Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[N:7]=[C:6]([CH:10](OCC)[O:11]CC)[N:5]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>>[CH:1]1([C:4]2[N:8]([CH3:9])[N:7]=[C:6]([CH:10]=[O:11])[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCOC(OCC)c1nc(C2CC2)n(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(C=O)nc1C1CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 61.9 %

Procedure:
In a 2 L round-bottomed flask containing the crude 5-cyclopropyl-3-(diethoxymethyl)-1-methyl-1H-1,2,4-triazole from Step 2, a solution of 2 N HCl (125 mL) was added and the reaction was allowed to stir at room temperature for 23 h, at which point, LC/MS analysis confirmed the formation of the aldehyde. The mixture was then treated with solid sodium hydroxide until a pH of 13 was obtained. The aqueous mixture was extracted with dichloromethane (3×150 mL), and the combined organic layers dried over sodium sulfate, filtered and the solvent evaporated under vacuum. The crude material was distilled Kugel-Rhor distillation at 135° C.-146° C. to afford 11.4 g (61.9%) the title product as a yellow-colored oil. This material contained 4.8 wt % of the self-condensed side-product, 3,5-dicyclopropyl-1-methyl-1H-1,2,4-triazole, by 1H NMR. 1H NMR (300 MHz, DMSO-d6): δ 0.96 (m, 2H), 1.10 (m, 2H), 2.22 (m, 1H), 4.00 (s, 3H), 9.78 (s, 1H). LC/MS (APCI) calcd for C7H9N3O: 151.07, found (M+H+): 152.1 m/z.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:15])[CH:13]=[O:14])=[CH:3][CH2:4][O:5][C:6](=[O:8])[CH3:7].CC(=CC)C.P([O-])(O)(O)=[O:22].[Na+].Cl([O-])=O.[Na+].Cl>C(O)(C)(C)C.O.C(OCC)(=O)C>[C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:15])[C:13]([OH:22])=[O:14])(=[O:8])[CH3:7]
Reactant: CC(=O)OCC=C(C)CCC=C(C)C=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)OCC=C(C)CCC=C(C)C(=O)O
Reaction time: 8 h
Yield: 130.5 %

Procedure:
To a solution of aldehyde 230a (19.5 g, 92.7 mmol) in 300 mL of tert-butyl alcohol was added 2-methyl-2-butene (98.0 mL, 925 mmol). To this was added a solution of sodium dihydrogen phosphate (44.5 g, 371 mmol) in 300 mL of water. Sodium chlorite (33.6 g, 371 mmol) was added in several portions. The resulting mixture was rapidly stirred overnight at room temperature. Ethyl acetate was added and the aqueous layer was acidified to pH 3 by addition of 1 M HCl. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine, dried over MgSO4, and reduced to dryness in vacuo. The crude product (27.4 g, 121 mmol, >100% yield) was used in the next step without further purification:
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH:25]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>C(O)(C)C>[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH:25]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27]
Reactant: CC(C)CC(C(=O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: CC(C)CC(C(O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Yield: 40.3 %

Procedure:
Aluminum isopropoxide (125.6 g, 615 mmcl) was added to a suspension of 2-(1,3-dioxo-2-azaindane-2-yl)-4-methyl-1-phenylpentane-1-one (72.3 g, 225 mmcl) in isopropanol (1,000 ml). The mixture was heated under reflux for 6.5 hours. The isopropanol was removed by distillation under reduced pressure and the residue was added with ethyl acetate (800 ml) and further with an aqueous solution of sodium sulfate. The resulting organic layer was decanted and the residue was washed twice with ethyl acetate (200 ml). The combined organic layer was washed with brine. The organic solution was dried and the solvent was removed by distillation under reduced pressure. The residue was recrystallized twice from benzene to obtain 29.3 g of the intended compound as white crystals (yield: 40%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:19]([CH2:25][CH3:26])=[N:20][CH:21]=[CH:22][C:23]=1[Cl:24]>CN(C=O)C>[Cl:24][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:25][CH3:26])[C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1nccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nccc(Cl)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 12.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (382 mg, 2.7 mmol) was dissolved in anhydrous DMF (15 mL), and then potassium carbonate (1.12 g, 8.1 mmol) and 3-(bromomethyl)-4-chloro-2-ethylpyridine (3.5 mmol) in DMF (10 mL) were added. The mixture was stirred for 2.5 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 5-10% DCM/MeOH to afford 2-{[(4-chloro-2-ethylpyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (100 mg, 13% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.22 (t, J=7.4 Hz, 3H), 2.24 (s, 3H), 2.97 (q, J=7.4 Hz, 2H), 4.62 (s, 2H), 6.07 (bs, 1H), 7.44 (d, J=5.3 Hz, 1H), 8.40 (d, J=5.3 Hz, 1H).
Reaction SMILES: I[C:2]1[N:3]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:4]=[C:5]2[C:10]=1[CH2:9][N:8]([CH3:11])[CH2:7][N:6]2[CH2:12][CH:13]([CH3:15])[CH3:14].[CH2:27]([OH:31])[CH2:28][C:29]#[CH:30]>>[OH:31][CH2:27][CH2:28][C:29]#[C:30][C:2]1[N:3]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:4]=[C:5]2[C:10]=1[CH2:9][N:8]([CH3:11])[CH2:7][N:6]2[CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: C#CCCO
Reactant: CC(C)CN1CN(C)Cc2c1cn(Cc1cccc3ccccc13)c2I
Product: CC(C)CN1CN(C)Cc2c1cn(Cc1cccc3ccccc13)c2C#CCCO

