Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:24][CH3:25])[C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[CH2:7][CH2:6]1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[CH3:27][O:26][C:10]1[CH:9]=[C:8]2[C:17]3[C@H:16]([CH2:15][C@H:14]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:13][C:12]=3[C:11]=1[O:24][CH3:25])[C@H:5]([C:1]([OH:3])=[O:2])[CH2:6][CH2:7]2
Reactant: COC(=O)[C@@H]1CCc2cc(OC)c(OC)c3c2[C@@H]1C[C@H](c1ccccc1)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c3c(c1OC)C[C@@H](c1ccccc1)C[C@@H]3[C@H](C(=O)O)CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Crude [1R,8S,9aR]-1-carbomethoxy-5,6 dimethoxy 2,3,7,8,9,9a-hexahydro-8-phenyl-phenalene (0.8 g, 2.1 mmol) from Step 4, was dissolved in 100 mL of methanol and 8 mL of 1N aqueous sodium hydroxide was added. After stirring for 3 days at ambient temperature, the methanol was removed from the reaction mixture under reduced pressure. The residue was partitioned between 50 mL of diethyl ether and 75 mL of water. The aqueous phase was acidified to pH 2 with 6M hydrochloric acid solution and extracted with 3×25 mL of 1:1 ethyl acetate:diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 0.74 g (100% yield) of the title compound as an oil. DCI MS: (M+H)+ 253. 1H NMR (CDCl3) delta 2.0-2.3 (m, 2H), 2.65-2.85 (m, 2H), 2.9-3.1 (m, 6H), 3.2-3.3 (m, 1H), 3.73 (s, 3H), 3.83 (s, 3H), 6.56 (s, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=O)[NH:15][C:14]2=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.N#N.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C@@H:17]2[CH2:16][NH:15][CH2:14][C@H:13]2[C:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[CH2:6][CH2:5][CH2:4][N:3]4[CH:2]=2)=[CH:19]1
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c([C@@H]3CNC[C@H]3c3cn4c5c(cccc35)CCC4)c[nH]c2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione (WO2006086484A1, 8.34 g, 22.6 mmol) in anhydrous THF (400 mL) was purged with N2 and cooled to 0° C. LiAlH4 (226 mL, 1 M in THF, 226 mmol) was added dropwise. The reaction mixture was stirred at 60° C. overnight. The mixture was cooled with an ice-water bath and water (40 mL) added dropwise under N2 to quench excess LiAlH4. Water (500 mL) was added. The mixture was then acidified with 4M HCl to pH<2. 2M NaOH was added to adjust to pH>9. The mixture was extracted with EtOAc (2×800 mL). The combined EtOAc layer was washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated to give 1-[(3R,4R)-4-(1H-indol-3-yl)-pyrrolidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline as an orange/yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].O1CCCC1.C[O-].[Na+].[Cl:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:20][CH2:19][Cl:18]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1ccccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1OCCCl
Yield: 67.2 %

Procedure:
24.83 g (0.2 mole) of o-methoxyphenol and 100 ml of tetrahydrofuran were placed in a 500 ml-flask equipped with a stirring device and a cooling pipe. A solution in which sodium methoxide (0.2 mole) was dissolved in methanol was added to the flask while stirring the contents. Then tetrahydrofuran and methanol were eliminated at reduced pressure. 300 ml of tetrahydrofuran was added to the flask and then 46.94 g (0.2 mole) of 2-chloroethyl-p-toluene sulfonate was added thereto. The mixture was then stirred under heating reflux for 20 hours to promote reaction. After reaction, insoluble matters were eliminated by filtration, and the product was condensed at reduced pressure. The reaction mixture was then refined by column chromatography using silica gel, and 25.1 g of 2-(o-methoxyphenoxy)ethyl chloride was produced.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](=[O:29])SC2C=CC=CN=2)=[CH:3]1.[CH:30]([NH2:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:37]1([CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:43][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4](=[CH:3][C:2](=[O:1])[CH2:19][CH2:18]2)[CH2:5][CH2:6]4)=[O:29])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: NC(c1ccccc1)c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
Following a procedure similar to that described in Example 2(b), but using S-2-pyridyl 3-oxo-4-androstene-17β-thiocarboxylate [prepared as described in Example 2(a)] and benzhydrylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 85%.
Reaction SMILES: C1(C[N:8]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[NH:11][C:10]3[N:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)C=CC=CC=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[H-].[Na+].C1(O)C=CC=CC=1>CN(C)C=O>[N:32]1([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:11]2[C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[NH:8][C:9]3[CH:23]=[CH:22][CH:21]=[N:20][C:10]2=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: BrCCCCCCCN1CCCCC1
Reactant: O=C1c2ccccc2Nc2ncccc2N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: O=C1Nc2cccnc2N(CCCCCCCN2CCCCC2)c2ccccc21
Yield: 17 %

