Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CS(C)=O.CN(C=O)C>[O:12]=[C:7]1[NH:8][C:9]2[N:10]=[CH:11][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:3][C:4]=2[CH:5]=[CH:6]1
Reactant: O=c1ccc2cc(Br)cnc2[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)ccc2c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A reaction vessel was charged with 6-bromo-1,8-naphthyridin-2(1H)-one (1.5 g, 6.69 mmol), tert-butyl acrylate (4.86 mL, 33.45 mmol), and (i-Pr)2EtN (3.5 mL, 20.07 mmol) followed by DMF (40 mL). The solution was de-oxygenated with argon for 20 min. The mixture was treated with Pd(OAc)2 (150 mg, 0.67 mmol) and P(o-tol)3 (407 mg, 1.34 mmol) then heated to 100° C. for 15 h (overnight). A TLC analysis indicated that only the starting arylhalide is present. At this time the mixture was a yellow suspension. To this mixture was added 20 DMSO (20 mL) and an additional 75 mg of Pd(OAc)2. The mixture was heated at 100° C. for 24 h. After cooling, the dark mixture was filtered through celite and the filter cake was rinsed with EtOAc (100 mL). The filtrate was extracted with EtOAc (2×100 mL). The combined organic fractions were washed with brine (2×100 mL), H2O (100 mL), dried over MgSO4 and filtered through a pad of silica gel. The filtrate was concentrated to about 50 mL then treated with about 150 mL hexanes to form a precipitate. The precipitate was filtered to give the product as a light brown solid. Yield: 700 mg (39%); 1H-NMR (300 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.83 (d, 1H, J=2.3 Hz), 8.53 (d, 1H, J=2.3 Hz), 7.89 (d, 1H, J=9.0 Hz), 7.64 (d, 1H, J=18.0 Hz), 6.65 (d, 1H, J=18.0 Hz), 6.62 (m, 1H), 1.51 (s, 9H); ESI MS m/z 273 [C15H16N2O3+H]+
Reaction SMILES: [O:1]=[C:2]1[C:8](=[CH:9][OH:10])[C:7](=[O:11])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]1[CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:20].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:1]=[C:2]1[C:8](=[CH:9][O:10][S:34]([CH3:33])(=[O:36])=[O:35])[C:7](=[O:11])[N:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]1[CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)=[O:20]
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=CO)C2=O)C(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=COS(C)(=O)=O)C2=O)C(C)C)cc1

Procedure:
A solution of 2-[2,4-dioxo-3-(hydroxymethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (−12r, 0.500 g) in CH2Cl2 (10 mL) under argon was treated with methanesulfonyl chloride (0.266 mL) and diisopropylethylamine (0.598 mL). After several minutes, the reaction was transferred to a separatory funnel and washed with aqueous 1N NaHSO4. The aqueous layer was back-extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 2:3 ethyl acetate/hexane. Fractions containing the product were combined, evaporated in vacuo and triturated with hexane. Hexane was removed in vacuo and the residual solid was dried under high vacuum to provide 2-[2,4-dioxo-3-(methanesulfonyloxymethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (12s, 0.502 g) as a solid. The product was contaminated with approximately 40% of 2-[2,4-dioxo-3-methylene-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide which reacted equally well in the subsequent steps. 1H NMR (300 MHz, CDCl3) 1.10 (d, J=7 Hz, 6H), 3.15 (s, 3H), 3.89 (s, 3H), 3.96 (d, J=2 Hz, 2H), 4.92 (m, 4H), 6.03 (m, 2H), 7.00 (m, 2H), 7.18 (m, 2H), 7.40 (m, 5H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[C:14]2[C:13]3[CH:15]=CC=[CH:18][C:12]=3[O:11][C:10]=2[CH:9]=[CH:8][C:7]=1C=O.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C1COCC1>[CH:3]([C:2]1[CH:1]=[CH:18][C:12]2[O:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:14]=3[C:13]=2[CH:15]=1)=[CH2:4]
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2oc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
