Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[C:14](=[O:17])[CH2:15]Cl)(=[O:3])[CH3:2].[CH3:18][NH:19][CH3:20]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[C:14](=[O:17])[CH2:15][N:19]([CH3:20])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1C(=O)CCl)OCO2
Reactant: CNC
Product: CC(=O)Nc1cc2c(cc1C(=O)CN(C)C)OCO2

Procedure:
2'-Acetylamino-4',5'-methylenedioxy-2-chloroacetophenone, prepared in Example 1, part (B), is reacted with an excess of dimethylamine under similar conditions as taught in Example 1, part (H), to yield 2'-acetylamino-4',5'-methylenedioxy-2-dimethylaminoacetophenone which is turn is deprotected by the procedure of Example 1, part (E), to yield 2'-amino-4',5'-methylenedioxy-2-dimethylaminoacetophenone.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:9][S:10][CH:11]=1)(=O)=O.[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1O>>[Cl:17][C:14]1[S:13][C:12]([C:8]2[C:7]([CH2:6][O:5][C:24]3[C:23]([F:26])=[CH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[F:18])=[CH:11][S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Cl)s1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2csnc2-c2ccc(Cl)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(5-chlorothiophen-2-yl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.45 (d, J=2.5 Hz, 1H), 6.97 (d, J=2.5 Hz, 1H), 6.76 (d, J=7.0 Hz, 2H), 5.25 (s, 2H), 2.90 (d, J=6.3 Hz, 2H), 2.68 (d, J=6.3 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: Cc1ccc(C)c(CN)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: Cc1ccc(C)c(CNC(=O)C(C)c2cccc3cnccc23)c1

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,5-dimethylbenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 319 (M+H)+; MS (ESI−) m/z 317 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 2.09 (s, 3H), 2.12 (s, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 6.79 (s, 1H), 6.91 (d, J 7.8, 1H), 6.98 (d, J 7.8, 1H), 7.83 (t, J 7.8, 1H), 8.00 (d, J 6.5, 1H), 8.21 (d, J 8.1, 1H), 8.37 (d, J 6.4, 1H), 8.46 (t, J 5.8, 1H), 8.62 (d, J 6.2, 1H), 9.57 (s, 1H).
Reaction SMILES: N1C=CC(C2[C:8](C3C=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)=[N:9][NH:10]C=2)=CC=1.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44](=O)[CH2:45][C:46]2[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=2)=[C:40]([F:53])[CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:45]([C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)=[CH:8][NH:9][N:10]=2)=[C:40]([F:53])[CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc2nc(COc3ccc(-c4n[nH]cc4-c4ccncc4)cc3)ccc2c1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1F
Product: Fc1cc(OCc2ccccc2)ccc1-c1n[nH]cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[4-(4-Pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-(4-Benzyloxy-2-fluoro-phenyl)-2-pyridin-4-yl-ethanone provided the title compound. MS: (M+H m/z=346.3).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([OH:17])=[O:16]>>[N+:6]([C:13]1[CH:12]=[C:11]([C:15]([OH:17])=[O:16])[S:10][CH:14]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccs1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cs1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Sulfuric acid (3.0 mL, 5.505 g, 56.17 mmol) was added to nitric acid (2.0 mL, 2.98 g, 49.6 mmol) slowly at 0-10° C. After completion of the addition, thiophene-2-carboxylic acid (2.8 g, 21.87 mmol) was added to the above nitration mixture slowly for 15 min at the same temperature and stirred the mixture for 1 h. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitated solid was filtered, washed with cold water and dried. The filtrate was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The combined product was stirred with hexane (2×50 mL) and filtered the solid and dried to give the product as an off-white solid (2.8 g, 75%), mp 110-118° C. The product was a mixture of two compounds by HPLC and 1H NMR and was proceeded to the next step.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH:14]=[C:15]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C>[ClH:32].[CH:17]1[C:16]2[C:15](=[CH:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1CCCN(CCC=C2c3ccccc3Sc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCN(CCC=C2c3ccccc3Sc3ccccc32)C1

Procedure:
The above ester (0.74 g, 1.8 mmol) was dissolved in ethanol (25 ml) and 40% sodium hydroxide (6 ml) was added. The mixture was heated at reflux for 1 h. 10% Hydrochloric acid (25 ml) was added followed by dichloromethane (150 ml). The phases were separated and the organic phase was washed with water, dried (NaSO4) and the solvent was evaporated in vacuo to give 0.6 g of the title compound as a solid. M.p. 150°-160° C. A sample was dissolved in acetone and precipitated with diethyl ether. The solid formed was isolated by filtration and dried in vacuo.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH:16]=O)=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[NH2:40])[C:24]([NH:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:25].OOS([O-])=O.[K+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[NH:20][C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[CH:37]=[CH:38][C:39]=3[N:40]=2)=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1
Reaction time: 1 h