Procedure:
Prepared analogously to Example 18 by reacting 5,11-dihydro-5-(phenylmethyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one with 1-bromo-7-(1-piperidinyl)-heptane in the presence of sodium hydride and dimethylformamide and subsequent acidolytic cleaving of the phenylmethyl group by heating with 80% polyphosphoric acid in the presence of phenol. Yield: 17% of theory. Colourless crystals m.p. 118°-120° C. (after recrystallisation from diisopropyl ether and cyclohexane).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([O:16]C)[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([F:18])=[CH:10][CH:9]=3)[CH3:2].Cl>C(O)(=O)C>[CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([OH:16])[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([F:18])=[CH:10][CH:9]=3)[CH3:2]
Reactant: CCc1nnc2c(OC)nc3cc(F)ccc3n12
Agent: Cl
Solvent: CC(=O)O
Product: CCc1nnc2c(O)nc3cc(F)ccc3n12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 11.3 g (0.046 mole) of 1-ethyl-7-fluoro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 115 ml. of 1N hydrochloric acid and 345 ml. of glacial acetic acid was refluxed for a period of three hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice/water. The resulting mixture was then stirred for a period of 30 minutes, filtered and the recovered solid product subsequently washed with water and air-dried to ultimately afford 6.6 g. (62%) of pure 1-ethyl-7-fluoro-4-hydroxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p.>300° C. Mass Spectrum: m/e, 232 (P); m/e, 231 (P-1).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:6]1[C:22]2[CH2:21][C@H:20]3[N:23]([CH2:25][CH2:26][C@@:12]45[C@H:19]3[CH:18]=[CH:17][C@H:15]([OH:16])[C@@H:13]4[O:14][C:10]([C:11]=25)=[C:8](O)[CH:7]=1)[CH3:24].O.CN1[C@@H]2CC3=CC=C(O)C4O[C@H]5C(CC[C@@H]2[C@]5(C=43)CC1)=O>CCO.C(#N)C.CC(C)=O>[CH3:24][N:23]1[C@@H:20]2[CH2:21][C:22]3=[CH:6][CH:7]=[C:8]([O:2][S:1]([OH:5])(=[O:4])=[O:3])[C:10]4[O:14][C@H:13]5[C:15]([CH2:17][CH2:18][C@@H:19]2[C@:12]5([C:11]=43)[CH2:26][CH2:25]1)=[O:16]
Reactant: O=S(=O)(O)O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CN1CC[C@]23c4c5ccc(OS(=O)(=O)O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 81 °C
Yield: 84.5 %