22.7 g (63.7 mmol) of Methyl triphenylphosphonium bromide and 200 ml of dry THF are placed in a dried 500 ml three necked round bottomed flask, equipped with a magnetic stirrer and the reaction mixture is cooled to 0° C. internal temperature with a NaCl/ice bath. 41.8 ml (66.9 mmol) of 1.6 M Butyl lithium solution in Hexane are added within 30 minutes while keeping the internal temperature below 3° C. The reaction mixture is stirred at the same temperature for 45 minutes, then 47.2 mmol of Dibenzofuran-2-carboxaldehyde dissolved in 100 ml of dry THF are added within 30 minutes. After two hours the reaction mixture is warmed to room temperature, added to 500 ml of water and extracted three times with 500 ml of Ethylacetate. The combined organic phases are washed once with 500 ml of a 1:1 mixture of buffer pH=1 and brine, once with 30 ml of brine, dried over Magnesiumsulfate, filtered and evaporated. The crude product is dissolved in Dichloromethane, 100 g of silica are added and the solvent is evaporated. The resulting powder is added on top of 300 g of silica in a sintered glass funnel and the product eluted with Hexane/Ethylacetate=8:1. The product is crystallized from 2-Propanol. 2-Vinyl-dibenzofuran is isolated in 95% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[C:24]([C:29]2[C:30](=[O:43])[N:31]([CH3:42])[C:32]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33][CH:34]=2)[CH:25]=[CH:26][C:27]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:21][C:22]1[CH:23]=[C:24]([C:29]2[C:30](=[O:43])[N:31]([CH3:42])[C:32]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33][CH:34]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([CH3:18])[C:11]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
To a 10 mL round bottom flask was added 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (18.7 mg, 0.065 mmol; prepared according to the procedure of Example 43, Step E), 5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (13.5 mg, 0.043 mmol) and the solids were dissolved in DMF (0.5 mL). Potassium carbonate (9.0 mg, 0.065 mmol) was added followed by a 1M solution of potassium t-butoxide in THF (0.065 mL, 0.065 mmol), and the mixture was stirred at 110° C. for 18 hours. The reaction mixture was cooled to room temperature and then partitioned between water (5 mL) and ethyl acetate (10 mL). The organic layer washed with water, brine, dried over Na2SO3 and concentrated to afford 24.3 mg of crude oil. The crude product was triturated with ether to afford the desired product (16 mg, 65%) as a tan solid. LRMS (APCI pos) m/e 563.3 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[CH:15]=[C:14]([O:22][CH2:23][CH:24]=[CH2:25])[CH:13]=2)[O:9][N:8]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[C:14]([O:22][CH2:23][CH:24]=[CH2:25])[CH:13]=2)[O:9][N:8]=1
Reactant: C=CCOc1cc(C(=O)OC)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1cc(C(=O)O)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A stirred suspension of 3-(2-Pyridyl)-5-(3-allyloxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (1.8 g, 5.28 mmol) in methanol (40 mL) was treated with 1M sodium hydroxide (7.9 mL, 7.9 mmol) and the reaction stirred at ambient temperature for 36 hours. The solvent was removed in vacuo, and the residue was dissolved in water (30 mL) and then acidified (pH 4-5) by the addition of 2N hydrogen chloride. The resulting precipitate was collected and dried to afford 1.6 (94%) of 3-(2-pyridyl)-5-(3-allyloxy-5-carboxyphenyl)-1,2,4-oxadiazole: 1H NMR (DMSO): δ-8.81 (d, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 8.05 (m, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.65 (m, 1H), 6.09 (m, 1H), 5.47 (dd, 1H), 5.33 (dd, 1H), 4.80 (d, 2H).
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:13](OCCC(C)C)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[C:25]([CH3:33])[C:24]=1[CH3:34].[OH-].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:21][O:22][C:23]1[C:24]([CH3:34])=[C:25]2[C:26](=[CH:27][CH:28]=1)[NH:29][N:13]=[CH:33]2
Reactant: COc1ccc(NC(C)=O)c(C)c1C
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2[nH]ncc2c1C
Reaction time: 6 h
Yield: 54.3 %

Procedure:
Acetic anhydride (1.46 ml, 15.52 mmol), tetrabutylammonium bromide (83 mg, 0.259 mmol), potassium acetate (1.02 g, 10.35 mmol) and isoamyl nitrite (0.904 ml, 6.73 mmol) were added to a solution of N-(4-methoxy-2,3-dimethylphenyl)acetamide (1.0 g, 5.175 mmol) in ethyl acetate (10 ml) at room temperature, and the resulting mixture was refluxed. After 6 hours, the ethyl acetate was distilled off with heating, and a 6M-aqueous sodium hydroxide solution (10.35 ml, 62.1 mmol) was added dropwise to the residue at 60° C. After 1 hour, the reaction solution was adjusted to pH 8 to 9 with a 3M-aqueous hydrochloric acid solution and extracted with chloroform (50 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-methoxy-4-methyl-1H-indazole (456 mg, 54%).