Procedure:
A mixture of 3-(3,5-dichloro-4-formylphenyl)-propionic acid tert butyl ester (440 mg, 0.8 mmol), 3,4-diamino-N-quinolin-2-yl-benzamide (403 mg, 1 eq) and oxone (600 mg, 0.67 eq) in DMF (10 mL)/H2O (1 mL) was stirred vigorously open to air for 1 h. The mixture was partitioned between water and ethyl acetate. The ethyl acetate fractions were dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give 3-{3,5-dichloro-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-propionic acid tert-butyl ester as an orange foam. 1H-NMR (CDCl3, 400 MHz): δ 8.60 (d, J=8.97 Hz, 1H), 8.38 (s, 1H), 8.21-8.29 (m, 1H), 7.95 (dd, J=8.34, 1.26 Hz, 1H), 7.82-7.91 (m, 2H), 7.71 (ddd, J=8.37, 6.98, 1.33 Hz, 2H), 7.47-7.56 (m, 1H), 7.17-7.24 (m, 2H), 2.85 (t, J=7.33 Hz, 2H), 2.50-2.57 (m, 2H), 1.42-1.48 (m, 10H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 86.2 %

Procedure:
A heterogenous reaction mixture of 2-(S)-iodomethyl-pyrrolidine-1-carboxylic acid tert butyl ester (compound (4) obtained from above, 25 g, 0.08 mol), triethylamine (11.2 mL, 8.12 g, 0.08 mol) in methanol (250 mL) and 5% palladium on carbon (2.5 g, 10 wt %, Pd/C) was allowed to react at room temperature under a blanket of hydrogen gas overnight and until HPLC showed less than 1% starting material (˜7 hours). The reaction mixture was filtered and the filtrate was concentrated to a residue. The residue was dissolved in distilled water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with 1 M aqueous H3PO4 (2×100 mL) followed by saturated NaHCO3 (233 100 mL), dried over MgSO4, filtered, and concentrated to leave an oily residual product (12.78 g, 85.9% yield). 1H NMR (CDCl3): δ 1.16 (d, 3H, CH3), 1.47 (s, 9H, 3×CH3), 1.50–1.82 (m, 2H, CH2), 1.84–2.03 (m, 2H, CH2 ), 3.34 (m, 2H, CH2) and 3.86 (m, 1H, CH); [M+H]+ at m/z 186.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][O:4]1.N1C=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(Cl)(Cl)Cl>[O:9]=[C:7]1[CH2:6][CH2:5][O:4][CH:3]([CH2:2][O:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH2:8]1
Reactant: O=C1CCOC(CO)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1CCOC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of 2-hydroxymethyl-tetrahydro-pyran-4-one (625 mg, 4.81 mmol) in a mixture of pyridine (778 μl, 9.62 mmol) and chloroform (6.0 ml) at 0° C. under nitrogen was slowly added 4-nitrobenzenesulfonyl chloride (1.60 g, 7.22 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h. Chloroform (30 ml) was added and the solution washed with 2.0 N hydrochloric acid (3×10 ml), 5% NaHCO3 (3×10 ml) and water (3×10 ml). The organic phase was dried (Na2SO4), filtered and the solvent evaporated in. vacuo. The solid residue was purified by column chromatography on silica gel using a gradient of dichloromethane:hexane:ethyl acetate (1:1:0 to 8:0:2) as eluent. Pure fractions were collected and the volatiles were evaporated in vacuo affording 0.98 g (65%) of 4-nitro-benzenesulfonic acid 4-oxo-tetrahydro-pyran-2-ylmethyl ester as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][C:11]=1[O:19][CH3:20].[OH-].[K+]>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:14]1[C:13]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([O:19][CH3:20])[CH:12]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: Nc1ccccc1S
Agent: [K+]
Agent: [OH-]
Product: COc1cc(-c2nc3ccccc3s2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
A slurry of 2-aminothiophenol (357 mg, 2.85 mmol) in polyphosphoric acid (14.0 g) was heated to 110° C. and 4-hydroxy-3-methoxybenzoic acid (480 mg, 2.85 mmol) was added. After 2 h, the reaction mixture was cooled to rt. The mixture was poured carefully into ice cold water, and the solution was neutralized with KOH (3 M aqueous solution). The aqueous phase was extracted with EtOAc (2×). The combined organic layers were washed with Na2CO3 (1 M aqueous solution), HCl (1 M aqueous solution) and water, dried, and concentrated under reduced pressure. Purification by silica gel chromatography gave 22 mg (3%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H), 7.88 (d, 1H), 7.72 (s, 1H), 7.55 (d, 1H), 7.48 (m, 1H), 7.36 (m, 1H), 7.00 (d, 1H), 5.92 (s, 1H), 4.03 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O[C:15]1[C:23]2[CH:22]=[CH:21][S:20][C:19]=2[C:18]([CH:24]=[O:25])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([CH2:10][CH2:11][O:12][C:15]2[C:23]3[CH:22]=[CH:21][S:20][C:19]=3[C:18]([CH:24]=[O:25])=[CH:17][CH:16]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(O)c2ccsc12
Reactant: Cc1oc(C(C)(C)C)nc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1oc(C(C)(C)C)nc1CCOc1ccc(C=O)c2sccc12
Reaction time: 4 h
Yield: 47.5 %