Procedure:
A reaction flask was charged with morphine sulfate (40.0 g), water (30 mL), and EtOH (60 mL). The reaction mixture was agitated to form a suspension. The reactor was flushed with nitrogen and the reaction mixture was kept under nitrogen throughout the reaction. The flask was charged with acetone (0.4 mL) and the catalyst (RuCl3.xH2O, 0.60 g). The reaction mixture was heated to reflux (80-82° C.) and maintained at that temperature for 24 h. HPLC analysis indicated that 93% (area) hydromorphone was formed. Acetonitrile (6 mL) was added to the reaction mixture and the mixture was heater under reflux for 2 h. EtOH (180 mL) was added to the mixture, which was then cooled down to 10° C. for 2 h. The mixture was filtered, and the solid was washed with 95% EtOH (3×15 mL). The solid was dried at 90° C. for 28 h to give 32.2 g of hydromorphone sulfate as solids (purity>98% area).
Reaction SMILES: [OH:1][C:2]1[C:26]([CH3:27])=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:22]([O-])=O)=[C:11]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=2)=[C:4]([CH3:28])[CH:3]=1>[Pd].CO>[NH2:22][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:25]=[C:26]([CH3:27])[C:2]([OH:1])=[CH:3][C:4]=2[CH3:28])=[CH:12][C:11]=1[N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c(C)cc1O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c(C)cc1O
Yield: 90.2 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-hydroxy-2,5-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate (1.73 g), palladium on carbon (10%, 0.17 g) and methanol (50 ml) and the reaction mixture was purified to give the title compound (1.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH:33]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH3:31])[CH:33]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: CNC1CCN(C)C1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and methyl-(1-methyl-pyrrolidin-3-yl)-amine following General Procedure B.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5]1)[CH2:2][CH3:3].[NH4+].[OH-].[N+:19]([O-])([OH:21])=[O:20].O>O>[N+:19]([C:12]1[CH:11]=[C:10]([CH:6]2[O:7][CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]2)[CH:15]=[CH:14][C:13]=1[OH:16])([O-:21])=[O:20]
Reactant: CCCN1CCOC(c2ccc(O)cc2)C1
Reactant: O=[N+]([O-])O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCOC(c2ccc(O)c([N+](=O)[O-])c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
The phenol from example 29 (100 mg, 0.45 mmol) was dissolved in nitric acid:water (1:3) (2 ml) and stirred at room temperature for 10 minutes. The reaction mixture was then diluted with water (5 ml) and basified with NH4OH (1 ml), before extracting into ethyl acetate (3×10 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow solid (95 mg, 0.35 mmol, 79%). 1H NMR (CDCl3, 400 MHz) δ: 0.97 (t, 3H), 1.33 (t, 2H), 1.43-1.79 (bm, 4H), 2.02 (d, 3H), 4.06 (m, 2H), 7.17 (d, 1H), 7.60 (d, 1H), 8.16 (s, 1H), 10.55 (bs, 1H). LRMS: m/z 267 (M-H−).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[CH2:15]([O:17][CH2:18][CH2:19]O)[CH3:16].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:16][CH2:15][O:17][CH2:18][CH3:19])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1cccc(CC(=O)O)c1
Reactant: CCOCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCNc1cccc(CC(=O)OCCOCC)c1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 3-(allylamino)phenylacetic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 3-(allylamino)phenylacetate.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:46])(=[O:45])[N:26]([CH2:36][CH2:37][O:38]C4CCCCO4)[CH2:27][CH2:28][O:29]C4CCCCO4)[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.C([O-])(O)=O.[Na+]>C1COCC1>[OH:29][CH2:28][CH2:27][N:26]([CH2:36][CH2:37][OH:38])[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:23][CH2:22]2)(=[O:46])=[O:45]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)N(CCOC4CCCCO4)CCOC4CCCCO4)C4(CC4)C3)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=S(=O)(N(CCO)CCO)N1CCN(c2ncnc3[nH]ccc23)CC12CC2

Procedure:
4-(4-{Bis-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-sulfamoyl}-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 17) was treated with a mixture of TFA (0.5 mL), H2O (0.2 mL) and THF (0.2 mL) at 40° C. for 1 h. The crude reaction mixture was neutralised using sat. NaHCO3 and then extracted with EtOAc (3×10 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[Na].Br[CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:6]=[C:2]1[CH2:3][CH2:4][CH2:5][N:1]1[CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C1CCCN1
Reactant: COC(=O)c1ccc(OCCBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCN2CCCC2=O)cc1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
2-Pyrrolidinone (0.859 mL, 11.3 mmol, 2.6 eq) was added to a suspension of sodium hydride (452 mg of 60% w/w, 11.3 mmol, 2.6 eq.) in THF (10 mL). After 1 h, the suspension of the sodium salt of 2-pyrrolidinone thus formed was added to a solution of methyl 4-(2-bromoethoxy)benzoate (1.17 g, 4.52 mmol) and a catalytic amount of tetrabutylammonium iodide in dry THF (10 mL). The reaction was heated at reflux for 18 h. The reaction mixture was concentrated under reduced pressure then the residue partitioned between ethyl acetate (150 mL) and 2 N sodium hydroxide (50 mL). The aqueous layer was made acidic to pH 3 with conc. HCl; then the solvent was removed under reduced pressure. The resulting solid was triturated with ethyl acetate to give the acid as a white solid (523 mg, 46%).
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:19][NH:20][C:21]([NH2:23])=[O:22].C(OCC)(=O)C>C1C2C(=CC=CC=2)CCC1>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]2[NH:23][C:21](=[O:22])[N:20]([CH3:19])[C:14](=[O:16])[CH:13]=2)[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: CNC(N)=O
Solvent: c1ccc2c(c1)CCCC2
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Temperature: 170 °C
Yield: 40.3 %

Procedure:
To a solution of ethyl veratroylacetate (8.0 g) in tetralin (24 ml) was added N-methylurea (3.52 g) and the mixture was heated for an hour at 170° C. After being cooled to 95° C., ethyl acetate (33 ml) was added thereto. The precipitate was collected by filtration and washed with ethyl acetate to give 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (3.35 g).
Reaction SMILES: [CH2:1](N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.O>C(Cl)Cl>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: NCCCCCCN
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: O
Solvent: ClCCl
Product: NCCCCCCc1ccnc2cc(Cl)ccc12
Temperature: 150 °C

