Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:32])[F:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Cl:41])C(=O)C1>C(Cl)Cl>[Cl:41][C:15]1[C:14]2[CH:13]=[C:12]([O:11][CH2:10][C:9]3[CH:28]=[CH:29][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:7]([C:30]([F:33])([F:31])[F:32])[CH:8]=3)[CH:20]=[CH:19][C:18]=2[N:17]2[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Solvent: ClCCl
Product: O=C(O)CC1CCn2c1c(Cl)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a solution of 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (34 mg, 0.074 mmol) dissolved in DCM (0.500 mL) and cooled to 0° C. was added NCS (9.92 mg, 0.074 mmol). The reaction was stirred at 0° C. for 15 min in a 20 mL sealed scintillation vial. After 15 min, the reaction mixture was diluted with DCM and washed with water (2×10 mL), washed with sodium thiolsulfate pentahydrate (aq.) (2×10 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (32 mg). LCMS m/z=492.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.73 (m, 4H), 1.80-1.89 (m, 2H), 1.95-2.05 (m, 2H), 2.24-2.35 (m, 1H), 2.52-2.58 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.36, 4.11 Hz, 1H), 3.21-3.29 (m, 1H), 3.64-3.72 (m, 1H), 3.95-4.05 (m, 1H), 4.11-4.19 (m, 1H), 5.18 (s, 2H), 6.87 (dd, J=8.78, 2.46 Hz, 1H), 6.98 (d, J=2.27 Hz, 1H), 7.29 (d, J=8.84 Hz, 1H), 7.63 (d, J=7.96 Hz 1H), 7.69-7.76 (m, 2H), 12.35 (bs, 1H).
Reaction SMILES: CC1C(CCC(O)=O)=C(CC2NC(/C=C3/C(C=C)=C(C)C(N/3)=O)=C(C)C=2CCC(O)=O)NC=1/C=C1/C(C)=C(C=C)C(N/1)=O.[CH3:44][CH2:45][C:46]1[C:68]([CH3:69])=[C:67]2[NH:70][C:47]=1[CH:48]=[C:49]1[N:102]=[C:101]3[C:51]([C:52]([C@H:54]([C:103]([O:105][CH3:106])=[O:104])[C:55]3=[C:56]3[N:60]=[C:59]([CH:61]=[C:62]4[NH:71][C:65](=[CH:66]2)[C:64]([CH:72]=[CH2:73])=[C:63]4[CH3:74])[C@@H:58]([CH3:75])[C@@H:57]3[CH2:76][CH2:77][C:78]([O:80][CH2:81]/C=C(/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\C)=[O:79])=[O:53])=[C:50]1[CH3:107].S(=O)(=O)(O)O.ClCCl>CO>[CH3:44][CH2:45][C:46]1[C:47]2=[N:70][C:67](=[CH:66][C:65]3[NH:71][C:62]([CH:61]=[C:59]4[CH:58]([CH3:75])[CH:57]([CH2:76][CH2:77][C:78]([O:80][CH3:81])=[O:79])[C:56]([C:55]5[CH:54]([C:103]([O:105][CH3:106])=[O:104])[C:52](=[O:53])[C:51]6[C:101]=5[NH:102][C:49]([C:50]=6[CH3:107])=[CH:48]2)=[N:60]4)=[C:63]([CH3:74])[C:64]=3[CH:72]=[CH2:73])[C:68]=1[CH3:69]
Reactant: C=Cc1c(C)c2cc3nc(c4c5nc(cc6[nH]c(cc1[nH]2)c(C)c6CC)C(C)=C5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C
Agent: C=CC1=C(C)/C(=C/c2[nH]c(Cc3[nH]c(/C=C4\NC(=O)C(C)=C4C=C)c(C)c3CCC(=O)O)c(CCC(=O)O)c2C)NC1=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C

Procedure:
The green filtrate was evaporated and purified by flash chromatography on Grade V neutral Alumina, eluting first with n-hexane to remove a fast running yellow band and then with dichloromethane to obtain the major blue/gray peak containing pheophytin-a. Treatment of pheophytin-a with 500 ml sulfuric acid in methanol for 12 hours at room temperature in the dark under nitrogen was followed by dilution with dichloromethane. The reaction mixture was rinsed with water and then 10% aqueous sodium bicarbonate and the organic layer was dried, evaporated, and the residue recrystallized from dichloromethane/methanol to obtain 1.8 gm methyl pheophorbide-a. Methyl pheophorbide-a appears to be inactive in the in vivo tumorcidal activity assay when injected at a dose of 5 mg/kg.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[CH:14]([CH2:15][OH:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)O)C2C(=O)OC(C)(C)C)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(CO)C2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 2-tert-butyl ester (1.17 g, 2.65 mmoL) in 26.5 mL THF at 0° C. was added triethylamine (0.406 mL, 2.915 mmoL) followed by isobutyl chloroformate (0.378 mL, 2.915 mmoL). This suspention was allowed to stir for one hour. The suspention was then filtered into a dropping funnel which was added dropwise to a previously prepared sodium borohydride (321 mg, 8,48 mmoL) solution in 1.63 mL of water at 0° C. After 2.5 hours the solvent was stripped and the residue was diluted with ethyl acetate and water. The solution was washed once with 0.5N HCL, the layers separated, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica: 25% to 35% ethyl acetate in hexanes) to yield 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert butyl ester; MS: (M+H)+ =398, (M+NH4)+ =415.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: O=C1CCCN1
Product: O=C1CCCN1c1cnc2ccccc2c1
Yield: 99 %

