Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)=[O:1]
Reactant: O=C(NC1CCN(c2ccc(CO)cc2)CC1)c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1ccc(N2CCC(NC(=O)c3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a solution of N-(1-(4-(hydroxymethyl)phenyl)piperidin-4-yl)benzamide (1.1 g, 3.5 mmol) in CH2Cl2 (250 mL) was added TPAP (0.123 g, 0.35 mmol) and NMO (0.623 g, 5.3 mmol). After 1 hour, the mixture was filtered through Celite, concentrated, and purified by silica gel chromatography, eluting with 30% ethyl acetate/hexanes to 100% ethyl acetate, to afford N-(1-(4-formylphenyl)piperidin-4-yl)benzamide as a white solid (0.350 g, 32%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]>>[F:10][C:11]1[CH:16]=[C:15]([N+:1]([O-:4])=[O:2])[CH:14]=[CH:13][C:12]=1[F:17]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccccc1F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(F)c1
Temperature: -12 °C
Reaction time: 0.75 h

Procedure:
This material is prepared as described by R. W. Taft, G. B. Klingensmith, and S. Ehrenson (J. Am. Chem. Soc., 87, 3620 (1965). To a stirred mixture of 5.0 ml of concentrated nitric acid and 13.9 ml of concentrated sulfuric acid cooled to -12° C. is added 9.7 g (0.085 mole) of 1,2-difluorobenzene. A slight exotherm is observed and the mixture is cooled to -20° C. whereupon it solidifies. The mixture is stirred for 45 minutes at -5° to 0° and is then allowed to warm slowly to room temperature. After 1 hour the mixture is poured onto ice, and the mixture extracted with diethyl ether (3×75 ml). The combined ether extracts are washed with water, 10% aqueous Na2CO3, and water again. The ether solution is dried (MgSO4) and concentrated in vacuo without external heating to give the crude product (11.9g), which is distilled (kugelrohr apparatus) to give 10.2 g of colorless liquid. The nmr spectrum of this material is consistent with the structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.[CH2:13]1[O:15][CH2:14]1>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH2:13][CH2:14][OH:15]
Reactant: Cn1cnc(-c2ccccc2)c1
Reactant: C1CO1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)nc1CCO
Temperature: -78 °C
Reaction time: 18 h
Yield: 31.3 %

Procedure:
In a 25 ml flask were placed 11-2 (0.500 g, 3.16 mmol), and anhydrous THF (6 mL). The reaction was flushed with N2 gas and cooled to −78° C. Ethylene oxide (27.3 g, 31 mL, 31.6 mmol) was added dropwise via syringe. Upon completion of addition, the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was then quenched with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (24 g cartridge), eluting with 0-100% EtOAc/hexanes to give 200 mg (31%) of 11-3. LC/MS: m/z (M+H)=203.2.
Reaction SMILES: [N+](C1C=CC(S([N:13]2[C:17]3([CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:16][CH2:15][CH:14]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=O)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.C1(S)C=CC=CC=1>C(#N)C>[NH:13]1[C:17]2([CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH2:16][CH2:15][CH:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C1CCC2(CCOCC2)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of ethyl 1-[(4-nitrophenyl)sulfonyl]-8-oxa-1-azaspiro[4.5]decane-2-carboxylate (165) (1.47 g, 3.7 mmol) in anhydrous acetonitrile (25 mL) was added potassium carbonate (0.76 g, 5.5 mmol), 18-crown-6 (0.2 g, 0.7 mmol) and thiophenol (0.6 mL. 5.5 mmol) and the reaction stirred at room temperature for 18 h. The reaction was concentrated in vacuo and the residue dissolved in 0.1 N HCl. The aqueous layer was extracted twice with EtOAc and the organic layer was discarded. The aqueous layer was treated with solid potassium carbonate until the solution gave blue pH paper. It was extracted with 15% isopropanol/dichloromethane (3×) and the organic layer dried over sodium sulfate and concentrated in vacuo to afford the title compound as a clear oil (0.71 g, 90% yield).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:32]5[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccc(N)nc3)cc1OCC2
Yield: 62 %