Procedure:
17.1 Grams of hexane-1,6-diamine and 4.3 g of 4,7-dichloroquinoline were mixed together and heated to 150° C. for four hours. The reaction was cooled and water and methylene chloride were then added. The organic phase was washed, dried with anhydrous magnesium sulfate and evaporated thereby affording 1-amino-6-(7-chloro-4-quinolinyl)hexane having a melting point of 133°-134°.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][C:8]=1/[CH:17]=[C:18]1\[C:19](=[O:27])[NH:20][C:21]2[C:26]\1=[CH:25][CH:24]=[CH:23][CH:22]=2)C.[OH-].[Na+].Cl>CCO>[C:4]([CH2:5][CH2:6][C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][C:8]=1/[CH:17]=[C:18]1\[C:19](=[O:27])[NH:20][C:21]2[C:26]\1=[CH:25][CH:24]=[CH:23][CH:22]=2)([OH:28])=[O:3]
Reactant: CCOC(=O)CCc1c(/C=C2\C(=O)Nc3ccccc32)[nH]c2c1C(=O)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1c(/C=C2\C(=O)Nc3ccccc32)[nH]c2c1C(=O)CCC2
Temperature: 25 °C

Procedure:
To an EtOH solution (3.0 mL) containing (Z)-3-((3-(3-ethoxy-3-oxopropyl)-4-oxo-4,5,6,7-tetrahydro-1 H-indol-2-yl)methylene)indolin-2-one (0.50 mmol) was added 3.0 N aqueous NaOH (1.0 mL). The reaction was heated at reflux for 2.0 h and cooled to room temperature. The solution was acidified with 6 N HCl to pH 3.0. The resultant precipitate was filtered and washed with MeOH to provide the desired product. 1 H NMR (DMSO-d6) δ 13.76 (s, 1 H), 11.01 (s, 1 H), 7.77 (s, 1 H), 7.76 (d, 1 H), 7.17 (dd, 1 H), 7.01 (dd, 1 H), 6.89 (dd, 1 H), 3.15 (t, 2 H), 2.91 (t, 2H), 2.36-2.41 (m, 2 H), 2.06 (t, 2 H).
Reaction SMILES: [CH3:1][O-].[Na+].[Na].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:19]([OH:21])=[O:20])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.IC>CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:19]([O:21][CH3:1])=[O:20])[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[CH:10][CH:11]=1
Reactant: C[O-]
Reactant: O=C1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CI
Product: COC(=O)C1(c2ccc(F)cc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a stirred sodium methoxide solution, previously prepared starting from 1.3 parts of sodium in 160 parts of methanol, are added 13 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarboxylic acid and the whole is stirred and refluxed for 1 hour. After cooling to room temperature, 22.8 parts of iodomethane are added dropwise. Upon completion, the whole is heated to reflux and stirring is continued overnight at reflux temperature. The reaction mixture is evaporated and the residue is taken up in trichloromethane. The organic phase is washed successively with water, a 5% sodium hydroxide solution and again with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5 parts (36%) of methyl 1-(4-fluorophenyl)-4-oxocyclohexanecarboxylate as an oily residue.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[C:30]([CH3:37])[N:29]=1>CN(C=O)C>[CH3:26][O:27][C:28]1[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:32][CH:31]=[C:30]([CH3:37])[N:29]=1
Reactant: COc1nc(C)ccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: COc1nc(C)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methoxy-6-methylpyridine-3-boronic acid (CAS RN 1000802-75-4) and using DMF as reaction solvent. Off-white solid (42%). MS (ESI): m/z=469.8 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)c1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(Oc2ccc(N)nc2)c1
Reaction time: 6 h
Yield: 99.4 %

Procedure:
To a solution of tert-butyl 3-[(6-nitro-3-pyridyl)oxy]benzoate (1.0 g, 3.161 mmol), in ethyl acetate (20 mL) was added 10% Pd on carbon (0.2 g, 20% w/w), and reaction mixture was stirred under H2 gas balloon for 6 h. Completion of reaction was confirmed by TLC. Reaction mixture was filtered through celite pad washed with ethyl acetate, filtrate was concentrated under reduced pressure to afford pure product (0.9 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[CH:27]=3)=[CH:21][N:20]([S:36]([C:39]3[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:17]2=[N:18][CH:19]=1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[CH:27]=3)=[CH:21][N:20]([S:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=3)(=[O:38])=[O:37])[C:17]2=[N:18][CH:19]=1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4F)cnc32)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4F)cnc32)cc1
Yield: 76.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(2-fluoro-4-(piperazin-1-yl)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (120 mg. 0.192 mmol) was alkylated using (S)-2-methyloxirane (17 mg, 0.288 mmol), DIPEA (75 mg, 0.576 mmol) and ethanol (3 mL) to get 100 mg (76.3%) of the titled compound. MS: m/z=683.2 (M+1).