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2)C(O)=CC=C2C=1C=CC=C2.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.FC(F)(F)S(OC1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1OS(C(F)(F)F)(=O)=O)(=O)=O.C1(P(=O)C2C=CC=CC=2)C=CC=CC=1.[C:87]1([P:93]([C:123]2[CH:128]=[CH:127][CH:126]=[CH:125][CH:124]=2)([C:95]2[CH:104]=[CH:103][C:102]3[C:97](=[CH:98][CH:99]=[CH:100][CH:101]=3)[C:96]=2[C:105]2[C:114]3[C:109](=[CH:110][CH:111]=[CH:112][CH:113]=3)[CH:108]=[CH:107][C:106]=2[O:115]S(C(F)(F)F)(=O)=O)=[O:94])[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1.[OH-].[Li+]>C(Cl)Cl.N1C=CC=CC=1>[C:123]1([P:93]([C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=2)([C:95]2[CH:104]=[CH:103][C:102]3[C:97](=[CH:98][CH:99]=[CH:100][CH:101]=3)[C:96]=2[C:105]2[C:114]3[C:109](=[CH:110][CH:111]=[CH:112][CH:113]=3)[CH:108]=[CH:107][C:106]=2[OH:115])=[O:94])[CH:124]=[CH:125][CH:126]=[CH:127][CH:128]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(Oc1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12)C(F)(F)F
Agent: O=[PH](c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc2ccccc2c1-c1c(O)ccc2ccccc12

Procedure:
An optically active binaphthol (VII) as a starting material is reacted by a method described in the literature (M. Vondenhof and J. Mattay, Tetrahedron Lett., 1990, Vol. 31, pp . 985-988; L. Kurz, G. Lee, D. Morgans, Jr., M. J. Waldyke, and T. Ward, Tetrahedron Lett., 1990, Vol. 31, pp. 6321-6324) and by a method described in the literature (Y. Uozumi, A. Tanahashi, S. -Y. Lee, and T. Hayashi, J. Org. Chem., 1993, Vol. 58, pp. 1945-1948). That is, the binaphthol (VII) is reacted with trifluoromethanesulfonic anhydride (Tf2O) using pyridine in methylene chloride to convert compound (VII) to 2,2′-bis(trifluoromethanesulfonyl-oxy)-1,1′-binaphthyl (VIII), which is reacted with diphenylphosphine oxide (Ph2PHO) in the presence of a catalytic amount of a palladium-phosphine complex, whereby 2′-diphenylphosphinyl-2-trifluoromethanesulfonyloxy-1,1′-binaphthyl (IX) can be synthesized. Compound (IX) is hydrolyzed with lithium hydroxide (LiOH) to obtain 2′-diphenylphosphinyl-2-hydroxy-1,1′-binaphthyl (XVIII), which is brominated in dioxane to obtain 2′-diphenylphosphinyl-2-hydroxy-6-bromo-1,1′-binaphthyl (XIX). Compound (XIX) is reduced with trichlorosilane (HSiCl3) to obtain 2′-diphenylphosphino-2-hydroxy-6-bromo-1,1′-binaphthyl (XX), which is reacted with 2-vinyl-5,5-dimethyl-1,3-dioxa-2-borinane using a palladium catalyst by a method described in the literature (Y. Miyaura and A. Suzuki, J. C. S. Chem. Commun., 1979, p. 866) to obtain 2′-diphenylphosphino-2-hydroxy-6-vinyl-1,1′-binaphthyl (XXI).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][CH2:34][C:35](Cl)=[O:36].O>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]1)[C:35](=[O:36])[CH2:34][Cl:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(C(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)O1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OCC(C(CN(Cc2ccccc2)C(=O)CCl)c2ccc(Cl)c(Cl)c2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2RS)—N-benzyl-2-(3,4-dichlorophenyl)-2-[(4SR)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamine (3.72 g) and triethylamine (1.63 ml) in THF (30 ml) was added chloroacetyl chloride (0.783 ml) at 0° C., and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.99 g).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:39])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([O:36][CH2:37][CH3:38])=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:37]([O:36][C:29]1[C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:25]2[NH:24][C:23](=[O:39])[CH2:22][C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)=[N:27][C:26]=2[CH:28]=1)[CH3:38]
Reactant: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(N)(=O)=O)c3)c1)=N2

Procedure:
The title compound was prepared from 3′-(8-ethoxy-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulfonic acid tert-butylamide (Example 6) (238 mg, 0.4 mmol) and TFA (5 mL) according to the general procedure I step 2. Obtained as an off-white solid (147 mg, 69%). MS (ISP) 503.8 [(M+H)+]; mp 210-220° C. (dec).