Procedure:
Following the same procedure as for 182, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine provided 219 in 62% yield. LS/MS (ESI+): m/z 388 (M+H). 1H NMR (400 MHz, DMSO) δ 8.42 (d, J=8.4, 1H), 8.33 (d, J=2.4, 1H), 7.93 (d, J=6.5, 2H), 7.77 (dd, J=8.7, 2.5, 1H), 7.41 (dd, J=8.5, 1.9, 1H), 7.26 (d, J=1.8, 1H), 6.53 (d, J=8.6, 1H), 6.16 (s, 2H), 5.92 (dt, J=13.2, 6.6, 1H), 4.60-4.44 (m, 4H), 1.50 (d, J=6.6, 6H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][CH:19]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Yield: 147.6 %

Procedure:
In accordance with scheme C-I, 10 g of 2,5-dibromopyridine and 19.24 g of 4-benzyloxyphenylboronic acid are coupled analogously to Example 4a to give 21.2 g (73.9%) of 5-bromo-2-(4-benzyloxyphenyl)pyridine.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:35]=[C:34]([CH:33]=[CH:32][CH:31]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cccc(Cl)c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3-chlorophenol (6.40 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.9 mg, 40.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.35-7.10 (m, 7H), 7.02 (t, 1H, J=8.0 Hz), 6.90 (d, 1H, J=7.6 Hz), 6.84-6.75 (m, 2H), 6.65 (m, 1H), 5.09 (apparent dd, 1H, J=4.99, 8.1 Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.50 (m, 2H), 2.30-1.70 (m, 8H), 1.18 (d, 6H, J=6.8 Hz); ESMS m/e: 491.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[Cl:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20].O>C(C(C)=O)C>[Cl:10][C:3]1[C:4]([CH2:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:19](=[O:20])[O:21][CH3:22]
Reactant: CCc1nccc(N)c1Cl
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCC(C)=O
Product: CCc1nccc(NC(=O)OC)c1Cl
Temperature: -10 °C
Yield: 64 %

Procedure:
5.7 g (36.4 mmol) of 4-amino-3-chloro-2-ethylpyridine was dissolved in 50 ml of methyl ethyl ketone. Then, 5.5 g (54.6 mmol) of triethylamine was added thereto, and the mixture was stirred at -10° C. Then, 8.6 g (91.0 mmol) of methyl chloroformate was gradually added thereto so that the temperature would not exceed -5° C. After completion of the dropwise addition, the mixture was stirred for one hour at a temperature of from -10° to -5° C. and for further one hour at room temperature. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was recrystallized from isopropyl ether to obtain 5.0 g of the desired product as colorless prism crystals (melting point: 78° to 79° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:16](=[O:28])[NH:17][C:18]2=[O:27])=[N:13]1.Br[CH2:34][CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:16](=[O:28])[N:17]([CH2:34][CH2:35][OH:36])[C:18]2=[O:27])=[N:13]1
Reactant: OCCBr
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Cn1c(=O)n(CCO)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 2-bromoethanol using potassium carbonate as a base. Mass: 496.17 (M+H).
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[C:14]([N:21]([CH2:29][CH2:30][CH2:31]Cl)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C1COCC1>[C:17]([O:16][C:14]([N:21]1[CH2:29][CH2:30][CH2:31][CH:22]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(CCCCl)Cc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1ccccc1
Reaction time: 5 h
Yield: 65.3 %

Procedure:
To a solution of tetramethylethylenediamine (0.83 mL, 5.47 mmol) and n-BuLi (1.6 M/hexane, 3.31 mL, 5.3 mmol) cooled at −78° was added dropwise N-Boc-N-benzyl-3-chloropropylamine (1.0 g, 3.53 mmol) in THF. The resulting yellow solution was stirred at −78° for 5 h. The reaction mixture was then quenched with aqueous NH4Cl (20 mL) and diluted with Et2O (150 mL), the layers were separated and the aqueous layer was extracted twice with Et2O. The combined organic phases were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The resulting yellow oil was purified by flash chromatography (SiO2, 10% EtOAc-hexane) to give 2-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (0.57 g, 65% yield).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1B(O)O.O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[CH3:12])[C:7]1=2
Reactant: Brc1cccc2ccsc12
Reactant: Cc1ccncc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccncc1-c1cccc2ccsc12
Temperature: 90 °C
Yield: 89.5 %