Procedure:
Using general procedure C, 3-bromoquinoline was coupled with 2-pyrrolidinone with the reaction time of 15 h. Chromatography gave 210 mg (99%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 9.24 (d, 1H, J=2.7 Hz), 8.45 (d, 1H, J=2.4 Hz), 8.08 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=8.1 Hz), 7.66 (t, 1H, J=7.7 Hz), 7.55 (t, 1H, J=7.5 Hz), 4.04 (t, 2H, J=7.2 Hz), 2.69 (t, 2H, J=8.1 Hz), 2.28 (p, 2H, J=7.8 Hz).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[O:15][CH2:16][C@H:17]([OH:33])[CH2:18][NH:19][C:20]([CH3:32])([CH3:31])[CH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)#[N:3].C(=O)([O-])[O-].[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1.I[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]>CN(C=O)C>[ClH:1].[CH2:59]([O:13][C:12](=[O:14])[CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[C:5]([O:15][CH2:16][C@H:17]([OH:33])[CH2:18][NH:19][C:20]([CH3:31])([CH3:32])[CH2:21][CH:22]2[CH2:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30]2)[CH:6]=1)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]
Reactant: CCCCCCCCI
Reactant: CC(C)(CC1Cc2ccccc2C1)NC[C@@H](O)COc1cc(CCC(=O)O)ccc1C#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)CCc1ccc(C#N)c(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c1
Temperature: 70 °C

Procedure:
A solution of the compound from Example 5 (100 mg, 0.2 mmol) in dry DMF (15 mL) was treated with cesium carbonate (141 mg, 0.4 mmol) and 18-crown-6 (100 mg, 0.41 mmol) followed by 1-iodooctane (144 mg, 0.6 mmol). The resulting mixture was heated at 70° C. under argon for 20 h. The reaction was cooled, concentrated and the residue partitioned between water and ethyl acetate. The organic layer was washed with 10% Na2CO3 (aqueous), brine, dried over MgSO4 and evaporated. Purification by flash chromatography (4% MeOH in CH2Cl2) gave the ester as a yellow oil. The oil in ether was treated with HCl and filtered to give the above titled compound (50 mg, 46%). LC-MS m/e 549.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18]C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(Cl)(Cl)[Cl:29]>CCOC(C)=O>[ClH:29].[CH2:1]([O:8][C:9](=[O:26])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of trans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester (4.00 g, 11.0 mmol) in EtOAc (40 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). To the reaction mixture was added CHCl3 (10 mL) and the mixture was stirred at ambient temperature for 3 hr. To the reaction mixture was 4 M hydrogen chloride in EtOAc (20 mL) and the mixture was stirred at ambient temperature for 1.5 hr, filtered, washed with EtOAc, and dried under reduced pressure to give trans-(4-aminomethyl-cyclohexyl)-carbamic acid benzyl ester hydrochloride (2.96 g, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([O:17][CH2:18][CH:19]3[O:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:4][CH:3]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:26][CH:23]([CH3:25])[CH3:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(OCC2CO2)N1c1ccc(Cl)cc1
Reactant: CC(C)N
Solvent: Cc1ccccc1
Product: CC(C)NCC(O)COC1c2ccccc2C(=O)N1c1ccc(Cl)cc1

Procedure:
A solution of 2-(4-chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one (15 g.) and isopropyl-amine (75 cc.) in anhydrous toluene (250 cc.) is heated under reflux for 5 days. The reaction mixture is then evaporated to dryness under reduced pressure and the residue obtained is recrystallised from ethyl acetate (60 cc.). After drying, 2-(4-chlorophenyl)-3-(2-hydroxy-3-isopropylamino-propoxy)-isoindolin-1-one (13 g.), melting at 107° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH3:23])[N:4]=1
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N=C(OC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (3.19 g, 10.0 mmoles) in dichloromethane (25 ml) and pyridine (5.0 ml) under argon was cooled to 0° C. and was treated dropwise with ethyl chloroformate (1.2 ml of 0.7%, 12.0 mmoles). After the addition was completed, the reaction was allowed to warm to room temperature and stirred for 1 hour. It was then diluted with ethyl acetate and the resulting solution was washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to provide 2-methoxy-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester as a light yellow foam (3.71 g). This material was used in the next reaction without purification.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>O>[O:11]([C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccnc1Oc1ccccc1