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.C([O-])([O-])=O.[K+].[K+].CC(O)(C)C.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>O>[CH3:32][Si:3]([CH3:33])([CH2:2][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CN1CCCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A slurry of Compound 4 (60 mg) and K2CO3 (43 mg) in deionized water (1 mL) was stirred at room temperature for 30 min. To the resulting reaction mixture, t-BuOH (1 mL) and pyrrolidine (52 μL) were added and heated at 70° C. for 5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in acetic acid (10 mL) and stirred at room temperature for 2 hours. The acetic acid solution was concentrated again under vacuum. Finally, the residue was partitioned between chloroform (2×15 mL) and 7% aqueous NaHCO3 solution (5 mL). The collective organic layers were dried, concentrated and purified on a silica gel using 10% ethanol in dichloromethane to afford the required product in 83% yield (45 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:5]=[C:4]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 81 %

Procedure:
To a solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (63 mg; 0.16 mmol) in methanol (1.651 mL) was added a 10 N sodium hydroxide solution (165 μL; 1.651 mmol) and the mixture was heated at 100° C. for 18 h. The volatiles were removed under reduced pressure and the residue was dissolved in water, the mixture was then acidified by adding 6N hydrochloric acid until a precipitate formed. The solid was isolated by filtration and dried under reduced pressure over phosphorus pentoxide to give 47.6 mg (77%) of the title compound as a white solid. ESI/APCI(+): 368 (M+H). ESI/APCI(−): 366. 1H NMR (DMSO-d6) δ 7.29 (4H, m); 3.71 (4H, m); 3.68 (1H, m); 2.35 (3H, s); 2.28 (3H, s); 1.89 (1H, m); 1.60 (2H, m); 1.50 (4H, m); 1.44 (1H, m); 0.89 (2H, m); 0.59 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N:4]1[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: Clc1cccc(Cl)c1-n1cccc1
Yield: 83.3 %

Procedure:
A mixture of 5 g of 2,6-dichloroaniline, 4.5 g of 2,5-dimethoxytetrahydrofuran and 30 ml of acetic acid was heated to reflux for 10 hours. The reaction mixture was allowed to cool, poured into water, and extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 5.45 g of 1-(2,6-dichlorophenyl)-1H-pyrrole of the formula:
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:11](O)[CH2:12][OH:13].C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C.CCCCCCC>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:2]1([CH2:9][CH3:10])[O:13][CH2:12][CH2:11][O:1]1)[CH3:8]
Reactant: OCCO
Reactant: CCOC(=O)CC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(CC)OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of ethyl 3-oxopentanoate (5 g, 34.7 mmol), ethylene glycol (10.8 g, 174 mmol), triethyl orthoformate (5.14 g, 34.7 mmol), and p-toluenesulfonic acid monohydrate (598 mg, 3.14 mmol) was stirred at room temperature overnight. To the reaction mixture, heptane and ethyl acetate were added to dilute solution, which was washed with water. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, filtrated and the filtrate was concentrated under reduced pressure. The residue was dissolved in heptane and subjected to NH silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/0→10/1) to obtain the title compound (3.85 g, yield: 58.9%) as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH:22]=[CH2:23]>C(O)C>[CH2:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:25]1)[CH:22]=[CH2:23]
Reactant: C=CCN1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CCO
Product: C=CCN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
8.62 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 8.3 gm of 1-allyl-piperazine were refluxed in 100 ml of ethanol for 2 hours. The reaction mixture was then evaporated, and the crystalline precipitate was subsequently recrystallized from 30 ml of isopropanol and then from 94% ethanol in the presence of activated charcoal.
Reaction SMILES: [CH3:1][O:2][CH:3](P(=O)(OCC)OCC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].[N+:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[C:32]2=O)([O-:28])=[O:27].S([O-])(O)(=O)=O.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[C:32]1[C:31]2[C:35](=[CH:36][CH:37]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=2)[NH:34][C:33]1=[O:38])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)C(OC)c1ccc(OC)cc1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccc(OC)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
6.3 g (22 mmol) of diethyl [methoxy-(4-methoxyphenyl)-methyl]-phosphonate are dissolved in 40 ml of DMF under a nitrogen atmosphere. 5.1 g (45 mmol) of potassium tert.butoxide are added batchwise at −40° C. and the mixture is then stirred for another 30 minutes at −10° C. Then 3.84 g (20 mmol) of 5-nitroisatine are added. The mixture is stirred for 1 hour at ambient temperature and then poured onto ice water containing 20 ml of saturated potassium hydrogen sulphate solution. The precipitate is suction filtered and chromatographed over silica gel (dichloromethane/methanol=10:1).