Procedure:
The title compound was prepared from 5-iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl )-1 H -pyrrolo[3,4-d]pyrimidine-2,4(3 H, 6 H)-dione and 3-butyn-1-ol in a manner analogous to the method of Example 13 above.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:14][N:13]([C:15]3[N:16]([CH3:28])[C:17](=[O:27])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)[N:20]=3)[CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:29]([C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:14][N:13]([C:15]3[N:16]([CH3:28])[C:17](=[O:27])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)[N:20]=3)[CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1)#[N:30]
Reactant: Cn1c(N2CCCO[C@@H](c3cccc(Br)c3)C2)nc(-c2ccncn2)cc1=O
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: Cn1c(N2CCCO[C@H](c3cccc(C#N)c3)C2)nc(-c2ccncn2)cc1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of (S)-2-[2-(3-bromophenyl)-[1,4]oxazepan-4-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (A079) (1.0 g, 2.26 mmol) in N,N-dimethylacetamide (7.5 ml) was added zinc cyanide (0.292 g, 2.49 mmol) and tetrakis(triphenylphosphine) palladium(0) (523 mg, 0.452 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 110° C. for 8 hours. The resulting mixture was filtered through a pad of Celite and partitioned between aqueous sodium hydrogen carbonate and chloroform. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: chloroform/acetone=4/1) to afford (R)-2-[2-(3-cyanophenyl)-[1,4]oxazepan-4-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (A039) as pale yellow solid (745 mg, 85%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([Br:12])[N:6]2[N:5]=1.F[B-](F)(F)F.[O:19]=[N+:20]=[O:21]>C(#N)C>[CH3:1][O:2][CH2:3][C:4]1[C:13]([N+:20]([O-:21])=[O:19])=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([Br:12])[N:6]2[N:5]=1
Reactant: O=[N+]=O
Reactant: COCc1cc2cccc(Br)n2n1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 46 %

Procedure:
To a solution of (7-bromopyrazolo[1,5-a]pyridin-2-yl)methyl methyl ether (1.0 g) dissolved in acetonitrile (20 mL) was added nitronium tetrafluoroborate (606 mg) while stirring on ice. The obtained reaction mixture was added to ice water, extracted with ethyl acetate and then washed with water and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (546 mg) was obtained as light yellow crystals from the n-hexane:ethyl acetate (5:1) fraction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:17])=[CH:4][CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](B(O)O)=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[CH:33]2.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=[C:9]3[CH3:17])=[CH:4][CH:3]=2)=[C:36]2[C:41]=1[CH:40]=[CH:39][CH:38]=[CH:37]2
Reactant: Cc1nc2ccccc2n1-c1ccc(Br)cc1
Reactant: OB(O)c1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1nc2ccccc2n1-c1ccc(-c2c3ccccc3c(-c3ccc4ccccc4c3)c3ccccc23)cc1
Yield: 51.6 %

Procedure:
Dissolving 3.3 g (11 mmol) of 1-(4-bromophenyl)-2-methyl-1H-benzimidazole, 4.0 g (11 mmol) of 10-naphthalene-2-yl-anthracene-9-boronic acid and 0.27 g of tetrakis (triphenylphosphine) palladium into 40 milliliter of 1,2-dimethoxyethane, adding 20 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed with heating for 7 hours. After completion of the reaction, the precipitated solids were dissolved into the dichloro-methane, washed with water and dried with sodium sulfate. Removing the solvent by distillation and by refining the resultant product with the use of a silicagel column chromatography (dichloro methane-ethyl acetate), 2.9 g of yellowish white solids were obtained (yield: 49%). As a result of MS analysis, it was recognized that the yellowish white solids were identified as the aimed substance and that m/e=510 for molecular weight of 510.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: -25 °C