Procedure:
The two-step process for producing pure 1-azaxanthone starts from 2-chloronicotinic acid which is reacted with sodium phenoxide at 160°-200° C., the mixture is dissolved in water and acidified, the 2-phenoxynicotinic acid obtained is cyclized with a dehydrating agent, usually polyphosphoric acid, at 120°-200° C. The cooled mixture is dissolved in water and neutralized with an alkaline hydroxide, and the precipitated 1-azaxanthone is washed and recrystallized.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C@:15]12[CH2:23][N:22]([C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[C:21](=[O:32])[C@@H:20]1[CH2:19][CH:18]=[CH:17][CH2:16]2)=[O:14])(C)(C)C>ClCCl>[O:32]=[C:21]1[N:22]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[CH2:23][C@@:15]2([C:13]([OH:14])=[O:12])[C@H:20]1[CH2:19][CH:18]=[CH:17][CH2:16]2
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CC=CC[C@H]2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)O)CC=CC[C@H]2C1=O
Yield: 81.9 %

Procedure:
Trifluoroacetic acid (18.0 mL) was added to a solution of [(1S,6R)-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-en-1-yl]carboxylic acid tert-butyl ester (2.04 g, 5.99 mmol) in dichloromethane (18.0 mL) with stirring under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and trifluoroacetic acid was azeotropically distilled with toluene (×3). A 1 mol/L sodium hydroxide solution (15.0 mL) was added to the resulting residue under ice-cooling, and the mixture was washed with diethyl ether (40 mL×2). The aqueous layer was made acidic with 1 mol/L hydrochloric acid (20 mL) under ice-cooling. Then, the precipitated crystals were collected by filtration and washed with 0.5 mol/L hydrochloric acid, ethyl acetate, and diethyl ether. The resulting crystals were dried under reduced pressure at 50° C. overnight to give 1.40 g of the title compound as white crystals. The aqueous layer of the filtrate was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with water (150 mL) and brine (150 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 250 mg of the title compound as white crystals.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN(C)C=O.Cl.[NH2:21][CH:22]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:23]([O:25][CH3:26])=[O:24].CCN(C(C)C)C(C)C>O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:22]([NH:21][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[C:23]([O:25][CH3:26])=[O:24])=[CH:32][CH:31]=1
Reactant: COC(=O)C(N)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(C(=O)OC)c2ccc(F)cc2)c([N+](=O)[O-])c1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed methyl 4-fluoro-3-nitrobenzoate (15.4 g, 77.78 mmol, 1.00 equiv), N,N-dimethylformamide (100 mL), methyl 2-amino-2-(4-fluorophenyl)acetate hydrochloride (20.4 g, 93.15 mmol, 1.20 equiv), and DIEA (50.2 g, 389.15 mmol, 5.00 equiv). The reaction was stirred overnight at 35° C. in an oil bath. The resulting solution was diluted with 500 ml of H2O and the resulting solids were collected by filtration. This resulted in 15 g (53%) of methyl 4-(1-(4-fluorophenyl)-2-methoxy-2-oxoethylamino)-3-nitrobenzoate as a yellow solid.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Br:21])[C:19]=1[OH:20])[CH:15]=[O:16]>>[Br:21][C:18]1[C:19]([O:20][CH:2]([CH3:3])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[C:12]([O:11][CH3:10])[CH:13]=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: CC(C)CCCC(C)Br
Product: COc1cc(C=O)cc(Br)c1OC(C)CCCC(C)C