Procedure:
0.800 g of the above prepared (example 1, step f]) 2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethanol (4.37 mmol) was dissolved in 25 ml of toluene and treated successively at 0° C. with 0.778 g of 4-hydroxy-benzo[b]thiophene-7-carbaldehyde (4.37 mmol), 1.145 g of triphenylphosphine (4.37 mmol), and 0.883 g (4.37 mmol) of DIAD. The cooling bath was then removed and stirring continued for 4 h. Pouring onto crashed ice, twofold extraction with EtOEt, washing with dil. NaOH and water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=6/4) and crystallization from EtOEt, produced finally 0.713 g of the title compound as off-white crystals of mp. 140–42° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:36][CH2:35][CH2:34]1>>[N:33]1([CH2:23][CH2:22][C@@:19]2([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[O:18][C:17](=[O:32])[N:16]([C@H:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][CH:12]=3)[CH3:15])[CH2:21][CH2:20]2)[CH2:36][CH2:35][CH2:34]1
Reactant: C1CNC1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CCC2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using azetidine in Step 2. LC-MS Method 2 tR=1.193 min, m/z=477.2; 1H NMR (CD3OD) 1.57 (d, 3H), 2.16 (m, 2H), 2.26 (m, 2H), 2.48 (m, 1H), 2.50 (m, 2H), 3.01 (m, 1H), 3.11 (m, 1H), 3.25 (m, 1H), 3.40 (m, 2H), 4.20 (m, 2H), 5.59 (m, 1H), 7.08 (d, 2H), 7.14 (m, 4H), 7.33 (m, 2H), 7.37 (m, 2H), 7.54 (m, 2H).
Reaction SMILES: [I-].[K+].[Cu][C:4]#[N:5].FC1C=CC([CH:13]2[C:21]3[C:16](=[CH:17][C:18](Br)=[CH:19][CH:20]=3)[CH2:15][O:14]2)=CC=1.C1(C)C=CC=CC=1>CN(C)C=O.N>[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([C:4]#[N:5])=[CH:19][CH:20]=2)[CH2:15][O:14]1
Reactant: N#C[Cu]
Reactant: Fc1ccc(C2OCc3cc(Br)ccc32)cc1
Agent: N
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)COC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 133.3 %

