cyclohexyl hexanoate, as observed by GC, and confirmed by GC-MS by comparison with an authentic sample (Table 8, entry 3). The pure product was isolated by evaporation of the solvent followed by passing through a basic alumina plug and analysis by NMR and GC-MS. Use of the PNP complexes 2 or 3 resulted after 20 h in 58% or 17% yield of cyclohexyl hexanoate, respectively. Studying the scope of this new reaction with regard to the secondary alcohol, reaction of hexyl hexanoate with cyclopentanol in the presence of 1 mol % 1 was carried out. After 26 h reflux in toluene, cyclopentyl hexanoate (70% yield) was formed, with 71% conversion of hexyl hexanoate (Table 8, entry 4). Similarly, upon reaction of hexyl hexanoate with excess of 1-phenylethanol, 50% conversion of hexyl hexanoate with the formation of 49% of the acylated product was observed (Table 8, entry 5). The lower conversion of the ester is a result of facile dehydrogenation of 1-phenylethanol to acetophenone (49%). Because of the expected easy dehydrogenation of the isopropyl alcohol to acetone, transesterification with this alcohol was performed in a closed vessel, to retard this dehydrogenation process. Thus, heating hexyl hexanoate with excess of isopropyl alcohol resulted after 19 h in 83% conversion of hexyl hexanoate with the formation of isopropyl hexanoate in 67% yield (entry 6). The reaction of hexyl hexanoate and 3-pentanol led to 91% conversion of the ester with formation of 3-pentyl hexanoate in 90% yield after 26 h reflux (entry 7).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[C:19]1([C@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([NH:27][C@@H:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:26])=[O:17])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)O
Reactant: C[C@@H](N)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)N[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-hydroxy-acetic acid and (R)-1-phenyl-ethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32](=[O:34])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[B-].[Na+].CO>C(Cl)Cl>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32]([OH:34])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [B-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
To a 150 mL round-bottomed flask was added 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (1 g, 1.640 mmol) and sodium borohydrate (0.06 g, 1.640 mmol) in DCM (10 mL)-MeOH (10 mL). The suspension was stirred at room temperature for 16 h. The solution was quenched by saturated NH4Cl, extracted the aqueous with DCM (3×), the combined organic was dried over MgSO4, concentrated in vacuum to provide 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (0.9 g, 90% yield) as a yellow solid. m/z (ESI positive ion) m/z: 612 (M+H)+. 1H NMR (400 MHz, DMSO-d6): 6 ppm 1.36 (d, J=6.46 Hz, 3H) 2.57 (s, 3H) 3.74 (s, 3H) 3.91 (s, 3H) 4.75 (dd, J=6.26, 4.50 Hz, 1H) 4.83 (d, J=12.32 Hz, 4H) 5.25 (d, J=4.30 Hz, 1H) 6.82-6.97 (m, 4H) 7.19-7.35 (m, 4H) 7.98-8.14 (m, 2H) 8.30 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 11.68 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1.CC1(C)[O:33][CH2:32][CH:31]([CH2:34]O)[CH2:30][O:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NN=NN=C=NCC)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:34][CH:31]([CH2:32][OH:33])[CH2:30][OH:29])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1O
Reactant: CC1(C)OCC(CO)CO1
Agent: CCN=C=NN=NN=C=NCC
Agent: O=S(=O)(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
Toluene (0.4 ml) was added to 6-methoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinolin-7-ol (compound 329) (20 mg) and (2,2-dimethyl[1,3]dioxan-5-yl)-methanol (24 mg). Triphenylphosphine (43 mg) and a solution of diethylazocarbodiimide (29 mg) in toluene (0.2 ml) were added in that order to the mixture, and the mixture was stirred at room temperature for 4 hr. A 1 N aqueous sulfuric acid solution (1 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, the mixture was washed with ethyl acetate, and the ethyl acetate layer was extracted with 1 N hydrochloric acid. Aqueous layers were combined, the combined aqueous layers were made alkaline by the addition of potassium carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (4.7 mg, yield 19%).
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[C:14]1(=[O:28])[N:18]([CH2:19][C:20](=O)[CH3:21])[C:17](=[O:23])[C:16]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:15]12.O>CN(C)C=O>[O:23]=[C:17]1[C:16]2[C:15](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14](=[O:28])[N:18]1[CH2:19][C:20]([CH3:21])=[CH:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=C(C)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 80.7 %

Procedure:
A solution of methyl dimethylphosphonoacetate (21.5 g) in N,N-dimethylformamide (50 mL) was added dropwise to a suspension of sodium hydride (63%, 4.50 g) in N,N-dimethylformamide (100 mL) with stirring at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then, a solution of phthalimidoacetone (20.0 g) in N,N-dimethylformamide (50 mL) was added dropwise thereto, and the mixture was heated to room temperature and stirred overnight. To the reaction solution, water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (20.6 g).