Procedure:
2-bromo-6-methyl-heptane was reacted with 3-methoxy-4-hydroxy-5-bromo-benzaldehyde to obtain 5-bromo-4-[(1,5-dimethyl-hexyl)-oxy]-m-anisaldehyde (boiling point = 190°-193° C/0.1 mmHg);
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[NH:6][N:5]=1.[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[N:6]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[N:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=[N+]([O-])c1cnc2[nH]nc(Br)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(Br)c2cc([N+](=O)[O-])cnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
NaH (0.165 g, 4.11 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0° C.) solution of 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.5 g, 2.06 mmol) in dry DMF (20 mL). The reaction mixture was stirred at 0° C. for 10 minutes, and 2-(trimethylsilyl)ethoxymethyl chloride (0.617 mL, 3.50 mmol) was added dropwise via a syringe. The cold bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was placed in an ice bath, diluted with ethyl acetate (400 mL) and carefully quenched with water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (20:1) to give 3-bromo-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (0.636 g, 83%) as a solid.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=O)=[CH:10][C:9]([O:15][CH3:16])=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)(=[O:19])[CH3:18].N1CCCCC1>CO>[CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1/[CH:13]=[CH:18]/[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:19])=[CH:10][C:9]([O:15][CH3:16])=[CH:8][CH:7]=2)([CH3:3])[CH3:2]
Reactant: COc1ccc2[nH]c(C(C)C)c(C=O)c2c1
Reactant: CC(=O)c1ccncc1
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2[nH]c(C(C)C)c(/C=C/C(=O)c3ccncc3)c2c1
Temperature: 40 °C
Yield: 66.3 %

Procedure:
2-Isopropyl-5-methoxyindole-3-carboxaldehyde (105 mg, 0.48 mmol) was dissolved in anhydrous methanol (5 mL) under an atmosphere of Argon (g). 4-Acetylpyridine (87.2 mg, 0.72 mmol) and piperidine (61.3 mg, 0.72 mmol) were added to the reaction mixture and the solution was refluxed for 24 hours. A precipitate slowly formed which was collected, washed with cold MeOH (30 mL) and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator heated to 40° C. to yield a bright yellow powder (102 mg, 66%): TLC Rf 0.38 in 4:1 ethyl acetate/hexanes. Melting point=252-253° C. 1H NMR (600 MHz, d6-DMSO) δ 11.78 (s, 1H), 8.82-8.81 (m, 2H), 8.15-8.13 (d, 1H, J=15.24 Hz), 7.94 (m, 2H), 7.45 (d, 1H, J=2.28 Hz), 7.41-7.38 (d, 1H, J=15.18 Hz), 7.36-7.34 (d, 1H, J=8.7 Hz), 6.88-6.87 (dd, 1H, J1=2.34 Hz, J2=8.64 Hz), 3.87 (s, 3H), 3.54-3.49 (m, 1H), 1.35-1.34 (d, 6H, J=6.96 Hz); 13C NMR (150 MHz, d6-DMSO) δ 188.6, 155.7, 155.4, 151.1, 145.6, 139.6, 131.8, 126.6, 121.9, 113.5, 113.0, 111.6, 105.0, 104.4, 56.1, 26.0, 22.8. Elemental analysis calculated for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 74.78; H, 6.42; N, 8.68.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>ClCCl>[CH2:15]([N:17]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH2:18][CH3:19])[CH3:16]
Reactant: O=C(CCCBr)OCc1ccccc1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)CCCC(=O)OCc1ccccc1
Yield: 60 %

Procedure:
A mixture of benzyl 4-bromobutanoate (58.6 diethylamine (58.3 g) and dichloromethane (1000 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate gave benzyl 4-(N,N-diethylamino)butanoate (33.8 g, 60%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH2:17][C:18]([C:25]3[CH:30]=[C:29]([Cl:31])[C:28](Cl)=[C:27]([Cl:33])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[CH2:19][N:20]=2)=[CH:8][CH:7]=1)(=O)C.C[O-].[Na+]>CO>[Cl:33][C:27]1[CH:26]=[C:25]([C:18]2([C:21]([F:23])([F:24])[F:22])[CH2:17][C:16]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:6]([CH2:5][OH:4])=[CH:7][CH:8]=3)=[N:20][CH2:19]2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: CC(=O)OCc1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reaction time: 3 h

Procedure:
To a solution of {4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]naphthalen-1-yl}methyl acetate (0.66 g) in methanol (5 ml) was added sodium methoxide (76 mg) at room temperature. The mixture was stirred for 3 hours and concentrated under reduced pressure, and then added water. The mixture was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, to obtain the desired compound as crude product (0.6 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:25])[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)[CH:9]=2)=[CH:5][C:4]=1[N+:28]([O-])=O>CO.[Pd]>[NH2:28][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:3]=1[NH:2][CH3:1])[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:25])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CCN1CCN(CC(=O)Nc2cc(Oc3ccc(NC)c([N+](=O)[O-])c3)ccn2)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(CC(=O)Nc2cc(Oc3ccc(NC)c(N)c3)ccn2)CC1

Procedure:
The mixture containing N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide in methanol with a catalytic amount of 10% Pd/C poisoned with lead was hydrogenated until the disappearance of the yellow color. The reaction was then filtered to remove the catalyst and concentrated to yield N-(4-(3-amino-4-(methylamino)phenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide as a brown oil. HPLC=2.00 min; MS: MH+=385.