Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([NH2:26])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH3:5].[Li+].[OH-].Cl>C1COCC1.O.O>[NH2:26][C:17]1[CH:16]=[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][C@@H:4]([CH3:5])[C:3]([OH:27])=[O:2])=[O:8])[CH2:10][CH2:11]2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]=1
Reactant: COC(=O)[C@H](C)NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (2S)-2-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-propanoic acid-methyl ester (˜50 mg, 0.13 mmol), LiOH (100 mg) in THF-H2O (5 mL, 5:1) was stirred at rt for 3 h. The mixture was diluted with H2O, and acidified with 1.0 N HCl to pH˜5. The crude acid was obtained as a white solid by filtration.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH3:22].I([O-])(=O)(=O)=[O:24].[Na+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO>[CH3:22][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=1)=[O:24]
Reactant: CSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1c(-c2ccccc2S(C)=O)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a mixture of 3-methyl-2-(2-methylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.32 g), methanol (4 ml) and water (6 ml), sodium periodate (0.42 g) was added under ice-cooling. The mixture was heated to room temperature, and stirred for 1 hour, and then heated to 40° C., and stirred with heating for further 1 hour. Into the reaction mixture cooled to room temperature saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform 2 times. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.32 g of 2-(2-methylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 2).
Reaction SMILES: [Mg].CCOCC.BrBr.C([O:16][C:17]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])C1C=CC=CC=1>C1C=CC=CC=1>[CH2:26]([O:25][C:24]1[C:17]([OH:16])=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: BrBr
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=Cc1cccc(OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To magnesium (2.9 g, turnings, 0.12 mol) in a mixture of anhydrous ether (85 mL) and benzene (85 mL) at 0° C., bromine (3.4 mL, 0.066 mol) was added dropwise. When the reaction had started, stirring was commenced and the addition of bromine continued until complete. The ice bath was removed and the reaction mixture was heated until the solution was almost colorless. After cooling down, the reaction mixture was slowly added to a solution of 2,3-bis-benzyloxy-benzaldehyde (128, 20 g, 0.063 mol) in benzene (415 mL) at room temperature while stirring vigorously. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight, and then refluxed for 36 hours. After the reaction mixture was cooled down to room temperature, a solid was collected by filtration and washed with benzene, then boiled in hydrochloric acid (100 mL, 1.0 M) for 30 minutes. After cool down, the solution was extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. A light tan solid was obtained after removal of the solvent (129, 12.5 g, 87%).
Reaction SMILES: I[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:2]2[N:6]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[N:5]=[C:4]([CH3:13])[C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1
Reactant: CCOC(=O)c1c(C)nn(C2CCCCO2)c1I
Reactant: COCCOc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nn(C2CCCCO2)c1-c1cc(OCCOC)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
A mixture of (R/S) ethyl 5-iodo-3-methyl-1-(oxan-2-yl)-1H-pyrazole-4-carboxylate (440 mg, 1.21 mmol, 1.00 equiv), 2-[3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 1.44 mmol, 0.97 equiv), Pd(dppf)Cl2 (132 mg, 0.18 mmol, 0.12 equiv) and potassium carbonate (497 mg, 3.60 mmol, 2.40 equiv) in 1,4-dioxane (50 mL) and water (5 mL) was stirred under nitrogen at 100° C. for 3 h. The resulting mixture was cooled to room temperature then diluted with water (30 mL). The resulting solution was extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with 3×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 410 mg (74%) of (R/S) ethyl 5-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate as a yellow oil. LCMS (method D, ESI): RT=1.70 min, m/z=457.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7](OCC)=[O:8])[CH:4]=[CH:3][C:2]=1[C:12](OCC)=[O:13].[BH4-].[Na+].[Cl-].[Cl-].[Ca+2].OS(O)(=O)=O>CCO>[N:1]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[CH:3][C:2]=1[CH2:12][OH:13]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)nc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Product: OCc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