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][C:5](OC)=O.[Na].ClC1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].Cl>O.O1CCOCC1>[Cl:20][C:18]1[N:19]=[C:5]([CH2:4][C:3]([OH:2])=[O:9])[C:13]([C:14]#[N:15])=[CH:16][CH:17]=1
Reactant: COC(=O)CC(=O)OC
Reactant: N#Cc1ccc(Cl)nc1Cl
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(Cl)nc1CC(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of malonic acid dimethyl ester, sodium salt (8.067 g, 52.4 mmol), as prepared in the previous step, 2,6-dichloro-nicotinonitrile (4.53 g, 26.2 mmol), as prepared in Example 6b, and dioxane (40 mL) was stirred at 80° C. for 1 h. The resulting easily stirred reddish-brown opaque thin slurry was allowed to cool to rt, 6 M HCl (aq) (80 mL) was added, and the mixture was vigorously stirred at 65-70° C. for 5 h open to air. The resulting clear dark amber solution containing a small amount of dark material was allowed to cool to rt, diluted with water (80 mL), and extracted with DCM (3×100 mL). The organic layers were combined, dried (2×Na2SO4), and concentrated under reduced pressure at 60° C. to provide the crude title compound as a dark brown oil (6.2 g, quantitative yield). A NMR spectrum of the reaction following malonate addition indicated a ˜1:2 mixture of desired/undesired regioisomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>C1COCC1.O>[F:25][C:24]1[C:23]([F:26])=[CH:22][CH:21]=[C:20]([N+:27]([O-:29])=[O:28])[C:19]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
To a solution of aniline (1.6 g, 16.9 mmol) in THF (40 mL) at −78° C. was added LiHMDS (34 mL, 1M, 33.9 mmol) and the reaction mixture stirred at −78° C. for 10 min. This solution was added via cannula to a solution of 2,3,4-trifluoronitrobenzene (3 g, 16.9 mmol) in THF (10 mL) at −78° C. and the dark purple reaction mixture stirred at −78° C. for 30 min. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo to give the title compound as a dark orange solid (4.2 g, 100%). 1H NMR 400 MHz δ (CDCl3): 8.95 (1H, br s), 8.00 (1H, ddd, J=9.7, 5.4, 2.3 Hz), 7.31-7.25 (2H, m), 7.13-7.08 (1H, m), 7.04-6.99 (2H, m), 6.75-6.67 (1H, m).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:21]([NH:23][CH2:24][CH3:25])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH2:24]([NH:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:28]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:31][CH2:30]2)=[C:18]([F:17])[CH:19]=1)[CH3:25]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(F)c1
Temperature: 95 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (47.50 mg, 0.221 mmol), 3-fluoro-N-ethyl-4-(piperazin-1-yl)benzamide (69.3 mg, 0.276 mmol) and (cyanomethyl)trimethylphosphonium iodide (86 mg, 0.353 mmol) in Propiononitrile (Volume: 1.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.192 mL, 1.104 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide N-ethyl-3-fluoro-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.069 g, 0.221 mmol, 70.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.54-2.64 (m, 4 H) 3.07-3.17 (m, 4 H) 3.21-3.28 (m, 2 H) 3.63 (s, 2 H) 6.71-6.76 (m, 1 H) 7.01-7.10 (m, 2 H) 7.55-7.64 (m, 3 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.32 (t, J=5.43 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.58 (br. s., 1 H). ESI-MS: m/z 449.4 (M+H)+. mp=262.7-267.4° C.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:38](=[O:47])/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:22][C:23]([N:25]2[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26]2)=[O:24])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH2:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:23](=[O:24])[CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:20][CH:19]=2)[C:38](=[O:47])/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of [(S)-1-(2-{(4-phenoxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamic acid, tert-butyl ester 6 (60 mg) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 30 min, and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M NaOH, (×2), brine, dried (Na2SO4) and evaporated to dryness. The resultant residue was purified by column chromatography on silica gel, eluting with ethyl acetate/methanol/ammonium hydroxide (90:5:5) to give the title compound (10 mg). 1HNMR (300 MHz) (CDCl3) δ 1.6-2.3 (2H, m), 3.15-3.75 (5H, m), 4.40 (2H, m), 6.43 (1H, d, J=16 Hz), 7.02 (2H, d), 7.06 (2H, d), 7.15 (1H, t), 7.25-7.45 (9H, m) and 7.69 (1H, d J=16 Hz).