Procedure:
A solution of 4-methoxyphenyl magnesium bromide in tetrahydrofuran (0.5 M, 50 mL, 25 mmol) (Aldrich) was added dropwise to a suspension of 5-chloroisatin (1.82 g, 10 mmol) (Avocado) in tetrahydrofuran (20 mL) under argon with cooling in a −25° C. bath and magnetic stirring at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 1 hour, 15% aqueous ammonium chloride solution (50 mL) was added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 30 minutes and filtered to give crude rac-5-chloro-3-hydroxy-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a white powder. (Yield 2.57 g, 88.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@H:20]([CH2:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=O)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>CC(OC)(C)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@H:20]([CH2:21][CH2:22][CH2:23][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CCC(=O)N2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 6.0 g (14.0 mmol) of the compound obtained in Step D in 60 mL of MTBE and 14 mL of dichloromethane there are added 1.06 g (28 mmol) of LAH in portions over 5 minutes. The batch is stirred at ambient temperature for 15 hours. There are added, dropwise, 1.5 mL of water and stirring is carried out for 15 minutes. There are then added, dropwise, 1.5 mL of 5M sodium hydroxide solution and stirring is carried out for 15 minutes. The reaction mixture is then diluted with MTBE and dichloromethane. The suspension is then filtered and the precipitate is washed with MTBE and dichloromethane. The organic phase is then dried over MgSO4, filtered and concentrated to dryness. After purification by chromatography over silica gel using dichloromethane and ammonia-in-ethanol as eluants, the expected product is obtained in the form of an oil.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C:78]([NH2:80])=[O:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C:78]([NH2:80])=[O:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 27.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl) acetamide (80 mg, 0.120 mmol) was hydrolyzed with lithium hydroxide (11 mg, 0.240 mmol) in THF/methanol/water (5/2/1 mL) to yield 17 mg (27.8% yield) of desired product. 1H NMR (DMSO-d6, 400 MHz): δ 8.57-8.56 (d, 1H), 8.49-8.47 (m, 2H), 8.348-8.343 (d, 1H), 8.00-7.97 (m, 2H), 7.77-7.76 (d, 1H), 7.43-7.38 (m, 1H), 7.28 (s, 1H), 7.19-7.08 (m, 3H), 6.97-6.95 (d, 1H), 5.41 (s, 2H), 3.60-3.59 (t, 4H), 2.93 (s, 2H), 2.56-2.50 (t, 4H). MS: m/z=511.3 (M+1), HPLC: 90.86% in method A.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:6]1=2.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:6]1=2)[C:27](=[O:28])[O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCN1CCCCc2cc([N+](=O)[O-])ccc21
Solvent: ClCCl
Product: CN(CCN1CCCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 81.9 %

Procedure:
A solution of N,N-dimethyl-2-(7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethanamine (400 mg, 1.52 mmol) in 10 mL CH2Cl2 was treated dropwise with phenylchloroformate (286 μL, 2.28 mmol). The reaction was stirred at room temperature for 21 hours then partitioned between CH2Cl2 (100 mL) and 1N NaOH (20 mL). After extraction, the organic layer was separated and the aqueous layer was extracted with additional CH2Cl2 (50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a yellow residue. This residue was subjected to flash chromatography on silica gel using CH2Cl2 to give a yellow residue (460 mg, 82.0%). 1H-NMR (CDCl3) δ 7.99 (dd, J=2.7, 9.0 Hz, 1H), 7.93 (d, J=2.7 Hz, 1H), 7.40-7.34 (m, 2H), 7.23-7.18 (m, 1H), 7.10-7.04 (m, 2H), 6.87 (dd, J=6.3, 2.7 Hz, 1H), 3.65-3.55 (m, 4H), 3.39-3.31 (m, 2H), 3.11 and 3.05 (2×s, 3H), 2.88-2.85 (m, 2H), 1.85-1.65 (m, 4H). MS (ESI): 370.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][CH3:14].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>CCOC(C)=O>[CH2:17]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][CH3:14])[CH:16]=[CH2:15]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCCc1c(Br)ccc2c1COC2=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: C=CCc1ccc2c(c1CCC)COC2=O
Yield: 54.4 %