Procedure:
Potassium iodide (25 g), Copper (I) cyanide (11.8 g) were added to a solution of the [1-(3-dimethylamino)propyl)]-1-(4-fluorophenyl)-1,3-dihydro-5-bromoisobenzofuran (25 g) in dimethylformamide (25 ml). The reaction mixture was heated to 135–145° C. and maintained for 28 hours. The reaction mixture was cooled to 100° C. and poured in ammonia solution containing toluene and stirred for 2 hours to get a clear separation of layers. Then the organic layer after acid base treatment was separated and washed with water twice (2×100 ml), dried with anhydrous sodium sulfate and finally the toluene layer was distilled to get the crude 1-[3-(dimethylamino) propyl]-14-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile base 16.5 g, with the following HPLC profile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[O:17][CH2:18][C:19](=[O:26])[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCCCC1>C(O)C>[NH:27]1[C:35]2=[N:34][CH:33]=[CH:32][CH:31]=[C:30]2[C:29]([CH:36]=[C:18]2[O:17][C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=3)=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]2=[O:26])=[CH:28]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(NC(=O)OC(C)(C)C)cc2)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(NC(=O)OC(C)(C)C)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-({4-[(tert-butoxycarbonyl)amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.32 g, 0.88 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.88 mmol) in ethanol (5.0 mL), piperidine (0.18 mL, 1.8 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(tert-butoxycarbonyl)amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.095 g, y. 21%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[NH:15][N:14]=[CH:13][C:12]=2[N:11]2[CH:19]([CH3:25])[CH2:20][N:21]([CH3:24])[C:22](=[O:23])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[N:14]=[CH:13][C:12]=2[N:11]2[CH:19]([CH3:25])[CH2:20][N:21]([CH3:24])[C:22](=[O:23])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(C)C(=O)c2c(OCc3ccccc3)c3c(=O)[nH]ncc3n21
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1CN(C)C(=O)c2c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)ncc3n21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10-(benzyloxy)-6,8-dimethyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.12 g, 0.34 mmol), 4-fluorobenzyl bromide (63 μL, 0.34 mmol), and cesium carbonate (0.22 g, 0.68 mmol) in anhydrous DMF (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and the residue partitioned between ethyl acetate and aqueous citric acid. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated to provide the titled dione. The residue was subjected to column chromatography on silica gel eluted with a methanol-chloroform gradient to provide the titled product.
Reaction SMILES: [CH3:1][C:2]1([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1.C(=O)(O)[O-].[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:1])([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[O:3][CH2:4][CH2:5]2)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(c2cccnc2)OCCc2cc(O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Oc1ccc2c(c1)CCOC2(C)c1cccnc1
Reaction time: 1 h

Procedure:
A mixture of 1-methyl-1(3-pyridyl)-6isochromanol (5.0 g), described in Example 22, and acetic anhydride (50 ml) is heated on the steam bath for 4 hr. The mixture is poured upon ice, left at room temperature for 1 hr, rendered basic with sodium bicarbonate and then extracted with chloroform. The extracts are washed with brine, dried, evaporated, and the residue is crystallized from isopropanol to give the title compound, m.p. 113° - 115° C.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH:22]=[C:23]([C:29]([O:31]CC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1>CCOCC>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[NH:21][CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:29]2=[O:31]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(Br)cc2c1=O
Temperature: 240 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Diphenyl ether (870 mL) was heated to 240° C. then diethyl 2-[[(4-bromophenyl)amino]methylidene]propanedioate (75 g, 219.18 mmol) added portionwise. The mixture was stirred at 240° C. for 60 minutes in a flask fitted with clean-stark apparatus. After cooling (25° C.) a crystallized solid was formed. The mixture was diluted with Et2O and the solid was collected by filtration, washed with Et2O and dried to afford the desired material (59.9 g) as a beige crystallized solid, which was used without purification or characterisation.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH:15]=O)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH3-]C#N.[Na+]>CC(O)=O.CO>[CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=CC12CC1CCN(Cc1ccccc1)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CN2CCC3CC3(CNc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-Benzyl-3-aza-bicyclo[4.1.0]heptane-1-carbaldehyde (174) (300 mg, 1.39 mmol) in 5% HOAc in MeOH (2 ml) was added aniline (0.38 ml, 4.18 mmol) and NaCNBH3 (250 mg, 3.97 mmol). The mixture was stirred at room temperature 2 hrs. MeOH was removed by evaporation. Water (5 mL) was added to the residue. The mixture was neutralized with 2N KOH to pH=10. Extraction with CH2Cl2 (2×10 ml) followed by standard work-up provided crude 175 which was purified by silica gel chromatography (1% MeOH in CH2Cl2). LRMS (calculated for C20H25N2, M+1) 293, found 293.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]([C:7](Cl)=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[O:3]1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]([C:7]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[O:3]1
Reactant: c1c[nH]cn1
Reactant: CCCCCCC1(C)OC(C)(C)CN1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC1(C)OC(C)(C)CN1C(=O)n1ccnc1
Yield: 92 %

Procedure:
A mixture comprising 2.6 g (0.01 mole) of 2-methyl-2-n-hexyl-3-chlorocarbonyl-5,5-dimethyl-1,3-oxazolidine, 1.0 g (0.015 mole) of imidazole and 2.1 g (0.015 mole) of potassium carbonate was stirred with 30 ml of dimethylformamide (DMF) as the solvent at 50° C. to 60° C. for one hour. After completion of the reaction, water was added and then the mixture was extracted with toluene. The toluene layer was washed with water, dried and condensed, and then purified by a column chromatography, thereby obtaining 2.7 g of the title compound having pale yellow color.