Procedure:
A vessel capable of sealing was charged with a mixture of 7-bromobenzo[b]thiophene (370 mg, 1.736 mmol), 4-methylpyridin-3-ylboronic acid HCl (361 mg, 2.084 mmol), PdCl2(dppf)-CH2Cl2 adduct (70.9 mg, 0.087 mmol), dioxane (8 mL), and a 2.0 M aqueous solution of K3PO4 (3.47 mL, 6.95 mmol) and was purged with nitrogen for 10 min. The vessel was sealed and heated at 90° C. for 10 hours. Upon cooling, the reaction mixture was diluted with CH2Cl2 and filtered with CH2Cl2/MeOH washing. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by BIOTAGE® eluting with 10%-40% EtOAc/CH2Cl2 at 30 mL/min. Concentration of appropriate fractions provided the title compound (350 mg, 89% yield). LC/MS: Example 111A @ 1.50 min (RT) (Condition G). MS (ES): m/z=226.12.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 8.50-8.64 (2 hr, m), 7.89 (1 hr, dd, J=7.93, 1.13 Hz), 7.40-7.55 (3 hr, m), 7.25-7.33 (1 hr, m), 7.22 (1 hr, d, J=6.30 Hz), 2.21 (3 hr, s).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([O:12]CC)=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:15](=[O:24])[C:16]1[CH:17]=[CH:18][C:19]([S:22][CH3:23])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCc2c1sc(C)c2C(=O)c1ccc(SC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(C(=O)c2c(C)sc3c2CCC3C(=O)O)cc1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A 12.32 g (0.034 moles) sample of ethyl 5,6-dihydro-2-methyl-3-[4-(methyl-thio)benzoyl]-4H-cyclopenta[b]thiophene-6-carboxylate, the product of Example 1h., was dissolved in 200 ml of refluxing MeOH. 81.32 ml (0.044 moles) of 0.5M sodium hydroxide was added dropwise over 45 min. The reaction was stirred for an additional 20 min at reflux. The MeOH was evaporated in vacuo and the residue was poured into 3N hydrochloric acid and ice. A sticky solid was filtered off, washed with water and was taken up in Et2O. The ether was washed with brine and dried (MgSO4). Evaporation of the solvent gave a tan solid which was recrystallized from acetonitrile to give 10.00 g of 5,6-dihydro-2-methyl-3-(4-(methylthio)benzoyl)-4H-cyclopenta[b]thiophene-6-carboxylic acid (88%), mp 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Li])=[CH:4][N:3]=1.[I:10]I>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([I:10])=[CH:4][N:3]=1
Reactant: II
Reactant: [Li]c1cnc(Cl)c(Cl)c1
Product: Clc1cc(I)cnc1Cl

Procedure:
Briefly, in accordance with the present invention, 2,3-dichloro-5-iodopyridine is prepared by lithiating 5-bromo-2,3-dichloropyridine at a reduced temperature to form 2,3-dichloro-5-lithiopyridine. The 2,3-dichloro-5-lithiopyridine is then reacted with I2 at a reduced temperature to form 2,3-dichloro-5-iodopyridine. The resulting product is then extracted and recovered. 2,3-Dichloro-5-iodopyridine is in the form of a white solid and has a melting point of from 56.5° C. to 57.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][OH:12]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]=[O:12]
Reactant: O=[N+]([O-])c1cccc(CO)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc([N+](=O)[O-])c1Cl

Procedure:
9.2 g (49.05 mmol) of (2-chloro-3-nitrophenyl)methanol and 13.2 g (151.8 mmol) of activated manganese(IV) oxide in 50 ml of chloroform are heated under reflux for 20 h. The mixture is filtered through kieselguhr, concentrated and dried under high vacuum. The resulting title compound is directly reacted further.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCc2ccccc21
Product: O=C(NC1CCc2ccccc21)c1ccccc1

Procedure:
The title compound was prepared in 77% from (rac)-1-aminoindan (1.0 g, 7.5 mmole) and benzoyl chloride (2.1 g, 15 mmole), under the Schotten-Bauman conditions, according to J.Chem.Soc. 71, 251 (1897) and J.Org.Chem. 27, 4465 (1962), m.p.: 140°-2° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[S:10][C:3]=12.[CH:18]1([CH2:21][NH:22][C:23]([C:25]2[C:26]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:27]=3[S:28][C:29]=2[CH3:30])=[O:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:18]1([CH2:21][NH:22][C:23]([C:25]2[C:26]3[CH:34]=[CH:33][C:32]([O:35][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]6[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=6)[S:10][C:3]=45)=[CH:31][C:27]=3[S:28][C:29]=2[CH3:30])=[O:24])[CH2:20][CH2:19]1
Reactant: OCc1csc(-c2cc3nccc(Cl)c3s2)n1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nc(CO)cs5)sc34)ccc2c1C(=O)NCC1CC1
Yield: 37.4 %