Procedure:
To a flask charged with 5-bromo-4-propyl-2-benzofuran-1(3H)-one (130 mg, 0.51 mmol) and a stir bar was added allyl tri-n-butyltin (0.24 mL, 0.76 mmol), PdCl2(dppf)-DCM complex (42 mg, 0.051 mmol), lithium chloride (65 mg, 1.5 mmol), and tolene (5 mL). The mixture was sealed with a condensor, purged with nitrogen three times, and heated to reflux for 5 hours. The crude reaction was diluted with EtOAc, adsorbed onto silica gel, and purified by MPLC. Removal of solvent gave rise to 5-allyl-4-propyl-2-benzofuran-1(3H)-one (60 mg, 44% yield) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[C:13]([OH:14])=[CH:12][C:11]3[O:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[CH:20]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:13]([O:14][CH3:20])=[CH:12][C:11]3[O:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(Cc2cc3c(cc2O)OCO3)cc1
Reactant: c1ccccc1
Product: COc1ccc(Cc2cc3c(cc2OC)OCO3)cc1

Procedure:
(4-Methoxybenzyl)-3,4-methylenedioxy-6-methoxybenzene was prepared from 6-(4-methoxybenzyl)-3,4-methylenedioxyphenol (L. Jurd, Tetrahedron, Vol. 33, pp. 163-168 (1977) by methylation as described above in H. Colorless prisms were obtained from benzene-solve F, m.p. 56°-57° (Found: C, 70.5; H, 5.95. Calc. for C16H16O4 : C, 70.6; H, 5.92%); pmr spectrum: δ3.74, 3H, S; δ3.77, 3H, S; δ3.82, 2H, S; δ5.85, 2H, S; δ6.52, 1H, S; δ6.55, 1H, S; δ6.80, 2H, D (J=9 Hz); δ7.11, 2H, D (J=9 Hz).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15](=[NH:17])[NH2:16])=[N:13][N:12]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:9]2=[N:10][CH:11]=1.C([N:29](CC)CC)C.O.NN>C(O)C>[F:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15](=[NH:16])[NH:17][NH2:29])=[N:13][N:12]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[F:22])[C:9]2=[N:10][CH:11]=1
Reactant: N=C(N)c1nn(CCC(F)(F)C(F)(F)F)c2ncc(F)cc12
Reactant: CCN(CC)CC
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: N=C(NN)c1nn(CCC(F)(F)C(F)(F)F)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.62 g (0.901 mmol) of the compound from Example 9A (purity about 56%) were dissolved in 10.3 ml of ethanol, and 456 mg (4.506 mmol) of triethylamine and 70 mg (1.126 mmol) of hydrazine hydrate (80% strength solution in water) were added at 0° C. The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. This gave a crude compound which was directly reacted further.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5].CC1(C)OC(=O)[CH:23]([CH:27]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](=O)O1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>N1C=CC=CC=1>[C:28]1([CH:27]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:23][C:22]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:1]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1cccc(NC(=O)c2ccccc2N)c1
Reactant: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ccccc23)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: COc1cccc(-n2c(CC(c3ccccc3)c3c[nH]c4ccccc34)nc3ccccc3c2=O)c1
Yield: 25.8 %

Procedure:
2-Amino-N-(3-methoxyphenyl)benzamide (2.77 g, 11.5 mmol), 3-[α-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)benzyl]indole (4.00 g, 11.5 mmol), and PPTS (1.44 g, 5.7 mmol) in 20 ml of pyridine was refluxed for seven days. The reaction mixture was concentrated in vacuo to an oil and partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed (1N hydrochloric acid, saturated sodium bicarbonate, and brine), dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The reaction was incomplete. The product was therefore mixed with PPTS (3 g) and 10 ml of 2,4,6-collidine and refluxed for five hours. The product was worked up as above to provide an oil which, upon standing for about one month, began to crystallize. Trituration with ethyl acetate and filtration provided 1.4 g of the title product: mp 160°-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH2:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9](I)[CH:8]=3.CC1(C)C(C)(C)OB([C:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[Br:1][C:2]1[CH:14]=[C:13]2[C:5](=[C:4]([C:16](=[O:17])[NH2:18])[CH:3]=1)[NH:6][C:7]1[CH:8]=[C:9]([C:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=3)[CH:10]=[CH:11][C:12]2=1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(I)ccc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)cc23)CC1
Temperature: 105 °C

Procedure:
3-Bromo-7-iodo-9H-carbazole-1-carboxamide 481A (200 mg, 0.482 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (194 mg, 0.626 mmol), Pd(Ph3P)4 (35 mg, 0.030 mmol), and Na2CO3 (2M) (0.964 mL, 1.928 mmol) were mixed with toluene (10 mL) and MeOH (5 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 105° C. in an oil bath for 4 hrs. The mixture was used as it is. MS (ESI) m/z 468.22 (M−H)−.