To a solution of 33.5 g (0.15 mol) of diethyl pyridine-2,5-dicarboxylate in 300 mL of absolute EtOH was added 11.4 g (0.3 mol) of NaBH4 in several portions over a 30-min period. Then a solution of 33.3 g (0.3 mol) of anhydrous CaCl2 in 200 ml of EtOH was added dropwise over a 1-h period. The mixture was stirred at room temperature for 16 h, and then it was neutralized with 12 to 13 mL of concentrated H2SO4. The CaSO4, which precipitated, was removed by centrifugation (two EtOH washings). The combined supernatant was concentrated, dissolved in about 10 mL of H2O, and applied to a 4.5×18-cm column of Dowex 50W-X8 cation exchange resin (H+ form). The column was eluted with H2O until the eluate was no longer acidic, and then it was eluted with dilute NH4OH, which removed the 2,5-pyridinedimethanol from the column. Evaporation afforded 10.6 g (51% yield) of 2,5-pyridinedimethanol as a light brown hygroscopic solid: 1H NMR (Me2SO-d6) δ4.55 and 4.59 (2 s, 4, CH2OH), 5.23 (broad s, 2, CH2OH), 7.42 (d, J=8 Hz, 1, 3'--H), 7.72 (dd, J=2 Hz, J=8 Hz, 1, 4--H), 8.42 (d, J=2 Hz, 1, 6'--H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:6]=2[CH:22]=1.[Br:23]Br>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Br:23][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[CH:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: Fc1ccccc1C1=CCc2nncn2-c2ccc(Cl)cc21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Fc1ccccc1C1=CCc2nnc(Br)n2-c2ccc(Cl)cc21

Procedure:
8.5 g of 8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine are dissolved in 135 ml of chloroform and 3.3 ml of pyridine. 2.0 ml of bromine are added dropwise at room temperature while stirring. The mixture is then heated to 55°-60° for 50 minutes and evaporated in vacuo. The residue is chromatographed on 550 g of silica gel. By elution with chloroform which contains 0.3% or 0.4% methanol and crystallization of the obtained material from benzene there is obtained 1-bromo-8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine of melting point 222°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](OC)=[O:25])=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:29]=3[F:28])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cccc(C(F)(F)F)c3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 22.7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.100 g, 0.207 mmol) and 2-fluoro-3-trifluoromethyl aniline (0.044 g, 0.301 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.25 (s, 3H), 3.14 (s, 2H), 7.23-7.33 (m, 2H), 7.39-7.49 (m, 3H), 7.54 (s, 1H), 8.77 (m, 1H), 9.11 (s, 1H), 10.22 (s, 1H), 11.01 (s, 1H): MS [M−H]−: 531.08.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3](O)[CH:2]=1.[Cl-].[NH4+:15].S(=O)(O)[O-].[Na+].[OH-].[NH4+].Cl>C(OCC)(=O)C>[OH:13][C:1]1[CH:2]=[C:3]([CH:5]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:12]=1)[NH2:15]
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CCCCCc1cc(N)cc(O)c1

Procedure:
Olivetol (1.8 g., 0.01 M), ammonium chloride (2.65 g., 0.05 M), sodium bisulfite (5.2 g., 0.05 M) and ammonium hydroxide (12.5 ml.) are combined and heated in a steel bomb at 230° C. for a half-hour. The bomb is then cooled, the contents dissolved in ethyl acetate (350 ml.). Hydrochloric acid (300 ml. of 10%) is added, the mixture stirred and then the organic layer separated. The extraction is repeated two more times. The aqueous acid solution is neutralized with 6 N sodium hydroxide and then extracted with cholorform (3×300 ml.). The combined chloroform extracts are dried and concentrated. The residue is taken up in ethyl acetate, decolorized with charcoal and concentrated. The addition of hexane to the residue causes it to crystallize: 270 mg.; m.p. 88°-91° C. When recrystallized from hot ethyl acetate-hexane (1-1) it melts at 95°-96° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C=O)C.O>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=3[CH:13]=2)=[CH:24][CH:23]=1
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC1=Cc2cc(OCc3ccc(C(F)(F)F)cc3)ccc2OC1
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: A mixture of 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde (2.50 g, 14.2 mmol) and potassium carbonate (3.62 g, 38.4 mmol) in 50 ml of DMF is treated with 4-trifluoromethylbenzyl bromide (3.73 g, 15.6 mmol). The reaction is allowed to proceed overnight at room temperature. The mixture is diluted with water and extracted three times with dichloromethane. The combined organic layers are washed once with water, dried (MgSO4), and evaporated. Purification by silica gel chromatography (20% ethyl acetate/hexane) yields 6-(4-trifluoromethylbenzyloxy)-2H-1-benzopyran-3-carboxaldehyde, m.p. 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1>C(OCC)(=O)C.[Zn+2].[Br-].[Br-]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Nc1cnc(Cl)c(C(F)(F)F)c1
Reaction time: 20 h
Yield: 92.1 %

Procedure:
A mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (5.25 mmol, 1.19 g), ZnBr2 (1.05 mmol, 0.200 g) and 5% Pt © (1.58 mmol, 0.31 g) in ethyl acetate (50 ml) was stirred for 20 hours under hydrogen atmosphere. The catalyst was filtered off and the solid was washed with warmed ethanol. The solvent was evaporated affording the expected product (0.95 g, yield 92%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[CH2:11][C:12]#[N:13].[NH2:14][C:15]1[N:20]=[C:19]([NH2:21])[C:18]([CH:22]=O)=[CH:17][N:16]=1>C(OCCO)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[C:11]1[C:12]([NH2:13])=[N:21][C:19]2[N:20]=[C:15]([NH2:14])[N:16]=[CH:17][C:18]=2[CH:22]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1c(Br)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Product: Nc1ncc2cc(-c3c(Br)cccc3Br)c(N)nc2n1
Temperature: 0 °C
Yield: 63.3 %

Procedure:
To a solution of 0.23 g 60% sodium hydride suspension in 11.0 mL of 2-ethoxyethanol was added 4.18 g of 2,6-dibromophenylacetonitrile and 2.00 g of 2,4-diaminopyrimidine-5-carboxaldehyde. The reaction was refluxed for 4 hours, cooled, and poured into ice water. The residue was washed well with acetonitrile then diethyl ether to give 3.62 g of 6-(2,6-dibromophenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 422=M+ +C2H5, 396 (Base), 394=M+ +H, 393=M+ ; mp 284-289° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:16]=O.C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:28]O>O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:16]#[N:28]
Reactant: NO
Reactant: CC(C)Nc1ncnc2cc(O)c(C=O)cc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Nc1ncnc2cc(O)c(C#N)cc12
Temperature: 130 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
7-Hydroxy-4-(isopropylamino)quinazoline-6-carbaldehyde (310 mg, 1.34 mmol) is presented as an initial charge in acetic acid (7 mL, 81 mmol) and admixed with sodium acetate (366 mg, 3.3 mmol) and also hydroxylamine hydrochloride (186 mg, 2.68 mmol). The batch is stirred at 130° C. for 18 hours. After cooling to room temperature, the batch is diluted with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate. Removal of the solvent and also chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) of the residue gives the desired product in 38% yield (116 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=1.[H-].[Na+].[CH3:22][NH:23][C:24](=O)[O:25]C1C=CC=CC=1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:19][C:15]1[CH:14]=[C:13]([O:12][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][C:3]=2[O:2][CH3:1])[N:9]([C:24]([NH:23][CH3:22])=[O:25])[CH:8]=[CH:7]3)[CH:18]=[CH:17][N:16]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: COc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66 %

Procedure:
4-((6-Methoxy-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 1-4 (1.7 g, 6.66 mmol) was dissolved in N,N-dimethylformamide (25 mL), 50-72% oily sodium hydride (424 mg) was added under nitrogen atmosphere at 0° C., and then the mixture was stirred at room temperature for 45 minutes. The mixture was cooled to 0° C. again, phenyl methylcarbamate described in Production Example 1-7 (1.64 g, 10.8 mmol) was added, and the resultant was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture for partition. The aqueous layer was extracted with ethyl acetate once and the combined organic layer was washed with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, then the filtrate was concentrated under vacuum, and then the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:3-0:1-ethyl acetate:methanol=99:1-19:1). The target fraction was concentrated under vacuum and then the precipitate was collected by filteration and washed with ethyl acetate to obtain the title compound (1.37 g, 66%). The mixture fraction was concentrated under vacuum and purified with NH silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol—99:1-19:1). The target fraction was concentrated under vacuum, and then the precipitate was collected by filteration and washed with ethyl acetate twice to obtain the title compound (387 mg, 19%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41](=[O:50])[NH:42][CH2:43][CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[F:38][C:34]1[C:33]([CH3:39])=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][C:17]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:19]2[N:24]([C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][C@@H:9]([CH2:40][C:41]([NH:42][CH2:43][CH:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)=[O:50])[CH2:10]1)=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)NCC2CCOCC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN[C@@H](CC(=O)NCC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To a solution of the compound of step 3 (0.113 g, 0.17 mmol) in 1.65 ml of DCM cooled to 0° C. was added a 4 N solution of hydrogen chloride in dioxane (0.41 ml, 1.65 mmol). The mixture was stirred for 3 h at room temperature and then evaporated to dryness. The solid was triturated several times with diethyl ether and dried in vacuo at 40° C. to give 0.071 g of the title compound in the form of 2-{(S)-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-N-(tetrahydropyran-4-ylmethyl)-acetamide hydrochloride with the following characteristics:
Reaction SMILES: C([N:3](CC)CC)C.[Al+3].[Cl-].[Cl-].[Cl-].[N+]([C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][O:20][C:21]2=[O:22])=[CH:17][CH:16]=1)([O-])=O.CCOC(C)=O>ClCCCl>[OH:20][CH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[CH:24][C:23]=1[C:21]([NH2:3])=[O:22]
Reactant: CCN(CC)CC
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=O)c1ccccc1CO
Temperature: 17.5 °C
Yield: 30.6 %

Procedure:
A solution of triethylamine (TEA, 0.658 g, 0.91 ml, 6.50 mmol, 1.5 equiv.) in 1,2-dichloroethane (3 ml) was added dropwise under stirring and cooling with ice to a suspension of AlCl3 (0.635 g, 4.76 mmol, 1.1 equiv.) in 1,2-dichloroethane (7 ml). The temperature was maintained at 15-20° C. during the addition and the mixture was then allowed to warm up at room temperature. A solution of 1-dimethoxytrityl-6-amino-hexan-1-ol (16) (2.00 g, 4.76 mmol, 1.1 equiv., prepared as described by Woo and Fung (1996), International Pat. App. Pub. No. WO 96/05215) and 6-nitrophthalide (18) (0.766 g, 4.33 mmol, 1.0 equiv.) in 1,2-dichloroethane (3 ml) was added over a period of 20 min and the mixture was stirred at room temperature overnight. The completion of the reaction was confirmed by TLC analysis (EtOAc containing 1% TEA). The reaction mixture was then quenched with an ice-water mixture (30 ml) and stirred for an additional 30 min. The resulting suspension was filtered through a bed of Celite® and the filter cake was washed with 1,2-dichloroethane (10 ml). The organic phase of the combined filtrates was separated, washed with water (30 ml) and brine (20 ml), dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (35-75% EtOAc in hexanes, gradient elution) yielding 0.20 g (8%) of compound (20) as a pale yellow oil. Rf=0.2 (hexanes/EtOAc 1:1, v/v, containing 1% TEA). 1H NMR (300 MHz, CD3CN) δ 8.32-8.27 (m, 2H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 2H), 7.33-7.20 (m, 8H), 6.87 (d, J=9.1 Hz, 4H), 4.69 (d, J=5.9 Hz, 2H), 4.14 (t, J=5.9 Hz, 1H), 3.77 (s, 6H), 3.35 (q, J=6.5 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H), 1.64-1.55 (m, 4H), 1.43-1.28 (m, 4H). 13C NMR (75 MHz, CD3CN) δ 167.4, 158.8, 147.7, 145.9, 136.9, 130.1, 128.2, 128.0, 126.9, 125.1, 122.9, 113.2, 85.8, 63.3, 62.3, 55.1, 39.8, 29.8, 29.1, 26.7, 26.0.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O.[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N+]=[N-]>CO>[CH3:21][O:20][C:18]([C:17]1[NH:14][C:9]2[C:6]([CH:7]=1)=[C:5]([Br:4])[CH:12]=[C:11]([F:13])[CH:10]=2)=[O:19]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(Br)cc(F)cc2[nH]1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Dry methanol (5 ml) and NaOMe (0.9 ml, 3.93 mmol, 25% wt in MeOH) were added to a three-neck flask equipped with stirrer, low-temperature thermometer, and nitrogen line. The resulting solution was cooled in a dry ice/CH3CN bath to −40° C. A solution of 2-bromo-4-fluoro-benzaldehyde (195 mg, 0.96 mmol) and methyl azidoacetate (450 mg, 3.9 mmol) in dry MeOH (5 ml) was added dropwise. The mixture was allowed to stir at −40° C. for 30 minutes before warming up to room temperature. After stirring another 3 hours, the reaction solvent was removed under reduced pressure. The residue was added to xylene (15 ml), and the organic phase was washed with H2O, brine, followed by drying over MgSO4. The resulting solution was added dropwise to a flask of xylene (30 ml) and the solution was heated at reflux overnight. After cooling to room temperature, the reaction mixture was washed with H2O, and xylene was removed under reduced pressure to give 4-bromo-6-fluoro-1H-indole-2-carboxylic acid methyl ester as a white solid (178 mg, 68%). MS: 272.1 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[OH:26][C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:30]1[CH2:31][CH2:32][C:27]([OH:26])([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:28][CH2:29]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reactant: OC1(c2ccccc2)CCNCC1
Product: Cc1nc2ccc(N3CCC(O)(c4ccccc4)CC3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 32 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 4-hydroxy-4-phenylpiperidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 32%; MS: m/z=509 (M+H).