Procedure:
This material was prepared by reacting [2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]methanol (85 mg, 0.30 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid (cyclopropylmethyl)amide 130a (94 mg, 0.36 mmole) and Cs2CO3 (195 mg, 0.60 mmole) in a manner similar to that previously described for example 1 to give a yellow solid (57 mg, 25%). 1H NMR (DMSO-d6, 300 MHz) δ 8.56 (1H, d, J=5.46 Hz), 8.49 (1H, t, J=5.75 Hz), 8.17 (1H, s), 7.98 (1H, d, J=2.26 Hz), 7.84 (1H, d, J=8.67 Hz), 7.65 (1H, s), 7.36 (1H, dd, J=2.35, 8.76 Hz), 6.80 (1H, d, J=5.46 Hz), 4.60 (2H, s), 3.20 (2H, t, J=6.22 Hz), 2.62 (3H, s), 1.07 (1H, m), 0.47 (2H, m), 0.26 (2H, m).
Reaction SMILES: [F:1][C:2]1([F:54])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:42]([F:53])[C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:54][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:42]([F:53])[C:43]2[CH:44]=[CH:45][C:46]([C:49]([F:50])([F:52])[F:51])=[CH:47][CH:48]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncccn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)Cc2nc(C3CCN(c4ncccn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 1.28 g (1.70 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-[1-(pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 15, in 8 ml of 1,4-dioxane, 4 ml of 6 N hydrochloric acid was added, and the reaction solution was stirred at 70° C. for 3 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. n-Heptane was added to the obtained residue and the precipitate was obtained by filtration to provide 0.93 g of the title compound as a white solid (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([OH:10])=[C:4]([CH:11]([OH:15])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(#N)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=1[CH:11]([OH:15])[CH:12]([CH3:13])[CH3:14])[CH3:28]
Reactant: COc1cc(O)c(C(O)C(C)C)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(OC)c(Cl)cc1C(O)C(C)C
Temperature: 25 °C

Procedure:
To a solution of the above prepared 4-chloro-2-(1-hydroxy-2-methyl-propyl)-5-methoxy-phenol (1.080 g, 4.68 mmol) in 15 mL acetonitrile were successively added Cs2CO3 (1.98 g, 1.3 eq.) and ethyl bromoacetate (0.596 mL, 1.15 eq.) and the mixture vigorously stirred at ambient temperature over night. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left 1.57 g of the title compound as light brown oil, used directly for the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C(OCCO)C>[CH2:17]([NH:21][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Solvent: CCOCCO
Product: CCCCNc1c(C#N)cnc2cc(F)c(OC)cc12
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
A mixture of 4-chloro-7-fluoro-6-methoxy-3-quinolinecarbonitrile (300 mg, 1.27 mmol) and butylamine (205 mg, 2.80 mmol) in 10 mL of 2-ethoxyethanol is heated at 80° C. for 1.5 hours then cooled to room temperature. The reaction mixture is concentrated in vacuo and aqueous sodium bicarbonate is added to the residue. After stirring for 20 minutes, the solids are collected by filtration. Purification by preparative thin layer chromatography, eluting with 2% methanol in dichloromethane provides 230 mg of 4-butylamino-7-fluoro-6-methoxy-3-quinolinecarbonitrile, mp 155-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12][O:13]2)=[CH:18][CH:17]=1)(=[O:25])[CH3:24]
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1OC
Yield: 74 %

Procedure:
In a similar manner to Example 3.1 above, 3-(3,4-dimethoxyphenyl)-7-hydroxychromen-4-one (1.7 g) was reacted with acetic anhydride (10 ml) and pyridine (1.9 ml) to give 7-acetoxy-3-(3,4-dimethoxyphenyl)chromen-4-one as colourless prisms (1.44 g, 74%).
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:10])[CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)O.O>C(O)(=O)C.[Zn]>[Cl:1][C:2]([Cl:10])=[CH:3][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC(c1cccs1)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: ClC(Cl)=Cc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 36.3 g (0.555 mole) of zinc in 250 ml of glacial acetic acid, 64.2 g (0.277 mole) of 2,2,2-trichloro-1-(2-thienyl)ethanol was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 600 ml of cold water and the mixture extracted with three 250 ml portions of ethyl acetate. The combined organic extracts were dried with magnesium sulfate and filtered. The solvent was removed from the filtrate to give a liquid which was distilled under reduced pressure to give 2-(2,2-dichloroethenyl)thiophene; bp 60°-68° C./266 pa. The ir spectrum was consistent with the proposed structure.